Molecular mechanism of translocation and design of cell penetrating peptides based on molecular dynamics simulation

The lack of cell specificity of cell penetrating peptides(CPPs) remains a major issue for their clinical application. To successfully design disease targeting CPPs, it is necessary to improve our understanding of the molecular mechanism of membrane translocation of CPPs and locate the key factors that affect this mechanism. Molecular dynamics simulations have been proven to be a valuable tool to study the molecular mechanism of membrane penetration by small peptides. Molecular dynamics simulations have mainly been used to study the translocation process, including structural properties of transition states, free energy profiles, and the effect of cell membrane peptide sequence/structure variation on possible molecular mechanisms and delivery efficiency. With the development of enhanced sampling techniques, it is possible to obtain translocation free energy and possible transition pathways from one continuous simulation. Hence, molecular dynamics simulations will provide in depth mechanistic understanding for designing cell targeting CPPs that are critical for reducing side effects and enhancing the efficient delivery of drugs into target cells.