Multiscale models of antimicrobial peptides.

Abstract

Antimicrobial peptides (AMPs) are small proteins that constitute a first line of defense against invading pathogens in the innate immune systems of countless plant and animal species. Their mechanism of action relies to a large extent on selectively disrupting the cell membranes of bacteria, which makes them promising therapeutic agents in the fight against infectious pathogens, including antibiotic-resistant bacterial strains. However, AMPs also exhibit toxicity towards mammalian cells, which presents a significant bottleneck in the development of AMPs for antibiotic treatment in humans. Thus, before the full potential of AMPs as therapeutic agents can be unlocked, their fundamental mechanism of action must be understood in order to identify targets for mutation that can improve activity and ameliorate toxic effects. To this end, we carry out computer simulations and modeling studies in order to understand the interactions of protegrin, a particularly potent and well-studied AMP, with lipid bilayers that mimic the compositions of bacterial and mammalian cell membranes. In particular, we attempt to connect molecular-level thermodynamic information to biologically relevant membrane association equilibria; we elucidate the ion transport characteristics of protegrin pores, and show how the atomistic structure leads to experimentally observed conductance behavior; we provide multi-scale models that can quantitatively link the structure of protegrin and protegrin pores to the leakage of potassium ions from bacterial cells, which appears to be an essential element in the bactericidal mechanism of action of protegrin; finally, we investigate the structure of protegrin pores using molecular dynamics simulations with atomistic resolution. Our work reveals this link for the first time, and provides a united, quantitative connection between molecular-level structural and thermodynamic information and mesoscopic, measurable quantities. Our modeling tools can be easily extended to other AMPs, and protein-membrane systems in general.