Nitrogen-14 nuclear magnetic resonance of the amino terminal group of leu-enkephalin in aqueous solution

Gerothanassis, Ioannis P.; Karayannis, Theodoros; Sakarellos‐Daitsiotis, Maria; Sakarellos, C.; Marraud, Michel

doi:10.1016/0022-2364(87)90107-7

Cited by 7 publications

(4 citation statements)

References 11 publications

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“…Additional 14 N NMR data indicates that the hydration of the N‐terminus is also unaffected on going from neutral to low pH 27. The water oxygen first shell (<0.38 nm) coordination numbers were 5.0 and 5.1 for the neutral and low pH simulations, respectively.…”

Section: Resultsmentioning

confidence: 97%

A conformational analysis of leucine enkephalin as a function of pH

Aburi

Smith

2002

Biopolymers

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The conformations of Leu enkephalin in aqueous solution have been investigated as a function of pH using molecular dynamics simulations. The simulations suggest the peptide backbone exists as a mixture of folded and unfolded forms (approximately 50% each) at neutral pH, but is always unfolded at low or high pH. The folded form at neutral pH possesses a 2 --> 5 hydrogen bond and a close head to tail separation. No significant intramolecular hydrogen bonding of the carbonyl oxygens was observed in either the folded or unfolded forms of the peptide. Analysis of the Gly carbonyl oxygens and terminal groups indicated that, while the conformational population distribution of Leu enkephalin did vary noticeably as a function of pH, their hydration was essentially independent of pH and in agreement with the available NMR data. Further study indicated that the unfolded state of the peptide was not random in nature and consisted of one major unfolded backbone arrangement stabilized by a persistent hydrophobic interaction between the side chains of Tyr and Leu.

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Section: Resultsmentioning

confidence: 97%

A conformational analysis of leucine enkephalin as a function of pH

Aburi

Smith

2002

Biopolymers

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“…It was found by using mass spectrometry that two different peptides were present with the sequence Tyr-Gly-Gly-Phe-[Leu/Met] in a ratio of 3 or 4 Met to 1 Leu (Hughes et al, 1975). Since this discovery, scientists have tried to determine the conformation of these peptides in different solvents such as water and dimethyl sulfoxide (DMSO), using spectroscopic techniques, predominantly nuclear magnetic resonance (NMR) spectroscopy, but also circular dichroism (CD) and Fourier transform-infrared (FTIR) spectroscopy (Khaled et al, 1977;Garbay-Jaureguiberry et al, 1977;Stimson et al, 1979;Higashijima et al, 1979;Gupta et al, 1986;Motta et al, 1987a,b;Gerothanassis et al, 1987;Surewicz and Mantsch, 1988;Glasser and Scheraga, 1988;Sakarellos et al, 1989;Vesterman et al, 1989;Picone et al, 1990; Moret et al, 1990;Gerothanassis et al, 1992;Graham et al, 1992;Doi et al, 1994). In 1977 Khaled et al found that some of the physical properties of Met-enkephalin (M-Enk) and Leu-enkephalin (L-Enk), such as proton and carbon chem-bonds and two salt bridges.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations of Leu-enkephalin in water and DMSO

Spoel

Berendsen²

1997

Biophysical Journal

116

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The structure of Leu-enkephalin (L-Enk) and Met-enkephalin (M-Enk) have frequently been studied, in particular by nuclear magnetic resonance spectroscopy. After more than 20 years of research, it was concluded that enkephalins have no preferred structure in aqueous solution, but that they may have in other solvents. We have performed molecular dynamics simulations of zwitterionic L-Enk in water, and zwitterionic as well as neutral L-Enk dimethyl sulfoxide (DMSO). In water the peptide is very flexible, although there seems to be a preference for compact conformations. In DMSO, the peptide forms a clear salt bridge in the zwitterionic form, but has no preferred conformation in the neutral form. This difference in conformation may provide an explanation for measurements in DMSO in which multiple conformations were found to exist. In this paper we introduce a new formulation for a dihedral angle autocorrelation function, and apply it to study side-chain dynamics in L-Enk. We find that the side-chain dynamics of the large Tyr and Phe residues cannot be adequately sampled in 2.0-ns simulations, while this does seem to be possible for the smaller Leu side chain.

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“…On the other hand, the peptide chain of Met-Enk was fully extended in the crystal . For four decades, considerable NMR − and laser Raman/IR ,− spectroscopic measurements have been performed to investigate the preferred conformations of Leu-Enk in solution and in the solid state. It was known that Leu-Enk exists as a mixture of uncharged and zwitterionic species in dimethyl sulfoxide (DMSO), whereas it is a zwitterionic form in water. ,,, According to the results from laser Raman/IR spectroscopic measurements, − , Leu-Enk exists in different conformations in different solvents; i.e.…”

Section: Introductionmentioning

confidence: 99%

Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations

2022

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The conformational preferences of Leu-enkephalin (Leu-Enk) were explored by the conformational search and density functional theory (DFT) calculations. By a combination of low-energy conformers of each residue, the initial structures of the neutral Leu-Enk were generated and optimized using the ECEPP3 force field in the gas phase. These structures were reoptimized at the HF/3-21G(d) and M06-2X levels of theory with 6-31G(d) and 6-31+G(d) basis functions. We finally located the 139 structures with the relative energy <10 kcal mol –1 in the gas phase, from which the structures of the corresponding zwitterionic Leu-Enk were generated and reoptimized at the M06-2X/6-31+G(d) level of theory using the implicit solvation model based on density (SMD) in water. The conformational preferences of Leu-Enk were analyzed using Gibbs free energies corrected by single-point energies calculated at the double-hybrid DSD-PBEP86-D3BJ/def2-TZVP level of theory in the gas phase and in water. The neutral Leu-Enk dominantly adopted a folded structure in the gas phase stabilized by three H-bonds with a βII′-bend-like motif at the Gly3–Phe4 sequence and a close contact between the side chains of Phe4 and Leu5. The zwitterionic Leu-Enk exhibited a folded structure in water stabilized by three H-bonds with double β-bends such as a βII′ bend at the Gly2–Gly3 sequence and a βI bend at the Gly3–Phe4 sequence. The calculated ensemble-averaged distance between C Gly2 α and C Leu5 α of the zwitterionic Leu-Enk in water is consistent with the value estimated from the simulated annealing using the distance constraints derived from nuclear Overhauser effect spectroscopy (NOESY) spectra in water. Interestingly, the preferred conformations of the neutral and zwitterionic Leu-Enk are new folded structures not predicted by earlier computational studies. According to the refined model of the zwitterionic Leu-Enk bound to δ-opioid receptor (δOR), there were favorable interactions of the terminal charged groups of Leu-Enk with the side chains of charged residues of δOR as well as a favorable C Aryl ···H interaction of the Phe4 residue of Leu-Enk with Trp284 of δOR. Hence, these favorable interactions would induce the folded structure of the zwitterionic Leu-Enk with double β-bends isolated in water into the “bioactive conformation” like an extended structure when binding to δOR.

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Nitrogen-14 nuclear magnetic resonance of the amino terminal group of leu-enkephalin in aqueous solution

Cited by 7 publications

References 11 publications

A conformational analysis of leucine enkephalin as a function of pH

A conformational analysis of leucine enkephalin as a function of pH

Molecular dynamics simulations of Leu-enkephalin in water and DMSO

Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations

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