Concerted Rolling and Membrane Penetration Revealed by Atomistic Simulations of Antimicrobial Peptides

TL;DR

This study uses atomistic simulations and Markov State Modeling to elucidate the detailed membrane insertion mechanism of antimicrobial peptides, revealing the dynamic rolling process as a key kinetic step.

Contribution

It introduces a physics-based simulation approach to quantify peptide-membrane interactions, advancing understanding beyond data-driven prediction methods.

Findings

Membrane insertion involves a dynamic rolling process.

Simulation reveals the kinetics of peptide binding and insertion.

Provides detailed mechanistic insights into peptide-membrane interactions.

Abstract

Short peptides with antimicrobial activity have therapeutic potential for treating bacterial infections. Mechanisms of actions for antimicrobial peptides require binding the biological membrane of their target, which often represents a key mechanistic step. A multitude of data-driven approaches have been developed to predict potential antimicrobial peptide sequences; however, these methods are usually agnostic to the physical interactions between the peptide and the membrane. Towards developing higher throughput screening methodologies, here we use Markov State Modeling and all-atom molecular dynamics simulations to quantify the membrane binding and insertion kinetics of three prototypical and antimicrobial peptides (alpha-helical magainin 2 and PGLa and beta-hairpin tachyplesin 1). By leveraging a set of collective variables that capture the essential physics of the amphiphilic and cationic peptide-membrane interactions we reveal how the slowest kinetic process of membrane insertion is the dynamic rolling of the peptide from a prebound to fully inserted state. These results add critical details to how antimicrobial peptides insert into bacterial membranes.