A model of crossbridge action: the effects of ATP, ADP and Pi

Abstract

Summary We have explored a model of crossbridge kinetics that explains many of the effects on steady-state muscle contraction of ligands that bind to the nucleotide site on myosin. The mathematical model follows the basic framework for crossbridge function first established by A. F. Huxley. In the model, detached crossbridges initially bind in a weakly Attached, A.M.D.P_i state (A, actin; M, myosin; D, ADP; P_i, orthophosphate) at the beginning of the region of positive force production. P_i release then results in transition to a strongly-bound A.M.D state, as has been suggested by other investigators from both biochemical and mechanical data. Mg²⁺ ADP release and subsequent crossbridge detachment due to Mg²⁺ ATP binding to the A.M state occur at the end of the region of positive force production. Work in a number of laboratories has now defined the effects on steady-state contraction of variations in the concentrations of Mg²⁺ ATP, Mg²⁺ ADP and P_i. These data provide valuable constraints that can be used to further refine current models. The maximum velocity of shortening (V _max) and ATPase activity of muscle fibres exhibit classical saturation behaviour with respect to Mg²⁺ ATP concentration, with Mg²⁺ ADP acting as a competitive inhibitor. The model can reproduce this behaviour. The model also explains the observations that increasing [Mg²⁺ ATP] decreases isometric tension and increasing [Mg²⁺ ADP] increases tension. As the concentration of P_i increases, model predictions suggest that tension should decrease approximately as log[P_i], that ATPase activity should decrease less than tension and thatV _max should be almost unchanged, as has been found experimentally. The model also demonstrates that the connection between the parameters of contraction and the free energy of hydrolysis of Mg²⁺ ATP can be complex.