Including Thermal Fluctuations in Actomyosin Stable States Increases the Predicted Force per Motor and Macroscopic Efficiency in Muscle Modelling

Muscle contractions are generated by cyclical interactions of myosin heads with actin filaments to form the actomyosin complex. To simulate actomyosin complex stable states, mathematical models usually define an energy landscape with a corresponding number of wells. The jumps between these wells are defined through rate constants. Almost all previous models assign these wells an infinite sharpness by imposing a relatively simple expression for the detailed balance, i.e., the ratio of the rate constants depends exponentially on the sole myosin elastic energy. Physically, this assumption corresponds to neglecting thermal fluctuations in the actomyosin complex stable states. By comparing three mathematical models, we examine the extent to which this hypothesis affects muscle model predictions at the single cross-bridge, single fiber, and organ levels in a ceteris paribus analysis. We show that including fluctuations in stable states allows the lever arm of the myosin to easily and dynamically explore all possible minima in the energy landscape, generating several backward and forward jumps between states during the lifetime of the actomyosin complex, whereas the infinitely sharp minima case is characterized by fewer jumps between states. Moreover, the analysis predicts that thermal fluctuations enable a more efficient contraction mechanism, in which a higher force is sustained by fewer attached cross-bridges.Author Summary: Mathematical models are of fundamental importance in the quantitative verification of biological hypotheses. Muscle contraction models assume the existence of several stable states for the myosin head, whereas the transition rates between states are defined to fit experimental data. The ratio of the forward and backward rates is linked to the ratio of the probabilities of being in one or other stable state at equilibrium through a detailed balance condition. A commonly used assumption leads to a relatively simple expression for this balance condition that depends only on the values of the energy at the minima and not on the minima shape. Mathematically, this hypothesis corresponds to infinite sharpness at these minima; physically, it neglects the small thermal fluctuations within actomyosin stable states. In this work, we compare this classical approach with a model that includes thermal fluctuations within wide minima, and quantitatively assess how much this hypothesis affects the model outcomes at the single molecule, single fiber, and whole heart levels. It is shown that, using parameters compatible with known behavior in muscle mechanics, relaxing the infinitely sharp minima hypothesis improves the predicted force generation and efficiency at the macroscopic level.