How Omecamtiv Modulates Myosin Motion.

Myosin VI is a unique reverse-directed motor protein in the myosin family. The D179Y mutation in Myosin VI is associated with deafness in mammals. This mutation destroys the processive motion of myosin and inhibits its functional activity due to an elevated phosphate release rate. The current work explores the way by which this mutation affects the phosphate release rate and changes the action of Myosin VI. Our study involves a wide range of approaches comprising free energy-based simulations, contact map analysis, binding energy investigation, structural inspection, renormalization simulation, multiple sequence alignment, and bioinformatics analysis. It is found that when the evolutionary conserved aspartic acid (D179) of Myosin VI is mutated to tyrosine (Y179), it leads to premature phosphate release from Myosin VI. Most importantly, the drug omecamtiv rescues the processivity of the mutant by slowing down the actin-independent phosphate release from Myosin VI. Thus, we also explore the molecular mechanism behind the premature phosphate release of the D179Y mutant of Myosin VI and the actin-independent slowing down of the phosphate release in the presence of omecamtiv. This phosphate release modulation is related to Myosin VI's processivity as found experimentally. Overall, our proposed model indicates that omecamtiv significantly alters the interaction between the P-loop of Myosin VI and the interfacial residues, which is the driving force behind the slowing down of the phosphate release of the D179Y mutant in the presence of omecamtiv. Finally, our study provides additional support to our proposal that the directionality of myosins is determined by the highest barrier along the cycle and not by any dynamical effect.