Abstract
BackgroundProteins adapt to environmental conditions by changing their shape and motions. Characterising protein conformational dynamics is increasingly recognised as necessary to understand how proteins function. Given a conformational ensemble, computational tools are needed to extract in a systematic way pertinent and comprehensive biological information.ResultsHere, we present a method, Communication Mapping (COMMA), to decipher the dynamical architecture of a protein. The method first extracts residue-based dynamic properties from all-atom molecular dynamics simulations. Then, it integrates them in a graph theoretic framework, where it identifies groups of residues or protein regions that mediate short- and long-range communication. COMMA introduces original concepts to contrast the different roles played by these regions, namely communication blocks and communicating segment pairs, and evaluates the connections and communication strengths between them. We show the utility and capabilities of COMMA by applying it to three archetypal proteins, namely protein A, the tyrosine kinase KIT and the tumour suppressor p53.ConclusionOur method permits to compare in a direct way the dynamical behaviour either of proteins with different characteristics or of the same protein in different conditions. It is useful to identify residues playing a key role in protein allosteric regulation and to explain the effects of deleterious mutations in a mechanistic way. COMMA is a fully automated tool with broad applicability. It is freely available to the community at www.lcqb.upmc.fr/COMMA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0855-y) contains supplementary material, which is available to authorized users.
Highlights
Proteins adapt to environmental conditions by changing their shape and motions
Communication blocks in KIT protein and its oncogenic mutant KIT is a receptor tyrosine kinase of type III implicated in signalling pathways crucial for cell growth, differentiation and survival [44,45,46]
Communication Mapping (COMMA) was applied to the cytoplasmic region of KIT (331 residues), starting from 2 replicates of 50-ns molecular dynamics (MD) simulations of the wild-type and D816V-mutated proteins [33]
Summary
Proteins adapt to environmental conditions by changing their shape and motions. Characterising protein conformational dynamics is increasingly recognised as necessary to understand how proteins function. Computational tools are needed to extract in a systematic way pertinent and comprehensive biological information. Protein conformational dynamics are directly linked to protein functions [1, 2] They are sensitive to environmental changes, point mutations, ligand binding and posttranslational biochemical modifications [3,4,5]. Atomistic molecular simulation is a method of choice to explore a protein’s conformational space. It has become increasingly popular with the recent advances in computational power, force field accuracy and sampling algorithm development [6, 7]. The accumulation of molecular dynamics (MD) data calls for the development of methods able to extract pertinent biological information and visualise it in a comprehensive way.
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