Free Energy Calculations on the Water-Chain-Assisted and the Dehydration Mechanisms of Transmembrane Ion Permeation

Two permeation mechanisms, namely the water-chain-assisted mechanism and the dehydration mechanism, have been proposed for ions through lipid membranes. In previous studies, multiple reaction coordinates and potential of mean force calculations have been applied in studying such complex transmembrane processes of ions. To reduce the expensive computational cost, we develop two new reaction coordinates in our recent work and in this work to study the two permeation mechanisms. An intrinsically one-dimensional free energy calculation method developed in our recent work is successfully employed in these studies: First, one-dimensional umbrella samplings are performed using the two reaction coordinates. Then, bin segmentations are performed along the transition paths in multidimensional phase spaces. Finally, the weighted least-square analysis method (Welsam) is used for free energy analysis. Based on the new reaction coordinates and the one-dimensional free energy calculation method, we systematically study the two transmembrane permeation mechanisms of sodium ion and chloride ion through lipid bilayers with different thicknesses. Our results suggest that the water-chain-assisted mechanism is dominant for cations, whereas the dehydration mechanism is competitive for anions through thick membranes, which is consistent with previous experimental results.