title: Theoretical conformational analysis for neurotransmitters in the gas phase and in aqueous solution. Norepinephrine.
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.NH(3)(+) gauche and HO(alc).NH(3)(+) gauche arrangements. A strained intramolecular hydrogen bond was found for conformers (G1 and T) with close NH(3)(+) and OH groups. Upon rotation of the NH(3)(+) 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.NH(3)(+) arrangement and a water-exposed NH(3)(+) 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.
authors.affiliation: Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, Ohio 43606-3390, USA. pnagy@utnet.utoledo.edu
authors.forename: Peter I
authors.initials: PI
authors.lastname: Nagy
authors.forename: Giuliano
authors.initials: G
authors.lastname: Alagona
authors.forename: Caterina
authors.initials: C
authors.lastname: Ghio
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Novák
mesh_terms: D000588:Amines / Q000737:chemistry; D003198:Computer Simulation; D005740:Gases; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D009010:Monte Carlo Method; D009638:Norepinephrine / Q000737:chemistry*; D011199:Potentiometry; D011487:Protein Conformation; D011943:Receptors, Adrenergic, beta / Q000737:chemistry; D012996:Solutions; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D000588:Amines; D005740:Gases; D011943:Receptors, Adrenergic, beta; D012996:Solutions; D014867:Water; D009638:Norepinephrine