Molecular dynamics simulations of bacterial outer membrane lipid extraction: Adequate sampling?

Area of Science:

• Biophysics
• Computational Biology
• Microbiology

Background:

• Gram-negative bacteria outer membranes feature lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner leaflet.
• Lipopolysaccharide exhibits significantly slower diffusion than phospholipids, posing challenges for molecular dynamics simulations and adequate sampling.

Purpose of the Study:

• To evaluate simulation protocols for achieving convergence in lipopolysaccharide membrane simulations with the MARTINI coarse-grained force field.
• To assess methods for potential of mean force (PMF) calculations of lipid extraction and lateral mixing within the membrane phase.

Main Methods:

• Utilized the MARTINI coarse-grained force field for molecular dynamics simulations.
• Performed potential of mean force (PMF) calculations for lipid extraction.
• Investigated lateral mixing and sorting of lipopolysaccharide within model membranes.
• Employed Hamiltonian replica exchange for enhanced sampling.

Main Results:

• Decoupling cations cross-linking LPS headgroups during PMF calculations yielded convergence comparable to phospholipid extraction.
• Lateral mixing and sorting of lipopolysaccharide were observed to be very slow processes.
• Observed slow mixing rates were not readily improved even with Hamiltonian replica exchange.

Conclusions:

• Optimized protocols involving cation decoupling enhance the simulation of LPS extraction from membranes.
• The slow lateral diffusion of LPS limits the study of its mixing dynamics on microsecond timescales.
• Future studies should consider longer simulation times or alternative methods to address LPS lateral organization.