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Discarding functional residues from the substitution table improves predictions of active sites within three-dimensional structures.

ABSTRACT: Substitutions of individual amino acids in proteins may be under very different evolutionary restraints depending on their structural and functional roles. The Environment Specific Substitution Table (ESST) describes the pattern of substitutions in terms of amino acid location within elements of secondary structure, solvent accessibility, and the existence of hydrogen bonds between side chains and neighbouring amino acid residues. Clearly amino acids that have very different local environments in their functional state compared to those in the protein analysed will give rise to inconsistencies in the calculation of amino acid substitution tables. Here, we describe how the calculation of ESSTs can be improved by discarding the functional residues from the calculation of substitution tables. Four categories of functions are examined in this study: protein-protein interactions, protein-nucleic acid interactions, protein-ligand interactions, and catalytic activity of enzymes. Their contributions to residue conservation are measured and investigated. We test our new ESSTs using the program CRESCENDO, designed to predict functional residues by exploiting knowledge of amino acid substitutions, and compare the benchmark results with proteins whose functions have been defined experimentally. The new methodology increases the Z-score by 98% at the active site residues and finds 16% more active sites compared with the old ESST. We also find that discarding amino acids responsible for protein-protein interactions helps in the prediction of those residues although they are not as conserved as the residues of active sites. Our methodology can make the substitution tables better reflect and describe the substitution patterns of amino acids that are under structural restraints only.

SUBMITTER: Gong S

PROVIDER: S-EPMC2527532 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Discarding functional residues from the substitution table improves predictions of active sites within three-dimensional structures.

Gong Sungsam S Blundell Tom L TL

PLoS computational biology 20081003 10

Substitutions of individual amino acids in proteins may be under very different evolutionary restraints depending on their structural and functional roles. The Environment Specific Substitution Table (ESST) describes the pattern of substitutions in terms of amino acid location within elements of secondary structure, solvent accessibility, and the existence of hydrogen bonds between side chains and neighbouring amino acid residues. Clearly amino acids that have very different local environments i ...[more]

PMID: 18833291

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Project description: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 in varying degrees 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 phylogenetic correlations and indirect dependences through other residues within a protein or even through other molecules. Rapid growth of protein families with unknown folds requires an accurate de novo prediction method for protein structure. Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that inferred residue-residue proximities can be sufficient information to predict a protein fold without the use of known three-dimensional structures. Here, we propose an alternative method of inferring coevolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. Substitution probability and physico-chemical changes (volume, charge, hydrogen-bonding capability, and others) accompanied by substitutions at each site in each branch of a phylogenetic tree are estimated with the likelihood of each substitution, and their direct correlations between sites are used to detect concurrent and compensatory substitutions. In order to extract direct dependences between sites, partial correlation coefficients of the characteristic changes along branches between sites, in which linear multiple dependences on feature vectors at other sites are removed, are calculated and used to rank coevolving site pairs. Accuracy of contact prediction based on the present coevolution 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.

Dataset Information

Discarding functional residues from the substitution table improves predictions of active sites within three-dimensional structures.

Publications

Discarding functional residues from the substitution table improves predictions of active sites within three-dimensional structures.

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