Molecular characterization of the outer membrane of Pseudomonas aeruginosa

Discovery of new antibiotics effective against Gram-negative bacteria is hampered by the low permeability of the bacterial two-membrane cell envelopes. The outer membrane (OM) is an asymmetric bilayer of lipopolysaccharides (LPS) and phospholipids and is a significant permeability barrier to noxious compounds. Molecular characterization of the OM is essential for understanding how antibiotics penetrate this barrier, and for the development of new therapeutic strategies and rational drug design. We carry out all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations to characterize the fully assembled OM bilayer of Pseudomonas aeruginosa, a human pathogen resistant to most clinical antibiotics. These simulations were run using AA and CG parameters that we developed to model the most abundant LPS of P. aeruginosa, specifically the A band O-antigen. Our simulations reproduce several experimentally determined physical properties such as area per lipid, membrane stiffness and increased stability due to the interaction with divalent cations. These tested parameters allowed us to study various OM properties including the effect of divalent cations and OM electroporation. In addition, the massive and extended carbohydrate head groups increase water permeation, which propagates towards the aliphatic tails of the inner leaflet. This effect contributes to the low ordering of the lipids in the inner leaflet. Further, evaluation is needed to understand whether the increased solvation of outer membrane could modulate permeation of highly polar drugs. [Display omitted]