Abstract
Muscle contraction is powered by the cyclic interaction of skeletal myosin molecules with actin filaments. Recent experiments suggest cooperative actions between myosin molecules, when part of an ensemble. In order to gain more insight into the mechanism of intermolecular cooperativity between myosins in a myofilament, displacements of actin generated by ∼17 interacting myosins embedded in myosin-rod cofilament were measured by optical tweezers. Results showed stepwise displacements of actin (3-6 nm) under high loads of ∼30 pN at every 1-2 ms. Dwell times gradually increased with increasing loads, which is distinctively different from highly load-dependent characteristics of dwell time observed in single myosins, implying that the number of force generating myosins increases with increasing loads. These results suggest that stepwise displacements may be generated by synchronous force generations of myosin molecules. In order to elucidate potential mechanisms of synchronous actions between myosins, we developed the simulation model, consisting of 17 myosins arranged in series with six transition states defined during actomyosin mechanochemical cycles. We have two types of model, implemented with either one or two power strokes. Interestingly, two power stroke model generates stepwise movements of actin at loads up to 30 pN, but one power stroke model generates forces up to 20 pN. These differences in force output are attributed to modulation of number of synchronous power stroke motors. The numbers of synchronous power stroke motors increase with increasing loads from 1.5 to 3 molecules in two power stroke model on average, while they are virtually the same in one power stroke model. Combined with results from both in-vitro and in-silico experiments, multiple power stroke states associated with strain-dependent kinetics are essential for synchronous force generations between myosins, that is a key feature for force enhancement of myosin ensembles.
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