Proteins Flexibility as a Criterion for Elucidation of Activating Mutants in Personalized Cancer Medicine

Abstract

We developed a new strategy for elucidation of functional impact of mutations in proteins. Using molecular dynamics simulations, we explore flexibility of proteins in the sites of their binding to the other proteins. Binding of two or more proteins go through the stage of intermediate binding complexes. On this stage the number of possible conformations of the proteins’ binding sites are interacting with each other. Increasing flexibility in the binding sites increase a probability of the best-energy docking of proteins. Our computational simulations demonstrated that a missense alteration of MET (p.Tyr501Cys), which lead to an increase of flexibility of the protein, may improve the binding of the receptor with its ligand HGF (hepatocyte growth factor) and thus be considered as activating. Accordingly to this conclusion, a patient presenting a hepatocellular carcinoma MET Y501C-mutated showed a good response when treated by a potent MET inhibitor (cabozantinib), with a decrease of −65% of the alpha-foeto-protein (AFP).