Improved Coarse-Grained Modeling of Cholesterol-Containing Lipid Bilayers

Area of Science:

• Biophysics
• Computational Biology
• Materials Science

Background:

• Cholesterol is vital for mammalian cell function, influencing membrane structure and dynamics.
• Accurate coarse-grained (CG) models are needed to simulate cholesterol's micro- to millisecond effects on membranes.
• Existing MARTINI force-field parameters for cholesterol inaccurately represent its effects on membrane properties.

Purpose of the Study:

• To systematically optimize CG force-field parameters for cholesterol and phospholipids.
• To improve the accuracy of CG simulations for predicting membrane properties influenced by cholesterol.
• To develop a more transferable CG model for lipid-cholesterol interactions.

Main Methods:

• Reference atomistic simulations were used to guide modifications of MARTINI force-field parameters.
• Bonded parameters, particularly pseudo-bond angles and cholesterol tail representations, were systematically revised.
• Radial distribution functions and membrane properties (thickness, order) were compared between simulations and experimental data.

Main Results:

• An 'angle-corrected model' showed slight improvements but overestimated effects at high cholesterol concentrations.
• Revised representation of cholesterol's methyl groups and a finer-grained tail improved predictions of membrane thickness and lipid tail order.
• The optimized model demonstrated improved performance and generalizability in DOPC/cholesterol simulations.

Conclusions:

• Systematic parameter optimization is crucial for accurately modeling biologically important molecules like cholesterol in CG simulations.
• The developed model enhances the prediction of cholesterol's impact on membrane biophysical properties.
• Improved CG models are essential for advancing our understanding of cholesterol trafficking and cellular membrane dynamics.