Molecular Insights into Pore Formation Mechanism, Membrane Perturbation, and Water Permeation by the Antimicrobial Peptide Pleurocidin: A Combined All-Atom and Coarse-Grained Molecular Dynamics Simulation Study.

The antimicrobial peptide (AMP) pleurocidin has a broad antimicrobial activity against Gram-negative and Gram-positive bacteria by perturbation and permeabilizing their membranes; however, understanding the mechanism of action of pleurocidin, a promising AMP for replacing current antibiotic agents, has tremendous importance for future applications. Hence, we applied all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations to provide molecular-level insights into the pore-forming process. The early stages of pore formation were examined by 500 ns AA simulations. The results demonstrated that pleurocidin has the ability to create a pore with two peptides through which water molecules can flow. However, the results of the 25 μs CG simulations indicate that the final pore will be created by accumulation of more than two peptides. The results show that after 2.5 μs of simulations, peptides will aggregate and create a channel-like pore across the membrane. Pleurocidin can construct a more efficient and stable pore in the anionic membranes than in the zwitterionic membranes. Moreover, the structure amphipathicity, polarity, and basic residues play crucial roles in the pore formation and flow of water molecules across the lipid bilayers. In general, the findings revealed that based on the lipid compositions of the membranes, pleurocidin could act by forming either toroidal or disordered toroidal pores with different peptide arrangements.