Free energy analyses of cell-penetrating peptides using the weighted ensemble method

TL;DR

This study employs the weighted ensemble method to analyze the free energy profiles of cell-penetrating peptides interacting with model membranes, providing insights into their translocation mechanisms.

Contribution

It demonstrates the application of the weighted ensemble method to study CPP-membrane interactions and presents free energy profiles for Arg9 and Tat peptides.

Findings

Free energy profiles of peptide penetration were obtained.

Different lipid compositions were compared.

Translocation was not observed in simulations.

Abstract

Cell-penetrating peptides (CPPs) have been widely used for drug-delivery agents; however, it has not been fully understood how they translocate across cell membranes. The Weighted Ensemble (WE) method, one of powerful and flexible path sampling techniques, can be helpful to reveal translocation paths and free energy barriers along those paths. Within the WE approach we show how Arg9 (nona-arginine) and Tat interact with a DOPC/DOPG (4:1) model membrane, and we present free energy (or potential mean of forces, PMFs) profiles of penetration, although a translocation across the membrane has not been observed in the current simulations. Two different compositions of lipid molecules were also tried and compared. Our approach can be applied to any CPPs interacting with various model membranes, and it will provide useful information regarding the transport mechanisms of CPPs.