Adsorption and insertion of polyarginine peptides into membrane pores: The trade-off between electrostatics, acid-base chemistry and pore formation energy

RAMÍREZ, PEDRO G.; DEL PÓPOLO, MARIO G.; VILA, JORGE A.; SZLEIFER, I.; LONGO, GABRIEL S.

JOURNAL OF COLLOID AND INTERFACE SCIENCE

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2019 vol. 552 p. 701 - 711

0021-9797

The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes isnot entirely understood. In the present work, we develop a molecular theory that allows to investigate theadsorption and insertion of ARCPPs on membranes bearing hydrophilic pores. This method accounts for size,shape, conformation, protonation state and charge distribution of the peptides; it also describes the state ofprotonation of acidic membrane lipids. We present a systematic investigation of the effect of pore size, peptideconcentration and sequence length on the extent of peptide adsorption and insertion into the pores.Weshow that adsorption on the intact (non-porated) lipid membrane plays a key role on peptide translocation.For peptides shorter than nona-arginine, adsorption on the intact membrane increases significantly withchain length, but it saturates for longer peptides. However, this adsorption behavior only occurs at relativelylow peptide concentrations; increasing peptide concentration favors adsorption of the shorter molecules.Adsorption of longer peptides increases the intact membrane negative charge as a result of further deprotonationof acidic lipids. Peptide insertion into the pores depends non-monotonically on pore radius, whichreflects the short range nature of the effective membrane-peptide interactions. The size of the pore that promotesmaximum adsorption depends on the peptide chain length. Peptide translocation is a thermally activatedprocess, so we complement our thermodynamic approach with a simple kinetic model that allows torationalize the ARCPPs translocation rate in terms of the free energy gain of adsorption, and the energy costof creating a transmembrane pore with peptides in it. Our results indicate that strategies to improve translocationefficiency should focus on enhancing peptide adsorption.