Protein side-chain rearrangement in regions of point mutations

A major problem in predicting amino acid side-chain rearrangements following point mutations is the potentially large search space. We analyzed a nonredundant data set of 393 Protein Data Bank protein pairs, each consisting of structures differing in one amino acid, to determine the number of residues changing conformation in the region of mutation. In 91-95% of cases, two or fewer residues underwent side-chain conformational change. If mutation sites with backbone displacements were excluded, the number increased to 97%. The majority of rearrangements (over 60%) were due to the inherent flexibility of side-chains, as derived from analysis of a control set of protein subunits whose crystal structures were determined more than once. Different amino acids demonstrated different degrees of flexibility near mutation sites. Large polar or charged residues, and serine, are more flexible, while the aromatic amino acids, and cysteine, are less so. This pattern is common to the inherent side-chain flexibility, as well as the increased flexibility at ligand binding sites and mutation sites. The probability for conformational change was correlated with B-factor, frequency of the side-chain conformation in proteins and solvent accessibility. The last trend was stronger for aromatic and hydrophilic residues than for hydrophobic ones. We conclude that the search space for predicting side-chain conformations in the region of mutation can be effectively restricted. However, the overall ability to predict a particular side-chain conformation, or to check predictions according to individual existing structures, is limited. These findings may be useful in deriving empirical rules for modeling side-chain conformations.