Electronic Polarization Leads to a Drier Dewetted State for Hydrophobic Gating in the Big Potassium Channel.

ABSTRACT

In the hydrophobic gating mechanism proposed for some ion channels, ion permeation is not blocked by the physical dimension of the channel pore but by its dewetted state which constitutes the energetic bottleneck. A major source of uncertainty in the mechanism is that the dewetted state was not observed in experiments and only probed in simulations using nonpolarizable force fields, which do not accurately represent the properties of confined water. Here we analyze hydration of the central cavity in the pore-gate domain of the Big Potassium channel using molecular dynamics and grand canonical Monte Carlo simulations with enhanced sampling techniques. Including polarization leads to a much drier dewetted state and a higher barrier for the transition to the wet state, suggesting more effective hydrophobic gating. The simulations also identify two backbone carbonyls at the bottom of the selectivity filter as good candidates for characterizing the dewetted state using infrared spectroscopies.