Deterministic design of peptide-membrane interactions

Antimicrobial peptides (AMPs) are present in virtually every multi-cellular organism and comprise an important component of the innate host defense system. Collectively, AMPs have broad spectrum and selective microbicidal effects. A general mechanism of AMP activity is destabilization of the physical integrity of cell plasma membranes leading to depolarization, leakage, and eventual cell death. This thesis provides a detailed molecular model how AMPs destabilize membranes specifically, based upon their fundamental structural motif: they are amphipathic and cationic. Generic electrostatic and hydrophobic interactions between a cationic, amphipathic AMP and a cell membrane lead to strong binding between the peptide and membrane and subsequent partial insertion of the peptide into the bilayer. The physical chemistry of AMPs leads to a whole taxonomy of local membrane distortions, specific combinations of which are topologically active and can lead to membrane destabilization. AMPs permeabilize model bacterial membranes but not model eukaryotic membranes by selectively generating topologically active saddle-splay ('negative Gaussian') curvature in membranes rich in negative curvature lipids and anionic lipids, compositions characteristic of bacterial cell membranes. A mechanism of action based on saddle-splay membrane curvature generation is broadly enabling, since it is a necessary condition for processes such as pore formation, blebbing, budding, vesicularization, all of which destabilize the barrier function of cell membranes. The topological requirement for saddle-splay curvature places constraints on the amino acid compositions of membrane disruptive peptides. In AMPs decreasing arginine content is offset by a simultaneous increase in lysine and hydrophobic content. This 'saddle-splay curvature design rule' is consistent with the amino acid compositions of 1,080 known cationic AMPs. Furthermore, good correspondence is observed between membrane curvature generation and the microbicidal profiles of prototypical AMPs, suggesting that curvature generation is an indicator of AMP activity. Finally, this thesis concludes with brief discussions on the possibility of other AMP design rules, as well as the presence of amphipathic domains in other curvature generating proteins which generate similar or distinct curvatures to AMPs depending on their structural motifs.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Physics

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2012

Author dc:creator

• Schmidt, Nathan

Contributors dc:contributor

• Wong, Gerard C.L.
• Schweizer, Kenneth S.
• Clegg, Robert M.

• antimicrobial peptide
• lipid membrane
• saddle-splay curvature
• membrane curvature
• amphipathic peptide
• peptide-membrane interactions

Statement dc:rights

• Copyright 2011 Nathan Schmidt

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/29632

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/29632