Combined use of molecular dynamics simulations and NMR to explore peptide bond isomerization and multiple intramolecular hydrogen-bonding possibilities in a cyclic pentapeptide, cyclo(Gly-Pro-D-Phe-Gly-Val)

Z. P. Liu, L. M. Gierasch

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11 Citations (Scopus)

Abstract

The conformational behavior of a model cyclic pentapeptide-cyclo(Gly-L- Pro-D-Phe-Gly-L-Val)-has been explored through the combined use of in vacuo molecular dynamics simulations and a range of nmr experiments (preceding paper). The molecular dynamics analysis suggests that, despite the conformational constraints imposed by formation of the pentapeptide cycle, this pentapeptide undergoes conformational transitions between various hydrogen-bonded conformations, characterized by low energy barriers. An inverse γ turn with Pro in position i + 1 and a γ turn with D-Phe in position i + 1 are two alternatives occurring frequently. Like other DLDDL cyclic pentapeptides, cyclo(Gly-Pro-D-Phe-Gly-Val) is also stabilized by an inverse γ-turn structure with the β-branched Val residue in position i + 1, and this hydrogen bond is retained in the different conformational families. The γ-turn around D-Phe3 and the inverse γ turn around Val5 are consistent with the nmr observations. 3J(NH-CHα) coupling constants of the all-trans forms were calculated from one of the molecular dynamics trajectories and are comparable to nmr experimental data, suggesting that the conformational states visited during the simulation are representative of the conformational distribution in solution. In addition to the equilibrium among various hydrogen-bonded all-trans conformers, the observation in nmr spectra of two sets of resonances for all peptide protons indicated a slow conformational interconversion of the Gly-Pro peptide bond between trans and cis isomers. The activation energy between these two conformers was determined experimentally by magnetization transfer and was calculated by high temperature constrained molecular dynamics simulation. Both methods yield a free energy of activation of ca. 20 kcal/mol. Furthermore, the free energy of activation is dependent on the direction of rotation of the Gly-Pro peptide bond.

Original languageEnglish (US)
Pages (from-to)1727-1739
Number of pages13
JournalBiopolymers
Volume32
Issue number12
DOIs
StatePublished - Dec 1992

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Molecular Dynamics Simulation
Hydrogen Bonding
Isomerization
Peptides
Molecular dynamics
Hydrogen bonds
glycylproline
Nuclear magnetic resonance
Hydrogen
Computer simulation
Free energy
phenylalanylglycine
Chemical activation
Energy barriers
Isomers
Dynamic analysis
Conformations
Protons
Magnetization
Activation energy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

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title = "Combined use of molecular dynamics simulations and NMR to explore peptide bond isomerization and multiple intramolecular hydrogen-bonding possibilities in a cyclic pentapeptide, cyclo(Gly-Pro-D-Phe-Gly-Val)",
abstract = "The conformational behavior of a model cyclic pentapeptide-cyclo(Gly-L- Pro-D-Phe-Gly-L-Val)-has been explored through the combined use of in vacuo molecular dynamics simulations and a range of nmr experiments (preceding paper). The molecular dynamics analysis suggests that, despite the conformational constraints imposed by formation of the pentapeptide cycle, this pentapeptide undergoes conformational transitions between various hydrogen-bonded conformations, characterized by low energy barriers. An inverse γ turn with Pro in position i + 1 and a γ turn with D-Phe in position i + 1 are two alternatives occurring frequently. Like other DLDDL cyclic pentapeptides, cyclo(Gly-Pro-D-Phe-Gly-Val) is also stabilized by an inverse γ-turn structure with the β-branched Val residue in position i + 1, and this hydrogen bond is retained in the different conformational families. The γ-turn around D-Phe3 and the inverse γ turn around Val5 are consistent with the nmr observations. 3J(NH-CHα) coupling constants of the all-trans forms were calculated from one of the molecular dynamics trajectories and are comparable to nmr experimental data, suggesting that the conformational states visited during the simulation are representative of the conformational distribution in solution. In addition to the equilibrium among various hydrogen-bonded all-trans conformers, the observation in nmr spectra of two sets of resonances for all peptide protons indicated a slow conformational interconversion of the Gly-Pro peptide bond between trans and cis isomers. The activation energy between these two conformers was determined experimentally by magnetization transfer and was calculated by high temperature constrained molecular dynamics simulation. Both methods yield a free energy of activation of ca. 20 kcal/mol. Furthermore, the free energy of activation is dependent on the direction of rotation of the Gly-Pro peptide bond.",
author = "Liu, {Z. P.} and Gierasch, {L. M.}",
year = "1992",
month = "12",
doi = "10.1002/bip.360321214",
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T1 - Combined use of molecular dynamics simulations and NMR to explore peptide bond isomerization and multiple intramolecular hydrogen-bonding possibilities in a cyclic pentapeptide, cyclo(Gly-Pro-D-Phe-Gly-Val)

