Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

摘要: The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural functional about the dimer complexes, molecular basis paradoxical phenomenon is poorly understood remains largely hypothetical. In this work, we explored relationships between inhibitor binding, protein dynamics allosteric signaling in dimers using a network-centric approach. Using theoretical framework, combined simulations with coevolutionary analysis modeling residue interaction networks to determine determinants activation. We investigated effects produced paradox inducer PLX4720, Dabrafenib, Vemurafenib breaker PLX7904. Functional binding free energy analyses complexes suggested negative cooperativity effect dimer-promoting potential could be important drivers introduced structure network model which dependencies dynamic maps correlations are integrated construction networks. results shown residues structures assemble into independent modules form global may promote dimerization. also found modulate centrality communication propensities mediating centers By simulating pathways structures, determined activate specific routes correlate extent While facilitate rapid efficient via an optimal single pathway, broader ensemble suboptimal less routes. central finding our study PLX7904 mimic structural, features inactive BRAF-WT monomer required for evading rationalize existing structure-functional experiments offering rationale phenomenon. argue amplify intervene serve as effective breakers cellular environment.