"Simulation and Modeling of Ion Channel Functional Mechanisms and Transport"

Ion channels play vital cellular functions.  How an external simulation (e.g., cross-membrane voltage, binding of a ligand, or decrease in external pH) triggers the opening of an ion channel is at the core of its functional mechanism.  We have used molecular dynamics simulations and other computational techniques to develop models for the functional mechanisms of several ion channels, including a nicotinic acetylcholine receptor, an AMPA-subtype glutamate receptor, and the M2 proton channel of the influenza virus.  A very useful way to validate these mechanistic models is to compare changes in residue solvent accessible areas against substituted cysteine accessibility measurements.  For the M2 proton channel, we have developed a theory for calculating the rate of ion transport, based on the proposed functional mechanism.  The permeant proton is modeled as binding obligatorily to a histidine tetrad within the channel pore and then being released to the other side of the membrane, and the rate constants are calculated by modeling these steps as diffusion-influenced reactions.  This calculation of the ion transport rate bridges two traditional approaches that have been pitted against each other, one based on modeling ion permeation as continuous diffusion and the other based on modeling the transport by discrete-state rate equations.  We show that the two approaches give the same ion transport rate and thus settle a long-standing debate.