Theoretical conformational analysis for neurotransmitters in the gas phase and in aqueous solution. Norepinephrine

Peter I. Nagy, Giuliano Alagona, Caterina Ghio, K. Takács-Novák

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Abstract

The natural neurotransmitter (R)-norepinephrine takes the monocationic form in 93% abundance at the physiological tissue pH of 7.4. Ab initio and DFT/B3LYP calculations were performed for 12 protonated conformers of (R)-norepinephrine in the gas phase with geometry optimizations up to the MP2/6-311++G** level, and with single-point calculations up to the QCISD(T) level at the HF/6-31G*-optimized geometries. Four monohydrates were studied at the MP2/6-31G*//HF/6-31G* level. In the gas phase, the G1 conformer is the most stable with phenyl⋯NH3 + gauche and HO(alc)⋯NH3 + gauche arrangements. A strained intramolecular hydrogen bond was found for conformers (G1 and T) with close NH3 + and OH groups. Upon rotation of the NH3 + group as a whole unit about the Cβ-Cα axis, a 3-fold potential was calculated with free energies for barriers of 3-12 kcal/mol at the HF/6-31G* level. Only small deviations were found in MP2/ 6-311++G** single-point calculations. A 2-fold potential was calculated for the phenyl rotation with free energies of 11-13 kcal/mol for the barriers at T = 310 K and p = 1 atm. A molecular mechanics docking study of (R)-norepinephrine in a model binding pocket of the β-adrenergic receptor shows that the ligand takes a conformation close to the T(3) arrangement. The effect of aqueous solvation was considered by the free energy perturbation method implemented in Monte Carlo simulations. There are 4-5 strongly bound water molecules in hydrogen bonds to the conformers. Although hydration stabilizes mostly the G2 form with gauche phenyl⋯NH3 + arrangement and a water-exposed NH3 + group, the conformer population becomes T > G1 > G2, in agreement with the PMR spectroscopy measurements by Solmajer et al. (Z. Naturforsch. 1983, 38c, 758). Solvent effects reduce the free energies for barriers to 3-6 and 9-12 kcal/ mol for rotations about the Cβ-Cα and the C1(ring)-Cβ axes, respectively.

Original languageEnglish
Pages (from-to)2770-2785
Number of pages16
JournalJournal of the American Chemical Society
Volume125
Issue number9
DOIs
Publication statusPublished - Mar 5 2003

ASJC Scopus subject areas

  • Chemistry(all)

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