Molecular Dynamics Simulations and Structural Network Analysis of c-Abl and c-Src Kinase Core Proteins: Capturing Allosteric Mechanisms and Communication Pathways from Residue Centrality

摘要: The Abl and Src tyrosine kinases play a fundamental regulatory role in orchestrating functional processes cellular networks represent an important class of therapeutic targets. Crystallographic studies these have revealed similar structural organization multidomain complexes that confers salient features their mechanisms. Molecular characterization the interaction residues by which SH3 SH2 domains act cooperatively with catalytic domain to suppress or promote kinase activation presents active area structural, biochemical, computational investigations. In this work, we combine biophysical simulations modeling residue characterize allosteric mechanisms regulation gain insight into differential sensitivity c-Abl c-Src specific drug binding. Using approaches, examine dynamics cooperative rearrangements elucidate responsible for modulation activity. We found global network parameters such as centrality can unambiguously distinguish sites are mediating interactions assemblies. This study has mechanistic aspects communication pathways may exert influence on also high be linked each other form efficient robust routes transmit signals between spatially separated regions. presented results demonstrated serve transparent indicators accurately pinpoint key residues.