Data-driven computational analysis of allosteric proteins by exploring protein dynamics, residue coevolution and residue interaction networks

Abstract

BackgroundComputational studies of allosteric interactions have witnessed a recent renaissance fueled by the growing interest in modeling of the complex molecular assemblies and biological networks. Allosteric interactions in protein structures allow for molecular communication in signal transduction networks. MethodsIn this work, we performed a large scale comprehensive and multi-faceted analysis of >300 diverse allosteric proteins and complexes with allosteric modulators. By modeling and exploring coarse-grained dynamics, residue coevolution, and residue interaction networks for allosteric proteins, we have determined unifying molecular signatures shared by allosteric systems. ResultsThe results of this study have suggested that allosteric inhibitors and allosteric activators may differentially affect global dynamics and network organization of protein systems, leading to diverse allosteric mechanisms. By using structural and functional data on protein kinases, we present a detailed case study that that included atomic-level analysis of coevolutionary networks in kinases bound with allosteric inhibitors and activators. ConclusionsWe have found that coevolutionary networks can form direct communication pathways connecting functional regions and can recapitulate key regulatory sites and interactions responsible for allosteric signaling in the studied protein systems. The results of this computational investigation are compared with the experimental studies and reveal molecular signatures of known regulatory hotspots in protein kinases. General significanceThis study has shown that allosteric inhibitors and allosteric activators can have a different effect on residue interaction networks and can exploit distinct regulatory mechanisms, which could open up opportunities for probing allostery and new drug combinations with broad range of activities.