Antimicrobial Peptide-Membrane Interactions: Insights from Molecular Simulations

Abstract

Antimicrobial peptides (AMPs) are found in the innate immune systems of most living organisms. These peptides exhibit cell selectivity, and activity against a broad spectrum of microorganisms, making them promising candidates as antimicrobial biomaterials. The AMPs are anchored with polymer tethers and biologically synthesized as functionalized biomaterials. We successfully prepared LL-37 conjugated biopolymer materials with antimicrobial activity, which switch to micelles at temperatures between 27-30 oC. Understanding the peptide-membrane interactions represents the basis for AMP's selectivity for bacterial cell membranes. We hypothesized that peptide insertion is assisted by membrane curvature. Models of a gram-negative bacterial outer membrane comprising POPE/DMPG/CL (90:5:5) and a membrane with the composition DMPC/DMPG/CL (90:5:5) were investigated using molecular dynamics simulations. The antimicrobial peptide LL-37 was arranged on the surface of the membranes as “carpets” of ordered peptides. We also performed all-atom molecular dynamics simulations using NAMD 2.13 to visualize the carpet-to-barrel or toroidal-pore transition. To determine the energetically favorable model, the non-bonded interactions between the carpet and pore models were compared using the NAMD energy. From our in-silico observations, the pore model is more favorable than the carpet model for the same peptide/lipid ratio. Critical values of the peptide/lipid ratio required for cell penetration were investigated to determine the rate of peptide insertion into the membrane with different LL-37 concentrations. From the simulation timescale (in microseconds), as the peptide/lipid ratio increased, partial insertion and membrane curvature were observed in the bacterial mimic model. Further, the C-terminal helix of LL-37 was observed to unfold when interacting with phosphate head groups of the lipids. The propensity for AMPs to insert into the lipid bilayer via the N-terminus or C-terminus was similar. These observations from molecular dynamics simulations provide a basis for designing more advanced functionalized antimicrobial-biomaterials.