Use of propensities of amino acids to the local structural environments to understand effect of substitution mutations on protein stability.

Abstract

Advances in site-directed mutagenesis and other genetic engineering techniques have made it possible to create novel proteins of interest. A challenging aspect of these studies is to understand the effect of substitution mutations on folding and stability of natural proteins. We present an analysis of protein structure data, available from the literature, for which substitution mutations have been made and changes in stability characteristics are reported. Amino acid structural environment parameters have been computed for a set of 304 non-homologous best resolved protein structures. The structural environment parameters were used to calculate each of the 20 amino acid propensities to a given structural environment. The observed increase or decrease in stability upon mutation was found to be correlated with the average residue structural environment propensity of wild-type residue versus mutant residue. The analysis presented here helps identification of less optimally placed residues in a given protein structure, and suggests possible substitution mutations to a residue with higher propensity to the corresponding local structural environment. We propose that such substitution mutations, suggested based on amino acid propensities to local structural environments, should bestow higher stability to the protein structure.