Steered molecular dynamics simulations revealed that a double mutation (E258K + E441K) in cMyBP-C encourages the formation of a rigid complex requiring a large amount of force and long time to unbind.
Key HCM-causing mutations in cMyBP-C significantly modify the native affinity required for domain assembly, which may explain their role in altering normal cardiac function.
The molecular interactions of the sarcomeric proteins are essential in the regulation of various cardiac functions. Mutations in the gene MYBPC3 coding for cardiac myosin-binding protein-C (cMyBP-C), a multi-domain protein, are the most common cause of hypertrophic cardiomyopathy (HCM). The N-terminal complex, C1-motif-C2 is a central region in cMyBP-C for the regulation of cardiac muscle contraction. However, the mechanism of binding/unbinding of this complex during health and disease is unknown. Here, we study possible mechanisms of unbinding using steered molecular dynamics simulations for the complex in the wild type, in single mutations (E258K in C1, E441K in C2), as well as in a double mutation (E258K in C1 + E441K in C2), which are associated with severe HCM. The observed molecular events and the calculation of force utilized for the unbinding suggest the following: (i) double mutation can encourage the formation of rigid complex that required large amount of force and long-time to unbind, (ii) C1 appears to start to unbind ahead of C2 regardless of the mutation, and (iii) unbinding of C2 requires larger amount of force than C1. This molecular insight suggests that key HCM-causing mutations might significantly modify the native affinity required for the assembly of the domains in cMyBP-C, which is essential for normal cardiac function.
Krishnamoorthy et al. (Wed,) conducted a other in Hypertrophic cardiomyopathy. Steered molecular dynamics simulations of cMyBP-C mutations (E258K, E441K, double mutation) vs. Wild type cMyBP-C was evaluated on Mechanism of binding/unbinding and force utilized for unbinding. Steered molecular dynamics simulations revealed that a double mutation (E258K + E441K) in cMyBP-C encourages the formation of a rigid complex requiring a large amount of force and long time to unbind.