Transmembrane Permeation Mechanism of Charged Methyl Guanidine.

The mechanism of transmembrane ion permeation is studied using charged methyl guanidine as a model ion. With a widely applied reaction coordinate, our umbrella sampling results reveal a significant finite-size effect in small simulation systems and a serious hysteresis in large systems. Therefore, it is important to re-examine the simulation techniques for studying transmembrane permeation mechanism of ions suggested in previous works. In this work, two novel collective variables are designed to acquire a continuous trajectory of the permeation process and small statistical errors through umbrella sampling. A water-bridge mechanism is discussed in detail. In this mechanism, a continuous water chain (or a chain of water molecules and lipid head groups) is formed across the membrane to conduct the transmembrane permeation of charged methyl guanidine. We obtain a continuous transition trajectory by combining the two-dimensional umbrella sampling in the local region of the saddle state and a one-dimensional sampling in the out region. Our free energy analysis shows that, with the presence of the water bridge, the energy barrier of the transmembrane permeation of ions is reduced significantly. Our analysis suggests that the water-bridge mechanism is common for permeation of ions across thick membranes, including palmitoyloleoyl phosphocholine and dipalmitoylphosphatidylcholine membranes.