Molecular simulations suggest how a branched antimicrobial peptide perturbs a bacterial membrane and enhances permeability.

A covalently, branched antimicrobial peptide (BAMP) B2088 demonstrating enhanced antimicrobial effects and without additional toxicity when compared to its linear counterpart, has been developed. Atomistic molecular dynamics simulations have been used to investigate the mode of interaction of B2088 with model bacterial and mammalian membranes. These simulations suggest that both long-range electrostatic interactions and short-range hydrogen bonding play important roles in steering B2088 toward the negatively charged membranes. The reason why B2088 is selective towards the bacterial membrane is postulated to be the greater density of negative charges on the bacterial membrane which enables rapid accumulation of B2088 on the bacterial membrane to a high surface concentration, stabilizing it through excess hydrogen bond formation. The majority of hydrogen bonds are seen between the side chains of the basic residues (Arg or Lys) with the PO4 groups of lipids. In particular, formation of the bidentate hydrogen bonds between the guanidinium group of Arg and PO4 groups are found to be more favorable, both geometrically and energetically. Moreover, the planar gaunidinium group and its hydrophobic character enable the Arg side chains to solvate into the hydrophobic membrane. Structural perturbation of the bacterial membrane is found to be concentration dependent and is significant at higher concentrations of B2088, resulting in a large number of water translocations across the bacterial membrane. These simulations enhance our understanding of the action mechanism of a covalently branched antimicrobial peptide with model membranes and provide practical guidance for the design of new antimicrobial peptides.