Molecular dynamics simulation studies of small molecules interacting with cell membranes

Biomembranes are an indispensable element of all cells, whether prokary-otic or eukaryotic. They function as the barriers that allow for cellular compartmentalization, as a first line of defense against harmful foreign substances, and as a medium for cellular communication. Membranes are composed of a mélange of lipids, sterols, proteins, and even exogenous molecules. As such, the interaction of small molecules with lipid membranes is of great importance for membrane functions. In this review, we will give account of the recent progress in molecular simulations of small molecule-lipid bilayer interactions. We will first discuss how the chemical and physical properties (e.g., hydrophobic thickness mismatch and phase behavior) of the lipid bilayers affect the distribution and orientation of small molecules within the membranes. This will be followed by an account of simulation studies on how the presence of small molecules modulates the structure and dynamics of lipid membranes. Finally, we will review emerging mechanisms by which small molecules (e.g., A-tocopherol) traverse a cell membrane as revealed by molecular simulations using advanced sampling techniques. Detailed knowledge of these mechanisms will have significant implication for understanding physiological distribution, pharmacokinetics, and resistance of drug molecules.