Modeling the Interactions of Antimicrobial Peptides with Cell Membranes

Abstract

Antimicrobial peptides (AMPs) are key molecules of the innate immune system, found among a wide variety of living organisms, including animals, plants, and humans. It is typically composed of cationic and has a unique property known as cell selectivity: It has a stronger affinity toward bacterial membranes, which contain a large fraction of anionic lipids; in contrast, the outer layer of eukaryotic cell membranes consists electrically neutral. This distinctive characteristic causes peptide selectivity toward bacterial cells over the host cells, allowing AMPs to bind and rupture bacterial membranes preferentially. Optimized AMPs are thus considered novel candidates for the next generation of antibiotics. Despite its significance, the detailed picture of how their interactions with cell membranes influence peptide selectivity still remains unclear. The work in this thesis is aimed at gaining a deeper understanding of how AMPs interact with and permeabilize cell membranes from a theoretical perspective. First, we investigate the cell-density dependence of peptide activity and selectivity. In particular, we examine how the presence of host cells is implicated in peptide activity and selectivity. Second, we explore the effects of salt ions on the interactions of AMPs with cell membranes and their impacts on peptide activity and selectivity. Last, we examine the interactions between the outer bacterial membranes, especially the lipopolysaccharide (LPS) layer, against AMPs. To this end, we view LPS molecules as forming a polymer brush grafted to a charged surface and clarify the relative significance of various factors such as brush-peptide interactions, the electrostatic interactions between peptides and LPS headgroups, and brush lengths. Through this thesis, we introduced biophysical models for describing the interactions of AMPs with cell membranes and quantified the activity and selectivity under various biologically-relevant conditions. Additional efforts related to the work carried out in this thesis will be beneficial in searching for ideal AMPs as therapeutic agents.