CROSS REFERENCE TO RELATED APPLICATION 
     This application is a continuation of application Ser. No. 07/892,716 filed May 29, 1992, abandoned which in turn is a continuation of application Ser. No. 07/450,988 abandoned filed Dec. 15, 1989, which is a continuation-in-part of prior application Ser. No. 284,502 filed 14 Dec. 1988, abandoned. 
    
    
     FIELD OF INVENTION 
     This invention relates to novel antibacterial agents and a method for predicting the activity thereof relative to penicillin. More particularly, this application describes a molecular modelling technique for determining the fit and reactivity of candidate compounds with bacterial cell wall receptors, and hence a method for predicting structural types that exhibit activity. 
     BACKGROUND OF INVENTION 
     It has been known since the 1940&#39;s that β-lactam antibiotics, such as the penicillins and cephalosporins, are effective by reason of their interference with the integrity of bacterial cell walls. It has also been discovered that the interference is effected by covalent bonding to the active site serine residue of one or more of a group of enzymes termed penicillin binding proteins (PBP&#39;s). These enzymes serve to complete bacterial cell wall synthesis by a cross linking of peptidoglycan chains, and are essential to the cells. All known PBP&#39;s include a sequence -Ser-X-X-Lys- and the simplest kinetic description of the reaction between a PBP and a β-lactam antibiotic is given in equation 1, below, where A is a generalized structure. Since the PBP is regenerated in the deacylation step, useful antibacterial activity is considered to require k 3  /K≧1000M -1  sec -1  and k 4  ≦1×10 -4  sec -1 . ##STR2## 
     The question is, therefore, what is the correlation, if any, between antibacterial activity and the &#34;lock and key&#34; interactions which take place between the PBP and the antibiotic. 
     OBJECT OF THE INVENTION 
     It is, therefore, an object of the present invention to determine the correlation between antibacterial activity and the lock and key interactions between PBP&#39;s and selected antibiotics and thus provide a means by which the &#34;fit&#34; (Step 1) and &#34;reactivity&#34; (Step 2) of any selected candidate structure relative to the fit and reactivity of penicillin may be predicted with some degree of quantitative accuracy. 
     It is another object of this invention to design with this model novel non β-lactam compounds having antibacterial activity. 
     BRIEF STATEMENT OF INVENTION 
     Thus by one aspect of this invention there is provided a method for determining fit and reactivity of any selected candidate antibacterial compound comprising (a) simulating the reaction of said compound with a model of a penicillin binding protein which includes a serine-lysine active site, by determining the relative ease of formation of a four-centred relationship between OH of said serine and a reactive site of said compound; and (b) determining the activation energy for the four-centred reaction of the chemically active functional group of said compound with methanol relative to the activation energy of the corresponding reaction of methanol with N-methylazetidinone. 
     By another aspect of this invention there is provided a example of a non-β-lactam containing compound characterized in that said compound is capable of forming a four-centred transition structure which includes a serine OH group contained in a model of a penicillin binding protein, reacted therewith; said compound having an activation energy for reaction with methanol not greater than 3 kcal/mol higher than the activation energy exhibited by N-methylazetidinone. 
     Another aspect of this invention provides compounds of the formula: ##STR3## where X═S, O, CH 2 , NH, NR 7 , Se 
     Y═OH, NH 2 ,NHCOR 8 ,SH 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  -alkyl, aryl 
     R 8  is a β-lactam active side chain, and pharmaceutically acceptable salts thereof. 
     β-lactam active side chains are side chains known to be active in β-lactam antibiotics. As used herein, the substituents acceptable in beta-lactam antibiotics may be any of the wide range of permissible substituents disclosed in the literature pertaining to penicillin and cephalosporin compounds. Such substituents may, for example, comprise a group of the formula 
     
         --XQ 
    
     wherein X represents oxygen or sulfur and Q represents C 1-4  alkyl (e.g., methyl or ethyl), C 2-4  alkenyl (e.g. vinyl or propenyl) or aryl C 1-4  alkyl (e.g., phenyl C 1-4  alkyl such as benzyl). 
     Such substituents also may be, for example, an unsaturated organic group, for example, a group of the formula ##STR4## Wherein R 1  and R 2  which may be the same or different, and are each selected from hyudrogen, carboxy, cyano, C 2-7  alkoxycarbonyl (e.g., methoxycarbonyl or ethoxycarbonyl), and substituted or unsubstituted aliphatic (e.g., alkyl, preferably C 1  -C 6  alkyl such as methyl, ethyl, isopropyl or no-propyl). Specific substituted vinyl groups of the above formula include 2-carboxyvinyl, 2-methoxycarbonylvinyl, 2-ethoxycarbonylvinyl and 2-cyanovinyl. 
     Alternatively, the β-lactam acceptable substituent may also be an unsubstituted or substituted methyl group depicted by the formula 
     
         --CH.sub.2 Y 
    
     wherein Y is a hydrogen atom or a nucleophilic atom or group, e.g., the residue of a nucleophile or a derivitive of a residue of a nucleophile. Y may thus, for example, be derived from the wide range of nucleophilic substances characterized by possessing a nucleophilic nitrogen, carbon, sulfur or oxygen atom. Such nucleophiles have been widely described in the patent and technical literature respecting β-lactam chemistry and are exemplified, for example, in Foxton et al U.S. Pat. No. 4,385,177 granted May 24, 1983, at column 4, line 42--column 8, line 24 and column 34, line 51--column 36, line 17, the disclosure of which is incorporated by this reference herein. 
     Yet another aspect of this invention provides compounds of the formula: ##STR5## where X═S, O, CH 2 , NH, NR 8 , Se 
     Y═OH, NH 2 , NHCOR 9 , SH 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  -alkyl, aryl 
     R 9  is a list of 30-40 side chains known to be active in β-lactam antibiotics, and pharmaceutically acceptable salts thereof 
     A further aspect of this invention provides compounds of the formula: ##STR6## where X--Y═S--S, CH 2  CH 2 , S--CH 2 , CH 2  --S, S--NR 8 , NR 8  --S, CH 2  H--O, O--CH 2 , O--NR 8 , NR 9  --O, Se--Se, CH 2  --CH 2 , Se--CH 2  Z═OH, NH 2 , NHCOR 9 , SH 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8  -alkyl, aryl 
     R 7  ═alkyl, aryl 
     R 9  is a list of 30-40 side chains known to be active in β-lactam antibiotics, and pharmaceutically acceptable salts thereof. 
     A still further aspect of the invention provides compounds of the formula: ##STR7## where X═S, O, CH 2 , NH, NR 6 , Se 
     Y═N, CH, CR 7   
     Z═OH, NH 2 , SH, NHCOR 8  (when Y═N) 
     Z--R 9  (when Y═CH, CR 7 ) 
     R 1  ═R 2  ═R 3  ═R 4  ═R 6  ═R 7  ═alkyl, aryl 
     R 5  ═H, alkyl, aryl 
     R 8  is a list of 30-40 side chains known to be active in β-lactam antibiotics ##STR8## where R 10  ═alkyl, aryl, and R 11  ═OH, NH 2 , NHCOR 8  SH 
     and pharmaceutically acceptable salts thereof. 
     Another aspect of the invention provides compounds of the formula: ##STR9## where X═S, O, CH 2 , NH, NR 5 , Se 
     Y═NR 6  --Z 
     R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are each H, alkyl, or aryl Z is OH, SH, NH 2 , or NHCOR 7   
     R 7  is a β-lactam active side chain, and pharmaceutically acceptable salts thereof. Preferably, R 6  is hydrogen and Z is NHCOR 9  where R 9  is lower alkyl and particularly benzyl. 
     As used herein, the term &#34;alkyl&#34; includes alkyl groups containing up to twenty carbon atoms, preferably C 1-6  alkyl groups, which can optionally be monosubstituted, distributed or polysubstituted by functional groups, for example by free, etherified is esterified hydroxyl or mercapto groups, such as lower alkoxy or lower alkylthio; optionally substituted lower alkoxycarbonyloxy or lower alkanoyloxy; halogen; oxo; nitro; optionally substituted amino, for example lower alkylamino, di-lower alkylamino, lower alkanoyloxy; halogen; oxo; nitro; optionally substituted amino, for example lower alkylamino, di-lower alkylamino, lower alkyleneamino, as well as acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halogeno-lower alkoxycarbonylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, and also sulfoamino which is optionally present in the form of a salt, such as in the form of an alkali metal salt, azido, or acyl, such as lower alkanoyl or benzoyl; 
     Optionally functionally modified carboxyl, such as carboxyl present in the form of a salt, esterfied carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl and also optionally substituted ureidocarbonyl or guanidinocarbonyl; nitrile; optionally functionally modified sufo, such as sulfamoyl or sulfo present in the form of a salt; or optionally O-monosubstituted or O, O-disubstituted phosphone, which may be substituted, for example, by optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, it also being possible for O-unsubstituted or O-monosubstituted phosphono to be in the form of a salt, such as in the form of an alkali metal salt. 
     As used herein, the term &#34;aryl&#34; includes carbocyclic, hetrocyclic aryl. The carbocyclic aryl includes phenyl and naphthyl, optionally substituted with up to three halogen, C 1-6  alkyl, C 1-6  alkoxy, halo (C 1-6 ) alkyl, hydroxy, amino, carboxy, C 1-6  alkoxycarbonyl, C 1-6  alkoxycarbonyl-(C 1-6 )-alkyl, nitro, sulfonamido, C 1-6  alkylcarbonyl, amido (--CONH 2 ), or C 1-6  alkylamino groups. 
     The term &#34;heterocyclic&#34; includes single or fused rings comprising up to four hetro atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three halogen C 3-6  alkyl, C 1-6  alkoxy, halo (C 1-6 ) alkyl, hydroxy, amino, carboxy, C 1-6  alkoxycarbonyl, C 1-6  alkoxycarbonyl (C 1-6 ) alkyl, aryl, oxo, nitro, sulphonamido, C 1-6  alkyl-carbonyl, amido or C 1-6  alkylamino groups. 
     Suitable C 1-6  alkyl groups may be straight or branched chain and include methyl, ethyl n- or iso-propyl, n-, sec-, iso-, or tert-butyl. In those cases where the C 1-6  alkyl group carries a substituent the preferred C 1-6  alkyl groups include methyl, ethyl and n-propyl. 
    
    
     BRIEF DESCRIPTION OF DRAWINGS 
     FIG. 1 is the structure of a model of a penicillin receptor whose docking to penicillins and cephalosporins leads uniformly to four-centred interactions between C--O--H of serine and (O)C--N of the penicillin or cephalosporin. 
     FIG. 2 is a stereoscopic view of penicillin V docked to the peptide of FIG. 1. 
     FIG. 3 is a stereoscopic view of a Δ 3  -cephalosporin docked to the peptide of FIG. 1. 
     FIG. 4 is a stereoscopic view of a Δ 2  -cephalosporin docked to the peptide of FIG. 1. 
     FIG. 5 is a stereoscopic view of a 4-epi-Δ 2  -cephalosporin docked to the peptide of FIG. 1. 
     FIG. 6 is a close-up view of the four-centred interaction between C--O--H of serine and (O)C--N of the β-lactam ring which exists in FIG. 2. 
     FIG. 7 is the N-protonated transition structure for the attack of methanol upon the exo face of N-methylazetidinone (ab initio calculation). 
     FIG. 8 is the O-protonated transition structure for the attack of methanol upon the exo face of N-methylazetidinone (ab initio calculation). 
     FIG. 9 is a stereoscopic view of the transition structure calculated using MINDO/3 for the reaction of methanol with a penicillin via an N-protonated pathway. 
     FIG. 10 is a stereoscopic view of the transition structure calculated using MINDO/3 for the reaction of methanol with a penicillin via an O-protonated pathway. 
     FIG. 11 is a stereoscopic view of the transition structure for the reaction of methanol with penam via endo-attack. 
     FIG. 12 is a stereoscopic view of the complexation of 5 to the peptide of FIG. 1. 
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     Possible structures for peptides, penicillins and cephalosporins were examined using the computer programme MMP2(85) which is available from the Quantum Chemistry Program Exchange (QCPE) at the University of Indiana, Bloomington, Ind., U.S.A. This programme calculates the strain energy of a molecule in terms of contributions to this energy associated with stretching of bonds, bending of bond angles, torsion about bonds, and electrostatic and van der Waals interactions of non-bonded atoms. To carry out the calculation, it is necessary to enter the cartesian coordinates of all atoms, and define lists of connected and attached atoms. If the types of atoms present in the molecule of interest are known to the programme, the strain energy is minimized by application of the Newton-Raphson procedure to an unconstrained multivariable non-linear function that includes all of the individual contributions noted above. This function is termed the force field. For the minimization to proceed in a reliable manner it is important that the geometry entered at the beginning of the calculation already be reasonably accurate, and close to the bottom of an energy well. 
     For each different molecule to be examined with MMP2(85), it is first necessary to determine the parameters associated with the types of atoms present within this molecule. These parameters include, inter alia, standard bond lengths and bond angles, and stretching and bending force constants. Bond lengths and angles are available from compilations of vibrational data, and others can be calculated by molecular orbital (MO) procedures. The general strategy for parameter development can be found in the monograph &#34;Molecular Mechanics&#34;, by U. Burkert and N. L. Alinger, published by the American Chemical Society, Washington, 1982. Since the parameters for peptides (e.g., enzymes), penicillins and cephalosporins in the force field of MMP2(85) were previously unknown, these were first determined and tested for their ability to reproduce known experimental crystal structures, and known effects of solvent upon the conformations (three-dimensional structures) of the different structural types. The parameters are termed PEPCON (Table 1) (for peptides), PENCON (Table 2) (for penicillins), and CEPARAM (Table 3) (for cephalosporins). 
     
