Conductance of a potassium channel in the limit of zero membrane potential

Potassium (K⁺) channels have been studied computationally since the late 1990s, yet a complete quantitative description of their permeation properties has not been achieved. One important metric to validate the computational models is to compare the calculated channel conductance with experiment. One approach to calculate the channel conductance is to carry out nonequilibrium molecular dynamics (MD) simulations in the presence of a membrane potential to determine the mean ionic current as a function of voltage. However, because MD trajectories are of limited length, it is often necessary to apply a fairly large membrane potential to determine the mean current from a statistically meaningful number of ion permeation events. For this reason, a quantitative estimate of the channel conductance at small, physiologically relevant membrane potentials is lacking. Using Green-Kubo linear response theory, we formulate an alternative approach to estimate the conductance of the MthK K⁺ channel by relying on MD simulations under equilibrium conditions. The channel conductance at 400 mM KCl estimated from equilibrium MD with the nonpolarizable AMBER force field and polarizable Drude force field is on the order of 5-9 pS-about 30-60 times less than the experimental value. For both AMBER and Drude, the ion conduction process occurs according to a hard-knock mechanism, via direct ion-ion contacts with no water molecules between the ions.