Abstract

Abstract: The explosive growth in the number of protein sequences gives rise to the possibility of using natural variation in sequences of homologous proteins to find residues that control different protein phenotypes. Because in many cases phenotypic changes are controlled by a group of residues, the mutations that separate one phenotype from another will be correlated. We show that correlations between amino acid mutations at different sites in a protein can be used to predict, de novo, tertiary protein structure of both globular and transmembrane proteins from large sequence alignments.

In addition, residues that determine the specificity of protein interactions can be identified from inter-protein residue pairs that co-vary. Those amino acids whose mutation patterns are most highly constrained by evolution are found to often involve known functional sites of proteins, such as enzyme active sites, and ligand binding sites. These findings raise questions about the relationship between protein structure and function, and the evolutionary constraints that this relationship imposes on different proteins.