A mechanistic perspective on the effect of cholesterol in phospholipid bilayers

TL;DR

This study uses molecular dynamics simulations to analyze how cholesterol influences phospholipid bilayers, revealing that local cholesterol arrangements primarily drive interactions and domain formation, with implications for understanding membrane raft behavior.

Contribution

The paper provides a systematic, simulation-based analysis of cholesterol's structural and enthalpic effects in lipid bilayers, emphasizing local arrangements over total concentration.

Findings

Interaction effects depend mainly on local cholesterol arrangement.

Cholesterol influences are primarily entropic rather than enthalpic.

Interaction functions remain stable from binary to ternary mixtures.

Abstract

Cholesterol (CHOL) is one of the most important components of plasma membranes of higher cells and one of the main factors for the formation of (nano)domains. In this work, molecular dynamics simulations of mixtures of CHOL with DPPC (saturated lipid) and DLiPC (unsaturated lipid) as standard phospholipids (PLs) are presented in a wide range of CHOL concentrations. The key idea is to systematically extract all structural and enthalpic properties relevant to the formulation of a lattice model of these systems and express them in dependence of the acyl chain order parameters. Detailed interpretation is simplified by the observation that, to a good approximation, the interaction effects do not depend on the total CHOL concentration, but only on the local CHOL arrangement. The resulting information can be used to motivate the agglomeration of CHOL molecules, the relevance of entropic rather than enthalpic effects for understanding the stronger influence of CHOL on DPPC compared to DLiPC, or the thermodynamic background of raft formation. It is verified that the interaction functions hardly change during the transition from binary to ternary mixtures, suggesting the applicability of the concepts to more complex mixtures.