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The voltage sensitivity of membrane proteins is reflected in the response of the voltage sensing domains (VSDs) to the changes in membrane potential. This response is implicated in the displacement of positively charged residues, associated with the conformational changes of VSDs. The displaced charges generate nonlinear (i.e., voltage-dependent) capacitance current called the gating current (and its corresponding gating charge), which is a key experimental quantity that characterizes voltage activation in VSMP. However, the relevant theoretical/computational approaches, aimed to correlate the structural information on VSMP to electrophysiological measurements, have been rather limited, posing a broad challenge in computer simulations of VSMP. Concomitant with the development of our coarse-graining (CG) model of voltage coupling, we apply our theoretical framework for the treatments of voltage effects in membrane proteins to modeling the VSMP activation, taking the VSDs (Ci-VSD) derived from the Ciona intestinalis voltage sensitive phosphatase (Ci-VSP) as a model system. Our CG model reproduces the observed gating charge of Ci-VSD activation in several different perspectives. In particular, a new closed-form expression of the gating charge is evaluated in both nonequilibrium and equilibrium ways, while considering the fluctuation-dissipation relation that connects a nonequilibrium measurement of the gating charge to an equilibrium measurement of charge fluctuations (i.e., the voltage-independent linear component of membrane capacitance). In turn, the expression uncovers a novel link that connects an equilibrium measurement of the voltage-independent linear capacitance to a nonequilibrium measurement of the voltage-dependent nonlinear capacitance (whose integral over voltage is equal to the gating charge). In addition, our CG model yields capacitor-like voltage dependent free energy parabolas, resulting in the free energy difference and the free energy barrier for the Ci-VSD activation at "zero" (depolarization) membrane potential. Significantly, the resultant voltage dependent energetics enables a direct evaluation of capacitance-voltage relationship (C-V curve) as well as charge-voltage relationship (Q-V curve) that is in a good agreement with the observed measurement of Ci-VSD voltage activation. Importantly, an extension of our kinetic/thermodynamic model of voltage dependent activation in VSMP allows for novel derivations of voltage-dependent rate constants, whose parameters are expressed by the intrinsic properties of VSMP. These novel closed-form expressions offer a physicochemical foundation for the semiempirical Eyring-type voltage dependent rate equations that have been the cornerstone for the phenomenological (kinetic) descriptions of gating and membrane currents in the mechanistic study of ion channels and transporters. Our extended theoretical framework developed in the present study has potential implications on the roles played by gating charge fluctuations for the spike generations in nerve cells within the framework of the Hodgkin-Huxley-type model.

A Microscopic Capacitor Model of Voltage Coupling in Membrane Proteins: Gating Charge Fluctuations in Ci-VSD