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Atomistic Molecular Simulations Suggest a Kinetic Model for Membrane Translocation by Arginine-Rich Peptides

Sun, Delin; Forsman, Jan LU and Woodward, Clifford E. (2015) In The Journal of Physical Chemistry Part B 119(45). p.14413-14420
Abstract
Arginine-rich cell penetrating peptides (ARCPPs) are known to quickly permeate cell membranes through a non-endocytotic pathway. Potential clinical applications of this facility have prompted enormous effort, both experimental and theoretical, to better understand how ARCPPs manage to overcome the prodigious thermodynamic cost of lipid bilayer permeation by these highly charged peptides. In this work we report the results of all-atom simulations, which suggest that a kinetic (rather than thermodynamic) mechanism may explain how ARCPPs are able to achieve this. Our simulations reveal that octaarginine significantly hinders the closing of membrane pores, either individually or via aggregation in the membrane pore, while octalysine (not an... (More)
Arginine-rich cell penetrating peptides (ARCPPs) are known to quickly permeate cell membranes through a non-endocytotic pathway. Potential clinical applications of this facility have prompted enormous effort, both experimental and theoretical, to better understand how ARCPPs manage to overcome the prodigious thermodynamic cost of lipid bilayer permeation by these highly charged peptides. In this work we report the results of all-atom simulations, which suggest that a kinetic (rather than thermodynamic) mechanism may explain how ARCPPs are able to achieve this. Our simulations reveal that octaarginine significantly hinders the closing of membrane pores, either individually or via aggregation in the membrane pore, while octalysine (not an ARCPP) lacks this ability. Our proposed mechanism is an alternative to current attempts to explain pore-mediated translocation of ARCPPs. It asserts that ARCPPs need not lower the equilibrium thermodynamic cost of pore formation. Instead, they can achieve rapid bilayer translocation by instead slowing down the kinetics of naturally occurring thermal pores. Linking the pore lifetime to the characteristic time for peptide diffusion out of the pore, ARCPPs are able to cooperatively permeate the membrane pore. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of Physical Chemistry Part B
volume
119
issue
45
pages
14413 - 14420
publisher
The American Chemical Society
external identifiers
  • wos:000364796500008
  • scopus:84946865875
ISSN
1520-5207
DOI
10.1021/acs.jpcb.5b08072
language
English
LU publication?
yes
id
cca7bf52-9e8d-46b2-8d50-1a124579f93d (old id 8370707)
date added to LUP
2015-12-17 12:48:39
date last changed
2017-09-03 04:15:47
@article{cca7bf52-9e8d-46b2-8d50-1a124579f93d,
  abstract     = {Arginine-rich cell penetrating peptides (ARCPPs) are known to quickly permeate cell membranes through a non-endocytotic pathway. Potential clinical applications of this facility have prompted enormous effort, both experimental and theoretical, to better understand how ARCPPs manage to overcome the prodigious thermodynamic cost of lipid bilayer permeation by these highly charged peptides. In this work we report the results of all-atom simulations, which suggest that a kinetic (rather than thermodynamic) mechanism may explain how ARCPPs are able to achieve this. Our simulations reveal that octaarginine significantly hinders the closing of membrane pores, either individually or via aggregation in the membrane pore, while octalysine (not an ARCPP) lacks this ability. Our proposed mechanism is an alternative to current attempts to explain pore-mediated translocation of ARCPPs. It asserts that ARCPPs need not lower the equilibrium thermodynamic cost of pore formation. Instead, they can achieve rapid bilayer translocation by instead slowing down the kinetics of naturally occurring thermal pores. Linking the pore lifetime to the characteristic time for peptide diffusion out of the pore, ARCPPs are able to cooperatively permeate the membrane pore.},
  author       = {Sun, Delin and Forsman, Jan and Woodward, Clifford E.},
  issn         = {1520-5207},
  language     = {eng},
  number       = {45},
  pages        = {14413--14420},
  publisher    = {The American Chemical Society},
  series       = {The Journal of Physical Chemistry Part B},
  title        = {Atomistic Molecular Simulations Suggest a Kinetic Model for Membrane Translocation by Arginine-Rich Peptides},
  url          = {http://dx.doi.org/10.1021/acs.jpcb.5b08072},
  volume       = {119},
  year         = {2015},
}