BPS2026 – Modeling lipopolysaccharides with Martini 3: A transferable framework for bacterial outer membranes

Lipopolysaccharides (LPS) are essential components of the gram-negative bacterial outer membrane (OM), where they maintain structural integrity and mediate environmental and host interactions. All-atom molecular dynamics (AA-MD) simulations capture LPS behavior at atomic resolution but are limited in accessing biologically relevant length and timescales. To overcome this, we developed transferable coarse-grained (CG) parameters for LPS within the Martini 3 framework. Using the Bartender tool, we parameterized ∼60 unique disaccharide units, which were combined and manually refined to construct complete LPS molecules from multiple clinically important pathogens, including Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , and Salmonella enterica . We then carried out extensive AA and CG simulations of asymmetric bilayers composed of phospholipids in the inner leaflet and LPS in the outer leaflet, enabling direct validation across multiple scales. Comparisons included O-antigen tilt, end-to-end extension, density distributions, membrane thickness, and area per LPS. The CG simulations, performed up to 50 μs per system, showed close agreement with AA benchmarks, confirming that the new parameter set robustly reproduces key structural and dynamic properties. This framework provides a powerful platform for probing LPS-mediated membrane mechanics, bacterial defense mechanisms, and interactions with antibiotics or host immune factors at biologically relevant scales.