Coupling of Lever Arm Swing and Biased Brownian Motion in Actomyosin

Abstract

An important unresolved problem associated with actomyosin motors is the role of Brownian motion in the process of force generation. On the basis of structural observations of myosins and actins, the widely held lever-arm hypothesis has been proposed, in which proteins are assumed to show sequential structural changes among observed and hypothesized structures to exert mechanical force. An alternative hypothesis, the Brownian motion hypothesis, has been supported by single-molecule experiments and emphasizes more on the roles of fluctuating protein movement. In this study, we address the long-standing controversy between the lever-arm hypothesis and the Brownian motion hypothesis through in silico observations of an actomyosin system. We study a system composed of myosin II and actin filament by calculating free-energy landscapes of actin-myosin interactions using the molecular dynamics method and by simulating transitions among dynamically changing free-energy landscapes using the Monte Carlo method. The results obtained by this combined multi-scale calculation show that myosin with inorganic phosphate (Pi) and ADP weakly binds to actin and that after releasing Pi and ADP, myosin moves along the actin filament toward the strong-binding site by exhibiting the biased Brownian motion, a behavior consistent with the observed single-molecular behavior of myosin. Conformational flexibility of loops at the actin-interface of myosin and the N-terminus of actin subunit is necessary for the distinct bias in the Brownian motion. Both the 5.5–11 nm displacement due to the biased Brownian motion and the 3–5 nm displacement due to lever-arm swing contribute to the net displacement of myosin. The calculated results further suggest that the recovery stroke of the lever arm plays an important role in enhancing the displacement of myosin through multiple cycles of ATP hydrolysis, suggesting a unified movement mechanism for various members of the myosin family.

Nucleotide-dependent structural fluctuations and regulation of microtubule-binding affinity of KIF1A

“…We expect that the binding regulation mechanism using allosteric structural fluctuations applies also to other rail‐motor systems, such as other kinesins, actomyosin and the dynein‐MT system. In fact, a recent simulation studies of myosin II using a coarse‐grained model reported that structural fluctuation of loops regulates binding of the myosin to the actin filament. In the case of myosin V, the allosteric regulation of the affinity to actin filament through a large structural fluctuation of the helix H18 was also suggested by a molecular dynamics simulation .…”

Allostery and molecular stripping mechanism in profilin regulated actin filament growth

“…Molecular dynamics (MD) simulations have shown great success in the studies of structural dynamics of actin filament due to the unprecedented spatial and temporal resolutions [23][24][25][26][27]. However, the molecular events involved in the filament growth typically occur at the time scales longer than millisecond, which are far beyond the capability of conventional all-atom MD simulations.…”

Physical driving force of actomyosin motility based on the hydration effect

“…In order to describe the driving force acting on myosin S1 along F‐actin on the basis of chemical thermodynamics, a mechanism with decreasing chemical potential of myosin S1 along F‐actin is required. The binding free energy between myosin S1 and F‐actin was calculated by molecular dynamics (MD) taking into account the electrostatic interactions and intermolecular interactions using the reproduced 3D coordinates of myosin S1 with/without ADP or ADP.Pi and F‐actin (Nie et al, ). This study showed a long distance driving force up to 11 nm after releasing ADP.…”