1. Abstract
We have performed molecular simulations to study spatial distribution and orientation of cholesterol molecules within three symmetric lipid bilayer systems: two binary lipid mixtures, namely, DOPC/CHOL (1, 2-dioleoyl-sn-glycero-3-phosphocholine/cholesterol) and SM/CHOL (d20:1/20:0 sphingomyelin /Cholesterol), and a tertiary mixture of DOPC/SM/CHOL. We have studied the behavior of these bilayers at temperatures varying from 400 K to 210 K and cholesterol molar concentration from 0% to 60%.We observe that the spatial distribution of cholesterol is strongly correlated with the phase of the bilayer. In the disordered phase, cholesterol molecules are predominantly present near the center of the bilayer. In the ordered phase, cholesterol molecules are mainly present in the leaflets. At the order - disorder transition temperature, the fraction of cholesterol molecules is equal in the two leaflets and the center. In the leaflets, cholesterol molecules are oriented parallel to the bilayer normal, while near the center, cholesterol molecules are randomly oriented. In agreement with previous experimental studies, we find that increasing the cholesterol concentration favors ordered phase of the bilayers. The preference of cholesterol molecules to be present in the leaflets in the ordered phase is attributed to their favorable hydrophobic interactions with the lipid tails.
Statement of Significance Cholesterol has an important role in governing the physical properties of lipid bilayers, including their structural integrity, phase behavior and permeability. The spatial distribution of cholesterol in lipid bilayers is not well-understood because of the challenges associated with performing experiments for such a measurement. We show, via molecular simulations, that the spatial distribution of cholesterol molecules is strongly correlated with the phase behavior of the lipid bilayers. In the ordered phase, cholesterol molecules are predominantly present in the leaflets, whereas in the disordered phase, cholesterol molecules are in the center region of the bilayer. These results are important for understanding the relationship between lipid bilayer composition and their biological function and response.
