Protective Role of Glucose in Alcohol-Stressed Phospholipid Membranes: An MD Simulation Approach

Abstract

Lipid bilayers, the fundamental components of biological cell membranes, are known to be stabilized and functionally preserved in the presence of certain small saccharides-under various environmental stresses. In contrast, short-chain aliphatic alcohols are well-documented for their disruptive effects on membrane structure. Their interaction with lipid bilayers often leads to increased permeability, uncontrolled solute transport, and leakage of essential cofactors. While lipid-saccharide interactions and alcohol-induced membrane alterations have been extensively studied individually, the molecular mechanisms governing these effects remain incompletely understood. In this study a series of atomistic molecular dynamics simulations were carried out to explore the effects of glucose with varying concentrations on fully hydrated DMPC bilayers exposed to different ethanol concentrations. It was observed that the thickness of the lipid bilayer dropped significantly with the increase in glucose concentration, and expanded laterally at high glucose levels due to the intercalation of glucose between the headgroups of adjacent lipids. We observed that ethanol reduces thickness, enhances tail disorder, and promotes lipid diffusion. Glucose reversed these effects in a concentration-dependent manner by localizing at the bilayer interface, forming abundant hydrogen bonds with lipid headgroups. This interaction inhibits ethanol binding and penetration into the hydrophobic core, particularly at higher glucose concentrations, as observed from the electron density and minimum-distance distribution functions analyses. We explored ethanol and glucose-driven or suppressed curvature effects, lipid order parameters, and translational mobility. Our findings, in detail, will provide insights into the molecular mechanisms governing solute-membrane interactions and underscore the protective role of glucose in stabilizing lipid bilayers under alcohol-induced stress.