Identification of coevolving residues and coevolution potentials emphasizing structure, bond formation and catalytic coordination in protein evolution.
The structure and function of a protein is dependent on coordinated interactions between its residues. The selective pressures associated with a mutation at one site should therefore depend on the amino acid identity of interacting sites. Mutual information has previously been applied to multiple sequence alignments as a means of detecting coevolutionary interactions. Here, we introduce a refinement of the mutual information method that: 1) removes a significant, non-coevolutionary bias and 2) accounts for heteroscedasticity. Using a large, non-overlapping database of protein alignments, we demonstrate that predicted coevolving residue-pairs tend to lie in close physical proximity. We introduce coevolution potentials as a novel measure of the propensity for the 20 amino acids to pair amongst predicted coevolutionary interactions. Ionic, hydrogen, and disulfide bond-forming pairs exhibited the highest potentials. Finally, we demonstrate that pairs of catalytic residues have a significantly increased likelihood to be identified as coevolving. These correlations to distinct protein features verify the accuracy of our algorithm and are consistent with a model of coevolution in which selective pressures towards preserving residue interactions act to shape the mutational landscape of a protein by restricting the set of admissible neutral mutations.
Little
Daniel Y
DY
Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
Chen
Lu
L
D000465:Algorithms; D000595:Amino Acid Sequence; D002384:Catalysis; D019143:Evolution, Molecular; D008957:Models, Genetic; D009154:Mutation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012641:Selection, Genetic; D016415:Sequence Alignment
D011506:Proteins