Transmembrane
Permeation Mechanism of Charged Methyl
Guanidine
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Abstract
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