TY - JOUR
T1 - Residue-Level Allostery Propagates through the Effective Coarse-Grained Hessian
AU - Lake, Peter T.
AU - Davidson, Russell B.
AU - Klem, Heidi
AU - Hocky, Glen M.
AU - McCullagh, Martin
N1 - Funding Information:
This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. We specifically acknowledge the San Diego Supercomputer Center Comet and Pittsburgh Super Computing Bridges resources used under XSEDE allocation CHE160008 awarded to MM.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/5/12
Y1 - 2020/5/12
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jctc.9b01149
DO - 10.1021/acs.jctc.9b01149
M3 - Article
C2 - 32251581
AN - SCOPUS:85084692865
SN - 1549-9618
VL - 16
SP - 3385
EP - 3395
JO - Journal of chemical theory and computation
JF - Journal of chemical theory and computation
IS - 5
ER -