                       TABLE 1______________________________________PEPCON______________________________________159  39    9     123  39          78.505    6     1     5    0.00  0.00  0.305    3     9     1    0.00  15.00 0. 003    9     1     6    0.00  0.00  0.009    1     6     5    -2.50 3.00  -1.006    1     9     14   0.00  0.00  0.001    1     1     1    0.20  0.27  0.091    1     1     3    0.26  0.00  0.061    1     1     5    0.00  0.00  0.271    1     1     8    0.00  0.00  0.061    1     1     9    0.00  0.00  0.061    1     1     13   0.00  0.00  0.401    1     1     15   0.00  0.00  0.801    1     1     19   0.00  0.00  0.601    1     2     2    0.00  0.00  0.101    1     3     7    0.00  0.00  -0.041    1     3     9    0.00  0.00  -0.041    1     3     11   0.00  0.00  -0.091    1     3     12   0.00  0.00  -0.201    1     4     4    0.00  0.00  0.101    1     4     26   0.00  0.00  0.101    1     4     27   0.00  0.00  0.101    1     6     21   0.00  0.00  0.301    1     8     23   0.00  0.00  0.301    1     9     1    0.00  0.00  0.121    1     9     3    0.00  0.00  0.061    1     9     14   0.00  0.00  0.061    1     13    23   0.00  0.00  0.201    1     15    1    0.00  0.00  0.701    1     15    15   0.00  0.00  0.801    1     15    25   0.00  0.00  0.201    1     19    2    0.00  0.00  0.051    1     19    23   0.00  0.00  0.051    2     2     2    0.00  3.50  0.001    2     2     5    0.00  3.50  0.001    3     9     1    1.80  6.49  0.001    3     9     1    1.80  19.00 0.001    3     9     14   0.00  2.66  0.001    3     12    24   0.60  0.00  3.201    4     4     5    -0.30 3.80  0.001    4     4     26   0.00  3.50  0.001    4     26    4    0.00  5.00  0.001    4     26    23   0.00  5.00  0.001    4     27    2    -0.30 3.80  0.001    4     27    27   0.00  3.50  0.001    9     1     3    0.00  0.00  0.121    9     1     5    0.00  0.00  0.121    9     3     7    0.00  7.19  0.001    15    1     5    0.00  0.00  0.701    15    15    1    0.00  -7.60 1.701    19    2     8    0.00  4.50  0.00  *1    19    2     19   0.00  4.50  0.002    1     1     3    0.26  0.00  0.062    1     1     5    0.00  0.00  0.272    1     1     8    0.00  0.00  0.062    1     1     9    0.00  0.00  0.062    1     1     13   0.00  0.00  0.062    1     3     7    0.00  0.00  -0.352    1     3     9    0.00  -0.50 -1.702    2     1     3    0.00  0.00  0.902    2     1     5    0.00  0.00  0.052    2     2     2    -0.30 3.80  0.002    2     2     5    0.00  3.50  0.002    2     2     6    0.00  3.80  0.002    2     2     27   -0.30 3.80  0.002    2     6     21   0.00  1.80  0.002    2     27    4    0.00  3.50  0.002    2     27    26   0.00  3.50  0.002    2     27    27   -0.30 3.80  0.002    19    1     5    0.00  0.00  0.052    27    4     4    0.00  3.50  0.002    27    26    4    0.00  5.00  0.002    27    26    23   0.00  5.00  0.002    27    27    2    -0.30 3.80  0.002    27    27    4    0.00  3.50  0.002    27    27    26   0.00  3.50  0.003    1     1     3    0.26  0.00  0.063    1     1     4    0.26  0.00  0.063    1     1     5    0.00  0.00  0.163    1     1     6    0.26  0.00  0.063    1     1     8    0.00  0.00  0.063    1     1     9    0.00  0.00  0.083    1     1     13   0.00  0.00  0.063    1     1     15   0.26  0.00  0.063    1     8     23   0.00  0.00  0.303    1     9     3    0.00  0.00  0.063    1     9     14   0.00  0.00  0.063    1     13    23   0.00  0.00  0.303    9     1     5    0.00  0.00  0.064    1     1     5    0.00  0.00  0.274    1     1     8    0.00  0.00  0.064    1     1     9    0.00  0.00  0.064    1     1     13   0.00  0.00  0.064    4     1     5    0.00  0.00  0.104    4     26    4    0.00  5.00  0.004    4     26    23   0.00  5.00  0.004    4     26    27   0.00  5.00  0.004    4     27    27   -0.30 3.80  0.004    26    4     5    0.00  5.00  0.004    26    4     26   0.00  5.00  0.004    26    27    27   0.00  5.00  0.004    27    2     5    -0.30 3.80  0.004    27    27    26   -0.30 3.80  0.005    1     1     5    0.00  0.00  0.245    1     1     6    0.00  0.00  0.505    1     1     8    0.00  0.49  0.165    1     1     9    0.00  0.49  0.165    1     1     13   0.00  0.00  0.405    1     1     15   0.00  0.00  0.405    1     1     19   0.00  0.00  0.305    1     3     7    0.00  0.00  -0.045    1     3     9    0.00  0.00  -0.045    1     3     11   0.00  0.00  -0.095    1     3     12   0.00  0.00  -0.065    1     4     26   0.00  0.00  0.105    1     4     27   0.00  0.00  0.105    1     6     21   0.00  0.00  0.305    1     8     23   0.00  0.00  0.305    1     9     14   0.00  0.00  0.065    1     13    23   0.00  0.00  0.205    1     15    15   0.00  0.00  0.805    1     15    25   0.00  0.00  0.505    1     19    23   0.00  0.00  0.055    2     2     5    -0.30 3.80  0.005    2     2     6    -0.30 3.80  0.005    2     2     27   0.00  3.50  0.005    2     27    26   0.00  3.50  0.005    2     27    27   0.00  3.50  0.005    3     9     14   0.00  2.33  0.05    4     4     26   0.00  3.50  0.005    4     4     27   0.00  3.50  0.005    4     26    23   0.00  5.00  0.005    4     26    27   0.00  5.00  0.006    1     1     8    0.00  0.00  0.066    1     1     9    0.00  0.00  0.066    1     1     13   0.00  0.00  0.067    3     1     8    0.00  0.00  -0.047    3     1     9    0.00  0.00  -0.047    3     1     13   0.00  0.00  -0.047    3     9     14   0.00  2.66  0.007    3     12    24   0.00  0.00  3.108    1     1     15   0.00  0.00  0.068    1     3     9    0.00  0.00  -0.098    1     3     11   0.00  0.00  -0.098    1     3     12   0.00  0.00  -0.069    1     1     15   0.00  0.00  0.069    1     3     9    0.00  0.00  -0.049    1     3     11   0.00  0.00  -0.099    1     3     12   0.00  0.00  -0.069    3     1     13   0.00  0.00  -0.0611   3     1     13   0.00  0.00  -0.0912   3     1     13   0.00  0.00  -0.0613   1     1     15   0.15  0.00  0.1019   2     19    23   0.00  4.50  0.0019   2     8     23   0.00  4.50  0.00  *23   19    2     8    0.00  4.50  0.00  *23   26    4     26   0.00  5.00  0.0023   26    27    27   0.00  5.00  0.0026   4     4     26   -0.30 3.80  0.0026   4     4     27   0.00  3.80  0.01    1      4.40     1.525                     1.510     FC ST1    2      4.48     1.5041    3      4.75     1.5261    4      4.40     1.5041    5      4.60     1.0811    6      5.36     1.4251    8      5.10     1.4611    9      5.47     1.4521    13     5.15     1.4721    15     3.21     1.8151    19     5.27     1.460                     *5    6      4.60     0.9682    2      9.60     1.3822    5      4.60     1.1012    6      6.20     1.3812    8      5.10     1.331                     *2    19     5.10     1.3312    27     6.51     1.4003    5      4.8      1.1033    6      5.05     1.3303    7      10.01    1.2293    9      7.74     1.3303    11     5.11     1.2503    12     5.05     1.3286    21     4.60     0.9684    4      7.19     1.3714    5               4.60 1.1014    26     5.69     1.3944    27     5.39     1.4598    23     6.10     1.0159    14     5.78     0.99112   24     7.20     0.97213   23     6.03     1.02315   15     3.10     2.02415   25     3.80     1.35419   23     5.95     1.00723   26     6.05     1.01026   27     5.94     1.38027   27     6.21     1.4191    1     0.000                BOND DIPOLE1    2     0.1001    3     -1.0201    4     -0.1801    5     0.0001    6     2.5301    8     3.9801    9     2.6505    6     -1.9601    13    1.7201    15    -0.6711    19    2.058                *2    2     0.0002    5     -0.0582    6     0.8102    8     4.524                *2    19    3.2602    27    -0.7003    5     0.03    6     0.0003    7     3.0103    9     3.3203    11    3.9503    12    1.850                *6    21    -1.9604    4     0.0004    5     0.0004    26    2.1204    27    1.1208    23    -1.4109    14    -1.81012   24    0.00013   23    -1.35015   15    0.00015   25    0.00019   23    -2.27023   26    1.43026   27    -1.03027   27    0.0004     0.044                1.94011    0.066                1.78012    0.050                1.74013    0.030                1.90014    0.017                0.93019    0.055                1.82025    0.036                1.25026    0.055                1.82027    0.044                1.9401    1     1     0.45     110.30                           11    1     1     0.45     111.20                           21    1     1     0.45     112.40                           31    1     2     0.58     114.001    1     3     0.67     107.80                           11    1     3     0.67     110.80                           21    1     3     0.67     112.20                           31    1     4     0.71     113.101    1     5     0.36     109.391    1     6              0.56  109.10                                 11    1     6     0.56     104.10                           21    1     6     0.56     109.40                           31    1     8     0.57     109.471    1     9     0 56     109.40                           11    1     9     0.56     109.60                           21    1     9     0.85     111.10                           31    1     13    0.90     111.201    1     15    0.63     108.801    1     19    0.75     111.201    2     2     0.55     121.401    2     5     0.36     118.201    3     7     0.86     120.601    3     9     0.78     116.401    3     11    0.64     117.001    3     12    0.70     115.001    4     4     0.80     129.801    4     26    0.80     121.701    4     27    0.80     128.601    6     21    0.35     108.401    8     23    0.48     109.501    9     1     0.45     111.901    9     2     0.75     123.201    9     3     0.49     120.60                           11    9     3     0.35     121.70                           21    9     14    0.54     124.001    13    23    0.40     109.501    15    1     0.78     97.601    15    15    1.17     103.901    15    25    0.48     96.001    19    2     0.56     123.201    19    23    0.38     118.402    1     3     0.47     110.22    1     5     0.36     109.402    2     2     0.43     120.002    2     5     0.36     120.002    2     6     0.75     121.002    2     27    0.96     120.002    6     21    0.35     113.002    8     23    0.50     120.002    9     23    0.50     120.002    19    23    0.38     120.002    27    4     0.90     134.902    27    26    0.35     132.802    27    27    0.90     122.703    1     5     0.37     107.903    1     8     0.82     110.743    1     9     0.44     110.00                           13    1     9     0.47     109.70                           23    1     9     0.56     110.80                           33    1     13    0.90     110.743    9     14    0.50     122.503    12    24    0.74     106.104    1     5     0.38     109.504    4     5     0.36     126.304    4     26    0.80     107.904    4     27    0.43     106.404    26    4     0.80     106.304    26    23    0.40     126.404    26    27    0.80     111.604    27    27    0.95     108.805    1     5     0.32     109.405    1     6     0.43     103.105    1     8     0.46     108.805    1     9     0.36     109.39                           15    1     9     0.36     109.41                           25    1     9     0.36     110.00                           35    1     13    0.50     108.805    1     15    0.36     112.005    1     19    0.38     109.00      *5    2     27    0.36     120.005    3     7     0.37     112.05    3     9     0.40     122.35    4     26    0.36     120.007    3     9     0.85     124.107    3     12    1.13     124.508    2     19    0.80     120.00      *11   3     11    0.85     126.0014   9     14    0.50     120.0019   2     19    0.80     120.0023   8     23    0.50     106.8023   19    23    0.50     120.0023   13    23    0.50     109.5023   26    27    0.40     124.2026   4     26    0.90     110.9026   27    27    0.90     104.401    6     5     0.35     108.409    1     6     0.62     111.003      11    0.83      12    0.89      14    0.052      27    0.052      1     0.05            ADDED O.P.A. (MM2)2      2     0.052      5     0.052      6     0.052      8     0.052      19    0.05                  *KY3      1     0.83      5     0.8                      *KY3      7     0.83      9     0.89      1     0.059      3     0.054      26    0.054      4     0.0527     27    0.0527     2     0.0527     4     0.0526     27    0.054      1     0.054      5     0.054      27    0.0527     26    0.05______________________________________ 
    
     
                       TABLE 2______________________________________PENCON______________________________________    117    25    6    70    25    1      1     3    6     0.40       -0.30 -0.07    1      3     9    20    1.80       6.49  -6.23    1      6     2    2     3.53       2.30  -2.53    1      6     3    7     -1.66      8.98  0.00    1      6     3    16    -2.50      1.39  0.00    1      8     20   5     0.00       0.00  0.52    1      8     20   22    -0.20      0.73  0.80    1      8     20   26    0.00       0.00  0.00    1      16    1    5     0.00       0.00  0.27    1      16    15   22    -1.00      3.01  1.86    1      16    16   3     -0.26      1.00  -0.80    1      16    16   5     0.00       0.00  -0.90    1      16    16   27    -0.26      0.70  -0.06    1      25    6    19    0.00       0.00  0.00    1      25    25   25    0.00       3.50  0.00    2      1     3    9     0.00       -0.50 -1.70    2      2     1    3     0.00       0.00  0.50    2      2     2    6     0.00       3.80  0.00    2      2     2    25    -0.30      3.50  0.00    2      2     25   19    0.00       1.00  0.30    2      2     25   25    0.00       1.00  0.30    2      6     1    3     0.00       0.00  -0.60    2      6     1    5     0.00       0.00  0.53    2      25    19   6     0.00       4.50  0.00    2      25    25   3     0.00       3.50  0.00    3      6     1    6     -1.00      -5.00 0.00    3      9     20   5     0.00       0.00  0.51    3      9     20   22    0.00       0.00  0.01    3      9     20   26    -3.50      -0.05 -4.30    3      16    16   15    -1.75      0.60  1.50    3      16    27   22    -1.00      -0.80 0.40    3      16    27   26    -1.00      -0.53 1.13    3      25    25   1     0.00       5.00  0.00    3      25    25   6     0.00       3.80  0.00    3      25    25   19    0.00       3.80  0.00    5      1     16   15    0.00       0.00  0.40    5      1     16   16    0.00       0.00  0.27    5      1     25   6     0.00       0.00  0.54    5      1     25   25    0.00       0.00  0.05    5      2     2    6     -0.30      3.80  0.00    5      2     2    25    0.00       3.50  0.00    5      16    3    6     0.00       0.00  -0.02    5      16    3    7     0.00       0.00  -0.04    5      16    3    29    0.00       0.00  -0.04    5      16    3    30    0.00       0.00  -0.09    5      16    16   15    0.00       0.00  -0.80    5      16    27   22    0.00       0.00  0.40    5      16    27   26    0.00       0.00  0.04    5      20    9    14    0.00       0.00  0.00    5      20    22   5     0.00       0.00  1.30    5      20    22   15    0.00       0.00  0.04    5      20    22   27    0.00       0.00  0.10    5      20    26   27    0.00       0.00  -0.09    5      20    26   28    0.00       0.00  0.21    5      22    15   16    0.00       0.00  0.00    5      22    20   8     0.00       0.00  0.20    5      22    20   9     0.00       0.00  0.20    5      22    20   12    0.00       3.00  0.40    5      22    20   13    0.00       5.00  0.20    5      22    20   26    0.00       0.00  0.87    5      22    27   16    0.00       0.00  0.00    5      22    27   26    0.00       0.00  0.98    6      1     3    7     0.00       0.00  -0.04    6      1     3    9     0.00       0.00  -0.04    6      3     16   16    0.40       -0.30 -0.07    6      3     16   27    0.00       0.00  0.50    6      19    25   25    0.00       4.50  0.00    6      25    25   25    0.00       3.80  0.00    7      3     9    20    0.00       7.19  0.00    7      3     16   16    0.00       0.00  -0.04    7      3     16   27    0.00       0.00  -0.04    7      3     25   25    4.00       0.40  2.40    9      3     25   25    4.30       0.40  2.90    8      20    22   27    0.00       0.00  0.40    8      20    26   27    -4.30      5.00  -1.50    8      20    26   28    -3.50      3.00  8.00    9      20    22   15    0.50       0.00  1.00    9      20    22   27    0.00       0.00  0.40    9      20    26   27    -4.30      5.00  -1.50    9      20    26   28    -3.50      3.00  8.00    12     20    22   15    0.00       0.00  0.04    12     20    22   27    0.00       0.00  0.50    12     20    26   27    0.00       0.00  -0.09    12     20    26   28    0.00       0.00  0.21    13     20    22   15    0.50       -2.75 3.00    13     20    22   27    0.00       0.00  1.40    13     20    26   27    -4.30      5.00  -1.50    13     20    26   28    -1.50      5.00  8.00    14     9     3    25    0.00       2.66  0.00    14     9     20   22    0.00       0.00  0.01    14     9     20   26    0.00       0.00  0.01    15     16    16   27    -0.75      2.00  -0.90    15     22    20   26    0.00       1.00  1.00    15     22    27   16    -3.00      7.00  0.00    15     22    27   26    0.00       1.00  0.30    16     15    22   20    -2.50      3.60  -3.00    16     15    22   27    -2.50      3.00  -1.00    16     16    3    29    0.00       0.00  -0.20    16     16    3    30    0.00       0.00  -0.09    16     16    15   22    0.00       2.50  0.40    16     16    27   22    -1.00      -2.50 0.40    16     16    27   26    -0.50      0.50  2.50    16     27    22   20    0.00       1.00  -0.50    16     27    26   20    -4.00      3.00  0.40    16     27    26   28    -1.00      3.00  2.00    19     6     25   25    0.00       3.50  0.00    19     25    25   25    0.00       3.80  0.00    20     9     3    25    1.80       6.49  -5.234   20     22    27   26    1.50       10.00 1.004   20     26    27   22    -1.00      8.50  5.004   22     20    26   27    -1.00      9.00  3.00    22     20    26   28    0.20       3.50  -2.50    22     27    26   28    0.20       8.00  -4.70    25     6     19   25    0.00       3.50  0.004   26     20    22   27    -2.65      6.10  0.20    27     16    3    29    0.00       0.00  -0.06    27     16    3    30    0.00       0.00  -0.09    1      16         5.26        1.525    1      25         5.48        1.512    2      25         9.60        1.526    3      16         4.45        1.550    3      25         9.60        1.332    5      16         4.60        1.070    5      20         4.39        1.080    5      22         4.38        1.090    6      19         4.32        1.410    6      25         4.09        1.350    8      20         5.10        1.510    9      20         5.47        1.449    12     20         3.23        1.793    13     20         2.30        1.926    15     16         3.98        1.851    15     22         3.98        1.810    16     16         4.50        1.565    16     27         4.30        1.476    19     25         6.50        1.310    20     22         2.56        1.553    20     26         2.58        1.527    20     27         4.30        1.484    25     25         5.83        1.380    26     27         4.79        1.393    26     28         8.65        1.201    1      16         0.000    1      25         0.100    2      25         0.000    3      16         5.872    3      25         0.000    5      16         0.000    5      20         0.000    5      22         0.000    6      19         0.081    6      25         0.212    8      20         3.980    9      20         0.000    12     20         1.940    13     20         1.790    15     16         4.464    15     22         3.653    16     16         0.000    16     27         2.304    19     25         0.330    25     25         0.000    20     22         -0.062    20     26         1.547    22     27         0.712    26     27         2.280    26     28         1.533      16         0.044       1.920      20         0.044       1.920      25         0.044       1.920      26         0.044       1.920      27         0.055       1.820      28         0.066       1.740    1      6     2          0.77       117.00    1      8     20         0.63       110.00    1      16    1          0.45       110.90      1    1      16    1          0.45       111.20      2    1      16    1          0.45       112.40      3    1      16    5          0.36       109.40    1      16    15         0.63       109.80    1      16    16         0.45       110.30      1    1      16    16         0.45       111.20      2    1      16    16         0.45       112.40      3    1      25    6          0.50       117.00    1      25    25         0.55       134.00    2      2     25         0.43       120.00    2      25    19         0.43       120.00    2      25    25         0.43       128.00    3      1     6          0.70       106.00    3      9     20         0.49       121.20    3      16    5          0.37       107.90    3      16    16         0.67       113.90    3      16    27         0.44       111.30    3      25    25         0.60       129.00    5      1     16         0.36       109.40    5      1     25         0.36       109.40    5      16    15         0.36       112.00    5      16    16         0.36       113.36    5      16    27         0.50       100.00    5      20    8          0.36       98.90    5      20    9          0.36       98.90    5      20    22         0.33       113.50    5      20    26         0.63       113.50    5      22    15         0.36       112.00    5      22    20         0.45       119.30    5      22    27         0.37       112.40    6      3     16         0.65       107.10    6      19    25         0.90       106.00    6      25    25         1.38       109.00    7      3     25         0.50       118.00    7      3     16         0.86       110.60    8      20    22         0.56       117.30    8      20    26         0.56       115.00    9      3     25         0.50       115.00    9      20    22         0.56       118.70    9      20    26         0.56       116.50    12     20    13         1.03       111.11    12     20    22         0.35       115.30    12     20    26         0.35       114.70    13     20    22         0.36       117.70    13     20    26         0.36       110.50    14     9     20         0.54       137.90    15     16    16         0.95       104.10    15     22    20         0.63       119.50    15     22    27         0.95       104.10    16     15    22         1.10       93.00    16     16    27         0.95       105.70    16     27    22         0.70       117.40    16     27    26         0.95       126.10    19     6     25         0.71       109.00    19     25    25         1.46       111.004   20     22    27         0.27       87.504   20     26    27         0.52       92.20    20     26    28         -0.02      136.804   22     20    26         0.30       85.204   22     27    26         0.35       93.40    27     26    28         1.59       130.60      2     25         0.05      3     16         0.80      3     25         0.80      9     20         0.05      20    26         0.80      26    27         0.80______________________________________ 
    
