Multiscale Coarse-Graining of Mixed Phospholipid/Cholesterol Bilayers

Area of Science:

• Biophysics
• Computational Chemistry
• Materials Science

Background:

• Coarse-grained (CG) models are essential for simulating large biological systems like lipid bilayers.
• Accurate CG models require systematic parameterization against high-fidelity simulations.
• Simulating mixed lipid bilayers, particularly those with cholesterol, presents significant challenges.

Purpose of the Study:

• To develop and validate multiscale coarse-graining (MS-CG) models for dimyristoylphosphatidylcholine (DMPC)/cholesterol lipid bilayers.
• To explore different coarse-graining strategies for cholesterol representation.
• To ensure the developed CG models accurately reproduce structural properties observed in all-atom molecular dynamics (MD) simulations.

Main Methods:

• Utilized the multiscale coarse-graining (MS-CG) method for systematic parameterization.
• Derived model parameters from reference all-atom molecular dynamics (MD) simulations of DMPC/cholesterol bilayers.
• Developed CG models with varying numbers of sites for cholesterol (four-site and seven-site) and a one-site model for TIP3P water.
• Performed constant NPT ensemble simulations using the developed MS-CG models.

Main Results:

• Successfully constructed MS-CG models for DMPC/cholesterol lipid bilayers.
• The MS-CG method enabled accurate fitting of bonded/nonbonded interactions and system pressure.
• Models with different cholesterol representations were developed and validated.
• Simulations using the MS-CG models accurately reproduced structural properties seen in all-atom MD simulations.

Conclusions:

• The MS-CG method provides a robust framework for developing accurate CG models of complex lipid bilayers.
• The developed models offer a computationally efficient way to study DMPC/cholesterol bilayers while maintaining high structural fidelity.
• These CG models are suitable for large-scale simulations of biological membranes containing cholesterol.