title: Prediction of allosteric sites and mediating interactions through bond-to-bond propensities.
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.
authors: Department of Chemistry, Imperial College London, London SW7 2AZ, UK.|Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
authors: B R C
authors: BR
authors: Amor
authors: Department of Mathematics, Imperial College London, London SW7 2AZ, UK.
authors: M T
authors: MT
authors: Schaub
authors: Department of Chemistry, Imperial College London, London SW7 2AZ, UK.|Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
authors: S N
authors: SN
authors: Yaliraki
authors: Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.|Department of Mathematics, Imperial College London, London SW7 2AZ, UK.
authors: M
authors: M
authors: Barahona