     
                       TABLE 3______________________________________CEPARAM______________________________________125     19     6     68    18                78.51       3      16    16    0.34       11.10  0.001       3      16    32    0.00       0.00   -0.091       3      9     20    1.80       6.49   -6.231       6      2     2     3.53       2.30   -2.531       8      20    5     0.00       0.00   0.521       8      20    22    -0.20      0.73   0.801       8      20    31    0.00       0.00   0.001       15     22    5     0.00       0.00   0.001       15     22    20    2.50       3.60   0.001       15     22    32    2.50       3.00   1.001       16     1     5     0.00       0.00   0.271       16     1     15    1.68       1.11   -0.201       16     1     32    0.00       0.00   0.001       16     15    22    -1.00      3.01   1.861       16     16    3     0.00       15.00  0.001       16     16    5     0.00       0.00   -0.901       16     16    15    -0.45      27.10  -0.781       16     16    32    0.00       15.00  0.001       20     9     3     0.00       0.00   0.061       20     22    5     0.0        0.0    2.01       20     22    27    0.00       0.00   0.101       20     26    27    0.0        0.00   -0.091       20     26    28    0.0        0.00   0.271       32     22    15    4.97       6.13   5.471       32     22    20    0.0        1.00   -0.561       32     22    5     0.0        0.0    0.01       32     31    20    -4.00      3.00   0.401       32     31    28    -1.00      3.00   2.002       1      3     9     0.00       -0.50  -1.702       2      1     3     0.00       0.00   0.502       6      1     3     0.00       0.00   -0.602       6      1     5     0.00       0.00   0.533       1      16    1     0.00       0.00   0.003       1      32    22    -1.00      -0.08  0.403       1      32    31    -1.00      -0.53  1.133       9      20    5     0.00       0.00   0.513       9      20    22    0.00       0.00   0.013       9      20    31    -3.50      -0.05  -4.303       16     16    15    -1.75      0.30   1.503       16     32    22    -1.00      -0.80  0.403       16     32    31    -1.00      -0.53  1.135       1      3     16    0.00       0.00   0.005       1      3     30    0.00       0.00   -0.095       1      15    22    0.00       0.00   0.005       1      16    15    0.00       0.00   0.405       1      16    16    0.00       0.00   0.275       1      20    9     0.00       0.49   0.165       1      20    22    0.00       0.00   0.275       1      20    26    0.00       0.00   0.165       1      32    22    0.00       0.00   0.405       1      32    31    0.00       0.00   0.045       16     3     7     0.00       0.00   -0.045       16     3     29    0.00       0.00   -0.045       16     3     30    0.00       0.00   -0.095       16     15    22    0.00       0.00   -0.105       16     16    15    0.00       0.00   -0.805       16     32    22    0.00       0.00   0.405       16     32    31    0.00       0.00   0.045       20     9     14    0.00       0.00   0.005       20     22    5     0.00       0.00   1.305       20     22    15    0.00       0.00   0.045       20     22    32    0.00       0.00   0.105       20     31    32    0.00       0.00   -0.095       20     31    28    0.00       0.00   0.215       22     15    16    0.00       0.00   0.005       22     20    8     0.00       0.00   0.205       22     20    9     0.00       0.00   0.205       22     20    12    0.00       3.00   0.405       22     20    13    0.00       5.00   0.205       22     20    31    0.00       0.00   0.875       22     32    16    0.00       0.00   0.005       22     32    31    0.00       0.00   0.986       1      3     7     0.00       0.00   -0.046       1      3     9     0.00       0.00   -0.047       3      9     20    0.00       7.19   0.007       3      16    16    0.00       0.00   -0.047       3      16    32    0.00       0.00   -0.048       20     22    32    0.00       0.00   0.408       20     31    32    -4.30      5.00   -1.508       20     31    28    -3.50      3.00   8.009       20     22    15    0.50       0.00   1.009       20     22    32    0.00       0.00   0.409       20     31    32    -4.30      5.00   -1.509       20     31    28    -3.50      3.00   8.0012      20     22    15    0.00       0.00   0.0412      20     22    32    0.00       0.00   0.5012      20     31    32    0.00       0.00   -0.0912      20     31    28    0.00       0.00   0.2113      20     22    15    0.50       -2.75  3.0013      20     22    32    0.00       0.00   1.4013      20     31    32    -4.30      5.00   -1.5013      20     31    28    -1.50      5.00   8.0014      9      20    22    0.00       0.00   0.0114      9      20    26    0.00       0.00   0.0114      9      20    31    0.00       0.00   0.0115      1      16    16    1.68       1.10   -0.3315      16     16    32    -0.75      2.00   -0.9015      22     20    31    0.00       1.00   1.0015      22     32    16    -3.00      7.00   0.0015      22     32    31    0.00       1.00   0.3016      1      3     30    0.00       0.00   -0.3516      1      15    22    1.67       1.11   -0.1816      1      32    22    -1.00      -2.50  0.4016      1      32    31    -0.50      0.50   2.5016      15     22    20    -2.50      3.60   -3.0016      15     22    32    -2.50      3.00   -1.0016      16     1     3     0.00       0.00   0.9016      16     1     32    0.         0.     0.16      16     3     29    0.00       10.00  0.0016      16     3     30    0.00       10.00  0.0016      16     15    22    0.00       2.50   0.4016      16     32    22    6.34       8.05   3.1616      16     32    31    -3.34      6.00   0.0016      32     22    20    0.00       1.00   -0.5016      32     31    20    -4.00      3.00   0.4016      32     31    28    -1.00      3.00   2.004    20     22     32  31    1.50       10.00  1.004    20     31     32  22    -1.00      8.50   5.004    22     20     31  32    -10.00     9.00   3.0022     20     31  28    0.20       3.50   -2.5022     32     31  28    0.20       8.00   -4.704    31     20     22  32    -2.65      6.10   0.2032      16     3     29    0.00       0.00   -0.0632      1      3     30    0.00       0.00   -0.0932      16     3     30    0.00       0.00   -0.091       15           3.02        1.8061       32           4.10        1.44915      22           2.72        1.7521       16           4.55        1.48615      16           3.45        1.79016      16           10.10       1.31016      32           5.34        1.4133       16           3.05        1.5503       30           10.01       1.2405       16           5.18        1.10122      32           4.55        1.41331      32           4.57        1.39620      22           4.58        1.5649       20           5.70        1.44920      31           4.53        1.52728      31           12.48       1.1991       5            4.39        1.0815       22           4.20        1.0815       20           4.53        1.0811       16           0.0003       16           5.8723       30           3.9505       20           0.0005       22           0.0009       20           0.0001       15           -1.34715      22           0.67215      16           0.75515      22           0.4481       32           0.75616      16           0.00016      32           1.19220      22           -0.34320      31           -1.62822      32           0.97731      32           2.11728      31           -1.659   16           0.044       1.920   20           0.044       1.920   30           0.066       1.740   31           0.044       1.920   32           0.055       1.820   28           0.066       1.7401       3      16          0.40       115.001       3      30          0.64       116.501       6      2           0.77       110.801       8      20          0.63       110.001       15     22          0.76       96.001       16     1           0.74       113.901       16     1           0.45       111.201       16     1           0.45       112.401       16     5           0.36       109.401       16     15          0.22       109.801       16     16          1.05       122.001       32     22          0.97       127.002       32     31          0.95       136.703       1      6           0.70       106.003       1      32          0.83       108.403       9      20          0.53       121.203       16     5           0.45       107.903       16     16          0.59       113.903       16     32          0.83       111.305       1      16          0.36       109.405       1      5           0.39       110.605       1      15          0.44       108.305       1      16          0.46       106.005       1      32          0.36       110.005       16     15          0.47       112.005       16     16          0.47       113.365       16     32          0.58       100.005       20     8           0.36       98.905       20     9           0.54       98.905       20     22          0.50       115.105       20     31          0.38       112.205       22     15          0.36       107.905       22     20          0.49       114.105       22     32          0.55       118.007       3      16          0.86       110.608       20     22          0.56       117.308       20     31          0.56       115.009       20     22          0.74       118.709       20     31          0.73       116.5012      20     13          1.03       111.1112      20     22          0.35       115.3012      20     31          0.35       114.7013      20     22          0.36       117.7013      20     31          0.36       110.5014      9      20          0.53       137.9015      1      16          1.09       117.0015      16     16          1.07       131.1015      22     20          0.39       116.0015      22     32          0.62       111.0016      1      3           0.67       112.7016      1      32          1.04       110.6016      3      30          1.17       116.5016      15     22          1.04       97.6016      16     32          1.16       120.0016      32     22          0.97       126.1016      32     31          0.41       134.004    20     22     32        1.17       88.304    20     31     32        0.94       90.3020     31     28        0.69       138.004    22     20     31        1.24       85.804    22     32     31        1.01       94.6030     3      30        0.85       126.0032     31     28        0.67       132.00       3      16        0.80       3      30        0.80       9      20        0.05       20     31        0.80       31     32        0.80______________________________________ 
    
     A second necessary requirement for the use of MMP2(85) is the provision of the initial set of cartesian coordinates. For small molecules, such as penicillins and cephalosporins, the coordinates of an experimental crystal structure can be used. Minimization with the appropriate parameters then leads to a calculated structure that reproduces the experimental structure. From this structure it is possible to proceed to other conformations and to the global minimum of the molecule by a series of dihedral drives around each of the dihedral angles of the molecule. This is an option available in MMP2(85), and it works well. However, such a strategy is impractical for the analysis of a peptide because of the very large number of dihedral angles that would have to be examined for any such molecule which contains more than two or three amino acid residues. 
     Therefore, the computer programme ECEPP (Empirical Conformational Energy Program for Peptides), which is available from QCPE, was modified to allow a random number generator to calculate the one-point energies of 200,000 initial structures containing permutations of the most probable backbone and dihedral angles. The fifty lowest energy structures identified in this manner are read out, minimized using a quadratic minimization procedure, and then converted to the MMP2(85) format for final minimization by the Newton-Raphson procedure. The objective of this initial search is to identify, for example, Damascus as a closer starting point than Tokyo in a search for the Dead Sea. This strategy has been tested extensively, works well, and has been applied to the treatment of a PBP, as described below. 
     With these procedures in place, an initial series of nine penicillins (1a-1i) was examined. Of these nine compounds, 1a-1d are highly active antibiotics widely used in medicine (ampicillin, syncillin, penicillin G, penicillin V), 1e-1f are significantly less active, and 1g-1i are biologically inactive. The conformational analyses of these compounds revealed that antibacterial activity is associated specifically with a three dimensional structure in which the carboxyl group and side chain N--H project onto the convex face, and engage in hydrogen bonding lock and key interactions with the receptor, i.e., the PBP. ##STR10## 
     Next a conformational analysis was performed on the cephalosporins 2a-2c. Each of these has the phenoxyacetyl side chain, and can therefore be compared to penicillin V (1d). The Δ 3  -isomer 2a is biologically active, but undergoes a facile equilibration with the Δ 2  -isomer 2b, which is biologically inactive. The reason for the lack of activity of 2b has not previously been established, but it has been suggested that the 4-epi-Δ 2  -isomer 2c would exhibit a better fit to the PBP receptor, and possess antibacterial activity. However, such compounds are also inactive. The reason for this lack of activity is, therefore, also unknown. 
     Each of 2a-2c, like the penicillins 1a-1d, is found to prefer a conformation in which the side chain N--H occupies the convex face of the molecule. As with the penicillins, it can thus be postulated that lock and key interactions with the receptor involve primary binding by the carboxyl group and this side chain N--H. ##STR11## 
     The active site serine D-alanyl carboxypeptidase-transpeptidase of Streptomyces R61 has been crystallized with incorporation of β-lactam compounds, and the crystal structure has been partially solved. The pH-dependence of the same enzyme has also been examined. Both kinds of studies suggest that the carboxyl group of a penicillin is closely associated with the protonated terminal amino group of the lysine residue of X-X-Lys. The crystal structure confirms that, in the complex, the β-lactam ring of penicillin is in close proximity to the active site serine; the pH-dependence study rules out involvement of a histidine residue in the chemical process, in contrast to the behaviour of chymotrypsin and related serine proteases. This result means that the serine O--H participates in the chemical reaction with the substrate. 
     These observations suggest that a valid model of the active site of a PBP can be obtained in terms of the amino acids that surround the unique serine residue, i.e., in this case, Val-Gly-Ser-Val-Thr-Lys. Accordingly, the peptide Ac-Val-Gly-Ser-Val-Thr-Lys-NH-CH 3  was subjected to an ECEPP search of 200,000 initial structures, followed by MMP2(85) refinement of 50 low energy structures identified in this search. One low energy structure having the lysine and serine side chains in proximity was found. This structure is characterized by the set of dihedral angles summarized in Table 4, and is shown as FIG. 1. 
     
                                           TABLE 4__________________________________________________________________________Dihedral angles of the model of the active site of the PBP ofStreptomyces R61Dihedral angle (deg)Residueφ    ψ         ω             χ.sup.1                 χ.sup.2                     χ.sup.3                         χ.sup.4                            χ.sup.5__________________________________________________________________________Ac            180Val  -72 121  180 -60 178 180Gly  160 -179 178Ser  79  -62  -177             -55 62Val  72  -86  177 -52 180 180Thr  -71 152  176 -172                 176 -179Lys  -69 -47  179 -179                 62  176 180                            180__________________________________________________________________________ 
    
     The structure of FIG. 1 has several features of interest. The convex face is mainly hydrophobic, and the concave face, which includes the serine and lysine side chains, is mainly hydrophilic. The concave face also contains the amide oxygen of the N-terminal acetyl group. These three sites are noted on FIG. 1 as S (serine), L (lysine) and A (acetyl). The existence of a lock and key relationship between the concave face of FIG. 1 and the previously determined convex face of penicillin and cephalosporin now seems clear. In terms of such a relationship, contact is required between the carboxyl group of the antibiotic and the terminal amino group of lysine, and also between the side chain N--H of the antibiotic and the acetyl oxygen. 
     The construction of a supermolecule in which the receptor is docked to a substrate through NH 3   + . . .  -  O 2  C and N--H . . . O═C hydrogen bonds is, therefore, desirable. To obtain the structure and energy of such a supermolecule using MMP2(85), it is necessary to devise a procedure for the generation of a starting set of cartesian coordinates. 
     A computer programme has been written based on the following approach to the problem. Let A refer to a receptor molecule containing N 1  atoms, and B a substrate molecule containing N 2  atoms, which is to be docked to A. We assume that the geometries of A and B are known in Cartesian or internal coordinates, and that transformation between the two types of coordinate systems is possible. We thus begin with (3N 1  -6) and (3N 2  -6) predetermined internal coordinates. To describe the geometry of the supermolecule containing (N 1  +N 2 ) atoms requires 3(N 1  +N 2 )-6 internal coordinates, i.e., six new internal coordinates must be determined and minimized. These comprise, typically, one bond length, two bond angles, and three dihedral angles, and they may be termed &#34;intermolecular&#34; internal coordinates. 
     To use the computer programme, summarized in Table 5, one of the desired hydrogen bonding interactions is selected, and its distance set at 1.7-2.5 Å, a typical intermolecular hydrogen bonding distance. Initial values are then given to the five remaining variables, and the energy is minimized, with the second hydrogen bond distance as a probe. The geometry of the resulting supermolecule, now expressed in Cartesian coordinates, is considered appropriate for MMP2(85) minimization when the second hydrogen bond distance is 1.7-2.5 Å. 
     
