Using Molecular Dynamics Simulations to Characterize the Role Played by Basic Residues in Interactions of HDAPs and Bacterial Lipid Membranes

Abstract

Antimicrobial peptides are small, cationic peptides that induce bacterial cell death via cell lysis or interactions with intracellular components. Currently, with growing bacterial resistance to existing antimicrobial drugs there is an urgent need to study the potentcy of antimicrobial peptides and find ways to improve their activity. Most AMPs include positively charged amino acids that allow binding to negatively-charged bacterial membranes. Previous studies have shown that an increased composition of arginine versus lysine enhances the activity of two histone-derived antimicrobial peptides (HDAPs), buforin II (BF2) and DesHDAP1. Variants of these peptides with all basic residues modified to arginine had increased antibacterial activity and membrane translocation but unchanged membrane permeabilization. In this study, we use molecular dynamics simulations to study how the arginine-modified peptides interact with model bacterial lipid membranes (1:3 POPG:POPE) differently than wild-type and lysine-modified peptides. Simulations were performed with one and four peptides for wild type BF2 (BF2wt), arginine-modified BF2 (BF2R), and lysine-modified BF2 (BF2K). The results of 100ns simulations of each system show that BF2R has increased interactions with the lipid membrane and structural stability compared to the other peptides. The analysis of hydrogen bonding per lipids supports that anionic POPG lipids interact more with the peptides than zwitterionic POPE lipids, further emphasizing the role of the basic residues. Analogous simulations considering the lipid interactions of DesHDAP1 and its arginine and lysine mutants are ongoing. Our findings elucidate mechanistic details of peptide-lipid interactions that will become helpful in the development of AMPs with improved activity.