Driving engineering of novel antimicrobial peptides from simulations of peptide–micelle interactions

Abstract

Simulations of antimicrobial peptides in membrane mimics can provide the high resolution, atomistic picture that is necessary to decipher which sequence and structure components are responsible for activity and toxicity. With such detailed insight, engineering new sequences that are active but non-toxic can, in principle, be rationalized. Armed with supercomputers and accurate force fields for biomolecular interactions, we can now investigate phenomena that span hundreds of nanoseconds. Although the phenomena involved in antimicrobial activity, (i.e., diffusion of peptides, interaction with lipid layers, secondary structure attainment, possible surface aggregation, possible formation of pores, and destruction of the lipid layer integrity) collectively span time scales still prohibitively long for classical mechanics simulations, it is now feasible to investigate the initial approach of single peptides and their interaction with membrane mimics. In this article, we discuss the promise and the challenges of widely used models and detail our recent work on peptide-micelle simulations as an attractive alternative to peptide-bilayer simulations. We detail our results with two large structural classes of peptides, helical and beta-sheet and demonstrate how simulations can assist in engineering of novel antimicrobials with therapeutic potential.

Binding modes of protegrin-1, a beta-strand antimicrobial peptide, in lipid bilayers

“…To date, only a small number of MD simulation studies have been performed on the interactions of PG-1 with lipid membranes [30,32,33]. Langham et al [30] performed simulations of PG-1 with sodium-dodecyl-sulfate (SDS) and dodecyl-phospho-choline (DPC) micelles.…”

“…Most of these simulations have focused on the alpha-helical class of AMPs such as magainins and its derivatives, ovispirins, etc. To date, very few studies have focused on beta-strand peptides such as protegrins [30,32,33].…”

Multiscale models of antibiotic probiotics

“…Atomistic molecular dynamics simulations of PG-1 have been conducted in lipid micelles and lipid bilayers as membrane mimics [13-18]. Nowadays bilayers with more than 500 lipid molecules can be modeled, and with realistic bacterial membrane-like compositions.…”

Study of the antimicrobial peptide indolicidin and a mutant in micelle medium by molecular dynamics simulation

“…Micelles were used instead of bilayers so that comparisons with experimental data could be made. Another fact that must be taken into account is that the dynamics of micelles is faster than the dynamics of membranes, so simulation convergence is reached with lower computational cost (Khandelia et al, 2006). The aim of the present study was to observe whether the molecular dynamics and experimental data are sufficiently correlated, so that a detailed description of the interaction of the antimicrobial peptide IND and CP10A with a model of the zwitterionic interface provided by a hydrated micelle system could be obtained.…”