Mechanisms of Ion Permeation through Gramicidin a Channels

Abstract

Gramicidin A (gA) channels make an ideal system to test all-atom molecular dynamics (MD) of membrane proteins and mechanisms of ion permeation. In addition to being the most studied membrane “protein”, gA channels are tiny, allowing for long MD runs and calculations of potential of mean force (PMF) in tractable time. The binding sites at either end of the gA channel can both hold a single cation. At low concentration, permeation occurs as a series of independent events in which one cation at a time moves across the pore. Ion permeation usually is described using the ion position z in the direction of the pore axis as a “reaction coordinate”. But it is not known whether z is a good reaction coordinate to describe the process. A powerful tool to characterize the mechanism of ion permeation in the gA channel is the “committor” probability: the fraction of trajectories initiated from a given position that first commit to the left or right binding site of the channel. We evaluate the committor probability distribution function to identify the physical reaction coordinates of a K+ in gA using extensive MD calculations. At high concentration, permeation is dominated by 2-ion processes where cations are bound at either ends of the small pore. To understand the impact of double ion occupancy on the mechanism of ion permeation, we calculate the 2-ion PMF. The results show that if the first ion resides in the inner binding sites at one end of the channel, then the outer and inner binding sites for the second ion at the other end of the channel become shallow. The energetics of double occupancy is explained by considering the dipole moment fluctuation of the single-file water molecules inside channel. [Supported by NIH grant GM070971].