                                           TABLE 5__________________________________________________________________________PROGRAMME FOR DOCKING OF TWO MOLECULES__________________________________________________________________________                                            SUP00010                                            SUP00020                                            SUP00030PARAMETER (NT = 150)                             SUP00040PARAMETER (NG = 300)                             SUP00050CHARACTER*2 ASYM, TITLE                          SUP00060INTEGER TYPEA, TYPEB, TYP                        SUP00070COMMON/COOD/COORD(3, NG), CHARGE(NG)             SUP00080COMMON/TYPE/TYPEA(NT), TYPEB(NT), TYP(NG)        SUP00090COMMON/SYMM/ASYM(NG), TITLE(40)                  SUP00100COMMON/PARAM/VEP(NG), VRA(NG)                    SUP00110COMMON/CORD/XA(NT), YA(NT), ZA(NT), XB(NT), YB(NT), ZB(NT)                                            SUP00120COMMON/FINAL/TXB(NT), TYB(NT), TZB(NT), CA(NT), CB(NT)                                            SUP00130COMMON/INFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP00140COMMON/PATH/MYWAY                                SUP00150DIMENSION X(5), E(5)                             SUP00160DATA E/5*0.01/                                   SUP00170READ(8, 10) TITLE                                SUP00180FORMAT(40A2)                                     SUP00190READ(8, *) IP1, IP2, IP3, IP4, MYWAY, R1, R2, SC SUP00200MYWAY = 1: DISTANCE                              SUP00210MYWAY = 2: ENERGY                                SUP00220SC = SPECIAL CHARGE                              SUP00230CALL COMBIN(NA, NB)                              SUP00240READ(8, *) THETA, PI, XROT, YROT, ZROT, SCALE, JCON, EE1                                            SUP00250E(1) = EE1                                       SUP00260E(2) = EE1                                       SUP00270E(3) = EE1                                       SUP00280E(4) = EE1                                       SUP00290E(5) = EE1                                       SUP00300READ(5, *) (E(I), I = 1, 5)                      SUP00310SPECIAL CHARGE FOR IP2 AND IP4                   SUP00320CIP2 = SC                                        SUP00330CIP4 = -SC                                       SUP00340IPRINT = 1                                       SUP00350ICON = 1                                         SUP00360CONVERT DEGREE TO RADIAN                         SUP00370DEGREE = 57.29577951D0                           SUP00380X(1) = THETA/DEGREE                              SUP00390X(2) = PI/DEGREE                                 SUP00400X(3) = XROT/DEGREE                               SUP00410X(4 )= YROT/DEGREE                               SUP00420X(5) = ZROT/DEGREE                               SUP00430NVAR = 5                                         SUP00440                                            SUP00450READ COORDINATE WITH MM FORMAT                   SUP00460READ(4, 20) (XA(I), YA(I), ZA(I), TYPEA(I), I = 1, NA)                                            SUP00470FORMAT(2(3F10.5, 15, 5X))                        SUP00480READ(5, 20) (XB(I), YB(I), ZB(I), TYPEB(I), I = 1, NB)                                            SUP00490CALL SYMBOL                                      SUP00500CALL IWRITE                                      SUP00510CALL PARM                                        SUP00520CALL CHARG                                       SUP00530                                            SUP00540WRITE(6, 22) (CHARGE (I), I = 1, 12)             SUP00550FORMAT(3X, 6F10.4)                               SUP00560                                            SUP00570CALL OPTIM(X, NVAR, SCALE, IPRINT, ICON, E)      SUP00580                                            SUP00590CONVERT RADIAN TO DEGREE                         SUP00600DO 30 J = 1, 5                                   SUP00610X(J) = X(J)*DEGREE                               SUP00620WRITE(6, 35) X                                   SUP00630FORMAT(4X, `OPTIMIZED THETA-PI-X-Y-Z ANGLES`, //, 3X, 5(F10.5,                                            SUP00640WRITE BOND DISTANCE BETWEEN IP2 AND IP4          SUP00650X1 = XA(IP2)                                     SUP00660Y1 = YA(IP2)                                     SUP00670Z1 = ZA(IP2)                                     SUP00680X2 = TXB(IP4)                                    SUP00690Y2 = TYB(IP4)                                    SUP00700Z2 = TZB(IP4)                                    SUP00710R12 = DIST(X1, Y1, Z1, X2, Y2, Z2)               SUP00720WRITE(6, 40) IP2, IP4, R12                       SUP00730DO 50 K = 1, NA                                  SUP00740COORD(1, K) = XA(K)                              SUP00750COORD(2, K) = YA(K)                              SUP00760COORD(3, K) = ZA(K)                              SUP00770CONTINUE                                         SUP00780NTOT = NA + NB                                   SUP00790DO 60 KK = 1, NB                                 SUP00800COORD(1, NA + KK) = TXB(KK)                      SUP00810COORD(2, NA + KK) = TYB(KK)                      SUP00820COORD(3, NA + KK) = TZB(KK)                      SUP00830CONTINUE                                         SUP00840FORMAT(//, `BOND LENGTH BETWEEN `,I3,` OF A AND `,I4,` OF B                                            SUP008501, F10.5, `ANGSTROM`, //)                        SUP00860                                            SUP00870CALL CHEMG(NTOT)                                 SUP00880CALL MMDATA                                      SUP00890WRITE FINAL CARTESIAN COORDINATE FOR CHEMGRAF    SUP00900WRITE(6, `(//10X, &#34;FINAL CARTESIAN COORDINATES&#34;,/)`0                                            SUP00910WRITE(6, `(4X, &#34;NO.&#34;, 7X, &#34;ATOM&#34;, 9X, &#34;X&#34;,       SUP009201 9X, &#34;Y&#34;, 9X, &#34;Z&#34;,/)`)                          SUP00930WRITE(6, `(I6, 8X, A2, 4X, 3F10.5)`)             SUP009401 (I, ASYM(I), (COORD(J, I), J = 1, 3), I = 1, NTOT)                                            SUP00950                                            SUP00960STOP                                             SUP00970END                                              SUP00980ROUTINE FOR OUTPUT IF INITIAL COORDINATES        SUP00990SUBROUTINE IWRITE                                SUP01000PARAMETER (NT = 150)                             SUP01010PARAMETER (NG = 300)                             SUP01020CHARACTER*2 ASYM TITLE                           SUP01030INTEGER TYPEA, TYPEB TYP                         SUP01040COMMON/COOD/ COORD(3, NG), CHARGE(NG)            SUP01050COMMON/TYPE/TYPEA(NT), TYPEB(NT), TYP(NG)        SUP01060COMMON/SYMM/ASYM(NG), TITLE(40)                  SUP01070COMMON/CORD/XA(NT), YA(NT), ZA(NT), XB(NT), YB(NT), ZB(NT)                                            SUP01080COMMON/FINAL/TXB(NT), TYB(NT), TZB(NT), CA(NT), CB(NT)                                            SUP01090COMMONIINFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP01100WRITE(6, 15) TITLE                               SUP01110FORMAT(1H1, /////,                               SUP011201 10X, `******************************************`,/,                                            SUP011302 10X, `COORDINATES OF SUPERMOLECULE`,/,         SUP011403 15X, 40A2,/,                                   SUP011504 10X, `******************************************`)                                            SUP01160WRITE CARTESIAN COORDINATE                       SUP01170WRITE(6, `(//10X, &#34;INITIAL CARTESIAN COORDINATES OF A &#34;,/)`)                                            SUP01180WRITE(6, `(4X, &#34;NO.&#34;, 7X, &#34;ATOM&#34;, 9X, &#34;X&#34;,       SUP011901 9X, &#34;Y&#34;, 9X, &#34;Z&#34;,/)`)                          SUP01200WRITE(6, `(I6, 8X, A2, 4X, 3F10.5)`)             SUP012101 (I, ASYM(I), XA(I), YA(I), ZA(I), I = 1, NA)   SUP01220                                            SUP01230WRITE(6, `(////10X, &#34;INITIAL CARTESIAN COORDINATES OF B                                            SUP01240WRITE(6, `(4X, &#34;NO.&#34;, 7X, &#34;ATOM&#34;, 9X, &#34;X&#34;,       SUP012501 9X, &#34;Y&#34;, 9X, &#34;2&#34;,/)`)                          SUP01260WRITE(6, `(I6, 8X, A2, 4X, 3F10.5)`)             SUP012701 (I, ASYM(NA + I), XB(I), YB(I), ZB(I), I = 1, NB)                                            SUP01280WRITE(6, `(///)`)                                SUP01290RETURN                                           SUP01300END                                              SUP01310SUBROUTINE OPTIM (X, N, ESCALE, IPRINT, ICON, E) SUP01320PARAMETER (NT = 150)                             SUP01330DIMENSION W(1000), X(5), E(5)                    SUP01340MAXIT = 100                                      SUP01350DDMAG = 0.1*ESCALE                               SUP01360SCER = 0.05/ESCALE                               SUP01370JJ = N*N + N                                     SUP01380JJJ = JJ + N                                     SUP01390K = N + 1                                        SUP01400NFCC = 1                                         SUP01410IND = 1                                          SUP01420INN = 1                                          SUP01430DO 1 I = 1, N                                    SUP01440DO 2 J = 1, N                                    SUP01450W(K) = 0.                                        SUP01460IF(I - J)4, 3, 4                                 SUP01470W(K) = ABS(E(I))                                 SUP01480W(I) = ESCALE                                    SUP01490K = K + 1                                        SUP01500CONTINUE                                         SUP01510CONTINUE                                         SUP01520ITERC = 1                                        SUP01530ISCRAD = 2                                       SUP01540CALL CALCFX(N, X, F, EVV, ECO, EIDS)             SUP01550FKEEP = ABS(F) + ABS(F)                          SUP01560ITONE = 1                                        SUP01570FP = F                                           SUP01580SUM = 0.                                         SUP01590IXP = JJ                                         SUP01600DO 6 I = 1, N                                    SUP01610IXP = IXP + 1                                    SUP01620W(IXP) = X(I)                                    SUP01630CONTINUE                                         SUP01640IDIRN = N + 1                                    SUP01650ILINE = 1                                        SUP01660DMAX = W(ILINE)                                  SUP01670DACC = DMAX*SCER                                 SUP01680DMAG = MIN (DDMAG, 0.1*DMAX)                     SUP01690DMAG = MAX(DMAG, 20.*DACC)                       SUP01700DDMAX = 10.*DMAG                                 SUP01710GO TO (70, 70, 71), ITONE                        SUP01720DL = 0.                                          SUP01730D = DMAG                                         SUP01740FPREV = F                                        SUP01750IS = 5                                           SUP01760FA = F                                           SUP01770DA = DL                                          SUP01780DD = D - DL                                      SUP01790DL = D                                           SUP01800K = IDIRN                                        SUP01810DO 9 I = 1, N                                    SUP01820X(I) = X(I) + DD*W(K)                            SUP01830K = K + 1                                        SUP01840CONTINUE                                         SUP01850CALL CALCFX(N, X, F, EVV, ECO, EDIS)             SUP01860NFCC = NFCC + 1                                  SUP01870GO TO (10, 11, 12, 13, 14, 96), IS               SUP01880IF(F - FA)15, 16, 24                             SUP01890IF (ABS(D) - DMAX) 17, 17, 18                    SUP01900D = D + D                                        SUP01910GO TO 8                                          SUP01920WRITE(6, 19)                                     SUP01930FORMAT(5X, 44NVA04A MAXIMUM CHANGE DOES NOT ALTER FUNCTION)                                            SUP01940GO TO 500                                        SUP01950FB = F                                           SUP01960DB = D                                           SUP01970GO TO 21                                         SUP01980FB = FA                                          SUP01990DB = DA                                          SUP02000FA = F                                           SUP02010DA = D                                           SUP02020GO TO (83, 23), ISGRAD                           SUP02030D = DB + DB - DA                                 SUP02040IS = 1                                           SUP02050GO TO 8                                          SUP02060D = 0.5*(DA + DB - (FA - FB)/(DA - DB))          SUP02070IS = 4                                           SUP02080IF((DA - D)*(D - DB))25, 8, 8                    SUP02090IS = 1                                           SUP02100IF(ABS(D - DB) - DDMAX)8, 8, 26                  SUP02110D = DB + SIGN(DDMAX, DB - DA)                    SUP02120IS = 1                                           SUP02130DDMAX = DDMAX + DDMAX                            SUP02140DDMAG = DDMAG + DDMAG                            SUP02150IF(DDMAX - DMAX)8, 8, 27                         SUP02160DDMAX = DMAX                                     SUP02170GO TO 8                                          SUP02180IF(F - FA)28, 23, 23                             SUP02190FC = FB                                          SUP02200DC = DB                                          SUP02210FB = F                                           SUP02220DB = D                                           SUP02230GO TO 30                                         SUP02240IF(F - FB)28, 28, 31                             SUP02250FA = F                                           SUP02260DA = D                                           SUP02270GO TO 30                                         SUP02280IF(F - FB)32, 10, 10                             SUP02290FA = FB                                          SUP02300DA = DB                                          SUP02310GO TO 29                                         SUP02320DL = 1.                                          SUP02330DDMAX = 5.                                       SUP02340FA = FP                                          SUP02350DA = -1.                                         SUP02360FB = FHOLD                                       SUP02370DB = 0.                                          SUP02380D = 1.                                           SUP02390FC = F                                           SUP02400DC = D                                           SUP02410A = (DB - DC)*(FA - FC)                          SUP02420B = (DC - DA)*(FB - FC)                          SUP02430IF((A*B)*(DA - DC))33, 33, 34                    SUP02440FA = FB                                          SUP02450DA = DB                                          SUP02460FB = FC                                          SUP02470DB = DC                                          SUP02480GO TO 26                                         SUP02490D = 0.5*(A*(DB + DC) + B*(DA + DC))/(A + B)      SUP02500DI = DB                                          SUP02510FI = FB                                          SUP02520IF(FB-FC)44, 44, 43                              SUP02530DI = DC                                          SUP02540FI = FC                                          SUP02550GO TO (86, 86, 85), ITONE                        SUP02560ITONE = 2                                        SUP02570GO TO 45                                         SUP02580IF (ABS(D - DI) - DACC) 41, 41, 93               SUP02590IF (ABS (D - DI) - 0.03*ABS(D)) 41, 41, 45       SUP02600IF (DA - DC)*(DC - D)) 47, 46, 46                SUP02610FA = FB                                          SUP02620DA = DB                                          SUP02630FB = FC                                          SUP02640DB = DC                                          SUP02650GO TO 25                                         SUP02660IS = 2                                           SUP02670IF ((DB - D)*(D - DC)) 48, 8, 8                  SUP02680IS = 3                                           SUP02690GO TO 8                                          SUP02700F = FI                                           SUP02710D = DI - DL                                      SUP02720DD = SQRT((DC - DB)*(DC - DA)*(DA - DB)/(A + B)) SUP02730DO 49 I = 1, N                                   SUP02740X(I) = X(I) + D*W(IDIRN)                         SUP02750W(IDIRN) = DD*W(IDIRN)                           SUP02760IDIRN = IDIRN + 1                                SUP02770CONTINUE                                         SUP02780W(ILINE) = W(ILINE)/DD                           SUP02790ILINE = ILINE + 1                                SUP02800IF(IPRINT - 1)51, 50, 51                         SUP02810WRITE(6, 52)ITERC, NFCC, F                       SUP02820WRITE(7, 52)ITERC, NFCC, F                       SUP02830FORMAT (3X, `ITERATION`, I5, I9, `FUNCTION VALUE = `, F15.8)                                            SUP02840WRITE(6, 68) EVV, ECO, EDIS                      SUP02850WRITE(7, 68) EVV, ECO, EDIS                      SUP02860FORMAT(3X, `REP. = `, F12.5,` ATT. = , `F12.5,` R = `, F10.4)                                            SUP02870GO TO(51, 53), IPRINT                            SUP02880GO TO (55, 38), ITONE                            SUP02890IF (FPREV - F - SUM) 94, 95, 95                  SUP02900SUM = FPREV - F                                  SUP02910JIL = ILINE                                      SUP02920IF (IDIRN - JJ) 7, 7, 84                         SUP02930GO TO (92, 72), IND                              SUP02940FHOLD = F                                        SUP02950IS = 6                                           SUP02960IXP = JJ                                         SUP02970DO 59 I = 1, N                                   SUP02980IXP = IXP + 1                                    SUP02990W(IXP) = X(I) - W(IXP)                           SUP03000CONTINUE                                         SUP03010DD = 1.                                          SUP03020GO TO 58                                         SUP03030GO TO (112, 87), IND                             SUP03040IF (FP - F) 37, 91, 91                           SUP03050D = 2.*(FP*F - 2.*FHOLD)/(FP - F)**2             SUP03060IF (D*(FP - FHOLD - SUM)**2 - SUM) 87, 37, 37    SUP03070J = JIL*N + 1                                    SUP03080IF (J - JJ) 60, 60, 61                           SUP03090DO 62 I = J, JJ                                  SUP03100K = I - N                                        SUP03110W(K) = W(I)                                      SUP03120CONTINUE                                         SUP03130DO 97 I = JIL, N                                 SUP03140W(I - 1) = W(I)                                  SUP03150CONTINUE                                         SUP03160IDIRN = IDIRN - N                                SUP03170ITONE = 3                                        SUP03180K = IDIRN                                        SUP03190IXP = JJ                                         SUP03200AAA = 0.                                         SUP03210DO 65 I = 1, N                                   SUP03220IXP = IXP + 1                                    SUP03230W(K) = W(IXP)                                    SUP03240IF (AAA - ABE(W(K)/E(I))) 66, 67, 67             SUP03250AAA = ABS(W(K)/E(I))                             SUP03260K = K - 1                                        SUP03270CONTINUE                                         SUP03280DDMAG = 1.                                       SUP03290W(N) = ESCALE/AAA                                SUP03300ILINE = N                                        SUP03310GO TO 7                                          SUP03320IXP = JJ                                         SUP03330AAA = 0.                                         SUP03340F = FHOLD                                        SUP03350DO 99 I = 1, N                                   SUP03360IXP = IXP + 1                                    SUP03370X(I) = X(I) - W(IXP)                             SUP03380IF (AAA*ABS(E(I)) - ABS(W(IXP))) 98, 99, 99      SUP03390AAA = ABS(W(IXP)/E(I))                           SUP03400CONTINUE                                         SUP03410GO TO 72                                         SUP03420AAA = AAA*(1. + DI)                              SUP03430GO TO (72, 106), IND                             SUP03440IF (IPRINT - 2) 53, 50, 50                       SUP03450GO TO (109, 88), IND                             SUP03460IF (AAA - 0.1) 89, 89, 76                        SUP03470GO TO (20, 116), ICON                            SUP03480IND = 2                                          SUP03490GO TO (100, 101), INN                            SUP03500INN = 2                                          SUP03510K = JJJ                                          SUP03520DO 102 I = 1, N                                  SUP03530K = K + 1                                        SUP03540W(K) = X(I)                                      SUP03550X(I) = X(I) + 10.*E(I)                           SUP0356OCONTINUE                                         SUP03570FKEEP = F                                        SUP03580CALL CALCFX(N, X, F, EVV, ECO, EDIS)             SUP03590NFCC = NFCC + 1                                  SUP03600DDMAG = 0                                        SUP03610GO TO 108                                        SUP03620IF (F - FP) 35, 78, 78                           SUP03630WRITE(6, 80)                                     SUP03640FORMAT (5X, 37HVA04A ACCURACY LIMITED BY ERRORS IN F)                                            SUP03650GO TO 500                                        SUP03660IND = 1                                          SUP03670DDMAC = 0.4*SQRT(FP - F)                         SUP03680IF(DDMAG.GE.1.0EG0) DDMAG = 1.0E60               SUP03690ISCRAD = 1                                       SUP03700ITERC = ITERC + 1                                SUP03710IF (ITERC - MAXIT) 5, 5, 81                      SUP03720WRITE(6, 82)MAXIT                                SUP03730FORMAT(15, 30H ITERATIONS COMPLETED BY VA04A)    SUP03740IF (F - FKEEP) 500, 500, 110                     SUP03750F = FKEEP                                        SUP03760DO 111 I = 1, N                                  SUP03770JJJ = JJJ4 - 1                                   SUP03780X(I) = W(JJJ)                                    SUP03790CONTINUE                                         SUP03800GO TO 20                                         SUP03810JIL = 1                                          SUP03820FP = FKEEP                                       SUP03830IF (F - FKEEP) 105, 78, 104                      SUP03840JIL = 2                                          SUP03850FP = F                                           SUP03860F = FKEEP                                        SUP03870IXP = JJ                                         SUP03890DO 113 I = 1, N                                  SUP03890IXP = IXP + 1                                    SUP03900K = IXP + N                                      SUP03910GO TO (114, 115), JIL                            SUP03920W(IXP) = W(K)                                    SUP03930GO TO 113                                        SUP03940W(IXP) = X(I)                                    SUP03550X(I) = W(K)                                      SUP03960CONTINUE                                         SUP03970JIL = 2                                          SUP03980GO TO 92                                         SUP03990IF (AAA - 0.1) 20, 20, 107                       SUP04000WRITE(6, 200)                                    SUP04010WRITE(6, 201)                                    SUP04020WRITE(7, 201)                                    SUP04030FORMAT(5X, `THE FUNCTION VALUE HAS BEEN MINIMIZED.