The Structural and Thermodynamic Basis for the Formation of Self‐Assembled Peptide Nanotubes

Ghadiri, Mojtaba; Kobayashi, Kenji; Granja, Juan R.; Chadha, Raj K.; McRee, Duncan E.

doi:10.1002/anie.199500931

Cited by 243 publications

(182 citation statements)

References 32 publications

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“…Experimentally, when self-assembly occurs, not only would the dimer form, but the trimer and longer assemblies would also be present. The 1 H NMR and IR studies by Ghadiri et al 5 showed that cyclo [(-L-Phe-D-N-MeAla-) 4 -] displays several conformational isomers in polar solvents, such as deuterated methanol or dimethyl sulfoxide (DMSO), which slowly interconvert as a result of the cis-trans isomerization of secondary amides. This inhibits the dimerization process in polar solvent for the capped dimer.…”

Section: Resultsmentioning

confidence: 99%

“…5 It was found that the peptide subunit cyclo [(-L-Phe-D-N-MeAla-) 4 -] adopts a flat-ring-shaped conformation, which energetically favors ring stacking and intermolecular hydrogen-bonding interactions over the nonassembled form by 4.0-5.6 kcal mol -1 , depending on the solvent. The free energy of the dimerization process is accessible via steered MD (SMD) simulations using Crooks theorem 16,17 in the form of the Jarzynski equality.…”

Section: Introductionmentioning

confidence: 99%

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Self-Assembling Cyclic Peptides: Molecular Dynamics Studies of Dimers in Polar and Nonpolar Solvents

et al. 2006

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The self-assembly of cyclic D,L-R-peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo [(-L-Trp-D-N-MeLeu-) 4 -] 2 and cyclo [(-L-Trp-D-Leu-) 4 -] 2 subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the and ψ dihedral angles of a single uncapped ring in nonane lie in the -sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Self-Assembling Cyclic Peptides: Molecular Dynamics Studies of Dimers in Polar and Nonpolar Solvents

et al. 2006

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“…Free energy of binding 15 The PMF curves obtained from the US simulations corresponding to the transport of 5FU through the WL and QAEA systems are given in Figure interaction. The energy barrier for the diffusion of the Na + ion through the CPNT is estimated as 2.0 kcal/mol.…”

Section: Hydrophobic Interactionsmentioning

confidence: 99%

Theoretical studies on the transport mechanism of 5-fluorouracil through cyclic peptide based nanotubes

Vijayaraj

Damme

Bultinck

et al. 2013

Phys. Chem. Chem. Phys.

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Cyclic peptide nanotubes (CPNTs) formed by the self-assembly of cyclic peptides (CPs) with an even number of alternate L/D amino acids are typically used in the field of the transport of ions and drug molecules across the lipid bilayer. This study investigates the transport mechanism of the antitumor drug molecule, 5-Fluorouracil (5FU), through the CPNT using classical and steered molecular dynamics simulations combined with umbrella sampling.During the transport of 5FU through the CPNT, 5FU is partially desolvated because the lumen of the CPNT is too small to allow for water molecules solvating it. 5FU forms Hbonding interactions with the backbones of CPNT and at the same time, also forms hydrophobic contacts with the backbone Cα and C atoms of CPNT. The cooperative breaking of the H-bond and hydrophobic interactions between CPNT and 5FU increases the pulling force to transport the 5FU from the mid-Cα region to the Cα one. The calculated free energies of binding reveal that the energy barriers for the transport of 5FU are ~ -6.0 and ~ -2.0 kcal/mol in the mid-Cα and Cα plane regions, respectively.

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“…[8][9][10][11][12] Depending on the hydrophilic or hydrophobic nature of the side chain of amino acids, the cyclic peptide nanotubes can be found either in water solution or in lipid bilayers. Due to their properties related to ion transport, they have been considered to be an antibacterial agent or a potential ion sensor.…”

Section: Introductionmentioning

confidence: 99%

Potential of Mean Force Calculations for Ion Selectivity in a Cyclic Peptide Nanotube

Choi¹,

Kwon²,

Kim³

et al. 2012

Bulletin of the Korean Chemical Society

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Ion selectivity in a simple cyclic peptide nanotube, composed of four cyclo[-(D-Ala-Glu-D-Ala-Gln)2-] units, is investigated by calculating the PMF profiles of Na + , K + , and Cl − ions permeating through the peptide nanotube in water. The final PMF profiles of the ions obtained from the umbrella sampling (US) method show an excellent agreement with those from the thermodynamic integration (TI) method. The PMF profiles of Na + and K + display free energy wells while the PMF curve of Cl − features free energy barriers, indicating the selectivity of the cyclic peptide nanotube to cations. Decomposition of the total mean force into the contribution from each component in the system is also accomplished by using the TI method. The mean force decomposition profiles of Na+ and K + demonstrate that the dehydration free energy barriers by water molecules near the channel entrance and inside the channel are completely compensated for by attractive electrostatic interactions between the cations and carbonyl oxygens in the nanotube. In the case of Cl − , the dehydration free energy barriers are not eliminated by an interaction between the anion and the peptide nanotube, leading to the high free energy barriers in the PMF profile. Calculations of the coordination numbers of the ions with oxygen atoms pertaining to either water molecules or carbonyl groups in the peptide nanotube reveal that the stabilization of the cations in the midplane regions of the nanotube arises from the favorable interaction of the cations with the negatively charged carbonyl oxygens.

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The Structural and Thermodynamic Basis for the Formation of Self‐Assembled Peptide Nanotubes

Cited by 243 publications

References 32 publications

Self-Assembling Cyclic Peptides: Molecular Dynamics Studies of Dimers in Polar and Nonpolar Solvents

Self-Assembling Cyclic Peptides: Molecular Dynamics Studies of Dimers in Polar and Nonpolar Solvents

Theoretical studies on the transport mechanism of 5-fluorouracil through cyclic peptide based nanotubes

Potential of Mean Force Calculations for Ion Selectivity in a Cyclic Peptide Nanotube

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