A Three-Ion Selectivity Filter Potential Energy Landscape Of A Putative Open-Conductive Kcsa

Potassium channels are tetrameric integral membrane proteins that passively allow rapid potassium conduction through the cell membrane while being strongly selective over other monovalent cations. A narrow region known as the selectivity filter, conserved in both structure and sequence, presents a series of backbone carbonyls towards the permeating ion. Here, we have performed a full three-ion permeation free energy landscape calculation for the selectivity filter region using all-atom umbrella sampling molecular dynamics simulations of the KcsA channel in a membrane with explicit lipids and solvent. The cases of pure potassium conduction and of a single sodium chaperoned by potassium ions were examined. The Potential of Mean Force (PMF) dependent on the Z-coordinates of three ions was calculated on the basis of a new unpublished high-resolution crystal structure of KcsA in a conformation which includes both an open gate and a conductive filter. The effect of flipping of Valine 76 was examined as well as the permeation and selectivity in a model with Glycine 77 replaced by a D-Alanine.