Potassium ion permeation mechanism revealed by a novel MD simulation approach

Our novel non-equilibrium MD simulation approach which is then combined with non-linear WHAM can be used to generate 2D and 1D PMFs. The 2D PMF has revealed a general pattern that is in consistent with the results from umbrella sampling approach. The knock-on mechanism derived is the well known S₂-S₄ or S₁-S₃ configurations of permeation. In addition, we are also able to extract 1D PMFs, which allow us to analyze the permeation pathways in details that are not easily reachable by 2D PMF. From 1D PMFs, we observed three possible permeation mechanisms. Beside the widely accepted S₂-S₄ or S₁-S₃ configurations, there are possibilities that four K⁺ ions occupy all four binding sites, or three K⁺ ions occupy S₄-S₃-S₂ at the same time. We observed that a water molecule could exists in between K⁺ ions that occupy S₃ and S₂ by pushing the carbonyl oxygen of the backbone residue away and its own oxygen participates in coordinating with the K⁺ ion. We hypothesize that this process could help the K⁺ ion dissociates from the stable binding site S₂. Further investigations need to be done to determine quantitatively whether the carbonyl oxygen “flipping” event helps lowering the energy barriers.