Molecular Dynamics Simulations On Mechanisms Of Passive Ion Permeation Through Membranes

Passive or unassisted ion permeation through lipid bilayers involves a type of rare events by which cells regulate their salt concentrations and p H.It is important to understand its mechanism in order to develop technologies of,for example,delivering or maintaining small drug-like molecules inside cells.In earlier simulations of passive ion permeations,the commonly used sampling methods usually define the positions of ions relative to the membrane plane as a measure of permeation,i.e.,the collective variable,ignoring the active participations of other particles.Newly defined collective variables involving the movements of ions,lipids and water molecules allow us to identify the transition paths on the free energy landscape using the 2D umbrella sampling techniques.In this work,this technique was used to study the permeation processes of some well-known ions,sodium,potassium,and chloride.It was found that permeations of sodium and potassium are assisted by important lipid bilayer deformations and massive water solvation,while chloride may not.Chloride may have two different possible pathways,in which the energetic favorable one is similar to the solubility-diffusion model.The free energy barriers for the permeation of these ions are in semiquantitative agreement with experiments.Further analyses on the distributions of oxygens and interaction energies suggests,the electrostatic interactions between ions and polar headgroups of lipids may greatly influence membrane deformation as well as the waterwire,and furthermore the free energy barriers of waterwire mediated pathways.For chloride,the non-waterwire pathway may be energetically favorable.Our previous studies found that permeation of Na~+and K~+,in contrast with Cl~-,causes significant membrane deformation and formation of a water wire in the membrane hydrophobic domain.Clearly,positive charges have a propensity to interact more strongly with lipids and thus induce serious defects to membrane.Since calcium is one of the most common and important metal in biology,we made the unprecedented effort to bring it across the bio-membrane.It is observed that permeation of+2 charge would badly disturb the bilayer structure,even lipid“flip-flop”is quite common,and cause leakage of water molecules by a widely-reported“All or None”manner,suggesting unassisted permeation of small molecules with 2 or more positive charges to besevere threats to cell membranes.More importantly,we found“All or None”leakage is closely related to the“game”of hydrophilic and hydrophobic forces caused by high positive charges.Our findings may be enlightening for the exploration of underlying mechanisms of the antimicrobial peptides and similar positively charged molecules acting on membranes.