Stoichiometry-driven Protein Folding: A Comment
Mittal et al. (1) have examined the frequency distributions of amino acid residue proximities in the secondary and tertiary structures of almost 4000 proteins, and have concluded that there are no preferences related to side-chain chemistry. Irrespective of the size and three-dimensional shape of a protein, the probability that two residues will be close together depends mainly, if not entirely, on how many of each there are within that protein. This result sits uncomfortably with major current ideas about protein folding, such as the evolution of wonderfolds (2), the proteomic code (3), and the ‘first-in-last-out’ hypothesis (4). It may not be logically inconsistent with these ideas, but it will be considered surprising. On the simplest level: it is common knowledge that polar residues cluster with other polar residues rather than hydrophobic ones, and vice versa, and this almost-universal pattern is crucial for the spatial structuring of globular proteins. Preferential interaction between amino acids is the basis of the development of knowledge-based potentials, which in turn form the underpinning of protein structure prediction. Nowadays, determination of protein structure by modeling and simulation, based on preferential contacts and interactions, has become a common practice (5, 6 and references therein).