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Multistep Molecular Dynamics Simulations Identify the Highly Cooperative Activity of Melittin in Recognizing and Stabilizing Membrane Pores.

Sun, Delin; Forsman, Jan LU and Woodward, Clifford E (2015) In Langmuir 31(34). p.9388-9401
Abstract
The prototypical antimicrobial peptide, melittin, is well-known for its ability to induce pores in zwitterionic model lipid membranes. However, the mechanism by which melittin accomplishes this is not fully understood. We have conducted all-atom and coarse-grained molecular dynamics simulations which suggest that melittin employs a highly cooperative mechanism for the induction of both small and large membrane pores. The process by which this peptide induces membrane pores appears to be driven by its affinity to membrane defects via its N-terminus region. In our simulations, a membrane defect was deliberately created through either lipid flip-flop or the reorientation of one adsorbed melittin peptide. In a cooperative response, other... (More)
The prototypical antimicrobial peptide, melittin, is well-known for its ability to induce pores in zwitterionic model lipid membranes. However, the mechanism by which melittin accomplishes this is not fully understood. We have conducted all-atom and coarse-grained molecular dynamics simulations which suggest that melittin employs a highly cooperative mechanism for the induction of both small and large membrane pores. The process by which this peptide induces membrane pores appears to be driven by its affinity to membrane defects via its N-terminus region. In our simulations, a membrane defect was deliberately created through either lipid flip-flop or the reorientation of one adsorbed melittin peptide. In a cooperative response, other melittin molecules also inserted their N-termini into the created defect, thus lowering the overall free energy. The insertion of these peptide molecules ultimately allowed the defect to develop into a small transmembrane pore, with an estimated diameter of ∼1.5 nm and a lifetime of the order of tens of milliseconds. In the presence of a finite membrane tension, we show that this small pore can act as a nucleation site for the stochastic rupture of the lipid bilayer, so as to create a much larger pore. We found that a threshold membrane tension of 25 mN/m was needed to create a ruptured pore. Furthermore, by actively accumulating at its edge, adsorbed peptides are able to cooperatively stabilize this larger pore. The defect-mediated pore formation mechanism revealed in this work may also apply to other amphipathic membrane-active peptides. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Langmuir
volume
31
issue
34
pages
9388 - 9401
publisher
The American Chemical Society
external identifiers
  • pmid:26267389
  • wos:000360773000015
  • scopus:84940733137
ISSN
0743-7463
DOI
10.1021/acs.langmuir.5b01995
language
English
LU publication?
yes
id
2eecdbce-7a45-4a37-9066-b7b03238c407 (old id 7844126)
date added to LUP
2015-09-13 20:40:10
date last changed
2017-11-19 03:20:05
@article{2eecdbce-7a45-4a37-9066-b7b03238c407,
  abstract     = {The prototypical antimicrobial peptide, melittin, is well-known for its ability to induce pores in zwitterionic model lipid membranes. However, the mechanism by which melittin accomplishes this is not fully understood. We have conducted all-atom and coarse-grained molecular dynamics simulations which suggest that melittin employs a highly cooperative mechanism for the induction of both small and large membrane pores. The process by which this peptide induces membrane pores appears to be driven by its affinity to membrane defects via its N-terminus region. In our simulations, a membrane defect was deliberately created through either lipid flip-flop or the reorientation of one adsorbed melittin peptide. In a cooperative response, other melittin molecules also inserted their N-termini into the created defect, thus lowering the overall free energy. The insertion of these peptide molecules ultimately allowed the defect to develop into a small transmembrane pore, with an estimated diameter of ∼1.5 nm and a lifetime of the order of tens of milliseconds. In the presence of a finite membrane tension, we show that this small pore can act as a nucleation site for the stochastic rupture of the lipid bilayer, so as to create a much larger pore. We found that a threshold membrane tension of 25 mN/m was needed to create a ruptured pore. Furthermore, by actively accumulating at its edge, adsorbed peptides are able to cooperatively stabilize this larger pore. The defect-mediated pore formation mechanism revealed in this work may also apply to other amphipathic membrane-active peptides.},
  author       = {Sun, Delin and Forsman, Jan and Woodward, Clifford E},
  issn         = {0743-7463},
  language     = {eng},
  number       = {34},
  pages        = {9388--9401},
  publisher    = {The American Chemical Society},
  series       = {Langmuir},
  title        = {Multistep Molecular Dynamics Simulations Identify the Highly Cooperative Activity of Melittin in Recognizing and Stabilizing Membrane Pores.},
  url          = {http://dx.doi.org/10.1021/acs.langmuir.5b01995},
  volume       = {31},
  year         = {2015},
}