AU - Liu, Z. P.

AU - Gierasch, L. M.

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N2 - The conformational behavior of a model cyclic pentapeptide-cyclo(Gly-L- Pro-D-Phe-Gly-L-Val)-has been explored through the combined use of in vacuo molecular dynamics simulations and a range of nmr experiments (preceding paper). The molecular dynamics analysis suggests that, despite the conformational constraints imposed by formation of the pentapeptide cycle, this pentapeptide undergoes conformational transitions between various hydrogen-bonded conformations, characterized by low energy barriers. An inverse γ turn with Pro in position i + 1 and a γ turn with D-Phe in position i + 1 are two alternatives occurring frequently. Like other DLDDL cyclic pentapeptides, cyclo(Gly-Pro-D-Phe-Gly-Val) is also stabilized by an inverse γ-turn structure with the β-branched Val residue in position i + 1, and this hydrogen bond is retained in the different conformational families. The γ-turn around D-Phe3 and the inverse γ turn around Val5 are consistent with the nmr observations. 3J(NH-CHα) coupling constants of the all-trans forms were calculated from one of the molecular dynamics trajectories and are comparable to nmr experimental data, suggesting that the conformational states visited during the simulation are representative of the conformational distribution in solution. In addition to the equilibrium among various hydrogen-bonded all-trans conformers, the observation in nmr spectra of two sets of resonances for all peptide protons indicated a slow conformational interconversion of the Gly-Pro peptide bond between trans and cis isomers. The activation energy between these two conformers was determined experimentally by magnetization transfer and was calculated by high temperature constrained molecular dynamics simulation. Both methods yield a free energy of activation of ca. 20 kcal/mol. Furthermore, the free energy of activation is dependent on the direction of rotation of the Gly-Pro peptide bond.

AB - The conformational behavior of a model cyclic pentapeptide-cyclo(Gly-L- Pro-D-Phe-Gly-L-Val)-has been explored through the combined use of in vacuo molecular dynamics simulations and a range of nmr experiments (preceding paper). The molecular dynamics analysis suggests that, despite the conformational constraints imposed by formation of the pentapeptide cycle, this pentapeptide undergoes conformational transitions between various hydrogen-bonded conformations, characterized by low energy barriers. An inverse γ turn with Pro in position i + 1 and a γ turn with D-Phe in position i + 1 are two alternatives occurring frequently. Like other DLDDL cyclic pentapeptides, cyclo(Gly-Pro-D-Phe-Gly-Val) is also stabilized by an inverse γ-turn structure with the β-branched Val residue in position i + 1, and this hydrogen bond is retained in the different conformational families. The γ-turn around D-Phe3 and the inverse γ turn around Val5 are consistent with the nmr observations. 3J(NH-CHα) coupling constants of the all-trans forms were calculated from one of the molecular dynamics trajectories and are comparable to nmr experimental data, suggesting that the conformational states visited during the simulation are representative of the conformational distribution in solution. In addition to the equilibrium among various hydrogen-bonded all-trans conformers, the observation in nmr spectra of two sets of resonances for all peptide protons indicated a slow conformational interconversion of the Gly-Pro peptide bond between trans and cis isomers. The activation energy between these two conformers was determined experimentally by magnetization transfer and was calculated by high temperature constrained molecular dynamics simulation. Both methods yield a free energy of activation of ca. 20 kcal/mol. Furthermore, the free energy of activation is dependent on the direction of rotation of the Gly-Pro peptide bond.

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