title: Characterization of a potent antimicrobial lipopeptide via coarse-grained molecular dynamics.
abstract: The prevalence of antibiotic-resistant pathogens is a major medical concern, prompting increased interest in the development of novel antimicrobial compounds. One such set of naturally occurring compounds, known as antimicrobial peptides (AMPs), have broad-spectrum activity, but come with many limitations for clinical use. Recent work has resulted in a set of antimicrobial lipopeptides (AMLPs) with micromolar minimum inhibitory concentrations and excellent selectivity for bacterial membranes. To characterize a potent, synthetic lipopeptide, C16-KGGK, we used multi-microsecond coarse-grained simulations with the MARTINI forcefield, with a total simulation time of nearly 46μs. These simulations show rapid binding of C16-KGGK, which forms micelles in solution, to model bacterial lipid bilayers. Furthermore, upon binding to the surface of the bilayer, these lipopeptides alter the local lipid organization by recruiting negatively charged POPG lipids to the site of binding. It is likely that this drastic reorganization of the bilayer has major effects on bilayer dynamics and cellular processes that depend on specific bilayer compositions. By contrast, the simulations revealed no association between the lipopeptides and model mammalian bilayers. These simulations provide biophysical insights into lipopeptide selectivity and suggest a possible mechanism for antimicrobial action. This article is part of a Special Issue entitled: Membrane protein structure and function.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Ave, Box 712, Rochester, NY 14642, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Horn
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Sengillo
authors.forename: Dejun
authors.initials: D
authors.lastname: Lin
authors.forename: Tod D
authors.initials: TD
authors.lastname: Romo
authors.forename: Alan
authors.initials: A
authors.lastname: Grossfield
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D055666:Lipopeptides / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation
chemical_list: D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D055666:Lipopeptides