Translocation of a single Arg9 peptide across a DOPC/DOPG(4:1) model membrane using the weighted ensemble method

TL;DR

This study demonstrates that the weighted ensemble method enables observation of Arg9 peptide translocation across a model membrane within tens of nanoseconds, revealing detailed mechanisms and energy profiles of the process.

Contribution

The paper introduces the application of the weighted ensemble method to observe spontaneous peptide translocation in MD simulations, overcoming time scale limitations of traditional approaches.

Findings

Arg9 translocates across the membrane within tens of nanoseconds.

Water molecules and peptide orientation influence translocation.

Single Arg9 translocation is energetically unfavorable.

Abstract

It is difficult to observe a spontaneous translocation of cell-penetrating peptides(CPPs) within a short time scale (e.g., a few hundred ns) in all-atom molecular dynamics(MD) simulations because the time required for the translocation of usual CPPs is on the order of minutes or so. In this work, we report a spontaneous translocation of a single Arg$_9$(R9) across a DOPC/DOPG(4:1) model membrane within an order of a few tens ns scale by using the weighted ensemble(WE) method. We identify how water molecules and the orientation of Arg$_9$ play a role in translocation. We also show how lipid molecules are transported along with Arg$_9$. In addition, we present free energy profiles of the translocation across the membrane using umbrella sampling and show that a single Arg$_9$ translocation is energetically unfavorable. We expect that the WE method can help study interactions of CPPs with various model membranes within MD simulation approaches.