Antimicrobial peptides and induced membrane curvature: Geometry, coordination chemistry, and molecular engineering

Abstract

Short cationic, amphipathic antimicrobial peptides are multi-functional molecules that have roles in host defense as direct microbicides and modulators of the immune response. While a general mechanism of microbicidal activity involves the selective disruption and permeabilization of cell membranes, the relationships between peptide sequence and membrane activity are still under investigation. Here, we review the diverse functions that AMPs collectively have in host defense, and show that these functions can be multiplexed with a membrane mechanism of activity derived from the generation of negative Gaussian membrane curvature. As AMPs preferentially generate this curvature in model bacterial cell membranes, the selective generation of negative Gaussian curvature provides AMPs with a broad mechanism to target microbial membranes. The amino acid constraints placed on AMPs by the geometric requirement to induce negative Gaussian curvature are consistent with known AMP sequences. This ‘saddle-splay curvature selection rule’ is not strongly restrictive so AMPs have significant compositional freedom to multiplex membrane activity with other useful functions. The observation that certain proteins involved in cellular processes which require negative Gaussian curvature contain domains with similar motifs as AMPs, suggests this rule may be applicable to other curvature-generating proteins. Since our saddle-splay curvature design rule is based upon both a mechanism of activity and the existing motifs of natural AMPs, we believe it will assist the development of synthetic antimicrobials.

Hydrophobic Surfactant Proteins Strongly Induce Negative Curvature

“…The structures formed by lipids with spontaneous curvature are determined by the balance between the energies of bending and chain packing (47,48). Several peptides with amphipathic helices, including both the combined surfactant proteins (37) and isolated SP-B (36), convert lamellar lipids to Q II phases (49,50). Other peptides with similar helical elements lower the temperature of the lamellar-to-H II transition (6,11,49,51,52).…”

The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage

“…By use of engineered LUVs, we found that GA is able to lyse both negatively charged and zwitterionic liposomes with similar specific activity, a property not shared with naturally occurring cathelidicins (39,54). However, compared with the activity of other engineered antimicrobial peptides such as novicidin (25), GA is only moderately effective and on a per-mg basis approximately 10-fold less active than α-synuclein, which is a confirmed cytolytic protein (55).…”

Gaussian curvature directs the distribution of spontaneous curvature on bilayer membrane necks

“…Furthermore, the formation of necks is a critical step in the interaction of toxins and viral fusion proteins with cellular membranes [6][7][8][9] . These structures are also observed in synthetic membrane systems such as in giant unilamellar vesicles subject to osmotic stress [10][11][12] , lipid heterogeneities 13,14 , protein insertion or crowding 15,16 , and membrane-substrate interactions 17 .…”