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

Pedro G. Ramírez, Mario G. Del Pópolo, Jorge A. Vila, Igal G Szleifer, Gabriel S. Longo*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes is not entirely understood. In the present work, we develop a molecular theory that allows to investigate the adsorption 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 of protonation of acidic membrane lipids. We present a systematic investigation of the effect of pore size, peptide concentration and sequence length on the extent of peptide adsorption and insertion into the pores. We show 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 with chain length, but it saturates for longer peptides. However, this adsorption behavior only occurs at relatively low 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 deprotonation of acidic lipids. Peptide insertion into the pores depends non-monotonically on pore radius, which reflects the short range nature of the effective membrane-peptide interactions. The size of the pore that promotes maximum adsorption depends on the peptide chain length. Peptide translocation is a thermally activated process, so we complement our thermodynamic approach with a simple kinetic model that allows to rationalize the ARCPPs translocation rate in terms of the free energy gain of adsorption, and the energy cost of creating a transmembrane pore with peptides in it. Our results indicate that strategies to improve translocation efficiency should focus on enhancing peptide adsorption.

Original languageEnglish (US)
Pages (from-to)701-711
Number of pages11
JournalJournal of Colloid And Interface Science
Volume552
DOIs
StatePublished - Sep 15 2019

Fingerprint

Peptides
Electrostatics
Membranes
Adsorption
Acids
Cell-Penetrating Peptides
Arginine
Membrane Lipids
Protonation
polyarginine
Chain length
Bearings (structural)
Deprotonation
Charge distribution
Free energy
Pore size
Conformations
Lipids
Thermodynamics

Keywords

  • Cell penetrating peptides
  • Molecular modeling

ASJC Scopus subject areas

  • Electronic, Optical and Magnetic Materials
  • Biomaterials
  • Surfaces, Coatings and Films
  • Colloid and Surface Chemistry

Cite this

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title = "Adsorption and insertion of polyarginine peptides into membrane pores: The trade-off between electrostatics, acid-base chemistry and pore formation energy",
abstract = "The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes is not entirely understood. In the present work, we develop a molecular theory that allows to investigate the adsorption 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 of protonation of acidic membrane lipids. We present a systematic investigation of the effect of pore size, peptide concentration and sequence length on the extent of peptide adsorption and insertion into the pores. We show 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 with chain length, but it saturates for longer peptides. However, this adsorption behavior only occurs at relatively low 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 deprotonation of acidic lipids. Peptide insertion into the pores depends non-monotonically on pore radius, which reflects the short range nature of the effective membrane-peptide interactions. The size of the pore that promotes maximum adsorption depends on the peptide chain length. Peptide translocation is a thermally activated process, so we complement our thermodynamic approach with a simple kinetic model that allows to rationalize the ARCPPs translocation rate in terms of the free energy gain of adsorption, and the energy cost of creating a transmembrane pore with peptides in it. Our results indicate that strategies to improve translocation efficiency should focus on enhancing peptide adsorption.",
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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, Igal G; Longo, Gabriel S.

In: Journal of Colloid And Interface Science, Vol. 552, 15.09.2019, p. 701-711.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Adsorption and insertion of polyarginine peptides into membrane pores

T2 - The trade-off between electrostatics, acid-base chemistry and pore formation energy

AU - Ramírez, Pedro G.

AU - Del Pópolo, Mario G.

AU - Vila, Jorge A.

AU - Szleifer, Igal G

AU - Longo, Gabriel S.

PY - 2019/9/15

Y1 - 2019/9/15

N2 - The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes is not entirely understood. In the present work, we develop a molecular theory that allows to investigate the adsorption 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 of protonation of acidic membrane lipids. We present a systematic investigation of the effect of pore size, peptide concentration and sequence length on the extent of peptide adsorption and insertion into the pores. We show 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 with chain length, but it saturates for longer peptides. However, this adsorption behavior only occurs at relatively low 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 deprotonation of acidic lipids. Peptide insertion into the pores depends non-monotonically on pore radius, which reflects the short range nature of the effective membrane-peptide interactions. The size of the pore that promotes maximum adsorption depends on the peptide chain length. Peptide translocation is a thermally activated process, so we complement our thermodynamic approach with a simple kinetic model that allows to rationalize the ARCPPs translocation rate in terms of the free energy gain of adsorption, and the energy cost of creating a transmembrane pore with peptides in it. Our results indicate that strategies to improve translocation efficiency should focus on enhancing peptide adsorption.

AB - The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes is not entirely understood. In the present work, we develop a molecular theory that allows to investigate the adsorption 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 of protonation of acidic membrane lipids. We present a systematic investigation of the effect of pore size, peptide concentration and sequence length on the extent of peptide adsorption and insertion into the pores. We show 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 with chain length, but it saturates for longer peptides. However, this adsorption behavior only occurs at relatively low 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 deprotonation of acidic lipids. Peptide insertion into the pores depends non-monotonically on pore radius, which reflects the short range nature of the effective membrane-peptide interactions. The size of the pore that promotes maximum adsorption depends on the peptide chain length. Peptide translocation is a thermally activated process, so we complement our thermodynamic approach with a simple kinetic model that allows to rationalize the ARCPPs translocation rate in terms of the free energy gain of adsorption, and the energy cost of creating a transmembrane pore with peptides in it. Our results indicate that strategies to improve translocation efficiency should focus on enhancing peptide adsorption.

KW - Cell penetrating peptides

KW - Molecular modeling

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SN - 0021-9797

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