Prediction and Evaluation of Side-chain Conformations for Protein Backbone Structures

P.S. Shenkin, H. Farid and J.S. Fetrow

Proteins: Structure, Function and Genetics, 26:323-352, 1996

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A common approach to protein modeling is to propose a backbone structure based on homology or threading and then to attempt to build side chains onto this backbone. A fast algorithm using the simple criteria of atomic overlap and overall rotamer probability is proposed for this purpose. The method was first tested in the context of exhaustive searches of side-chain configuration space in protein cores and was then applied to all side chains in forty-nine proteins of known structure, using simulated annealing to sample space. The latter procedure obtains the correct rotamer for 57% and the correct chi-1 value for 74% of the 6751 residues in the sample. When low-temperature Monte-Carlo simulations are initiated from the results of the simulated-annealing processes, consensus configurations are obtained which exhibit slightly more accurate predictions. The Monte -Carlo procedure also allows converged side-chain entropies to be calculated for all residues. These prove to be accurate indicators of prediction reliability. For example, the correct rotamer is obtained for 79% and the correct chi-1 value is obtained for 84% of the half of the sample residues exhibiting the lowest entropies. Side-chain entropy and predictability are nearly completely uncorrelated with solvent-accessible area. Some precedents for and implications of this observation are discussed.