Martini 3 as a Transferable Force Field for Lipopolysaccharide Parametrization

Lipopolysaccharides (LPS), as critical components of the outer membrane (OM) of Gram-negative bacteria, play essential roles in maintaining bacterial integrity and mediating environmental interactions. All-atom molecular dynamics (AA-MD) simulations provide detailed insights into LPS behavior at atomic resolution, but they remain computationally limited in accessing biologically relevant time scales. Coarse-grained (CG) models, such as Martini 3, offer a computationally efficient alternative while retaining sufficient accuracy for key biophysical properties. Although Martini 3 has been widely applied to proteins and phospholipids, only a few LPS models have been developed within this framework, limiting its utility for bacterial OM studies. To address this gap, we developed and validated CG parameters for LPS from multiple medically relevant pathogens, including Escherichia coli and Salmonella enterica, as well as two ESKAPE pathogens, Klebsiella pneumoniae and Pseudomonas aeruginosa. Our approach leverages the transferability of Martini parameters: we parametrized 57 unique disaccharide units using the Bartender tool, which automates CG-to-AA mapping and parametrization. These parameters were then combined and manually refined to accurately reproduce the complex dynamics of complete LPS molecules. We conducted extensive AA and CG simulations of asymmetric bilayers composed of phospholipids in the inner leaflet and LPS in the outer leaflet allowing detailed comparisons between the two for key structural and dynamic properties. The close agreement between the CG and AA simulations demonstrates the accuracy and robustness of our transferable parameter set, providing a valuable tool for simulating Gram-negative bacterial OMs at larger scales and longer time scales.