Reassessing DMSO-lipid interactions: Improved AMBER force fields emphasize solvent rather than bilayer effects in...

Area of Science:

• Biophysics
• Computational Chemistry

Background:

• Dimethyl sulfoxide (DMSO) is a common cryoprotectant, but its interaction with lipid membranes at low concentrations remains debated.
• Previous molecular dynamics (MD) simulations showed discrepancies with experimental findings regarding DMSO's effects on membrane structure.

Purpose of the Study:

• To re-evaluate the effects of low DMSO concentrations (1.5-10 vol%) on dimyristoyl phosphatidylcholine (DMPC) membranes using updated force fields.
• To assess DMSO's cryoprotective role by simulating its behavior in fluid, gel, and ice-forming conditions.

Main Methods:

• Molecular dynamics (MD) simulations using updated AMBER force fields (LIPID17, OPC, GAFF2).
• Simulations conducted at various temperatures (330K, 260K) and under ice-forming conditions.
• Analysis of membrane properties including thickness, area per lipid, hydration, and acyl-chain order.

Main Results:

• No statistically significant changes in DMPC membrane structure (thickness, area per lipid, hydration, order) were detected at low DMSO concentrations.
• DMSO showed mild enrichment at the lipid-water interface but remained mostly in the solvent.
• DMSO significantly slowed ice crystal growth (by ~5x), was excluded from ice, and formed an ice-free layer at the ice-membrane boundary.
• Ice formation in contact with the bilayer did not cause structural disruption, even without DMSO.
• DMSO inhibited temperature-driven variations in amorphous water density.

Conclusions:

• Low concentrations of DMSO do not perturb lipid bilayer structure, aligning with experimental observations.
• DMSO's cryoprotective mechanism at low concentrations is primarily due to its influence on water and ice behavior.
• Cryoinjury may involve factors beyond direct lipid membrane disruption by ice.