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Exploring Conformational Preferences of Leu-enkephalin Using the Conformational Search and Double-Hybrid DFT Energy Calculations.
| Content Provider | Europe PMC |
|---|---|
| Author | Park, Hae Sook Byun, Byung Jin Kang, Young Kee |
| Copyright Year | 2022 |
| Abstract | The conformational preferences of Leu-enkephalin (Leu-Enk)wereexplored by the conformational search and density functional theory(DFT) calculations. By a combination of low-energy conformers of eachresidue, the initial structures of the neutral Leu-Enk were generatedand optimized using the ECEPP3 force field in the gas phase. Thesestructures were reoptimized at the HF/3-21G(d) and M06-2X levels oftheory with 6-31G(d) and 6-31+G(d) basis functions. We finally locatedthe 139 structures with the relative energy <10 kcal mol–1 in the gas phase, from which the structures of the correspondingzwitterionic 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 analyzedusing Gibbs free energies corrected by single-point energies calculatedat the double-hybrid DSD-PBEP86-D3BJ/def2-TZVP level of theory inthe gas phase and in water. The neutral Leu-Enk dominantly adopteda folded structure in the gas phase stabilized by three H-bonds witha βII′-bend-like motif at the Gly3–Phe4 sequenceand a close contact between the side chains of Phe4 and Leu5. Thezwitterionic Leu-Enk exhibited a folded structure in water stabilizedby three H-bonds with double β-bends such as a βII′bend at the Gly2–Gly3 sequence and a βI bend at the Gly3–Phe4sequence. The calculated ensemble-averaged distance between CGly2α and CLeu5α of the zwitterionic Leu-Enk in water is consistent with the valueestimated from the simulated annealing using the distance constraintsderived from nuclear Overhauser effect spectroscopy (NOESY) spectrain water. Interestingly, the preferred conformations of the neutraland zwitterionic Leu-Enk are new folded structures not predicted byearlier computational studies. According to the refined model of thezwitterionic Leu-Enk bound to δ-opioid receptor (δOR),there were favorable interactions of the terminal charged groups ofLeu-Enk with the side chains of charged residues of δOR as wellas a favorable CAryl···H interaction ofthe Phe4 residue of Leu-Enk with Trp284 of δOR. Hence, thesefavorable interactions would induce the folded structure of the zwitterionicLeu-Enk with double β-bends isolated in water into the “bioactiveconformation” like an extended structure when binding to δOR. |
| Journal | ACS Omega |
| Volume Number | 7 |
| PubMed Central reference number | PMC9366962 |
| Issue Number | 31 |
| PubMed reference number | 35967045 |
| e-ISSN | 24701343 |
| DOI | 10.1021/acsomega.2c03942 |
| Language | English |
| Publisher | American Chemical Society |
| Publisher Date | 2022-07-26 |
| Access Restriction | Open |
| Rights License | 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/). © 2022 The Authors. Published by American Chemical Society |
| Content Type | Text |
| Resource Type | Article |
| Subject | Chemistry Chemical Engineering |
