Antimicrobial and Cell-Penetrating Peptides: Structure, Assembly and Mechanisms of Membrane Lysis via Atomistic and Coarse-Grained Molecular Dynamic Simulations

Antimicrobial peptides (AMPs) are short, cationic, membrane-interacting proteins that exhibit broad-spectrum antimicrobial activity, and are hence of significant biomedical interest. They exert their activity by selectively binding to and lysing target cell membranes, but the precise molecular details of their mechanism are not known. This is further complicated by the fact that their structural characteristics are dependent upon the local lipid environment. As a result, molecular dynamics (MD) simulations have been applied to understand the conformation and mechanism of AMPs, as well as related viral and cell-penetrating peptides. In particular, atomically detailed MD simulation studies on the timescale of tens to hundreds of nanoseconds have successfully helped to: (i) model or refine the conformation of AMPs and their aggregates in the presence of membrane-mimicking solvent mixtures, detergent micelles, and lipid bilayers; (ii) follow the process of adsorption of individual AMPs to membrane surfaces; and (iii) observe the spontaneous assembly of multiple peptides and subsequent cooperative membrane lysis. More recently, coarse-grained (CG) models have been developed to extend the time and length scales accessible to simulations of membrane/peptide systems. CG simulations on the order of microseconds have provided insight into AMP lytic mechanisms, and how they depend upon such factors as peptide concentration, lipid composition, and bilayer curvature. These studies have been supplemented by combined atomistic/CG and integrated multiscale models. Together, simulations have deepened our understanding of the interactions between AMPs and biological membranes, and will help to design new synthetic peptides with enhanced biomedical potential.