Residue-Level Allostery Propagates through the Effective Coarse-Grained Hessian

Peter T. Lake, Russell B. Davidson, Heidi Klem, Glen M. Hocky, Martin McCullagh

Research output: Contribution to journalArticlepeer-review


The long-ranged coupling between residues that gives rise to allostery in a protein is built up from short-ranged physical interactions. Computational tools used to predict this coupling and its functional relevance have relied on the application of graph theoretical metrics to residue-level correlations measured from all-atom molecular dynamics simulations. The short-ranged interactions that yield these long-ranged residue-level correlations are quantified by the effective coarse-grained Hessian. Here we compute an effective harmonic coarse-grained Hessian from simulations of a benchmark allosteric protein, IGPS, and demonstrate the improved locality of this graph Laplacian over two other connectivity matrices. Additionally, two centrality metrics are developed that indicate the direct and indirect importance of each residue at producing the covariance between the effector binding pocket and the active site. The residue importance indicated by these two metrics is corroborated by previous mutagenesis experiments and leads to unique functional insights; in contrast to previous computational analyses, our results suggest that fP76-hK181 is the most important contact for conveying direct allosteric paths across the HisF-HisH interface. The connectivity around fD98 is found to be important at affecting allostery through indirect means.

Original languageEnglish (US)
Pages (from-to)3385-3395
Number of pages11
JournalJournal of chemical theory and computation
Issue number5
StatePublished - May 12 2020

ASJC Scopus subject areas

  • Computer Science Applications
  • Physical and Theoretical Chemistry


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