Melittin vs E.coli: Insights from Molecular Dynamics Simulations

Abstract

The interactions of antimicrobial peptides with eukaryotic cell membranes have been well-studied by experimental and computational methods. However, the molecular-level interactions of these peptides with Gram-negative bacteria such as E.coli are more difficult to study, largely due to the complex nature of the asymmetric outer membrane of Gram-negative bacteria. While cell lysis is thought to proceed via destruction of the inner membrane, it is the outer membrane that is the first barrier encountered by antimicrobial peptides as they attempt to reach their target site.In the present work, we employ atomistic molecular dynamics simulations to study the interaction of melittin, the major component of honey bee toxin, with detailed models of the E.coli outer membrane. Experimental data (ref), has indicated that upon interaction, melittin induces reorganisation of the lipopolysaccharide (LPS) component of the bacterial outer membrane. We have simulated multiple copies of melittin in lipid bilayers composed of varying depths of LPS in the outer leaflet, and realistic mixtures of phospholipids in the inner leaflet. Our simulations reveal details of the melittin-outer membrane recognition process and the structural stability and dynamics of melittin as it interacts with the outer membrane. Furthermore, our simulations provide specific, molecular-level details of the interaction of melittin with the E.coli outer membrane that may aid the future design of novel antimicrobial agents.