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A conservation and rigidity based method for detecting critical protein residues.

ABSTRACT: BACKGROUND: Certain amino acids in proteins play a critical role in determining their structural stability and function. Examples include flexible regions such as hinges which allow domain motion, and highly conserved residues on functional interfaces which allow interactions with other proteins. Detecting these regions can aid in the analysis and simulation of protein rigidity and conformational changes, and helps characterizing protein binding and docking. We present an analysis of critical residues in proteins using a combination of two complementary techniques. One method performs in-silico mutations and analyzes the protein's rigidity to infer the role of a point substitution to Glycine or Alanine. The other method uses evolutionary conservation to find functional interfaces in proteins. RESULTS: We applied the two methods to a dataset of proteins, including biomolecules with experimentally known critical residues as determined by the free energy of unfolding. Our results show that the combination of the two methods can detect the vast majority of critical residues in tested proteins. CONCLUSIONS: Our results show that the combination of the two methods has the potential to detect more information than each method separately. Future work will provide a confidence level for the criticalness of a residue to improve the accuracy of our method and eliminate false positives. Once the combined methods are integrated into one scoring function, it can be applied to other domains such as estimating functional interfaces.

SUBMITTER: Akbal-Delibas B

PROVIDER: S-EPMC3952096 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A conservation and rigidity based method for detecting critical protein residues.

Akbal-Delibas Bahar B Jagodzinski Filip F Haspel Nurit N

BMC structural biology 20131108

<h4>Background</h4>Certain amino acids in proteins play a critical role in determining their structural stability and function. Examples include flexible regions such as hinges which allow domain motion, and highly conserved residues on functional interfaces which allow interactions with other proteins. Detecting these regions can aid in the analysis and simulation of protein rigidity and conformational changes, and helps characterizing protein binding and docking. We present an analysis of crit ...[more]

PMID: 24565061

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Project description:BackgroundPhylogenetic approaches are commonly used to predict which amino acid residues are critical to the function of a given protein. However, such approaches display inherent limitations, such as the requirement for identification of multiple homologues of the protein under consideration. Therefore, complementary or alternative approaches for the prediction of critical residues would be desirable. Network analyses have been used in the modelling of many complex biological systems, but only very recently have they been used to predict critical residues from a protein's three-dimensional structure. Here we compare a couple of phylogenetic approaches to several different network-based methods for the prediction of critical residues, and show that a combination of one phylogenetic method and one network-based method is superior to other methods previously employed.ResultsWe associate a network with each member of a set of proteins for which the three-dimensional structure is known and the critical residues have been previously determined experimentally. We show that several network-based centrality measurements (connectivity, 2-connectivity, closeness centrality, betweenness and cluster coefficient) accurately detect residues critical for the protein's function. Phylogenetic approaches render predictions as reliable as the network-based measurements, although, interestingly, the two general approaches tend to predict different sets of critical residues. Hence we propose a hybrid method that is composed of one network-based calculation--the closeness centrality--and one phylogenetic approach--the Conseq server. This hybrid approach predicts critical residues more accurately than the other methods tested here.ConclusionWe show that network analysis can be used to improve the prediction of amino acids critical for protein function, when utilized in combination with phylogenetic approaches. It is proposed that such improvement is due to the complementary nature of these approaches: network-based methods tend to predict as critical those residues that are highly connected and internal (i.e., non-surface), although some surface residues are indeed identified as critical by network analyses; whereas residues chosen by phylogenetic approaches display a lower overall probability of being surface inaccessible.

Dataset Information

A conservation and rigidity based method for detecting critical protein residues.

Publications

A conservation and rigidity based method for detecting critical protein residues.

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