The Physics and Physical Chemistry of Molecular Machines

Abstract

The concept of a “power stroke”—a free-energy releasing conformational change—appears in almost every textbook that deals with the molecular details of muscle, the flagellar rotor, and many other biomolecular machines. Here, it is shown by using the constraints of microscopic reversibility that the power stroke model is incorrect as an explanation of how chemical energy is used by a molecular machine to do mechanical work. Instead, chemically driven molecular machines operating under thermodynamic constraints imposed by the reactant and product concentrations in the bulk function as information ratchets in which the directionality and stopping torque or stopping force are controlled entirely by the gating of the chemical reaction that provides the fuel for the machine. The gating of the chemical free energy occurs through chemical state dependent conformational changes of the molecular machine that, in turn, are capable of generating directional mechanical motions. In strong contrast to this general conclusion for molecular machines driven by catalysis of a chemical reaction, a power stroke may be (and often is) an essential component for a molecular machine driven by external modulation of pH or redox potential or by light. This difference between optical and chemical driving properties arises from the fundamental symmetry difference between the physics of optical processes, governed by the Bose–Einstein relations, and the constraints of microscopic reversibility for thermally activated processes.

Simulating the dynamics of the mechanochemical cycle of myosin-V

“…Rather, in accordance with our previous study, the directionality and the stall force are decided by the relative overall barrier of the forward (plus-ended) over the backward (minus-ended) pathway. In short, our study supports the notion that myosin-V favors a Brownian-ratchet mechanism (21,22) rather than a mechanical PS mechanism, which relies heavily on coupling the ATP hydrolysis free energy to mechanical strain-mediated conformational change (i.e., downhill PS).…”

“…S2. According to our model (26) and similar concepts explained elsewhere (21,22), the most important parameter determining the directionality and stall force of chemically coupled molecular motors like myosin-V is the factor Δe = e * −e, namely, the difference in the barrier heights between the forward and backward pathways (further clarification of e and e* is provided in Fig. 2).…”

“…S2]. The importance of different forward/backward paths in the workings of molecular motors in general has been discussed in depth (21,22). In our model for myosin-V, the forward path is described by a chain of events starting with the TL binding ATP, releasing actin, performing the RS, and hydrolyzing the ATP, while diffusing in the plus-end direction.…”

“…The difference in the two paths stems from the asymmetrical energetics of performing the PS from the lever-up position, actin binding, and P i release in the forward path [steps VI→(VIII) in (21,22). In our model for myosin-V, the forward path is described by a chain of events starting with the TL binding ATP, releasing actin, performing the RS, and hydrolyzing the ATP, while diffusing in the plus-end direction.…”

“…It is frequently assumed that the PS must release the free energy that provides the basis for the directionality and resistivity of the motor against the force applied in the opposite direction. Unfortunately, the PS idea has not been demonstrated based on a clear, structure-based, free-energy landscape or by considering the principles of microscopic reversibility (21,22). Apparently, it is extremely challenging to understand the free-energy balance of the myosin-V mechanochemical action.…”