A quantitative stochastic model of the mechanochemical cycle of myosin, the protein that drives muscle contraction, is proposed. It is based on three premises: (i) the myosin head incorporates a lever arm, whose equilibrium position adjusts as each of the products of ATP hydrolysis dissociates from the nucleotide pocket; (ii) the chemical reaction rates are modified according to the work done in moving the arm; and (iii) the compliance of myosin's elastic element is designed to permit many molecules to work together efficiently. The model has a minimal number of parameters and provides an explanation, at the molecular level, of many of the mechanical and thermodynamic properties of steadily shortening muscle. In particular, the inf lexion in the forcevelocity curve at a force approaching the isometric load is reproduced. Moreover, the model indicates that when large numbers of myosin molecules act collectively, their chemical cycles can be synchronized, and that this leads to stepwise motion of the thin filament. The oscillatory transient response of muscle to abrupt changes of load is interpreted in this light.While the sliding-filament theory of muscle contraction (1, 2) is universally accepted, the detailed mechanism of transduction of chemical energy, derived from ATP hydrolysis, into mechanical work remains the object of intense research. In vitro motility assays have established that the relative motion of thick and thin filaments in the sarcomere is generated by myosin heads (3), which undergo an actin-activated ATPase cycle during which they form transient crossbridges between the filaments. How are the mechanical properties of muscle related to the structure and the biochemical kinetics of myosin? To what extent can the dynamics of sarcomere shortening be ascribed to events at the molecular level?This issue is explored here in the context of a model of the mechanochemical cycle of myosin, based on the "swinging lever arm" hypothesis (4)-a refinement of the swinging crossbridge picture (5, 6) that has been prompted by recent structural studies (7). I investigate how an ensemble of motor proteins generates sliding between a single pair of filaments, under conditions in which an external force opposes the motion, and report a striking correspondence with a number of features that are familiar from experiments on muscle. The Fenn effect and A.V. Hill's characteristic relation (8) between force and velocity are reproduced, and so are the deviations from Hill's law that have been detected in single muscle fibers (9). Most significantly, the model displays a transition from smooth sliding to stepwise motion at high load, because of the synchronization of the power strokes of a large fraction of the myosin molecules.Structural Properties of Myosin, Chemical Kinetics, and Their Interrelation. The model is illustrated in Fig. 1. Each myosin molecule is anchored in the thick filament, and its head binds stereospecifically to sites on the thin filament. The head contains a lever arm that amplifies any small...