Thermodynamically Consistent Modeling of ATP-Driven Cross-Bridge Dynamics in Muscle Contraction

Abstract

Muscle contraction is a prototypical multiscale chemomechanical process in which ATP hydrolysis at the molecular level drives force generation and mechanical work at larger scales. A central challenge is to incorporate the free energy supplied by ATP hydrolysis into a mechanical cross-bridge model in a way that is thermodynamically consistent and connects microscopic motor cycling to macroscopic force generation. Here we use the Energetic Variational Approach (EnVarA) to combine Hill's cycle-affinity viewpoint with Huxley's sliding-filament mechanics in a single thermodynamically consistent framework. We formulate a three-state Fokker--Planck--jump description for cross-bridge densities evolving on state-dependent free-energy landscapes, and treat ATP, ADP, and Pi as reacting and diffusing chemical species that share the same free-energy functional as the cross-bridge densities. ATP hydrolysis enters the model through local detailed balance, which biases the transition rates. Filament sliding velocity is incorporated as a convective transport term in the Fokker--Planck dynamics, so mechanical power output is defined directly from the energy balance law. Under chemostatted conditions and a fast-equilibration assumption for the two attached states, the model reduces to a closed two-state molecular motor description; in a further small-diffusion limit, this reduction recovers a Huxley-type transport-reaction equation whose effective attachment and detachment rates are derived from the underlying three-state cycle rather than prescribed phenomenologically, with their strain, ATP, and phosphate dependence fixed by the energy landscapes and local detailed balance. We calibrate the reduced model against cross-bridge-level observables and show that it reproduces key velocity-dependent trends and yields a Hill-like force--velocity relation comparable to established cross-bridge models.