Effect of Cholesterol on Membrane Dipole Potential: Atomistic and Coarse-Grained Molecular Dynamics Simulations

The effect of cholesterol on membrane dipole potential has been the subject of a great number of experimental and theoretical investigations, but these studies have yielded different findings and interpretations at high cholesterol concentrations. This suggests that the underlying mechanism of the cholesterol effect is not well addressed. Moreover, as far as we know, none of the previously proposed coarse-grained (CG) models (including MARTINI and its improved versions) have been successfully used to probe the effect of cholesterol on membrane dipole potential, owing to either an inaccurate description of water-cholesterol electrostatics or the neglect of the contribution of cholesterol to membrane dipole potential. In our previous works, we proposed a CG model CAVS (charge attached to virtual site) for lipid and water, showing the advantage of the CAVS model in the calculations of membrane dipole potential as compared to the MARTINI model. In this work, we present the CAVS model for cholesterol in order to enable us to investigate the effect of cholesterol on membrane dipole potential at large spatial scale. Our works showed that the CAVS and CHARMM models produced similar results in the study of the effects of cholesterol on lipid bilayer structures and membrane dipole potential. In particular, by combining the CHARMM and CAVS simulations, we explicitly calculated the individual contributions of membrane components (cholesterol, water, and lipid) to membrane dipole potential at different cholesterol concentrations, and we discovered that an increase in cholesterol content would result in a nonlinear variation of the individual contributions of water and lipid with cholesterol concentration. On the other side, we observed that the individual contribution of cholesterol to membrane dipole potential would nonlinearly increase with increasing cholesterol concentration. Thus, the effect of cholesterol on membrane dipole potential is complicated owing to the different variation of individual contributions of membrane components (water, lipid, and cholesterol) with cholesterol concentration.