`)                                            SUP04040WRITE(6, 200)                                    SUP04050FORMAT(/1X, `********************************************`/)                                            SUP04060RETURN                                           SUP04070INN = 1                                          SUP04080GO TO 35                                         SUP04090END                                              SUP04100                                            SUP04110SUBROUTINE PARM                                  SUP04120PARAMETER (NT = 150)                             SUP04130PARAMETER (NG = 300)                             SUP04140CHARACTER*2 ASYM, TITLE                          SUP04150INTEGER TYPEA, TYPEB TYP                         SUP04160COMMON/PARAM/VEP(NG), VRA(NG)                    SUP04170COMMON/rNFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP04180COMMON/TYPE/TYPEA(NT), TYPEB(NT), TYP(NG)        SUP04190DIMENSION VEPS(60), VRAD(60)                     SUP04200                                            SUP04210DATA VRAD/                                       SUP042201 1.900, 1.940, 1.940, 1.940, 1.500, 1.740, 1.740, 1.820, 1.820,                                            SUP042302 -1.0, 1.780, 1.740, 1.900, 0.930, 2.110, 1.920, -1.0,                                            SUP042403 1.820, 1.920, 1.200, 1.920, 1.325, 0.900, 1.25, 1.820,                                            SUP042504 1.740, 1.90, 1.780, 1.92, 1.82, -1.0 , -1.0 , -1.0, -1.0 ,                                            SUP042605 -1.0, -1.0, -1.0, -1.0 , -1.0, -1.0, 17* - 1.0/                                            SUP04270DATA VEPS/                                       SUP042801 0.044, 0.044, 0.044, 0.044, 0.047, 0.050, 0.066, 0.055,                                            SUP042902 -1.0, 0.066, 0.050, 0.030, 0.017, 0.202, 0.044, -1.0,                                            SUP043003 0.055, 0.044, 0.036, 0.044, 0.034, 0.015, 0.036, 0.055,                                            SUP043104 0.066, 0.044, 0.066, 0.044, 0.055, -1.0, -1.0, -1.0 , -1.0,                                            SUP043205 -1.0, -1.0, -1.0, -1.0, -1.0, -1.0, 17* - 1.0/ SUP04330IF(JCON.GT.0) THEN                               SUP04340DO 10 J = 1, JCON                                SUP04350READ(5, *) ITYPE, EPS, RAD                       SUP04360VEPS(ITYPE) = EPS                                SUP04370VRAD(ITYPE) = RAD                                SUP04380CONTINUE                                         SUP04390ENDIF                                            SUP04400DO 20 I = 1, NA                                  SUP04410VEP(I) = VEPS(TYPEA(I))                          SUP04420IF(VEP(I).LE - 0.0) THEN                         SUP04430WRITE(7, 25) TYPEA(I)                            SUP04440ENDIF                                            SUP04450VRA(I) = VRAD(TYPEA(I))                          SUP04460TF(VRA(I).LE.0.0) THEN                           SUP04470WRITE(7, 25) TYPEA(L)                            SUP04480FORMAT(4X, `CHECK YOUR VAN DER WAAL DATA OF ATOM TYPE`,                                            SUP04490ENDIF                                            SUP04500CONTINUE                                         SUP04510                                            SUP04520DO 30 I1 = 1, NB                                 SUP04530VEP(NA + I) = VEPS(TYPEB(I))                     SUP04540IF(VEP(NA + I).LE - 0.0) THEN                    SUP04550WRITE(7, 25) TYPEB(I)                            SUP04560ENNDIF                                           SUP04570VRA(NA + I) = VRAD(TYL)EB(I))                    SUP04580IF(VRA(NA + I).LE.0.0) THEN                      SUP04590WRITE(7, 25) TYPEB(I)                            SUP04600ENDIF                                            SUP04610CONTINUE                                         SUP04620RETURN                                           SUP04630END                                              SUP04640SUBROUTINE ENERGY(ETOT, EV, ETOT1, EDIS)         SUP04650FUNCTION PROGRAM FOR SUPER-MOLECULE              SUP04660PARAMETER (NT = 150)                             SUP04670PARAMETER (NG = 300)                             SUP04680CHARACTER*2 ASYM, TITLE                          SUP04690INTEGER TYPEA, TYPEB, TYP                        SUP04700COMMON/COOD/COORD(3, NG), CHARGE(NG)             SUP04710COMMON/TYPE/TYPEA(NT), TYPEB(NT) TYP(NG)         SUP04720COMMON/CORD/XA(NT)*YA(NT), ZA(NT), XB(NT), YB(NT), ZB(NT)                                            SUP04730COMMON/FINAL/TXB(NT), TYB(NT), TZB(NT), CA(NT), CB(NT)                                            SUP04740COMMON/PARAM/VEP(NG), VRA(NG)                    SUP04750COMMON/INFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP04760COMMON/PATH/MYWAY                                SUP04770CALCULATION OF VAN DER WALLS ENERGY(ONLY 1-5 AND HIGHTER                                            SUP04780DIELC = 78.5                                     SUP04790GO TO (1, 2), MYWAY                              SUP04800X1 = XA(IP2)                                     SUP04810Y1 = YA(IP2)                                     SUP04820Z1 = ZA(IP2)                                     SUP04830X2 = TXB(IP4)                                    SUP04840Y2 = TYB(IP4)                                    SUP04850Z2 = TZB(IP4)                                    SUP04860ETOT1 = DIST(X1, Y1, Z1, X2, Y2, Z2)             SUP04870ETOT1= ABS(ETOT1 - R2) *500.0                    SUP04880IF(MYWAY.EQ.1) THEN                              SUP04890ETOT = ETOT1                                     SUP04900RETURN                                           SUP04910ENDIF                                            SUP04920                                            SUP04930EV = 0.0                                         SUP04940EC = 0.0                                         SUP04950DO 500 I = 1, NA                                 SUP04960XI = XA(I)                                       SUP04970YI = YA(I)                                       SUP04980ZI = ZA(I)                                       SUP04990DO 500 K = 1, NB                                 SUP05000XK = TXB(K)                                      SUP05010YK = TYB(K)                                      SUP05020ZK = TZB(K)                                      SUP05030RIK = DIST(XI, YI, ZI, XK, YK, 2K)               SUP05040ECOUL = 332.0*CHARGE(I)*CHARGE(NA + K)/(DIELC*RIK)                                            SUP05050VEPI = VEP(I)                                    SUP05060VEPK = VEP(NA + K)                               SUP05070VRAI = VRA(I)                                    SUP05080VRAK = VRA(NA + K)                               SUP05090EPS = SQRT(VEPI*VEPK)                            SUP05100RV = VRAI + VRAK                                 SUP05110P = RV/RIK                                       SUP05120IF(P.GT.3.31) GO TO 30                           SUP05130IF(P.LT.0.072) THEN                              SUP05140E = EPS*(-2.25*p**6)                             SUP05150GO TO 35                                         SUP05160ENDIF                                            SUP05170E = EPS*(290000.0*EXP(-1.2.5/P) - 2.25*P**G)     SUP05180GO TO 40                                         SUP05190E = EPS*33G.176*p*p                              SUP05200CONTINUE                                         SUP05210EV = EV + E                                      SUP0520EC = EC - ECOUL                                  SUP05230CONTINUE                                         SUP05240ETOT = EV + ETOT1 + EC                           SUP05250ETOT = FV + ETOT1                                SUP05260X1 = XA(IP2)                                     SUP05270Y1 = YA(IP2)                                     SUP05280Z1 = ZA(IP2)                                     SUP05290X2 = TXB(IP4)                                    SUP05300Y2 = TYB(IP4)                                    SUP05310Z2 = TZB(IP4)                                    SUP05320EDIS = DIST(X1, Y1, Z1, X2, Y2, Z2)              SUP05330RETURN                                           SUP05340END                                              SUP05350FUNCTION DIST                                    SUP05360FUNCTION DIST(X1, Y1, Z1, X2, Y2, Z2)            SUP05370X = X1 - X2                                      SUP05380Y = Y1 - Y2                                      SUP05390Z = Z1 - Z2                                      SUP05400DIST = SQRT(X*X + Y*Y + Z*Z)                     SUP05410RETURN                                           SUP05420END                                              SUP05430SUBROUTINE CALCFX(NVAR, X, ETOT, EV, EC, EDIS)   SUP05440PARAMETER (NT = 150)                             SUP05450PARAMETER (NG = 300)                             SUP05460COMMON/CORD/XA(NT), YA(NT), ZA(NT), XB(NT), YB(NT), ZB(NT)                                            SUP05470COMMON/FINAL/TXB(NT), TYB(NT), TZB(NT), CA(NT), CB(NT)                                            SUP05480COMMON/INFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2 CIP2, CIP4,                                            SUP05490DIMENSION X(5), TX(150), TY(150), TZ(150), XROT(9), YROT(9),                                            SUP05500DIMENSION CTX(150), CTY(150), CTZ(150)           SUP05510CONVERSION OF POLAR COORDINATE TO CARTECIAN COORDINATE OF REF.                                            SUP05520DX = R1*SIN(X(1))*COS(X(2))                      SUP05530DY = R1*SIN(X(1))*SIN(X(2))                      SUP05540DX = R1*COS(X(1))                                SUP05550FIXING OF PROBE 2 APART FROM PROBE 1 BY R1 ANG. IN SPACE                                            SUP05560PX = XA(IP1) + DX                                SUP05570PY = YA(IP1) + DY                                SUP05580PZ = ZA(IP1) + DZ                                SUP05590CALCULATE DISTANCE VECTORS BETWEEN PROBE P(PX, PY, PZ) AND PROBE                                            SUP05600DVX = PX - XB(IP3)                               SUP05610DVY = PY - YB(IP3)                               SUP05620DVZ = PZ - ZB(IP3)                               SUP05630PARALLEL MOVEMENT OF B MOLECULE BY (DVX, DVY, DVZ)                                            SUP05640DO 10 IM = 1, NB                                 SUP05650TX(IM) = XB(IM) * DVX                            SUP05660TY(IM) = YB(IM) + DVY                            SUP05670TZ(IM) = ZB(IM) + DVZ                            SUP05680CONTINUE                                         SUP05690MOVE TO MAKE AN ORIGIN OF PROBE3(IP3) IN ORDER TO ROTATE                                            SUP05700DO 20 IO = 1, NB                                 SUP05710IF(IO.EQ.IP3) GO TO 20                           SUP05720TX(IO) = TX(IO) - TX(IP3)                        SUP05730TY(IO) = TY(IO) - TY(IP3)                        SUP05740TZ(IO) = TZ(IO) - TZ(IP3)                        SUP05750CONTINUE                                         SUP05760TX(IP3) = 0.0D0                                  SUP05770TY(IP3) = 0.0D0                                  SUP05780TZ(IP3) = 0.0D0                                  SUP05790ROTATION                                         SUP05800CSX = COS(X(3))                                  SUP05810SSX = SIN(X(3))                                  SUP05820CSY = COS(X(4))                                  SUP05830SSY = SIN(X(4))                                  SUP05340SCZ = COS(X(5))                                  SUP05850SSZ = SrN(X(5))                                  SUP05860X ROTATION                                       SUP05870DO 30 I = 1, 9                                   SUP05380XROR(I) = 0.0                                    SUP05890XROT(1) = 1.0                                    SUP05900XROT(5) = CSX                                    SUP05910XROT(6) = SSX                                    SUP05920XROT(8) = SSX                                    SUP05930XROT(9) = CSX                                    SUP05940DO 40 I = 1, 9                                   SUP05950YROT(I) = 0.0                                    SUP05960YROT(1) = CSU                                    SUP05970YROT(3) = SSY                                    SUP05980YROT(5) = 1.0                                    SUP05990YROT(7) = -SSY                                   SUP06000YROT(9) = CSY                                    SUP06010DO 50 I = 1, 9                                   SUP06020ZROT(I) = 0.0                                    SUP06030ZROT(1) = CSZ                                    SUP06040ZROT(2) = SSZ                                    SUP06050ZROT(4) = -SSZ                                   SUP06060ZROT(5) = CSZ                                    SUP06070ZROT(9) = 1.0                                    SUP06080DO 60 J = 1, NB                                  SUP06090COXX = XROT(1)*TX (J) + XROT(2)*TY(J) + XROT(3)* TZ(J)                                            SUP06100COXY = XROT(4)*TX (J) + XROT(5)*TY(J) + XROT(G)* TZ(J)                                            SUP06110COXZ = XROT(7)*TX (J) + XROT(8)*TY(J) + XROT(9)* TZ(J)                                            SUP06120COYX = YROT(1)*COXX + YROT(2)*COXY + YROT(3)*COXZ                                            SUP06130COYY = YROT(4)*COXX + YROT(5)*COXY + YROT(6)*COXZ                                            SUP06140COYZ = YROT(7)*COXX + YROT(8)*COXY + YROT(9)*COXZ                                            SUP06150CTX(J) = ZROT(1)*COYX + ZROT(2)*COYY + ZROT(3)*COYZ                                            SUP06160CTY(J) = ZROT(4)*COYX + ZROT(5)*COYY + ZROT(6)*COYZ                                            SUP06170CTZ(J) = ZROT(7)*COYX + ZROT(8)*COYY + ZROT(9)*COYZ                                            SUP06180CONTINUE                                         SUP06190RETURN TO POINT P                                SUP06200DO 70 I = 1, NB                                  SUP06210TXB(I) = CTX(I) + PX                             SUP06220TYB(I) = CTY(I) + PY                             SUP06230TZB(I) = CTZ(I) + PZ                             SUP06240CONTINUE                                         SUP06250                                            SUP06260CALL ENERGY(ETOT, EV, EC, EDIS)                  SUPOG270RETURN                                           SUP06280END                                              SUP06290                                            SUP06300SUBROUTINE COUL(ETOT, ER, EA)                    SUP06310PARAMETER (NT = 150)                             SUPO6320PARAMETER (NG = 300)                             SUP06330CHARACTER*2 ASYM, TITLE                          SUP06340COMMON/CORD/XA(NT), YA(NT), ZA(NT), XB(NT), YB(NT), ZB(NT)                                            SUP06350COMMON/FINAL/TXB(NT), TYB(NT), TZB(NT), CA(NT), CB(NT)                                            SUP06360COMMON/INFO/NA, NB, IP1, EP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP06370ER = 0.0                                         SUP06380DO 10 I = 1, NA                                  SUP06390X1 = XA(I)                                       SUP06400Y1 = YA(I)                                       SUP06410Z1 = ZA(r)                                       SUPO6420DO 20 J = 1, NB                                  SUP06430X2 = TXB(I)                                      SUP06440Y2 = TYB(I)                                      SUP06450Z2 = TZB(I)                                      SUP0646OER = ER + (CA(I)*CB(J))/DrST(X1, Y1, Z1, X2, Y2, Z2)                                            SUP06470CONTINUE                                         SUP06480CONTINUE                                         SUP06490EA = 0.0                                         SUP06500X1 = XA(IP2)                                     SUP06510Y1 = YA(IP2)                                     SUP06520Z1 = ZA(IP2)                                     SUP06530X2 = TXB(IP4)                                    SUP06540Y2 = TYB(IP4)                                    SUP06550Z2 = TZB(IP4)                                    SUP06560EA = EA + (CIP2*CIP4)/DIST(X1, Y1, Z1, X2, Y2, Z2)                                            SUP06570ETOT = ER + EA                                   SUP06580RETURN                                           SUP06590END                                              SUP06600                                            SUP06610SUBPROGRAM TO GENERATE ATOM TYPE AND NET ATOMIC CHARGE                                            SUP06620SUBROUTINE CHARG                                 SUP06630PARAMETER (NG = 300)                             SUP06640PARAMETER (NT = 150)                             SUP06650INTECER TYPEA, TYPEB, TYP                        SUP06660COMMON/COOD/COORD(3, NG), CHARGE(NG)             SUP06670COMMON/TYPE/TYPEA(NT), TYPEB(NT), TYP(NG)        SUP06680COMMON/INFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP06690DIMENSION DCHB(35)                               SUP06700DATA DCHB/0.241, 0.0, 0.515, 0.0, 0.0, -0.539, -0.490,                                            SUP067101 -0.267, -0.509, 0.0, -0.692, -0.54, -0.267, 0.243,                                            SUP067202 -0.135, 0.0, 0.0, 0.0, -0.622, 0.0, 0.304,     SUP067303 0.0, 0.243, 0.15, 0.131, -0.516, 0.0, 0.490,   SUP067404 0.0, -622, 0.515, 0.0, 0.0, 0.0, 0.0,/         SUP06750DO 20 I = 1, NA                                  SUP06760CHARGE(I) = DCHB(TYPEA(I))                       SUP06770CONTINUE                                         SUP06780SPECIAL SIDE CHAIN FOR CARBONE                   SUP06790CHARGES FOR HYDANTON                             SUP06800DO 30 I = 1, NB                                  SUP06810CHARGE(NA + I) = DCHB(TYPEB(I))                  SUP06820CONTINUE                                         SUP06830CHARGE(NA + 1) = -0.36                           SUP06840CHARGE(NA + 2) = 0.44                            SUP06850CHARGE(NA + 3) = -0.41                           SUP06860CHARGE(NA + 4) = 0.58                            SUP06870CHARGE(NA + 5) = -0.31                           SUP06880CHARGE(NA + 6) = 0.03                            SUP06890CHARGE(NA + 7) = - 0.41                          SUP06900CHARGE(NA + 20) = 0.19                           SUP06910CHARGE(NA + 21) = 0.20                           SUP06920CHARGE(IP2) = CIP2                               SUP06930CHARGE(NA + IP4) = CIP4                          SUP06940WRITE(6, 22) (CHARGE(I), I = 1, 12)              SUP06950FORMAT(3X, 6F10.4)                               SUP06960RETURN                                           SUP06970END                                              SUP06980                                            SUP06990SUBROUTINE SYMBOL                                SUP07000PARAMETER (NT = 150)                             SUP07010PARAMETER (NG = 300)                             SUP07020CHARACTER*2 ASYM, TITLE                          SUP07030INTEGER TYPEA, TYPEB, TYP, HH, NN, OO, CC        SUP07040COMMON/COOD/COORD(3, NG), CHARGE(NG)             SUP07050COMMON/TYPE/TYPEA(NT), TYPEB(NT), TYP(NG)        SUP07060COMMON/SYMM/ASYM(NG), TITLE(40)                  SUP07070COMMON/INFO/NA, NB, IP1, IP2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP07080DIMENSION HH(6), NN(7), OO(6), CC(10)            SUP07090DATA HH/5, 14, 23, 21, 24, 25/                   SUP07100DATA NN/8, 9, 13, 19, 26, 32, 28/                SUP07110DATA 00/6, 7, 11, 12, 28, 30/                    SUP07120DATA CC/1, 2, 3, 1, 16, 20, 22, 27, 29, 31/      SUP07130NTOT = NA + NB                                   SUP07140DO 1 I = 1, NA                                   SUP07150TYP(I) = TYPEA(I)                                SUP07160CONTINUE                                         SUP07170DO 2 I = 1, NB                                   SUP07180TYP(NA + 1) = TYPEB(I)                           SUP07190CONTINUE                                         SUP07700I = 0                                            SUP07210CONTINUE                                         SUP07220I - 0                                            SUP07230IF(I.GT.NTOT) GO TO 9                            SUP07240DO 20 K1 = 1, 6                                  SUP07250IF(TYP(I).EQ.HH(K1)) THEN                        SUP07260ASYM(I) = `H`                                    SUP07270GO TO 10                                         SUP07280ENDIF                                            SUP07290CONTINUE                                         SUP07300DO 30 K1 = 1, 7                                  SUP07310IF(TYP(I).EQ.NN(K1)) THEN                        SUP07320ASYM(I) = `N`                                    SUP07330GO TO 10                                         SUP07340ENDIF                                            SUP07350CONTINUE                                         SUP07360DO 40 K1 = 1, 6                                  SUP07370IF(TYP(I).EQ.OO(K1)) THEN                        SUP07380ASYM(I) = `O`                                    SUP07390GO TO 10                                         SUP07400ENDIF                                            SUP07410CONTINUE                                         SUP07420DO 50 K1 = 1, 10                                 SUP07430IF(TYP(I).EQ.CC(K1)) THEN                        SUP07440ASYM(I) = `C`                                    SUP07450GO TO 10                                         SUP07460ENDIF                                            SUP07470CONTINUE                                         SUP07480IF(TYP(I).EQ.15) THEN                            SUP07490ASYM(I) = `S`                                    SUP07500GO TO 10                                         SUP07510ELSE                                             SUP07520WRITE(6, 100) TYP(I), I                          SUP07530FORMAT(3X, `UNDEFINED ATOM TYPE: `, I3,` ON LINE 1, I4)                                            SUP07540ENDIF                                            SUP07550CONTINUE                                         SUP07560RETURN                                           SUP07570END                                              SUP07580SUBROUTINE CHEMG(NTOT)                           SUP07590                                            SUP07600CHARACTER NAME1*2, NAME2*3, CTEMP*80, TEMP*5, ASYM*2                                            SUP07610PARAXETER (NG = 300)                             SUP07620PARAMETER (NT = 150)                             SUP07630INTEGER IH, IN, IC, IO, IS, HH, NN, CC, OO, SS   SUP07640COMMON/COOD/COORD(3, NG), CHARGE(NG)             SUP07650COMMON/SYMM/ASYM(NG), TITLE(40)                  SUP07660                                            SUP07670J = 0                                            SUP07680IONE = 1                                         SUP07690WRITE(10, 1) NTOT, IONE, IONE                    SUP07700FORMAT(//, 13, 15, /, 16)                        SUP07710                                            SUP07720DO 33 I = 1, NTOT                                SUP07730READ(4, `(1X, 3F10.4, 5X, A1)`, END = 999) X, Y, Z, NAME1                                            SUP07740X = COORD(1, I)                                  SUP07750Y = COORD(2, I)                                  SUP07760Z = COORD(3, I)                                  SUP07770NAME1 = ASYM(I)                                  SUP07780IF(NAME1.EQ. `F`) GO TO 33                       SUP07790J = J + 1                                        SUP07800IF (NAME1.EQ. `H`) THEN                          SUP07810IH = IH + 1                                      SUP07820WRITE(NAME2, `(I3)`) IH                          SUP07830ELSEIF (NAME1.EQ. `N`) THEN                      SUP07840IN = IN + 1                                      SUP07850WRITE(NAME2, `(I3)`) IN                          SUP07860ELSEIF (NAME1.EQ. `C`) THEN                      SUP07870IC = IC + 1                                      SUP07880WRITE(NAME2, `(I3)`) IC                          SUP07890ELSEIF (NAME1.EQ. `O`) THEN                      SUP07900IO = 10 + 1                                      SUP07910WRITE(NAME2, `(I3)`) IO                          SUP07920ELSEIF (NAME1.EQ. `S`) THEN                      SUP07930IS = IS + 1                                      SUP07940WRITE(NAME2, `(I3)`) IS                          SUP07950ELSE                                             SUP07960WRITE(6, `(&#34;You have a problem on line&#34;, I4, &#34;in your CORD                                            SUP07970&amp;,`)I                                            SUP07980ENDIF                                            SUP07990IF (NAME2(1:1).EQ ` `) THEN                      SUP08000NAME2(1:1) = NAMEI(2:2)                          SUP08010NAME2(2:2) = NAME2(3:3)                          SUP08020NAME2(3:3) = ` `                                 SUP08030IF (NAME2(1:1).EQ. ` `) THEN                     SUP08040NAME2(1:1) = NAME2(2:2)                          SUP08050NAME2(2:2) = ` `                                 SUP08060ENDIF                                            SUP08070ENDIF                                            SUP08080WRITE(10, `(I4, A2, A3, 1X, 3F10.4)`) J, NAME1, NAME2, X, Y,                                            SUP08090CONTINUE                                         SUP08100ENDIF                                            SUP08110RETURN                                           SUP08120END                                              SUP08130SUBROUTINE WRIT(X, Y, Z)                         SUP08140DIMENSION X(150), Y(150), Z(150)                 SUP08150DO 5 I = 1, 6                                    SUP08160WRITE(6, 10) X(I), Y(I), Z(I)                    SUP08170FORMAT(4X, 3F12.5)                               SUP08180RETURN                                           SUP08190END                                              SUP08200                                            SUP08210SUBROUTINE COMBIN (NA, NB)                       SUP08220DIMENSION ICON(16), IAT1(150), IAT2(150)         SUP08230CHARACTER*2 TT(30)                               SUP08240READ(4, 10) NA                                   SUP08250FORMAT(62X, 13)                                  SUP08260READ(5, 10) NB                                   SUP08270NTOT = NA + NB                                   SUP08280IONE = 1                                         SUP08290TFOUR = 4                                        SUP08300TIME = 100.0                                     SUP08310WRITE(16, 20) NTOT, IFOUR, IONE, TIME            SUP08320FORMAT(60X, I5, I2, 3X, 15, F5.0)                SUP08330READ(4, 30) NCONA, NATA, NSPA                    SUP08340FORMAT(I5, 20X, I5, 15X, I5)                     SUP08350READ(5, 30) NCONB, NATB, NSPB                    SUP08360NCOT = NCONA*NCONB                               SUP08370NATT = NATA + NATB                               SUP08380NSPT = NSPA + NSPB                               SUP08390WRITE(16, 30) NCOT, NATT, NSPT                   SUP08400IF(NSPA.NE.0) THEN                               SUP08410DO 50 I = 1, NSPA                                SUP08420READ(4, 40) TT                                   SUP08430FORMAT(30A2)                                     SUP08440WRITE(16, 40) TT                                 SUP08450CONTINUE                                         SUP08460ENDIF                                            SUP08470IF(NSPB.NE.0) THEN                               SUP08480DO 60 I = 1, NSPB                                SUP08490READ(5, 40) TT                                   SUP08500WRITE(16, 40) TT                                 SUP08510CONTINUE                                         SUP08520ENDIF                                            SUP08530DO 70 IA = 1, NCONA                              SUP08540READ(4, 75) (ECON(I), I = 1, 16)                 SUP08550FORMAT(1615)                                     SUP08560DO 80 IZ = 1, 16                                 SUP08570ISZ = 16                                         SUP08580IF(ICON(IZ).EQ.0) THEN                           SUP08590ISZ = IZ - 1                                     SUP08600CO TO 85                                         SUP08610ENDIF                                            SUP08620CONTINUE                                         SUP08630WRITE(16, 75)(ICON(I), I = 1, ISZ)               SUP08640CONTINUE                                         SUP08650DO 90 IB = 1, NCONB                              SUP08660READ(5, 75) (ICON(I), I = 1, 16)                 SUP08670DO 100 IZ = 1, 16                                SUP08680ISZ = 16                                         SUP08690IF(ICON(IZ).EQ.0) THEN                           SUP08700ISZ = IZ - 1                                     SUP08710GO TO 95                                         SUP08720ENDIF                                            SUP08730CONTINUE                                         SUP08740DO 110 I = 1, ISZ                                SUP08750ICON(I) = ICON(I) + NA                           SUP08760WRITE(16, 75)(ICON(I), I = 1, ISZ)               SUP08770CONTINUE                                         SUP08780READ(4, 75) (IAT1(I), IAT2(I), I = 1, NATA)      SUP03790NATA1 = NATA + 1                                 SUP08800READ(5, 75) (IAT1(I), IAT2(I), I = NATA1, NATT)  SUP08810DO 120 IL = NATA1, NATT                          SUP08820IAT1(IL) = IAT1(IL) + NA                         SUP08830IAT2(IL) = IAT2(IL) + NA                         SUP08840CONTINUE                                         SUP08850WRITE(16, 75) (IAT1(I), IAT2(I), I = 1, NATT)    SUP08860RETURN                                           SUP08870END                                              SUP08880SUBROUTINE FOR MM INPUT                          SUP08690SUBROUTINE MMDATA                                SUP08900PARAMETER (NT = 150)                             SUP08910PARAMETER (NG = 300)                             SUP08920CHARACTER*2 ASYM, TITLE                          SUP08930INTEGER TYPEA, TYPEB TYP                         SUP08940COMMON/GOOD/COORD(3, NG), CHARGE(NG)             SUP08950COMMON/TYPE/TYPEA(NT), TYPEB(NT), TYP(NG)        SUP08960COMMON/SYMM/ASYM(NG), TITLE(40)                  SUP08970COMMON/PARAM/VEP(NG), VRA(NG)                    SUP08980COMMON/CORD/XA(NT), YA(NT), ZA(NT), XB(NT), YB(NT), ZB(NT)                                            SUP08990COMMON/FINAL/TXB(NT), TYB(NT), TZB(NT), CA(NT), CB(NT)                                            SUP09000COMMON/INFO/NA, NB, IP1, 1P2, IP3, IP4, R1, R2, CIP2, CIP4,                                            SUP09010NTOT = NA + NB                                   SUP09020WRITE(16, 20) (COORD (1, I), COORD(2, I), (COORD 3, I) TYP (I), I = 1,NTOT)                                            SUP09030FORMAT(2(3F10.5, I5, 5X))                        SUP09040RETURN                                           SUP09050END                                              SUP09060__________________________________________________________________________ 
    
