Recognizing native folds by the arrangement of hydrophobic and polar residues.

Central to the ab initio protein folding problem is the development of an energy function for which the correct native structure has a lower energy than all other conformations. Existing potentials of mean force typically rely extensively on database-derived contact frequencies or knowledge of three-dimensional structural information in order to be successful in the problem of recognizing the native fold for a given sequence from a set of decoy backbone conformations. Is the detailed statistical information or sophisticated analysis used by these knowledge-based potentials needed to achieve the observed degree of success in fold recognition? Here we introduce a novel pairwise energy function that enumerates contacts between hydrophobic residues while weighting their sum by the total number of residues surrounding these hydrophobic residues. Thus it effectively selects compact folds with the desired structural feature of a buried, intact core. This approach represents an advance over using pairwise terms whose energies of interaction that are independent of the position in the protein and greatly improves the discrimination capability of an energy function. Our results show that 85% of a set of 195 representative native folds were recognized correctly. The 29 exceptions were lipophilic proteins, small proteins with prosthetic groups or disulfide bonds, and oligomeric proteins. Overall, our method separates the native fold from incorrect folds by a larger margin (measured in standard deviation units) than has been previously demonstrated by more sophisticated methods. The arrangement of hydrophobic and polar residues alone as evaluated by our novel scoring scheme, is unexpectedly effective at recognizing native folds in general. It is surprising that a simple binary pattern of hydrophobic and polar residues apparently selects a give unique fold topology.