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 ≤ 6.4 Å 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 ≤ 4.0 Å) 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.