title: Compliant realignment of binding sites in muscle: transient behavior and mechanical tuning.
abstract: The presence of compliance in the lattice of filaments in muscle raises a number of concerns about how one accounts for force generation in the context of the cross-bridge cycle--binding site motions and coupling between cross-bridges confound more traditional analyses. To explore these issues, we developed a spatially explicit, mechanochemical model of skeletal muscle contraction. With a simple three-state model of the cross-bridge cycle, we used a Monte Carlo simulation to compute the instantaneous balance of forces throughout the filament lattice, accounting for both thin and thick filament distortions in response to cross-bridge forces. This approach is compared to more traditional mass action kinetic models (in the form of coupled partial differential equations) that assume filament inextensibility. We also monitored instantaneous force generation, ATP utilization, and the dynamics of the cross-bridge cycle in simulations of step changes in length and variations in shortening velocity. Three critical results emerge from our analyses: 1) there is a significant realignment of actin-binding sites in response to cross-bridge forces, 2) this realignment recruits additional cross-bridge binding, and 3) we predict mechanical behaviors that are consistent with experimental results for velocity and length transients. Binding site realignment depends on the relative compliance of the filament lattice and cross-bridges, and within the measured range of these parameters, gives rise to a sharply tuned peak for force generation. Such mechanical tuning at the molecular level is the result of mechanical coupling between individual cross-bridges, mediated by thick filament deformations, and the resultant realignment of binding sites on the thin filament.
authors.affiliation: Department of Zoology, University of Washington, Seattle 98195-1800, USA. danielt@zoology.washington.edu
authors.forename: T L
authors.initials: TL
authors.lastname: Daniel
authors.forename: A C
authors.initials: AC
authors.lastname: Trimble
authors.forename: P B
authors.initials: PB
authors.lastname: Chase
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001696:Biomechanical Phenomena; D055592:Biophysical Phenomena; D001703:Biophysics; D003187:Compliance; D004734:Energy Metabolism; D007537:Isometric Contraction / Q000502:physiology; D008954:Models, Biological; D009010:Monte Carlo Method; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D012518:Sarcomeres / Q000502:physiology
chemical_list: D000199:Actins