Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 133, Issue 17, Pages 6720-6727Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja200079a
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Funding
- DOE [DE-AC02-06CH11357]
- NIH [R01DK-044632, R01AI059346, R37AI022931, RO1AI058129, RO1DE15517, P50 HL-61234, P01 HL-091842, 1UO1 AI082192-01]
- Roy J. Carver Charitable Trust
- NSF [DMR-0409769]
- Direct For Mathematical & Physical Scien [1019626] Funding Source: National Science Foundation
- Division Of Materials Research [1019626] Funding Source: National Science Foundation
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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, alpha-defensins (Crp-4), beta-defensins (HBD-2, HBD-3), and theta-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.
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