EVALUATING MARTINI 2 AND MARTINI 3 FORCE FIELDS FOR LIPOPOLYSACCHARIDES AGGREGATES

Lipopolysaccharides (LPSs) are the major components of outer membranes (OM) of Gram-negative bacteria where they act as the first molecular barrier against the host cell defense system, antibiotics, and xenobiotic agents. The structure of a rough LPS molecule is formed by two main domains: a backbone called Lipid-A that contains a variable number of fatty acids, and a long polysaccharide chain organized into inner and outer cores. As an amphiphilic molecule, the LPSs can self-aggregate as micelles and assembly with phospholipids forming outer membrane vesicles (OMV) in aqueous solution. The aggregation and the dynamical behavior of these LPS aggregates in solution can be reproduced in molecular dynamics (MD) simulations using coarse grained (CG) force fields (FFs) that provide the sampling of large spatial and temporal scales. The Martini 2 is an example of a CG FF for building models of these complex membranes, which is available in the CHARMM-GUI Martini Maker. Recently, a new version of this FF, Martini 3, was developed and reported for bacterial OM. This update version is a substantial reformulation of the Martini FF since it improved the chemical specificity, hydration pattern, polarity description, dynamical properties, and the beads’ interactions. However, the potential of the Martini 3 FF for describing other LPS aggregates, such as OMV and micelles, remains still underexplored. In this context, this study aims to compare the use of Martini 2 and Martini 3 FFs for simulating and calculating structural and dynamical properties of LPS aggregates in aqueous solution. The MD simulations demonstrated that the LPS aggregates built with Martini 3 FF provided a better description of structural properties, including area per lipid, thickness, radius of gyration, and roundness in agreement with experimental data. The modulation of the water bead size also improved the description of both water permeation and solvation structure of these aggregates. These preliminary results reinforce the applicability of the Martini 3 FF for simulating complex LPS assemblies and highlight the need to integrate these updated models in the automatic tool of the CHARMM-GUI Martini Maker.

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Processo n°2023/02556-8.