Molecular Electroporation and the Transduction of Oligoarginines

TL;DR

This paper proposes a molecular electroporation model explaining how cell-penetrating peptides like polyarginine transduce into cells, supported by experimental data and offering testable predictions for the mechanism.

Contribution

It introduces a simple, testable model of CPP transduction based on molecular electroporation involving phosphatidylserines and CPPs.

Findings

Transduction depends on arginine number and CPP concentration.

Model aligns with empirical cargo size limits.

Predicts three testable outcomes.

Abstract

Certain short polycations, such as TAT and polyarginine, rapidly pass through the plasma membranes of mammalian cells by an unknown mechanism called transduction as well as by endocytosis and macropinocytosis. These cell-penetrating peptides (CPPs) promise to be medically useful when fused to biologically active peptides. I offer a simple model in which one or more CPPs and the phosphatidylserines of the inner leaflet form a kind of capacitor with a voltage in excess of 180 mV, high enough to create a molecular electropore. The model is consistent with an empirical upper limit on the cargo peptide of 40--60 amino acids and with experimental data on how the transduction of a polyarginine-fluorophore into mouse C2C12 myoblasts depends on the number of arginines in the CPP and on the CPP concentration. The model makes three testable predictions.