Computational characterization of the mutation impact on domain C5 of Myosin Binding Protein C

Three mutations of domain C5 of Myosin Binding Protein C are involved in Familial Hypertrophic Cardiomyopathy. We assess their impact through Molecular Dynamics simulations within the framework of a native-centric coarse-grained model. We characterize the clinical relevance of a mutation by: the extent of temperature shift it induces in the unfolding transition, the increase of the kinetic unfolding rates with respect to the wild type, and by &Fgr;-value analysis. Further analysis of folding stages based on the evolution of native contact probabilities reveals an entropy-driven pathway originating in the protein region close to Res115 and ending up in the area of Res28. The mutation of the former residue thus appears to be responsible for an early interruption of the folding process, leaving the protein largely unstructured and yielding a serious impairment of cardiac function. Mut28, on the contrary, thwarts a late stage of folding when the protein is almost completely native-like, leading to a mild phenotype. A bio-informatic analisys of the long and destabilizing CD loop finally shows an excess of negative charge and a low hydrophobicity indicating a possible classification as a natively unfolded sequence. Accordingly, the folding mechanism is suggested to be coupled with binding with a specific ligand.