Role of arginine and lysine in the antimicrobial mechanism of histone‐derived peptides

Abstract

Antimicrobial peptides can kill microbes via various mechanisms including cell lysis or translocation and interaction with intracellular components. Understanding how particular residues affect peptide mechanisms would advance the development of improved drugs. Previous research has shown translocating ability to be promoted by increased arginine content and impaired by increased lysine content in cell‐pentetrating peptides. However, there is little research in this area on antimicrobial peptides. To this end, this study analyzed the antimicrobial mechanism of three histone‐derived peptides – buforin II, DesHDAP1 and parasin – in comparison to their R→K and K→R mutants that contained only lysine or arginine, respectfully, for their positive residues. Analogous to cell‐penetrating peptides, the antibacterial activity of these peptides increased with increased arginine content. These changes can be explained through differences in the translocating, membrane permeabilizing and DNA‐binding ability of peptides. Experimental results were reinforced with explicit molecular dynamics simulations using a 3:1 POPC:POPG membrane. This work was supported by National Institute of Allergy and Infectious Diseases (NIH/NIAID) award R15AI079685.