Prediction of allosteric sites and mediating interactions through bond-to-bond propensities

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Title: Prediction of allosteric sites and mediating interactions through bond-to-bond propensities
Authors: Amor, BRC
Schaub, MT
Yaliraki, S
Barahona, M
Item Type: Journal Article
Abstract: Allostery is a fundamental mechanism of biological regulation, in which binding of a molecule at a distant location affects the active site of a protein. Allosteric sites provide targets to fine-tune protein activity, yet we lack computational methodologies to predict them. Here we present an efficient graph-theoretical framework to reveal allosteric interactions (atoms and communication pathways strongly coupled to the active site) without a priori information of their location. Using an atomistic graph with energy-weighted covalent and weak bonds, we define a bond-to-bond propensity quantifying the non-local effect of instantaneous bond fluctuations propagating through the protein. Significant interactions are then identified using quantile regression. We exemplify our method with three biologically important proteins: caspase-1, CheY, and h-Ras, correctly predicting key allosteric interactions, whose significance is additionally confirmed against a reference set of 100 proteins. The almost-linear scaling of our method renders it suitable for high-throughput searches for candidate allosteric sites.
Issue Date: 26-Aug-2016
Date of Acceptance: 27-May-2016
URI: http://hdl.handle.net/10044/1/33811
DOI: https://dx.doi.org/10.1038/ncomms12477
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 7
Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2016
Sponsor/Funder: Engineering & Physical Science Research Council (EPSRC)
Engineering & Physical Science Research Council (EPSRC)
Engineering and Physical Sciences Research Council
Funder's Grant Number: EP/I017267/1
EP/N014529/1
EP/L015498/1
Keywords: q-bio.BM
q-bio.BM
physics.bio-ph
physics.data-an
q-bio.QM
MD Multidisciplinary
Publication Status: Published
Article Number: 12477
Appears in Collections:Mathematics
Chemistry
Biological and Biophysical Chemistry
Applied Mathematics and Mathematical Physics
Faculty of Natural Sciences



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