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Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations
[Image: see text] 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 optimi...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366962/ https://www.ncbi.nlm.nih.gov/pubmed/35967045 http://dx.doi.org/10.1021/acsomega.2c03942 |
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author | Park, Hae Sook Byun, Byung Jin Kang, Young Kee |
author_facet | Park, Hae Sook Byun, Byung Jin Kang, Young Kee |
author_sort | Park, Hae Sook |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-9366962 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-93669622022-08-12 Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations Park, Hae Sook Byun, Byung Jin Kang, Young Kee ACS Omega [Image: see text] 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. American Chemical Society 2022-07-26 /pmc/articles/PMC9366962/ /pubmed/35967045 http://dx.doi.org/10.1021/acsomega.2c03942 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Park, Hae Sook Byun, Byung Jin Kang, Young Kee Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations |
title | Exploring Conformational
Preferences of Leu-enkephalin
Using the Conformational Search and Double-Hybrid DFT Energy Calculations |
title_full | Exploring Conformational
Preferences of Leu-enkephalin
Using the Conformational Search and Double-Hybrid DFT Energy Calculations |
title_fullStr | Exploring Conformational
Preferences of Leu-enkephalin
Using the Conformational Search and Double-Hybrid DFT Energy Calculations |
title_full_unstemmed | Exploring Conformational
Preferences of Leu-enkephalin
Using the Conformational Search and Double-Hybrid DFT Energy Calculations |
title_short | Exploring Conformational
Preferences of Leu-enkephalin
Using the Conformational Search and Double-Hybrid DFT Energy Calculations |
title_sort | exploring conformational
preferences of leu-enkephalin
using the conformational search and double-hybrid dft energy calculations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366962/ https://www.ncbi.nlm.nih.gov/pubmed/35967045 http://dx.doi.org/10.1021/acsomega.2c03942 |
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