Coarse-grained molecular dynamics study of cyclic peptide nanotube insertion into a lipid bilayer

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Abstract

Coarse-grained (CG) molecular dynamics (MD) simulations are performed to study the insertion of cyclic peptide nanotubes into cell membranes and to examine whether cyclic peptide nanotubes can function as an ion channel and thereby as an antibacterial agent. To do so, the two coarse-grained (CG) models for lipid molecules and for proteins developed by Marrink et al. (/. Phys. Chem. B 2004,108, 750) and by Shih et al. (/. Phys. Chem. B 2006,110, 3674), respectively, were extended and modified. These CG models were verified by performing CG MD and all-atom (AA) MD simulations for a cyclic peptide nanotube, 8 x cyclo[(-D- Ala-L-Glu-D-Ala-L-Gln-)2], in water and by comparing the results from the two simulations. Comparison between static and dynamic (water transport) properties obtained from both simulations shows good agreement. To study nanotube insertion, a CG cyclic peptide nanotube, 8 x cyclo[(-Trp-D-Leu-) 4], was prepared above the surface of a CG DPPC lipid bilayer, restrained with constraints, and equilibrated, and then a series of CG MD simulations were carried out by lifting the constraints imposed on the nanotube. The CG MD simulations show that the cyclic peptide nanotube spontaneously inserts into and reorients inside the lipid bilayer. After insertion, the long axis of the cyclic peptide nanotube is aligned approximately perpendicular to the bilayer plane indicating that the nanotube can function as an ion channel and as an antibacterial agent. Tilt structures of the cyclic peptide nanotubes inside the lipid bilayer are found to be in agreement with experiment and earlier AA simulations. Lipid flip-flop, a migration of lipid molecules from one leaflet to the other leaflet of the lipid bilayer, is also observed from the CG MD simulations. Finally, the CG MD simulations reveal that a lipid headgroup can be inserted into the cyclic peptide nanotube. This process is confirmed by an AA MD simulation.

Original languageEnglish
Pages (from-to)4780-4787
Number of pages8
JournalJournal of Physical Chemistry A
Volume113
Issue number16
DOIs
Publication statusPublished - Apr 23 2009

Fingerprint

Peptide Nanotubes
Cyclic Peptides
Lipid bilayers
peptides
lipids
Molecular dynamics
insertion
nanotubes
molecular dynamics
Computer simulation
simulation
Nanotubes
Lipids
Ion Channels
Atoms
Anti-Bacterial Agents
Molecules
Water
Flip flop circuits
Cell membranes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

Coarse-grained molecular dynamics study of cyclic peptide nanotube insertion into a lipid bilayer. / Hwang, Hyonseok; Schatz, George C; Ratner, Mark A.

In: Journal of Physical Chemistry A, Vol. 113, No. 16, 23.04.2009, p. 4780-4787.

Research output: Contribution to journalArticle

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abstract = "Coarse-grained (CG) molecular dynamics (MD) simulations are performed to study the insertion of cyclic peptide nanotubes into cell membranes and to examine whether cyclic peptide nanotubes can function as an ion channel and thereby as an antibacterial agent. To do so, the two coarse-grained (CG) models for lipid molecules and for proteins developed by Marrink et al. (/. Phys. Chem. B 2004,108, 750) and by Shih et al. (/. Phys. Chem. B 2006,110, 3674), respectively, were extended and modified. These CG models were verified by performing CG MD and all-atom (AA) MD simulations for a cyclic peptide nanotube, 8 x cyclo[(-D- Ala-L-Glu-D-Ala-L-Gln-)2], in water and by comparing the results from the two simulations. Comparison between static and dynamic (water transport) properties obtained from both simulations shows good agreement. To study nanotube insertion, a CG cyclic peptide nanotube, 8 x cyclo[(-Trp-D-Leu-) 4], was prepared above the surface of a CG DPPC lipid bilayer, restrained with constraints, and equilibrated, and then a series of CG MD simulations were carried out by lifting the constraints imposed on the nanotube. The CG MD simulations show that the cyclic peptide nanotube spontaneously inserts into and reorients inside the lipid bilayer. After insertion, the long axis of the cyclic peptide nanotube is aligned approximately perpendicular to the bilayer plane indicating that the nanotube can function as an ion channel and as an antibacterial agent. Tilt structures of the cyclic peptide nanotubes inside the lipid bilayer are found to be in agreement with experiment and earlier AA simulations. Lipid flip-flop, a migration of lipid molecules from one leaflet to the other leaflet of the lipid bilayer, is also observed from the CG MD simulations. Finally, the CG MD simulations reveal that a lipid headgroup can be inserted into the cyclic peptide nanotube. This process is confirmed by an AA MD simulation.",
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