Selecting near-native conformations in homology modeling: The role of molecular mechanics and solvation terms

A free energy function, combining molecular mechanics energy with empirical solvation and entropic terms, is used for ranking near-native conformation s that occur in the conformational search steps of homology modeling, i.e., side-chain search and loop closure calculations. Correlations between the free energy and RMS deviation from the X-ray structure are established. It is shown that generally both molecular mechanics and solvation/entropic ter ms should be included in the potential. The identification of near-native b ackbone conformations is accomplished primarily by the molecular mechanics term that becomes the dominant contribution to the free energy if tho backb one is even slightly strained, as frequently occurs in loop closure calcula tions. Both terms become equally important if a sufficiently accurate backb one conformation is found. Finally, the selection of the best side-chain po sitions for a fixed backbone is almost completely governed by the solvation term. The discriminatory power of the combined potential is demonstrated b y evaluating the free energies of protein models submitted to the first mee ting on Critical Assessment of techniques for protein Structure prediction (CASP1), and comparing them to the free energies of the native conformation s.