title: Fundamental molecular mechanism for the cellular uptake of guanidinium-rich molecules.
abstract: Guanidinium-rich molecules, such as cell-penetrating peptides, efficiently enter living cells in a non-endocytic energy-independent manner and transport a wide range of cargos, including drugs and biomarkers. The mechanism by which these highly cationic molecules efficiently cross the hydrophobic barrier imposed by the plasma membrane remains a fundamental open question. Here, a combination of computational results and in vitro and live-cell experimental evidence reveals an efficient energy-independent translocation mechanism for arginine-rich molecules. This mechanism unveils the essential role of guanidinium groups and two universal cell components: fatty acids and the cell membrane pH gradient. Deprotonated fatty acids in contact with the cell exterior interact with guanidinium groups, leading to a transient membrane channel that facilitates the transport of arginine-rich peptides toward the cell interior. On the cytosolic side, the fatty acids become protonated, releasing the peptides and resealing the channel. This fundamental mechanism appears to be universal across cells from different species and kingdoms.
authors.affiliation: Department of Physics, Applied Physics and Astronomy and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute , Troy, New York 12180, United States.
authors.forename: Henry D
authors.initials: HD
authors.lastname: Herce
authors.forename: Angel E
authors.initials: AE
authors.lastname: Garcia
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Cardoso
mesh_terms: D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D003198:Computer Simulation; D005227:Fatty Acids / Q000737:chemistry; D019791:Guanidine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions
chemical_list: D057846:Cell-Penetrating Peptides; D005227:Fatty Acids; D019791:Guanidine