Chemomechanical regulation of myosin Ic cross-bridges: Deducing the elastic properties of an ensemble from single-molecule mechanisms

Myosin Ic is thought to be the principal constituent of the motor that adjusts mechanical responsiveness during adaptation to prolonged stimuli by hair cells, the sensory receptors of the inner ear. In this context myosin molecules operate neither as filaments, as occurs in muscles, nor as single or few molecules, as characterizes intracellular transport. Instead, myosin Ic molecules occur in a complex cluster in which they may exhibit cooperative properties. To better understand the motor’s remarkable function, we introduce a theoretical description of myosin Ic’s chemomechanical cycle based on experimental data from recent single-molecule studies. The cycle consists of distinct chemical states that the myosin molecule stochastically occupies. We explicitly calculate the probabilities of the occupancy of these states and show their dependence on the external force, the availability of actin, and the nucleotide concentrations as required by thermodynamic constraints. This analysis highlights that the strong binding of myosin Ic to actin is dominated by the ADP state for small external forces and by the ATP state for large forces. Our approach shows how specific parameter values of the chemomechanical cycle for myosin Ic result in behaviors distinct from those of other members of the myosin family. Integrating this single-molecule cycle into a simplified ensemble description, we predict that the average number of bound myosin heads is regulated by the external force and nucleotide concentrations. The elastic properties of such an ensemble are determined by the average number of myosin cross-bridges. Changing the binding probabilities and myosin’s stiffness under a constant force results in a mechanical relaxation which is large enough to account for fast adaptation in hair cells.Author summary: Myosin molecules are biological nanomachines that transduce chemical energy into mechanical work and thus produce directed motion in living cells. These molecules proceed through cyclic reactions in which they change their conformational states upon the binding and release of nucleotides while attaching to and detaching from filaments. The myosin family consists of many distinct members with diverse functions such as muscle contraction, cargo transport, cell migration, and sensory adaptation. How these functions emerge from the biophysical properties of the individual molecules is an open question. We present an approach that integrates recent findings from single-molecule experiments into a thermodynamically consistent description of myosin Ic and demonstrate how the specific parameter values of the cycle result in a distinct function. The free variables of our description are the chemical input and external force, both of which are experimentally accessible and define the cellular environment in which these proteins function. We use this description to predict the elastic properties of an ensemble of molecules and discuss the implications for myosin Ic’s function in the inner ear as a tension regulator mediating adaptation, a hallmark of biological sensory systems. In this situation myosin molecules cooperate in an intermediate regime, neither as a large ensemble as in muscle nor as a single or a few molecules as in intracellular transport.