An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy

Mutations in the gene coding for cardiac myosin binding protein-C (cMyBP-C), a multidomain (C0-C10) protein, are a major causative factor for inherited hypertrophic cardiomyopathy. Patients carrying mutations in this gene have an extremely heterogeneous clinical cause with some progressing to end-stage heart failure. The cause of this variability is unknown. We here describe molecular modeling of a double mutation in domains C1 (E258K) and C2 (E441K) in a patient with severe phenotype. The 3D structure for the C1- motif-C2 complex was constructed, with both double and single mutations being introduced and performed molecular dynamics simulations for 10 ns under physiological conditions. The results showed that both E258K and E441K in isolation can predominantly affect the native domain as well as the nearby motif via conformational changes and resulted in an additive effect when they coexist. These changes involve important regions of the motif such as phosphorylation sites and potential actin binding region. Moreover, the charge reversal mutations altered the surface electrostatic properties. Double mutation affecting the regulatory N-terminal of cMyBP-C has the potential of synergistically interfering with the binding to neighbouring domains and to other sarcomeric proteins. These effects may account for the severe phenotype and clinical course observed in our patient.