Aggregation of Lipid A Variants: A Hybrid Particle-Field Model.

Lipid A is one of the three components of bacterial lipopolysaccharides constituting the outer membrane of Gram-negative bacteria, and is recognized to have an important biological role in the inflammatory response of mammalians. Its biological activity is modulated by the number of acyl-chains that are present in the lipid and by the dielectric medium, i.e., the type of counter-ions, through electrostatic interactions. In this paper, we report on a coarse-grained model of chemical variants of Lipid A based on the hybrid particle-field/molecular dynamics approach (hPF-MD). In particular, we investigate the stability of Lipid A bilayers for two different hexa- and tetra-acylated structures. Comparing particle density profiles along bilayer cross-sections, we find good agreement between the hPF-MD model and reference all-atom simulation for both chemical variants of Lipid A. hPF-MD models of constituted bilayers composed by hexa-acylated Lipid A in water are stable within the simulation time. We further validate our model by verifying that the phase behavior of Lipid A/counterion/water mixtures is correctly reproduced. In particular, hPF-MD simulations predict the correct self-assembly of different lamellar and micellar phases from an initially random distribution of Lipid A molecules with counterions in water. Finally, it is possible to observe the spontaneous formation and stability of Lipid A vesicles by fusion of micellar aggregates.