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Effect of arginine-rich cell penetrating peptides on membrane pore formation and life-times: a molecular simulation study

Sun, Delin; Forsman, Jan LU ; Lund, Mikael LU and Woodward, Clifford E. (2014) In Physical Chemistry Chemical Physics 16(38). p.20785-20795
Abstract
The molecular basis for the effectiveness of arginine-rich cell penetrating peptides (ARCPPs) traversing a cell membrane barrier is not well established. The fact that a threshold concentration of ARCPPs is required for efficient translocation in model membranes suggests cooperative action by ARCPPs. We used umbrella sampling simulations to calculate the free energies for membrane pore formation. Membrane-bound octaarginine (ARG8) peptides showed little cooperativity in lowering the free energy barrier to generate membrane pores by direct peptide translocation or by lipid flip-flop. Instead, high concentrations of ARG8 peptides were found to expand the surface area of the lipid bilayer due to the deep partitioning of guanidinium ions into... (More)
The molecular basis for the effectiveness of arginine-rich cell penetrating peptides (ARCPPs) traversing a cell membrane barrier is not well established. The fact that a threshold concentration of ARCPPs is required for efficient translocation in model membranes suggests cooperative action by ARCPPs. We used umbrella sampling simulations to calculate the free energies for membrane pore formation. Membrane-bound octaarginine (ARG8) peptides showed little cooperativity in lowering the free energy barrier to generate membrane pores by direct peptide translocation or by lipid flip-flop. Instead, high concentrations of ARG8 peptides were found to expand the surface area of the lipid bilayer due to the deep partitioning of guanidinium ions into the lipid glycerol regions. Surface-bound ARG8 peptides can also insert an arginine side chain into one existing transient membrane pore, and the lifetime of the transient membrane pore is significantly extended by arginine. This suggests a cooperative kinetic mechanism may act above a threshold adsorption concentration to facilitate the rapid uptake of these peptides. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Physical Chemistry Chemical Physics
volume
16
issue
38
pages
20785 - 20795
publisher
Royal Society of Chemistry
external identifiers
  • wos:000342072300061
  • scopus:84920829026
ISSN
1463-9084
DOI
10.1039/c4cp02211d
language
English
LU publication?
yes
id
e4da1e5c-533b-427c-8fe9-16b73df0e638 (old id 4709824)
date added to LUP
2014-10-24 08:14:19
date last changed
2017-11-05 03:58:44
@article{e4da1e5c-533b-427c-8fe9-16b73df0e638,
  abstract     = {The molecular basis for the effectiveness of arginine-rich cell penetrating peptides (ARCPPs) traversing a cell membrane barrier is not well established. The fact that a threshold concentration of ARCPPs is required for efficient translocation in model membranes suggests cooperative action by ARCPPs. We used umbrella sampling simulations to calculate the free energies for membrane pore formation. Membrane-bound octaarginine (ARG8) peptides showed little cooperativity in lowering the free energy barrier to generate membrane pores by direct peptide translocation or by lipid flip-flop. Instead, high concentrations of ARG8 peptides were found to expand the surface area of the lipid bilayer due to the deep partitioning of guanidinium ions into the lipid glycerol regions. Surface-bound ARG8 peptides can also insert an arginine side chain into one existing transient membrane pore, and the lifetime of the transient membrane pore is significantly extended by arginine. This suggests a cooperative kinetic mechanism may act above a threshold adsorption concentration to facilitate the rapid uptake of these peptides.},
  author       = {Sun, Delin and Forsman, Jan and Lund, Mikael and Woodward, Clifford E.},
  issn         = {1463-9084},
  language     = {eng},
  number       = {38},
  pages        = {20785--20795},
  publisher    = {Royal Society of Chemistry},
  series       = {Physical Chemistry Chemical Physics},
  title        = {Effect of arginine-rich cell penetrating peptides on membrane pore formation and life-times: a molecular simulation study},
  url          = {http://dx.doi.org/10.1039/c4cp02211d},
  volume       = {16},
  year         = {2014},
}