Mechanistic insights into effects of the cardiac myosin activator omecamtiv mecarbil from mechanokinetic modelling

The results suggest that major effects of OM such as large reduction of the maximum velocity with more limited effects on maximum isometric force and slowed actin-activated ATPase can be accounted for by two key molecular effects. These encompass a reduced difference in binding free energy between the pre- and post-power-stroke states and greatly increased activation energy for the lever arm swing during the power-stroke. Better quantitative agreement, e.g., isometric force minimally changed from the control value by OM is achieved by additional changes in model parameter values previously suggested by studies of isolated proteins.