     FIGS. 2-5 show stereoscopic views of the results of docking of the receptor model with, respectively, penicillin V, Δ 3  -cephalosporin V, Δ 2  -cephalosporin V and 4-epi-Δ 2  -cephalosporin V. It can be seen that, in each case, the serine O--H sits on the convex face of the β-lactam compound, in such a manner as to create a four-centred interaction between O--H and (O)C--N. This four-centred interaction is shown in closer detail for penicillin V in FIG. 6. 
     From the Cartesian coordinates of C--O--H and (O)N--C of the optimized complexes it is possible to compute the root mean square deviations (rms) in Å of the different four centred interactions, relative to a standard substrate, in this case penicillin V. When this is done for the series of penicillins 1a-1i, it is found that all active penicillins have rms less than 0.2 Å, and all inactive penicillins have rms greater than 0.4 Å. For the series shown in FIGS. 2-5, the rms deviations are 0.000, 0.149, 0.338 and 0.148 Å. This implies that the &#34;fits&#34; of the biologically active Δ 3  -cephalosporin and the biologically inactive 4-epi-Δ 2  -cephalosporin to the penicillin receptor are identical. The biologically inactive Δ 2  -cephalosporin has a poorer fit. 
     The biological activity of a drug depends not only on its ability to fit to a receptor, i.e., Step 1 of equation 1, but also on its ability to react chemically with the receptor, i.e., Step 2 of equation 1. The chemical reaction suggested by FIGS. 2-6 is a four centred process in which C7-0(Ser) (see A) and N--H(Ser) bond formation are concerted. This is an unprecedented chemical mechanism. 
     The hydrolysis and alcoholysis of β-lactam compounds has received much experimental and theoretical attention. In water above pH 8, the rate-determining step is addition to the carbonyl group to form a tetrahedral intermediate; below pH 6, there is rate-determining proton transfer to the β-lactam nitrogen, from the convex face of the molecule. Hydrolysis is extremely slow in the biologically relevant pH range 6-8, and the possible existence of a molecular (four-centred) mechanism in this region has not been established. Likewise, all previous theoretical studies of β-lactam hydrolysis have emphasized anionic addition to the β-lactam carbonyl group. 
     Molecular orbital (MO) calculations of the ab initio type represent an accepted and well established procedure for the probing of the mechanisms of chemical reactions. Such calculations can be performed using low level (STO-3G) and high level (3-21G) basis sets using the computer programmes GAUSSIAN 82 and GAUSSIAN 86, available from GAUSSIAN Inc., Pittsburgh, Pa, U.S.A. Molecular orbital calculations of the semi-empirical type can be performed on relatively large molecular systems, and are valid once they have been calibrated with respect to an ab initio calculation on the same system. The semi empirical procedures AM1, MNDO and MINDO/3 are available in the computer programme AMPAC, available from QCPE. 
     Table 6 summarizes the ab initio data (ΔΔE‡, kcal/mol) for the reactions of N-methylazetidinone with water and with methanol via exo-oriented N- and O-protonated structures. For the hydrolysis reactions, the O-protonated structure is favoured by 1.75 kcal/mol at the lower STO-3G level (STO-3G//STO-3G). One point calculations at the more appropriate 3-21G level (3-21G//3-21G) increases the preference for the N-protonated transition structure to 5.66 kcal/mol. Analogous results are seen for methanolysis of N-methylazetidinone. These results prove that the four-centred interaction seen in FIGS. 2-6 reflects a genuine chemical process and, indeed, the energetically preferred chemical process. The N- and O-protonated methanolysis transition structures are shown in FIGS. 7 and 8, respectively. 
     Table 6 also summarizes the semi-empirical results for the hydrolysis and methanolysis of N-methylazetidinone, and it is evident that only MINDO/3 correctly reproduces the preference for the N-protonated transition structure. Accordingly, MINDO/3 was used to examine the activation energies for the reactions of a large number of bicyclic azetidinones with methanol. These are summarized in Table 7. 
     
