Abstract
In contrast to processive molecular motors, skeletal myosins form a large motor ensemble for contraction of muscles against high loads. Despite numerous information on the molecular properties of skeletal myosin, its ensemble effects on collective force generation have not been rigorously clarified. Here we show 4 nm stepwise actin displacements generated by synthetic myofilaments beyond a load of 30 pN, implying that steps cannot be driven exclusively by single myosins, but potentially by coordinated force generations among multiple myosins. The simulation model shows that stepwise actin displacements are primarily caused by coordinated force generation among myosin molecules. Moreover, the probability of coordinated force generation can be enhanced against high loads by utilizing three factors: strain-dependent kinetics between force-generating states; multiple power stroke steps; and high ATP concentrations. Compared with other molecular motors, our findings reveal how the properties of skeletal myosin are tuned to perform cooperative force generation for efficient muscle contraction.
Highlights
Myosin II families, that is, skeletal, cardiac, smooth and nonmuscle myosins, form bipolar filaments that interacts with actin filaments, thereby generating actin sliding and force
A 1.2 mm-long myosin-rod cofilament was selected for force measurements such that B17 myosin molecules were expected to interact with a single actin filament (Methods), in accordance with our estimate of the number of interacting molecules[30]
To gain further insight into the mechanism by which synthetic myofilaments generate stepwise force, we developed a Monte Carlo-based simulation model[37] consisting of 17 myosin molecules arranged in parallel and interacting with a single actin filament attached to the spring, whose stiffness was equivalent to the trap stiffness of
Summary
Myosin II families, that is, skeletal, cardiac, smooth and nonmuscle myosins, form bipolar filaments that interacts with actin filaments, thereby generating actin sliding and force. The drag of negatively strained motors is greatly reduced by the nonlinear elasticity of the myosin head[30] These structural properties are partly responsible for the additive force generation of skeletal myosins as the number of motors increases[4,5,30,31]. Mechanical and X-ray diffraction studies of single muscle fibre preparations have provided potential evidence of the coordinated movements of myosin heads during force generation[32,33,34]. These findings suggest that skeletal myosins interact with actin filaments, not as independent force generators[35] but as cooperative force generators[32]. Our simulation further reveals that the molecular properties of skeletal myosins are tuned to perform cooperative force generation for efficient muscle contractions
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