Although the number of known protein structures is increasing, the number of protein sequences without determined structures is still much larger. Three-dimensional (3D) protein structure information helps in the understanding of functional mechanisms, but solving structures by X-ray crystallography or NMR is often a lengthy and difficult process. A relatively fast way of determining a protein's 3D structure is to construct a computer model using homologous sequence and structure information. Much work has gone into algorithms that comprise the ORCHESTRAR homology modeling program in the SYBYL software package. This novel homology modeling tool combines algorithms for modeling conserved cores, variable regions, and side chains. The paradigm of using existing knowledge from multiple templates and the underlying protein environment knowledgebase is used in all of these algorithms, and will become even more powerful as the number of experimentally derived protein structures increases. To determine how ORCHESTRAR compares to Composer (a broadly used, but an older tool), homology models of 18 proteins were constructed using each program so that a detailed comparison of each step in the modeling process could be carried out. Proteins modeled include kinases, dihydrofolate reductase, HIV protease, and factor Xa. In almost all cases ORCHESTRAR produces models with lower root-mean-squared deviation (RMSD) values when compared with structures determined by X-ray crystallography or NMR. Moreover, ORCHESTRAR produced a homology model for three target sequences where Composer failed to produce any. Data for RMSD comparisons between structurally conserved cores, structurally variable regions, side-chain conformations are presented, as well as analyses of active site and protein-protein interface configurations.
Algorithms Computer Simulation