Water Permeation and Flip-Flops Moving in Bilayer Membranes: A Dissipative Particle Dynamics Simulation
Authors: Inokuchi Takuya , Arai Noriyoshi 
Published: February 2020

Cells are covered with lipid bilayer membranes. Many biological reactions are observed in lipid membranes. The lipid membrane is formed by lipid molecules with hydrophilic groups and hydrophobic groups. Lipid bilayer membranes is very important to sustain life. Moreover, the lipid membrane ensure autonomous activity of intracellular systems by forming the boundary between intracellular and extracellular. Cell membranes provide unique local environments for biological reactions, where the diffusion of biomolecules as well as water molecules plays critical roles. The transport of water molecules and ions in the cells is controlled primarily by the channels. However, lipid membrane does not become the perfect barrier. It is known that a few of water molecules, ions and other molecules are passively transported across the membrane. Transport of nanoparticles across the membrane is very important in bioscience, pharmacological, and drug delivery systems. However, the anomalous diffusion of water molecules through the membrane is still not completely understood. Therefore, this phenomenon has been continued to be discussed.
On the other hand, lipid bilayers provide a flexible membrane deformation. It is known that lipid molecules in membranes can perform transverse motions between the bilayer leaflets (flip-flop motions). The transport of lipid molecules by flip-flop is important process for controlling the lipid composition of membranes. However, it is very difficult to observe directly the flip-flop of the lipid molecules in the membranes. Moreover, it is difficult to observe the detailed mechanism because such spontaneous events occur very rarely. Namely, little has been determined about the behavior of flip-flop, either experimentally, or in molecular simulations. Therefore, it is important to observe flip-flop motions at the molecular level using molecular simulations.
It is necessary to waste a large amount of the energy to occur the flip-flop because the hydrophilic parts of lipid needs to pass through the hydrophobic parts. Namely, the flip-flop movement is not preferred energy-wise. On the other hand, the transport of water in the lipid membrane is not limited to the aqua channel. Here we focus on the relationship between water transport without aqua channel and flip-flop movement, namely, we predict that we predict that the flip-flop is related to water transport. We observe the transport process of water in the lipid membrane by using molecular simulation. Here, we adopt first-passage-time (FPT) theory. In the early report (Calres Calero et al. Phys. Rev. E. 2011;83:021908), they reported the dynamics of chloride and potassium ions in the interior of the Outer membrane porin under the influence of an external electric field. They computed several first-passage-time quantities to characterize the dynamics of the ions in the interior of the channel. Moreover, they revealed the detailed dynamics of chloride ion and potassium ion. We investigate the transport of water in the membrane by using first passage time theory. The purpose of this study is to clarify the effect of flip-flop motion on water permeation.
As a result, it was observed that flip-flop motion affected hitting probability and mean exit time of water molecules. Moreover, a characteristic change was observed in the distance between hydrophilic groups and water molecules (Figure). These results anticipate that the flip-flop is occurred as water passes through.

Figure 1