                                           TABLE 6__________________________________________________________________________Relative E.sup.≠  for the Hydrolysis and Methanolysis of N-Methylazetidinone via N- and O-Protonated Transition Structures..sup.aTS  STO-3G  3-21G//STO-3G           3-21G//3-21G                   AM1                      MNDO MINDO/3__________________________________________________________________________HydrolysisN 1.75 0.00     0.00    8.46                      7.31 0.00O 0.00 4.41     5.66    0.00                      0.00 1.81MethanolysisN 2.26 0.00             9.21                      7.86 0.00O 0.00 4.39             0.00                      0.00 1.20__________________________________________________________________________ .sup.a Relative energies are in kcal/mol. 
    
     Within each row of Table 7, the reactions of the different structural types are compared to that of the parent penam ring system of penicillin, and the data are discussed row-by-row: (1) the relative reactivities are carbapenam&gt;penem&gt;oxapenam&gt;penam. Oxapenicillins and penems having the C3 and C6 substituents of penicillins are known to have antibacterial activity; although the carbapenam ring system is known, carbapenicillins have not yet been prepared. (2) in the comparison of the penam and cephem ring systems, the relative reactivities are penam&gt;&gt;Δ.sup. -cephem&gt;Δ 2  -cephem, acetoxymethyl-Δ 3  -cephem. With a common 
     
                                           TABLE 7__________________________________________________________________________Calculated ΔΔ.sub.E ‡ (kcal/mol, MINDO/3) Relativeto N-Methylazetidionefor the Methanolysis of β-Lactam Compounds via Exo Formation of aFour-Centred N-Protonated Transition Structure__________________________________________________________________________ ##STR12## ##STR13## ##STR14## ##STR15## ##STR16##__________________________________________________________________________ 
    
     acylamino side chain, penicillins are an order of magnitude more active than acetoxymethyl-Δ 3  -cephalosporins and the latter are, in general, an order of magnitude more active than 3-methyl Δ 3  -cephems; Δ 2  -cephems are inactive. (3) introduction of the C3α-carboxyl group enhances the reactivity. It is believed that the carboxyl group assists the methanolysis through hydrogen bonding, because epimerization (C3β) decreases the reactivity significantly. (4) introduction of C2-methyl substituents decreases the reactivity, unless a C3α-carboxyl group is present. (5) the 6β-acylamino substituent has almost no effect on the reactivity. Consequently, the chemical reactivity of a penicillin differs only slightly from that of the parent penam. 
     FIGS. 9-11 show, respectively, stereoscopic views of the N- and O-protonated transition structures for exo-methanolysis of a penicillin, and O-protonated endo-methanolysis of penam. Such endo-oriented transition structures are ca 1 kcal/mol higher in energy than the O-protonated exo-structures and 5-6 kcal/mol higher in energy than the N-protonated exo-structures. 
     Table 8 summarizes the &#34;fits&#34; of penicillin V and 2a-2c mentioned above, as well as the &#34;reactivities&#34; of the different ring systems, as given by ΔΔE‡ for the reaction of methanol with the carboxylated substrates shown. 
     The product rms×ΔΔE‡ represents a combination of fit and reactivity, and is seen to order correctly the different classes of antibiotics in the order of their biological activities. Based on this quantity, 2b is inactive because of its poorer fit to the receptor, and 2c is inactive because of its decreased reactivity. 
     The difference between 2b and 2c can be compared to the differences seen in Row 3 of Table 7. That difference is attributed to facilitation of the chemical process by hydrogen bonding of the attacking alcohol to the carboxyl group when this group is on the convex face of the molecule. Thus 2c recovers the fit lost in 2b but concomitantly becomes less reactive. These considerations suggest that the attachment of a hydrogen bonding donor substituent on the convex face of 2c will restore the chemical reactivity while retaining the acceptable fit to the receptor. Possible sites for the attachment of the required substituent are sulfur, C4 and C7 (see Table 8 d  for numbering). Attachment of F, CH 3  O and CH 2  OH to C4 and C7 in the required manner does not enhance the reactivity of 2c, but an alpha-oriented sulfoxide (3) exhibits reactivity superior to that of penicillin. Although a malonic acid derivative which combines the favourable properties of 2b and 2c (4) exhibits somewhat reduced reactivity compared to penicillin (ΔΔE‡=3.51 kcal/mol), the product rms×ΔΔE‡ is intermediate between the active and inactive entries of Table 8. Accordingly, 3 and 4 are novel β-lactam containing structural types of potential biological interest. 
     
                       TABLE 8______________________________________Root Mean Square (rms) Difference (Å), Relative toPenicillin V, of the Cartesian Coordinates of theCOH Atoms of Serine and the NCO Atoms ofthe Azetidinone Ring in the Complexes of β-LactamCompounds with a Model of the Penicillin Receptor;Activation Energies (kcal/mol) for the Reaction ofAzetidinones with Methanol, Relative to the PenamNucleus; and the Product rms x ΔΔE‡.substrate rms         ΔΔE‡                         rms × ΔΔE‡______________________________________2a        0.149       2.81.sup.a                         0.42penicillin V     0.000       0.00.sup.b                         0.002b        0.338       1.94.sup.c                         0.662c        0.148       4.65.sup.d                         0.69______________________________________ ##STR17## ##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23##  It is also possible to design entirely new structural types compatiblewith the combination of fit and reactivity developed here. Based on thedihedral angles of penicillin V, a carboxyl group oriented so that itmakes a dihedral angle of 150°-160° with a &#34;reactive site&#34;,and a hydrogen bonding donor such as N--H or O--H oriented so that itmakes a dihedral angle of -150 to -160° with the &#34;reactive site&#34;is required. The reactive site should be one that reacts with methanolvia a four-centred transition structure, and with ΔE ‡no greater than 3-4 kcal/mol higher than that for the reaction with anazetidinone. Systematic calculation of activation energies has identifiedthe imino moiety ##STR24##as a functional group possessing the required reactivity, and incorporation of this moiety into a cyclic structure possessing dihedral angles of the required magnitude has identified 5 as a candidate structure having antibacterial activity by a penicillin-cephalosporin mechanism. The result is shown in FIG. 12. 
    
