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

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*HHF/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 C-beta-C-alpha. 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 beta-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 C-beta-C-alpha and the C-1(ring)-C-beta axes, respectively.