The role of molecular simulations in understanding the mechanisms of cell-penetrating peptides

Cell-penetrating peptides (CPPs) offer an exciting approach to tackle the pharmacokinetic challenges associated with the delivery of large, polar molecules to intracellular targets. Since the discovery of the first CPPs in the early 1990s, vast amounts of research have been undertaken to characterise their cellular uptake mechanisms. Despite this, the precise mechanisms of cellular internalisation of many CPPs remain elusive owing to inconsistent experimental results. Molecular dynamics (MD) simulations provide an approach to probe specific aspects of the internalisation process and many published CPP studies have incorporated simulation data. This review provides a critical evaluation of the current approaches that are being used to simulate CPPs interacting with artificial lipid bilayers.