title: Criterion for amino acid composition of defensins and antimicrobial peptides based on geometry of membrane destabilization.
abstract: Defensins comprise a potent class of membrane disruptive antimicrobial peptides (AMPs) with well-characterized broad spectrum and selective microbicidal effects. By using high-resolution synchrotron small-angle X-ray scattering to investigate interactions between heterogeneous membranes and members of the defensin subfamilies, α-defensins (Crp-4), β-defensins (HBD-2, HBD-3), and θ-defensins (RTD-1, BTD-7), we show how these peptides all permeabilize model bacterial membranes but not model eukaryotic membranes: defensins selectively generate saddle-splay ("negative Gaussian") membrane curvature in model membranes rich in negative curvature lipids such as those with phosphoethanolamine (PE) headgroups. These results are shown to be consistent with vesicle leakage assays. A mechanism of action based on saddle-splay membrane curvature generation is broadly enabling, because it is a necessary condition for processes such as pore formation, blebbing, budding, and vesicularization, all of which destabilize the barrier function of cell membranes. Importantly, saddle-splay membrane curvature generation places constraints on the amino acid composition of membrane disruptive peptides. For example, we show that the requirement for generating saddle-splay curvature implies that a decrease in arginine content in an AMP can be offset by an increase in both lysine and hydrophobic content. This "design rule" is consistent with the amino acid compositions of 1080 known cationic AMPs.
authors.affiliation: Department of Physics, University of Illinois, Urbana-Champaign, Illinois 61801, USA.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mishra
authors.forename: Ghee Hwee
authors.initials: GH
authors.lastname: Lai
authors.forename: Matthew
authors.initials: M
authors.lastname: Davis
authors.forename: Lori K
authors.initials: LK
authors.lastname: Sanders
authors.forename: Dat
authors.initials: D
authors.lastname: Tran
authors.forename: Angie
authors.initials: A
authors.lastname: Garcia
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Tai
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.forename: André J
authors.initials: AJ
authors.lastname: Ouellette
authors.forename: Michael E
authors.initials: ME
authors.lastname: Selsted
authors.forename: Gerard C L
authors.initials: GC
authors.lastname: Wong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001419:Bacteria / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002463:Cell Membrane Permeability; D023082:Defensins / Q000737:chemistry / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: D023082:Defensins; D008081:Liposomes; D001120:Arginine