     EXAMPLE 1 
     Application of PEPCON to the Calculation of the Polypeptide Crambin 
     This polypeptide contains 46 amino acid residues, 327 heavy atoms, and 636 atoms including hydrogens. The published crystal structure includes diffraction data refined to 1.5 Å. The cartesian coordinates of the heavy (non-hydrogen) atoms of this crystal structure were used as input to MMP2(85), hydrogens were added using an option available in MMP2(85), and Newton-Raphson minimization was performed using PEPCON. The calculated structure shows an rms deviation from the experimental structure of 0.291 Å for the heavy atoms of the backbone, and 0.310 Å for all heavy atoms. 
     EXAMPLE 2 
     Application of PENCON to the Calculation of Penicillin V 
     Repetition of the experiment of Example 1, with the cartesian coordinates of the crystal structure of penicillin V and the PENCON parameters leads to an rms deviation of 0.1 Å for all atoms. 
     EXAMPLE 3 
     Application of CEPARAM to the Calculation of Cephalosporin 
     The cartesian coordinates of the crystal structure of a  2  -cephalosporin having the phenoxyacetyl side chain were entered, and the energy was minimized using MMP2(85) in conjunction with the CEPARAM parameters. The resulting rms deviation was 0.35 Å. 
     EXAMPLE 4 
     Application of the Random Number Strategy and ECEPP to the Conformational Analysis of a Peptide 
     The peptide Gly-Trp-Met-Asp-Phe-NH 2  was entered into ECEPP, and an initial search was performed on 200,000 initial conformations of this molecule. The fifty lowest energy structures identified in this manner were minimized in ECEPP using a quadratic minimization procedure, and then refined using the PEPCON parameters of MMP2(85). One structure was strongly preferred, and the dihedral angles of this structure are identical to those of the gastrin tetrapeptide, which contains the Trp-Met-Asp-Phe-NH 2  moiety of the above compound. 
     EXAMPLE 5 
     Calculation of the Structure of a Penicillin Receptor. 
     The peptide Ac-Val-Gly-Ser-Val-Thr-Lys-NHCH 3  was treated as described in Example 4, and the fifty final structures were examined. Only one structure possessed lysine and serine side chains on the same side of the molecule. This structure is shown in FIG. 1, and its dihedral angles are summarized in Table 4. 
     EXAMPLE 6 
     Docking of Penicillin V to a Model of the Penicillin Receptor 
     The receptor model of Example 5 was docked to penicillin V using the computer program of Table 5. Several conformations of the penicillin were examined, and the final lowest energy complex is shown in FIG. 2. 
     The invention will be further illustrated by way of the following specific examples of compounds that have been prepared: 
     EXAMPLE 7 
     Synthesis of 3-Carboxy-5-Hydroxymethyl-6, 6-Dimethyl-Δ4-1, 4-Thiazine 
     In formula I, X═S; Y═OH; R 1  ═R 2  ═CH 3 , R 3  ═R 4  ═H. Both D- and L- configurations at C 3  are prepared. ##STR25## 
     STEP 1 
     Methyl isopropyl ketone (15 mL, 140 moles) was added to a solution of potassium chloride (1.1 g, 14.8 moles) in water (9.6 mL). The mixture was stirred, warmed to 60° C., and illuminated with a 350 watt tungsten lamp mounted beside the flask. Bromine (11.9 g, 74.4 moles) was then added dropwise. When the colour of the first few drops had disappeared, the heating bath was replaced by a cold water bath, and the 350 watt bulb was replaced by a 60 watt bulb. Addition of bromine was continued at a rate sufficient to maintain the internal temperature at 40°-45° C. When the addition was complete (25 min) the reaction mixture was allowed to stand for 2 h and the orgainic phase was then separated, washed with wwater-magnesium oxide and dried over anhydrous calcium chloride. Fractional distallation afforded 7 g of Al, b.p. 82°-86°/145 torr. NMR (CDCl 3 ) 2.36 (3H, s), 1.77 (6H, s). ##STR26## 
     STEP 2 
     The bromeketine Al (4.65 g, 28 moles) was dissolved in glacial acetic acid (40 ml), and freshly recrystallized lead tetraacetate (12.5 g, 28.2 moles) was added. The mixture was heated at 100° C., with stirring, for 2 h and cooled to room temperature. Ethylene glycol (2 mL) was then added to destroy unreacted lead tetraacetate. The reaction mixture was diluted with ether (100 mL), washed successively with 10% sodium carbonate, water and saturated sodium chloride, dried and evaporated. The residue was distilled, and the fraction boiling at 57°-60° C./120 torr was further purified by chromatography (silica gel, 5%&gt;10%-&gt;15% ether-hexane) to give the bromoketoacetate B1. NMR (CDCl 3  : 5.16 (2H, s), 2.13 (3H, s), 1.87 (6H, s). ##STR27## 
     STEP 3 
     Triethylamine (140 mL) was added to methylene chloride (3 mL). The solution was cooled to -20° C., and gaseous hydrogen sulfide was introduced during 10 min. Then the bromoketoacetate B1 (200 mg), in methylene chloride (1.0 mL), was added dropwise with stirring during 10 min. The yellow solution was diluted with methlene chloride (30 mL)30, washed successively with 2N hydrochloric acid, water and saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to yield the mercaptoketoacetate C1. NMR (CDCl 3 ) 5.16 (2H, s), 2.18 (3H, s), 1.57 (6H, s), 1.55(1H, s). ##STR28## 
     STEP 4 
     To triphenylphosphine (258 mg, 0.98 mole) in dry tetrahydrofuran (1.0 mL0, at -78° C. under a nitrogen atomosphere, was added dropwise with stirring a solution of dimethylacetylenedicarboxylate (144 mg, 0.99 mole) in tetrahydrofuran (1.0 mL). The white slurry as maintained at -78° C. for 10 min, and a solution of Boc-L (or D-)-serine (184 mg, 0.90 mole) in tetrahydrofuran (1.0 mL) was added dropwise. The temperature was maintained at -78° C. for 20 min and the reaction mixture was then allowed to warm to room temperature (2 h). The solvent was removed and the residue was chromatographed on silica gel. Elution with 15%-&gt;22%-30%-&gt;35% ethyl acetate-hexane afforded the beta-lactone D1. NMR (CDCl 3 ) 5.29 (1H, br), 4.92 (1H, br), 4.34 (2H, br), 1.07 (9H, s) . ##STR29## 
     STEP 5 
     To a solution of C1 (79.6 mg, 0.45 mole) in dry degassed dimethylformamide (1.5 mL) was added dropwise a solution of lithium diisopropylamide (0.8 mole) in tetrahydrofuran (1.5 mL). The addition was carried out under nitrogen at -60° C. The reaction mixture was allowed to warm to -25° C. during 50 min, cooled again to -55° C., and a solution of D1 (56.4 mg, 0.30 mole) in dry degassed dimethylformamide (0.5 mL) was added dropwise. When the addition was complete, the mixture was warmed to -20° C., stirred for 25 min and then diluted with ethyl acetate (30 mL) and washed with 0.5N hydrochloric acid (2 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic extracts were washed with water (2×5 mL) and saturated sodium chloride (1×5 mL), dried and evaporated. The oily residue was purified by preparative layer chromatography on a 10×20 cm plate coated with silic gel, using methylene chloride-ethyl acetate acetic acid (1.7:0.3:0.05) as eluant to give E1 (77 mg, 70.3%). NMR (CDCl 3 ) 5.43 (1H, br), 5.20 (1H, d, 18 Hz), 5.04 (1H, d, 18 Hz), 4.46 (1H, br), 2.97 (1H, br), 2.78, 2.74 (1H, dd, 4.5, 9.0Hz), 2.17 (3H, s), 1.48(3H, s), 1.47 (3H, s), 1.44 (9H, s). ##STR30## 
     STEP 6 
     The acid E1 (77 mg) was dissolved in methylene chloride (10 mL) and treated at 0° C. with an ethereal solution of diazomethane. The solvent was removed and the residue was purified on a 5×10 cm silica gel plate using hexane-ethyl acetate (1.4:0.6) as eluant to give the ester F1 (48.2 mg). NMR (CDCl 3 ) 5.32 (1H, br d), 5.15 (1H, d, 11Hz), 5.07 (1H, d, 11Hz), 4.48 (1H, br, q), 3.76 (3H, s), 2.91 (1H, q, 4, 12Hz), 2.74 (1H, q, 5.5, 12 Hz), 1.47 (6H, d), 1.44 (9H, s). ##STR31## 
     STEP 7 
     The ester F1 (46 mg), in tetrahydrofuran (1 mL) was treated at room temperature with 0.25M lithium hydroxide (0.4 mL). After 25 min an additional 0.4 mL of lithium hydroxide was added. The mixture was stirred for 35 min and then diluted with ethyl acetate (10 mL) and washed with 0.5N hydrochloric acid (2×5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL) and the combined organic extracts were washed with water (1×5 mL), followed by saturated sodium chloride (1×5 mL), dried and evaporated. The residue was dissolved in the minimum of methylene chloride, treated with ethereal diazomethane, concentrated, and the residue was purified on a 10×20 cm silica gel plate. Elution with hexane-ethyl acetate (1.4:0.6) gave G1 (14.4 mg). NMR (CDCl 3 ) 5.22 (1H, br), 4.58 (2H, d), 4.48 (1H, br), 3.75 (3H, s), 3.06 (1H, br), 2.92 (1H, br), 2.74 (1H, dd, 5, 11Hz), 1.46 (9H, s), 1.44 (6H, s). ##STR32## 
     STEP 8 
     To a solution of G1 (5 mg, 0.015 mole) in freshly dried pyridine (0.2 mL) were added successively silver nitrate (3.4 mg, 0.02 mole) and t-butyldiphenylchlorosilane (6.3 mg, 0.023 mole). The solution was stirred for 15 min at room temperature under nitrogen. The solvent was then removed and the product was purified by preparative layer chromatography to give H1 (5.5 mg). NMR (CDCl 3 ) 7.69 (4H, m), 7.41 (6H, m), 5.07 (1H, br), 4.70 (2H, s), 4.41 (1H, br), 3.72 (3H, s), 2.70 (1H, dd), 2.55 (1H, dd), 1.43 (9H, s), 1.28(3H, s), 1.26(3H, s), 1.10 (9H, s). ##STR33## 
     STEP 9 
     The silyated ester H1 (5 mg) was treated at room temperature with formic acid (0.2 mL). After 33 min the reaction mixture was frozen and the solvent was removed by lyophilization to yield the enamine 11. NMR (CDCl 3 ): 7.69 (4H, m) , 7.40 (6H, m), 5.90 (1H, s), 4.65 (1H, br), 3.79 (3H, s), 3.76 (1H, br), 3.17 (1H, dd, 10, 15Hz), 3.00(1H, dd,3,15 Hz), 1.49(3H, s), 1.31(3H, s), 1.08(9H, s). ##STR34## 
     STEP 10 
     The thiazine 11 was treated with lithium hydroxide, as described in Step 7, to remove the ester protecting group. The silylated protecting group was also removed in part to afford a reaction mixture which contained 3-carboxy-5-hydroxymethyl-6,6-dimethyl 4-1,4-thiazine. 
     EXAMPLE 8 
     Synthesis of 3-Carboxy-5-(2-Hydroxypropyl)-6,6-Dimethyl-4-1,4-Thiazine 
     In formula II, X═S; Y═OH; R 1  ═R 2  ═CH 3  ; R 3  ═R 4  ═R 6  ═R 7  ═H; R 5  ═CH 3 . Both D- and L- configuration at C3 are prepared, but the R- and S- epimers at C8 have not been separated; the D- isomer is active. ##STR35## 
     STEP 1 
     A solution of ethyl 2-methylcyclopropanecarboxylate (5.0 g, 38.9 moles) in dry ether (5 mL0 was added dropwise, with stirring under nitrogen, to the Grignard reagent prepared from magnesium turnings (1.935 g, 0.080 g-atom) and methyl iodide (12.43 g, 87.6 moles) in dry ether (42 mL). The addition required 30 min; stirring was continued for 2.75 h at room temperature and then for 2 h under reflux. The reaction mixture was cooled in an ice-bath and saturated ammonium chloride (10 mL) wass added, with stirring. The layers were separated and the aqueous layer was extracted with ether (2×20 mL). The combined organic phase was dried, evaporated and the residue distilled at 132°-136° C. to give the tertiary alcohol A2 (4.24 g, 95%) ##STR36## 
     STEP 2 
     To the alcohol A2 (4.24 g, 37 moles) cooled in an ice-bath, was added ice-cold 48% hydrobromic acid (15 mL). The mixture was shaken vigorously in the ice-bath for 30 min. The two layers were then separated, the aqueous layer extracted with hexane (2×20 mL), and the combined organic phase was washed successively with saturated bicarbonate (2×10 mL), wate2 (2×10 mL) and saturated sodium chloride (2×10 mL), dried over anhydrous sodium sulfate, and evaporated. Distillation afforded 3.72 g (60%0 of the bromine B2, b.p. 46°-54° C./10 torr. ##STR37## 
     STEP 3 
     To a solution of the bromide B2 (3.72 g, 21 moles) in glacial acetic acid (20 mL) was added potassium acetate (3.1 g, 31.6 moles). The mixture was heated under reflux for 12 h, cooled, and poured into water (30 mL). Extraction with ether (3×30 mL), followed by succesive washing of the organic phae with aturated sodium carbonate, water and saturated sodium chloride, drying, and evaporation at room temperature yelded the acetate C2, 2.82 g (85%). NMR CDCl 3 ) 5.10 (1H, brt), 4.88 (1H, q, 6Hz), 2.30 (1H, m), 2.19 (1H, m), 2.02 (3H, s), 1.71 (3H, br s), 1.62 (3H, br s), 8.00 (3H, d, 6Hz). ##STR38## 
     STEP 4 
     The acetate C 2  (320 mg, 2.05 moles) was dissolved in methanol (2 mL) and treated dropwise with a 1.5M solution of potassium hydroxide in methanol (1.38 mL). The reaction mixture was allowed to stand for 6 h and was then neutralized with 1.5 Mmethanolic hydrogen chloride, and the solvent was removed. The residue was dissolved in methylene chloride, and this solution was washed successively with water and saturated sodium chloride, dried and evaporated to give the alcohol D2 (208 mg, 99%). ##STR39## 
     STEP 5A 
     The alcohol D2 (312 mg, 2.73 moles) was dissolved in dimethylformamide (2 mL) and to this solution were added successively t-butylidemethylchlorosilane (535 mg, 3.55 moles). The mixture was stirred for 2 h and then filtered. The insoluble material was triturated with ether (20 mL) and the combined organic material was washed successively with saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated to give the silyated compound E2A (620 mg, 100%). ##STR40## 
     STEP 5B 
     The alcohol D2 (25 mg, 0.22 mole) was dissolved in dimethylformamide (0.2 mL), and the solution was treated successively with pyridine (27 1, 0.33 mole), t-butyldiphenylchlorosilane (90 L, 0.35 mole) and silver nitrate (56 mg, 0.33 mole). The mixture was stirred at room temperature for 4 h, and the product was then isolated, as described in Step 5A, to yield E2B. ##STR41## 
     STEP 6A 
     The olefin E2A (624 mg, 2.73 moles) was dissolved in acetine (3 mL) and 18-crown-6 (100 mg, 0.27 mole) and acetic acid (0.16 mL) were added successively followed, dropwise, by a solution of potassium permanganate (603 mg, 3.82 moles) in water (7.5 mL). The mixture wa stirred for 1 hr and then diluted with methylene chloride (50 mL0. The organic phase was washed successively with 20% sodium bisulfite, 0.5N hydrochloric acid, saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated. The residue wa subjected to flash chromatography on silical gel (7 g). Elution with 4-&gt;15% ethyl acetate-hexane gave 479 mg (70%) of the ketol F2A. ##STR42## 
     STEP 6B 
     The olefin E2B (77.5 mg, 0.22 mole) was oxidized with potassium permangamate, as described in Step 6A, to yield the ketol F2B. NMR (CDCl 3 ): 7.72 (4H, m), 7.43 (6H, m), 4.43 (1H, q, 6Hz), 3.81 (1H,s), 2.81 (1H, dd, 5, 16Hz), 2.58 (1H, dd, 7, 16Hz), 1.31 (3H, s), 1.29 (3H, s), 1.10 (3H, d, 5Hz), 1.04 (9H, s) ##STR43## 
     STEP 7A 
     To a solution of the ketol F2A (478 mg, 1.83 moles) in methylene chloride (6 mL) were aded successively triethylamine (0.76 mL, 4.0 moles) and methanesulfonyl chloride (0.24 mL, 3.1 moles). The reaction mixture was stirred for 5 h at room temperature and then diluted with methylene chloride (80 mL). The solution was washed successively with water, 0.5N hydrochloric acid, saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated. Flash chromatography on silica gel (3 g) and elution with 7%-&gt;8%-&gt;9%-&gt;10% ethyl acetate-hexane gave G2A (432 mg, 70%). ##STR44## 
     STEP 7B 
     The ketol F2B (277 mg, 0.72 mole) was converted into the mesylate G2B (233 mg), as described in Step 7A. NMR (CDCl 3 ) 7.71 (4H, m), 7.41 (6H, m), 4.44 (1H, dq), 3.08 (3H, s), 2.95 (1H, dd, 6, 18Hz), 2.27 (1H, dd, 7, 18Hz), 1.63 (3H, s), 1.61 (3H, s), 1.15 (3H, d, 6Hz), 1.06 (9H, s). ##STR45## 
     STEP 8A 
     Methylene chloride (5 mL) was saturated with hydrogen sulfide at -20° C., and triethylamine (0.14 mL, 1 mole) and a solution of the mesylate G2A (233 mg, 0.5 mole) were added successively. The solution was stirred for 10 min at -20° C. and for 45 min at -20° C.-&gt;0° C., and was then diluted with methylene chloride (30 mL), washed successively with 0.5N hydrochloric acid, water and saturated ssodium chloride, dried and evaporated to give, after drying at 0.1 torr, the mercaptan H2A (170 mg, 85%). NMR(CDCl 3 ) 4.37 (1H, m), 2.98 (1H, dd, 5, 11Hz), 2.63 (1H, dd, 4, 11Hz), 1.98 (1H, s), 1.49 (3H, s), 1.48 (3H, s), 1.17 (3H, d, 5Hz), 0.84 (9H, s), 0.05 (3H, s), 0.01 (3H, s). ##STR46## 
     STEP 8B 
     The mesylate G2B was converted into the mercaptan H2B as described in Step 8A. NMR (CDCl 3 ) 7.71 (4H, m), 7.40 (6H, m), 3.00 (1H, dd, 6, 16Hz), 2.75 (1H, dd, 7, 16Hz), 1.93 (1H, s), 1.46 (3H, s), 1.45 (3H, s), 1.13 (3H, d, 6Hz), 1.05 (9H, s) ##STR47## 
     STEP 9 
     Under nitrogen, the nercaptan H2A (100 mg, 0.36 mole) was dissolved in degassed dimethylormamide (1.0 mL). The solution was cooled to -55° C. and treated with 0.45 mL of a solution of lithium diisopropylamide prepared from n-butyllithium (0.8 mL of a 1.6M hexane solution) and diisopropylamine (0.36 mL, 0.259 g, 2.56 moles) in degassed tetrahydrofuran (0.8 mL). The reaction mixture was stirred at -45° C. for 30 min, and a solution of the beta-lactone D1 (D- or L) (56.8 mg, 0.30 mole) in degassed dimethylformamide (0.8 mL) was added. The mixture was stirred at -30° C. for 20 min and then diluted with methylene chloride (10 mL0 and washed with 0.5N hydrochloric acid. The aqueous layer was extracted with methlene chloride (2×5mL) and the combined organic extracts were washed with water, then saturated sodium chloride, dried and evaporated. The residue was dried under high vacuum and purified by flash chromatography (silica gel, 4 g; 0%-&gt;8% ethyl acetate-methylene chloride (1% acetic acid)) to give the coupled product 12D or 12L 12D (88.6%, []D-2.27 (c 0.1, chloroform)). NMR (CDCl 3 ) (one isomer) 5.28 (1H, br t), 4.48 (1H, br) 4.32 (1H, m), 2.83, 2.71 (2H, m), 2.71, 2.62 (2H, m), 1.44 (9H, s), 1.43 (6H, s), 1.16 (3H, d, 6Hz), 0.85 (9H,), 0.05 (3H, s), 0.00 (3H, s). The nmr spectrum shows a 1:1 mixture of epimers in the 2-hydroxypropyl side chain. ##STR48## 
     12L (83%, []D+2.33 (c 0.1, chloroforum)). NMR (CDCl 3 ) (one isomer) 5.28 (1H, br t), 4.48 (1H, br), 4.32 (1H, m), 2.86, 2.79 (2H, m), 2.70, 2.61 (2H, m), 1.43 (9H, s), 1.42 (6H, s), 1.16 (3H, d, 6Hz), 0.83 (9H,s), 0.04 (3H, s), 0.00 (3H, s). The nmr spectrum shows a 1:1 mixture of epimers in the 2-hydroxypropyl side chain. ##STR49## 
     STEP 10A 
     To 12D (22.7 mg, 0.049 mole) was added formic acid (0.3 mL). The solution was shaken for 20 min at room temperature and the solvent was then removed by lyophilization. The residue wa dissolved in a mixture of ether (3 mL) and water (1 mL). The ether phase was extracted with water (1 mL), and the combined aqueous phase wa neutralized with 5% sodium bicarbonate and lyophilized to give 2(5 mg, 40%) having the D-configuration at C3, as a mixture of epimers in the 2-hydroxypropyl side chain. NMR (D2O) 4.23 (1H, m), 3.80 (1H, m), 3.30 (1H, q), 2.70-2.85 (3H, m), 1.40 (6H, s), 1.15(3H, d). ##STR50## 
     STEP 10B 
     The procedure of Step 10A was repeated on 12L to give 2 having the L-configuration at C3 ##STR51## 
     EXAMPLE 9 
     Bioassy of 2-D 
     The compound was assayed for antibacteral activity in plates inoculated either with Sarcina lutea or Escherichia coli. In the former case, penicillin G was employed as a standard. In the latter case, Cephalexin was employed as the standard. The compound was found to be 800 times less active than penicillin G, and 10 times less active than Cephalexin. The L-isomer of 2 was found to be inactive in both assays. 
     EXAMPLE 10 
     Synthesis of 2-Thia-4-Carboxy-6-(2-Hydroxypropyl)-7,7-Dimethyl-5-1,5-Thiazepine. 
     In formula III, X--Y═S--S; Z═OH; R 1  ═R 2  ═CH 3  ; R 3  ═R 4  ═R 5  ═R 6  ═R 7  ═CH 3 . Both D- and L- configurations of C 4  are prepared, but the R- and S- isomers at C9 have not been separated. The L-isomer is active (FIG. 13) ##STR52## 
     L-Cysteine hydrochloride (4.1 mg, 0.026 mole) was dissolved in 90% methanol-water (0.35 mL), and a solution of the mercaptan H2A (Example 2, Step 8A) (7.1 mg, 0.026 mole) in methanol (0.35 mL) wa added, followed by iodine (6.5 mg, 0.026 mole) and triethylamine (7 L, 0.050 mole). The reaction mixture was left for 30 min at room temperature and the solvent was then removed under reduced pressure. The residue was partitioned between pH 7 phosphate buffer (containing one drop of 10% sodium thiosulfate) and methylene chloride. The aqueous layer was extracted with ethyl acetate (1×5 mL) and lyophilized. The residue was triturated with methanol, and the methanol extract was combined with methylene chloride and ethyl acetate extracts and evaropated. The product was purified on 10×15 cm alumina plate using methylene chloride-methanol-water (1.8:0.2:0.15) as eluant to give the disulfide A4-L (8.9 mg, 80%). NMR (D 2  O): 4.19 (1H, m), 3.92 (1H, dd, 3.7 Hz), 3.18 (1H, m), 3.04 (1H, m), 2.92 (1H, m), 2.76 (1H, m), 1.43 (6H, s), 1.12 (3H, d, 7Hz). The compound is a mixture of epimers in the 2-hydroxypropyl chain. ##STR53## 
     Repetition of this experiment using D-cysteine in place of L-cysteine gave A4-D. ##STR54## 
     The amino acids A4-D and A4-L were dissolved in water containing sodium bicarbonate and asayed for antibacterial activity by plate assay using S. lutea. A zone of inhibition was observed with the L-isomer, but not with the D-isomer. The inhibition is ascribed to the formation of the cyclic tructure 3L, whose interaction with the model of the penicillin receptor is shown in FIG. 13. 
     EXAMPLE 11 
     Synthesis of 3-Carboxy-5-Oximino-1,4-Thiazine 
     In formula IV, X═S; R 1  ═R 2  ═CH 3  ; R 3  ═R 4  ═R 9  ═H; X═N; Z═OH. Both D- and L- isomers at C3 are ??. ##STR55## 
     STEP 1 
     To a solution of D-cysteine (605.8 mg, 5 moles) in methanol (10 mL) were added uccessively ethyl bromoacetate (0.99 g, 5.95 moles) and triethylamine (1.4 mL, 1.02 g, 10 moles). The solution was stirred for 20 min at room temperature and ether (20 mL) was then added. The product was collected by filtration, washed with ether and dried. Five hundred mg of tthis material were suspended in dimethylformamide (5 mL), and p-toluenesulfonic acid (458 mg, 2.41 moles) was added. The reulting solution wa treated portionwise with diphenyldiazomethane until the color of the diazo compound persisted, and the reaction mixture was stirred overnight. It was then diluted with ether (20 mL) and extracted with water (2×10 mL). The aqueous extract was made alkaline by addition of saturated sodium carbonate, and was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and saturated sodium chloride, dried and evaporated. A 370-mg portion of the residue (0.99 mole) was dissolved in 1,4-dioxane (8 mL), 2-pyridone (47 mg, 0.49 mole) was added, and the solution was heated under nitrogen at 102° C. for 7 h. Additional 2-pyridone (23.5 mg, 0.25 mole) was then added and heating was continued for 4 h. At this time the solvent was removed under reduced high pressure and the residue was purified on 15 g of silica gel. Elution with 8% ethyl acetate-hexane afforded 252 mg (78%) of the thiazinone benzhydryl ester A5-D. NMR (CDCl 3 ) 7.34 (10H, m), 6.96 (1H, s), 6.48 (1H, s), 4.46 (1H, m), 3.33 (2H, s), 3.21 (1H, dd, 4, 15Hz), 2.98 (1H, dd, 9, 15Hz) . ##STR56## 
     STEP 2 
     The thiazinone ester A5-D (252 mg, 0.77 mole) wa disolved in dry tetrahydrofuran (5 mL) under nitrogen, and the reagent prepared from phosphoru pentaulfide and diphenyl ether according to Tetrahedron Letters 3815 (1983) (244 mg, 0.46 mole) was added. The olution was tirred for 35 min, concentrated, and the residue wa purified on silica gel (8 g). Elution with 15% ethyl acetate-hexane afforded 214 mg (81%) of the thioamide B5-D. NMR (CDCl 3 ) 8.59. (1H, s) , 7.35 (10H, m), 6.98 (1H, s), 4.39 (1H, m), 3.79 (2H, s), 3.32 (1H, dd, 4, 15Hz), 3.02 (1H, dd, 8, 15Hz). ##STR57## 
     STEP 3 
     The thioamide B5-D (80 mg, 0.23 mole) was dissolved with stirring in ice-cold dry tetrahydrofuran 92 mL) under nitrogen and sodium hydride (80%, 8.4 mg, 0.28 mole) was added. After 5 min stirring in an ice-bath, the reaction mixture was treeated with 30 L (0.48 mole) of methyl iodide. Reaction was complete after 25 min. Dilution with ether, followed by successive extraction with water, saturated sodium bicarbonate and saturated sodium chloride, drying and evaporation gave a product which was purified on silica gel (3 g). Elution with 10% ethyl acetate-hexane afforded 59.1 mg (75%) of the thiomethylimine C5-D. NMR (CDCl 3 ) 7.35 (10H, m), 6.96 (1H, s), 4.53 (1H, m), 3.27 (1H, dt, 5, 18Hz), 3.15 (1H, dt, 5, 18Hz), 2.99 (1H, dd, 3, 13Hz), 2.81 (1H, dd, 4, 13Hz), 2.37 (3H, s). ##STR58## 
     STEP 4 
     The thiomethylimine C5-D (59 mg, 0.165 mole) was dissoled in tetrahydrofuran (0.5 mL) and added to a solution prepared under nitrogen from hydroxylamine hydrochloride (68.8 mg, 0.99 mole) and 1.65M methanolic sodium methylate (0.3 mL, 0.5 mole) in methanol (0.7 mL). The reaction wa complete in 10 min. The mixture was diluted with methylene chloride (10 mL), washed successively with aturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated. Chromatography on silica gel (1.5 g) and elution with 12% ethyl acetate-methylene chloride gave 52.7 mg (94%) of the oximino ester D5-D. NMR (CDCl 3 ) 7.34 (11H, m), 6.93 (1H, s), 5.97 (1H, s), 4.28 (1H, m), 3.30 (1H, d, 13Hz), 3.21 (1H, dd, 3, 13Hz), 3.16 (1H, d, 13Hz), 3.08 (1H, dd, 7, 13Hz). ##STR59## 
     STEP 5 
     The ester D5-D (47 mg) was dissolved in formic acid (1 mL). After 5 h at room temperature the reaction mixture was frozen and the solvent removed by lyophilization. The residue wa partitioned between ether and watter, the ether layer was extracted once with water, and the combined aqueous extracts were lyophilized again to yield 4-D. NMR (D 2  O): 4.15 (1H, m), 3.50 (1H, d, 14Hz), 3.34 (1H, d, 14Hz), 3.15 (1H, dd, 6, 15Hz), 3.02 (1H, dd, 6, 15 Hz). ##STR60## 
     The L-enantiomer of 4 was prepared as describbed above, but startin with L-cysteine in place of D-cysteine. ##STR61##
Novel six-membered hetero &#34;N&#34; compounds having antibiotic activity, represented by the formula: ##STR1## where X═S, O, CH 2 , or Se 
     Y═OH, NH 2 , NHCOR 9 , or SH 
     R 1 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 ,R 7  (which may be identical or different)═H, alkyl, or aryl 
     R 9  ═a β-lactam active side chain; 
     computer models for evaluating such compounds and processes for preparing them.