Inference of Co-Evolving Site Pairs: an Excellent Predictor of Contact Residue Pairs in Protein 3D structures

Abstract

Residue-residue interactions that fold a protein into a unique three-dimensional structure and make it play a specific function impose structural and functional constraints on each residue site. Selective constraints on residue sites are recorded in amino acid orders in homologous sequences and also in the evolutionary trace of amino acid substitutions. A challenge is to extract direct dependences between residue sites by removing indirect dependences through other residues within a protein or even through other molecules. Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that the strength of inferred residue pair couplings is an excellent predictor of residue-residue proximity in folded structures. Here, we report an alternative attempt of inferring co-evolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. First, branch lengths of a phylogenetic tree inferred by the neighbor-joining method are optimized as well as other parameters by maximizing a likelihood of the tree in a mechanistic codon substitution model. Mean changes of quantities, which are characteristic of concurrent and compensatory substitutions, accompanied by substitutions at each site in each branch of the tree are estimated with the likelihood of each substitution. Partial correlation coefficients of the characteristic changes along branches between sites are calculated and used to rank co-evolving site pairs. Accuracy of contact prediction based on the present co-evolution score is comparable to that achieved by a maximum entropy model of protein sequences for 15 protein families taken from the Pfam release 26.0. Besides, this excellent accuracy indicates that compensatory substitutions are significant in protein evolution.

17 pages, 4 figures, and 4 tables with supplementary information of 5 figures

References in corpus (3)

• Direct-coupling analysis of residue co-evolution captures native contacts across many protein families
• Identification of direct residue contacts in protein-protein interaction by message passing
• Selective Constraints on Amino Acids Estimated by a Mechanistic Codon Substitution Model with Multiple Nucleotide Changes

Cited by in corpus (8)

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• A unified statistical model of protein multiple sequence alignment integrating direct coupling and insertions
• Monte Carlo simulation of a statistical mechanical model of multiple protein sequence alignment
• Prediction of Structures and Interactions from Genome Information
• Cooperative "folding transition" in the sequence space facilitates function-driven evolution of protein families
• Liquid-theory analogy of direct-coupling analysis of multiple-sequence alignment and its implications for protein structure prediction
• Boltzmann machine learning and regularization methods for inferring evolutionary fields and couplings from a multiple sequence alignment