Membrane Electroporation Study by All-atom and Coarsed-grained Molecular Dynamics: from Pore Formation to Cell Penetrating Peptides Translocation

Cell membranes fulfil many important biological functions and are composed by an heterogeneous variety of lipids and proteins, which leads to the typical asymmetric bilayer structure. One of the main functions of cell membrane is to act as a filter to control the molecules traffic at the interface. The comprehension of the molecular transport across the membrane is hugely important in medicine, in particular in the development of effective drug delivery system. There are different routes for cellular uptake, some involving complex signalling pathways, some more simple. The easier way is the direct translocation through water pores. Indirect experimental evidences suggest the presence of small, short-lived pores for which todays experimental tools are unable to provide direct observation and atomistic detail. Here, through molecular modelling, the formation of these hydrophilic pores was observed and analysed. In particular, the focus was on the effect of the transmembrane potential, which has a strong influence on the transport of various small and large molecules across the membrane and leads to pore formation. In the present work, lipid pores were induced both applying an external, constant electric field and creating a physiologic-like charge imbalance across the membrane. Moreover, following the second approach, cellular uptake of seven different cell penetrating peptides (CPP) through direct translocation pathway driven by the membrane electrostatic potential was observed and studied. The opening of membrane pores due to the ion imbalance revealed to be broadly relevant for CPP uptake.