Routes to Multiple Equilibria for Mass-Action Kinetic Systems

In this work we explore two potential mechanisms inducing multiple equilibria for weakly reversible networks with mass-action kinetics. The study is performed on a class of polynomial dynamic systems that, under some mild assumptions, are able to accommodate in their state-space form weakly reversible mass-action kinetic networks. The contribution is twofold. We provide an explicit representation of the set of all positive equilibria attained by the system class in terms of a set of (positive parameter dependent) algebraic relations. With this in hand, we prove that deficiency-one networks can only admit multiple equilibria via folding of the equilibrium manifold, whereas a bifurcation leading to multiple branches is only possible in networks with deficiencies larger than one. Interestingly, some kinetic networks within this latter class are capable of sustaining multiple equilibria for any reaction simplex, as we illustrate with one example.

Three-dimensional stochastic model of actin–myosin binding in the sarcomere lattice

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.