title: Three-dimensional stochastic model of actin-myosin binding in the sarcomere lattice.
abstract: The effect of molecule tethering in three-dimensional (3-D) space on bimolecular binding kinetics is rarely addressed and only occasionally incorporated into models of cell motility. The simplest system that can quantitatively determine this effect is the 3-D sarcomere lattice of the striated muscle, where tethered myosin in thick filaments can only bind to a relatively small number of available sites on the actin filament, positioned within a limited range of thermal movement of the myosin head. Here we implement spatially explicit actomyosin interactions into the multiscale Monte Carlo platform MUSICO, specifically defining how geometrical constraints on tethered myosins can modulate state transition rates in the actomyosin cycle. The simulations provide the distribution of myosin bound to sites on actin, ensure conservation of the number of interacting myosins and actin monomers, and most importantly, the departure in behavior of tethered myosin molecules from unconstrained myosin interactions with actin. In addition, MUSICO determines the number of cross-bridges in each actomyosin cycle state, the force and number of attached cross-bridges per myosin filament, the range of cross-bridge forces and accounts for energy consumption. At the macroscopic scale, MUSICO simulations show large differences in predicted force-velocity curves and in the response during early force recovery phase after a step change in length comparing to the two simplest mass action kinetic models. The origin of these differences is rooted in the different fluxes of myosin binding and corresponding instantaneous cross-bridge distributions and quantitatively reflects a major flaw of the mathematical description in all mass action kinetic models. Consequently, this new approach shows that accurate recapitulation of experimental data requires significantly different binding rates, number of actomyosin states, and cross-bridge elasticity than typically used in mass action kinetic models to correctly describe the biochemical reactions of tethered molecules and their interaction energetics.
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115 smijailo@gmail.com.|Department of Medicine, Tufts University School of Medicine, Boston, MA 021115.|Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115.
authors.forename: Srboljub M
authors.initials: SM
authors.lastname: Mijailovich
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kayser-Herold
authors.affiliation: Faculty of Science, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Boban
authors.initials: B
authors.lastname: Stojanovic
authors.affiliation: Faculty of Science, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Djordje
authors.initials: D
authors.lastname: Nedic
authors.affiliation: Department of Biology, Illinois Institute of Technology, Chicago, IL 60616.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Irving
authors.affiliation: School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, England, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Geeves
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D008958:Models, Molecular; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D012518:Sarcomeres / Q000378:metabolism*
chemical_list: D000199:Actins; D009218:Myosins