Mechanokinetics of the swinging-lever-arm model


Molecular models of contractility in striated muscle require an integrated description of the action of myosin motors, firstly in the filament lattice of the half-sarcomere and then over the whole fiber. Because existing models do not adequately reflect the biochemistry of the myosin motor and its structural environment, we have reviewed the biochemical actin-myosin-ATP cycle and we have developed an updated (nine state) model of the actomyosin cycle, which include novel findings from solution kinetic experiments, atomic structures of myosin from X-ray diffraction and electron micrographs of myosin decorated actin filaments and the working stroke coupling to the release of Pi from A.M.ADP.Pi complex, or possibly the subsequent release of ADP. This model is described in detail in our publications and here we will only briefly outline the key new features of the model. The model includes two step binding process, in which two 4-5nm working strokes occur in succession, phosphate released after the first stroke, a small third stroke is associated with ATP-induced detachment from actin, and strain-induced detachment from actin. A comprehensive model of muscle contraction is defined by applying such a cycle to all myosin-S1 heads in the half-sarcomere, subject to generic constraints which include: (a) all strain-dependent kinetics required for actin-myosin interactions are derived from reaction-energy landscapes and applied to dimeric myosin, (b) actin-myosin interactions are controlled by selection rules derived from the structure of the filaments, and exact position within 3D sarcomere lattice so that each dimer may be associated with a unique set of target sites on actin (as described above) and (c) the myosin and actin filaments are treated as elastically extensible. Specific descriptions of specific parts of the model are described here.

A model actin-(myosin-S1)-ATP cycle, with two working strokes (4     5, 5    7) and coupled to Pi-release after the first or second stroke (5    6, 7    8). The second stroke is also required after Pi-release (6    8). Bound states are classified as ‘A’, ‘I’ or ‘R’ to denote the corresponding orientations of the lever arm. The R-states (rigor and near-rigor) are lumped together in state 8, and their population may be boosted by a small third stroke accompanying the release of ADP. Dashed arrows indicate slow transitions (                 ) which do not affect the isometric behavior of the model, but the slow 6     2 transition may be accelerated at large strains.