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Conformational preferences of cationic ?-peptide in water studied by CCSD(T), MP2, and DFT methods.

ABSTRACT: The conformational preferences of the cationic nylon-3 ?NM [(3R,4)-diaminobutanoic acid, dAba] dipeptide in water were explored as the first step to understand the mode of action of polymers of ?NM against phylogenetically diverse and intrinsically drug-resistant pathogenic fungi. The CCSD(T), MP2, M06-2X, ?B97X-D, B2PLYP-D3BJ, and DSD-PBEP86-D3BJ levels of theory with various basis sets were assessed for relative energies of the 45 local minima of the cationic Ac-dAba-NHMe located at the SMD M06-2X/6-31+G(d) level of theory in water against the benchmark CCSD(T)/CBS-limit energies in water. The best performance was obtained at the double-hybrid DSD-PBEP86-D3BJ/def2-QZVP level of theory with RMSD = 0.12 kcal/mol in water. The M06-2X/def2-QZVP level of theory predicted reasonably the conformational preference with RMSD = 0.38 kcal/mol in water and may be an alternative level of theory with marginal deviations for the calculation of conformational energies of relatively longer cationic peptides in water. In particular, the H 14-helical structures appeared to be the most feasible conformations for the cationic Ac-dAba-NHMe populated at 48-64% by relative free energies in water. The hexamer built from the H 14-structure of the cationic Ac-dAba-NHMe adopted a left-handed 314-helix, which has a slightly narrower radius and a longer rise than the regular 314-helix of ?-peptides. Hence, the 314-helices of oligomers or polymers of the cationic dAba residues are expected to be the active conformation to exhibit the ability to bridge between charged lipid head groups that might cause a local depression or invagination of the membrane of fungi.

SUBMITTER: Kang YK

PROVIDER: S-EPMC7452530 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Conformational preferences of cationic β-peptide in water studied by CCSD(T), MP2, and DFT methods.

Kang Young Kee YK Park Hae Sook HS

Heliyon 20200814 8

The conformational preferences of the cationic nylon-3 βNM [(3<i>R</i>,4)-diaminobutanoic acid, dAba] dipeptide in water were explored as the first step to understand the mode of action of polymers of βNM against phylogenetically diverse and intrinsically drug-resistant pathogenic fungi. The CCSD(T), MP2, M06-2X, <i>ω</i>B97X-D, B2PLYP-D3BJ, and DSD-PBEP86-D3BJ levels of theory with various basis sets were assessed for relative energies of the 45 local minima of the cationic Ac-dAba-NHMe located ...[more]

PMID: 32904383

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Project description: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 CGly2 α and CLeu5 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 CAryl···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.

Dataset Information

Conformational preferences of cationic ?-peptide in water studied by CCSD(T), MP2, and DFT methods.

Publications

Conformational preferences of cationic β-peptide in water studied by CCSD(T), MP2, and DFT methods.

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