Inter-residue potentials in globular proteins and the dominance of highly specific hydrophilic interactions at close separation

Residue-specific potentials between pairs of side-chains and pairs of sidechain-backbone interaction sites have been generated by collecting radial distribution data for 302 protein structures. Multiple atomic interactions have been utilized to enhance the specificity and smooth the distance-dependence of the potentials. The potentials are demonstrated to successfully discriminate correct sequences in inverse folding experiments. Many specific effects are observable in the non-bonded potentials; grouping of residue types is inappropriate, since each residue type manifests some unique behavior. Only a weak dependence is seen on protein size and composition. Effective contact potentials operating in three different environments (self, solvent-exposed and residue-exposed) and over any distance range are presented. The effective contact potentials obtained from the integration of radial distributions over the distance interval r less than or equal to 6.4 Angstrom are in excellent agreement with published values. The hydrophobic interactions are verified to be dominantly strong in this range. Comparison of these with a newly derived set of effective contact potentials for closer inter-residue separations (r less than or equal to 4.0 Angstrom) demonstrates drastic changes in the most favorable interactions. In the closer approach case, where the number of pairs with a given residue is approximately one, the highly specific interactions between charged and polar side-chains predominate. These closer approach values could be utilized to select successively the relative positions and directions of residue side-chains in protein simulations, following a hierarchical algorithm optimizing side-chain-side-chain interactions over the two successively closer distance ranges. The homogeneous contribution to stability is stronger than the specific contribution by about a factor of 5. Overall, the total non-bonded interaction energy calculated for individual proteins follows a dependence on the number of residues of the form of n(1.28), indicating an enhanced stability for larger proteins. (C) 1997 Academic Press Limited.