Scramblases and Insertases Facilitate Transmembrane Translocation of Amphiphilic Peptides

Translocation of amphiphilic peptides across a lipid membrane requires getting polar groups through the hydrophobic membrane core and is therefore prohibitively slow in a protein-free bilayer. Here we show that lipid scramblases can dramatically lower this barrier, effectively acting as bidirectional peptide translocases. Using coarse-grained molecular dynamics simulations, we calculated free energy profiles for the translocation of a model amphiphilic peptide across phospholipid membranes, each containing one of six scramblases or insertases. Most of these proteins reduce the free energy barrier by roughly 80%. Peptide translocation and lipid scrambling share the same mechanism: both proceed along the same hydrophilic groove on the protein surface, and the transition of both is enabled by local membrane defects induced by the groove. We further show that peptide and lipid transport are competitive, and that peptides can inhibit or completely block phospholipid scrambling. Scramblases and insertases thus provide a general route for moving amphiphiles across membranes, and offer a molecular rationale for the cytosolic entry of cell-penetrating peptides.