Atomistic simulation study reveals transduction of mechanical work generated by ATP hydrolysis onto myosin II functional loops

Myosin II is a paradigm of biological molecular energy transducers that convert the chemical energy of ATP, via hydrolysis, into mechanical work with high efficiency in living cells. The physicochemical mechanisms underlying energy conversion by myosin II have been extensively investigated. However, a remaining challenge concerns the initial stage of the ATP hydrolysis cycle, specifically the conversion of ATP-to-ADP:Pi, because of technical difficulties in directly and seamlessly observing atomic trajectories during this early step and the subsequent processes. Here, we simulate the consequences of the chemical reaction by switching force field parameters between reactant and product systems within classical molecular dynamics simulations. We consider two possible ATP hydrolysis mechanisms in which either singly protonated (Pi{superscript 2}-) or doubly protonated (Pi-) inorganic phosphate is produced. Our results indicate that, in both Pi-generating processes, the kinetic energy supplied by conversion of ATP-to-ADP:Pi increases only transiently, whereas myosin functional loops store several kcal/mol of potential energy. Meanwhile, the amount of potential energy stored in the Pi{superscript 2}--producing reaction is approximately five-fold larger than that in the Pi--producing reaction. Our analysis indicates that this difference emerges when ATP-derived mechanical work is transmitted into the functional loops via rearrangement of intermolecular hydrogen bonds with the hydrolysis products. Notably, these steric interactions remain stably established even when the kinetic energy input associated with ATP-to-ADP:Pi conversion is actively quenched. We therefore propose that transient storage of ATP-derived mechanical work as atomic-scale conformational strain within myosin molecules constitutes a critical step for efficient conversion of ATP chemical energy into mechanical work under conditions of intracellular thermal noise. SignificanceMyosin II converts chemical energy released by ATP hydrolysis into mechanical work with exceptionally high efficiency, even in the presence of substantial thermal fluctuations in living systems. It has long been proposed that release of inorganic phosphate (Pi) from myosin II is a critical step for efficient energy transfer. However, this prevailing view has been challenged by recent state-of-the-art experimental observations, necessitating a reexamination of the chemical steps responsible for ATP-derived energy storage. Here, we employ atomistic molecular dynamics simulations specifically designed to capture key aspects of ATP hydrolysis. We demonstrate that ATP hydrolysis increases the potential energy of myosin II functional loops while Pi remains bound, and that this increase occurs independently of heat release associated with the reaction. Together, these findings identify an alternative mechanism for energy retention and emphasize the intrinsic robustness of myosin II as a highly efficient molecular motor.