Ab initio and empirical methods were combined to optimize the partial atomic charges and Lennard-Jones parameters for two halogenated compounds, halothane (CF3CHClBr, a potent volatile anesthetic) and hexafluoroethane (CF3CF3, a nonanesthetic). Charge optimization was achieved using empirical calculations by systematically adjusting the charge assignments to fit minimum interaction energies and geometries between a TIP3 water molecule and the halogenated compounds to the corresponding values from the ab initio calculations, which were carried out at the HF/6-311+G(2d,p) and HF/6-31G(d) levels for halothane and hexafluoroethane, respectively. To optimize the Lennard-Jones parameters, the initial estimates were obtained from scaling the values from the ab initio minimum interaction energies and geometries between neon and the halogenated compounds calculated at the MP3/6-311++G(3d,3p) level. The Lennard-Jones parameters were further refined by fitting the empirical interaction energies to the corresponding ab initio values. The refined parameters were finalized by reproducing experimental values of the heats of vaporization and densities for liquid halothane and hexafluoroethane, using molecular dynamics simulations. The calculated heats of vaporization and liquid densities using the optimized parameters are in excellent agreement with the experimental values. The results indicate that the combination of ab initio and empirical approaches works well for obtaining the nonbonded parameters of molecules with heavy halogen atoms, such as Cl and Br. The refined nonbonded parameters are readily applicable in molecular dynamics simulations involving these halogenated compounds.

Density functional theory calculations of electron paramagnetic resonance (EPR) parameters, such as electronic g tensors and metal hyperfine interaction (A) tensors, have been completed for a series of VO2+ complexes. g tensors were calculated with the zeroth-order regular approximation (ZORA) for relativistic effects as incorporated into the Amsterdam Density Functional (ADF) program. The A tensors were calculated by relativistic and nonrelativistic methods as implemented in ADF and Gaussian98 programs, respectively. The best overall agreement with experimental A values was obtained with the nonrelativistic method and the half-and-half hybrid functionals, such as BHPW91, BHP86, and BHLYP. The isotropic A values (A iso) calculated nonrelativistically with the BHPW91 functional deviated by about 10% from the experimental A iso values. The A iso values calculated with the relativistic effects and pure generalized gradient correction (GGA) functionals, such as BP86, deviated systematically by approximately 40% compared to the experimental A iso values. The difference in performance of the two methods for these complexes is attributed to the improved performance of hybrid functionals for treating core shell spin polarization. The calculation of the anisotropic or dipolar hyperfine interactions, A D, was less sensitive to the choice of functional, and therefore, the relativistic and nonrelativistic calculations of A D exhibited comparable accuracy.

A three-dimensional model of the transmembrane domain of a neuronal-type nicotinic acetylcholine receptor (nAChR), (alpha4)2(beta2)3, was constructed from a homology structure of the muscle-type nAChR recently determined by cryo-electron microscopy. The neuronal channel model was embedded in a fully hydrated DMPC lipid bilayer, and molecular-dynamics simulations were performed for 5 ns. A comparative analysis of the neuronal- versus muscle-type nAChR models revealed many conserved pore-lining residues, but an important difference was found near the periplasmic mouth of the pore. A flickering salt-bridge of alpha4-E266 with its adjacent beta2-K260 was observed in the neuronal-type channel during the course of the molecular-dynamics simulations. The narrowest region, with a pore radius of approximately 2 A formed by the salt-bridges, does not seem to be the restriction site for a continuous water passage. Instead, two hydrophobic rings, formed by alpha4-V259, alpha4-L263, and the homologous residues in the beta2-subunits, act as the gates for water flow, even though the region has a slightly larger pore radius. The model offers new insight into the water transport across the (alpha4)2(beta2)3 nAChR channel, and may lead to a better understanding of the structures, dynamics, and functions of this family of ion channels.

A ternary mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and cholesterol (CHOL) works effectively for a functional conformation of nicotinic acetylcholine receptor (nAChR) that can undergo agonist-induced conformation changes, but POPC alone can stabilize only a desensitized state of nAChR. To gain insights into the lipid mixture that have strong impact to nAChR functions, we performed more than 50-ns all atom molecular dynamic (MD) simulations at 303 K on a fully hydrated bilayer consisting of 240 POPC, 80 POPA, and 80 CHOL (3:1:1). The MD simulation revealed various interactions between different types of molecular pairs that ultimately regulated lipid organization. The heterogeneous interactions among three different constituents resulted in a broad spectrum of lipid properties, including extensive distribution of average area per lipids and varied lipid ordering as a function of lipid closeness to CHOL. Higher percentage of POPA than POPC had close association with CHOL, which coincided with relatively higher ordering of POPA molecules in their acyl chains near lipid head groups. Lower fraction of gauche dihedrals was also found in the same region of POPA. Although the CHOL molecules had the effects on the enhancement of surrounding lipid order, relatively low lipid order parameters and high fraction of gauche bonds were observed in the ternary mixture. Collectively, these results suggest that the dynamical structure of the ternary system could be determinant for a functional nAChR.

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The vanadium hyperfine coupling constant for vanadyl−imidazole complexes depends on the orientation of the imidazole ring with respect to the vanadyl bond as illustrated by a recent electron paramagnetic resonance (EPR) study of vanadyl−imidazole model complexes (Pecoraro, et al. J. Am. Chem. Soc. 2000, 122, 767). In the study reported here, density functional theory (DFT) calculations of EPR hyperfine and quadrupole coupling constants for a model complex, [VO(imid)(H2O)4]2+, were used to elucidate the orientation dependence of the vanadium and nitrogen hyperfine coupling constants for an equatorially coordinated imidazole ligand. The computational results for the orientation dependence of the vanadium hyperfine coupling constant reproduce the functional dependence (A ∥(imidazole) = A + B sin(2θ − 90)) observed in the experimental EPR data. The computational results predict similar orientation dependence for the vanadium quadrupole coupling constant and for the nitrogen hyperfine coupling constant for the coordinated nitrogen of the imidazole ligand. These results have important implications for EPR and pulsed EPR studies of vanadoproteins.

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Relativistic density functional theory (DFT) calculations of transition metal hyperfine interaction (A) tensors have been completed for a series of Cu 2+ complexes including Cu(Quin) 2 , Cu(Acac) 2 , Cu(L-AlaO) 2 , and [Cu(Ox) 2 ] 2-. The A tensors were calculated with the zero order regular approximation (ZORA) for relativistic effects as implemented in the Amsterdam Density Functional (ADF) program. For the isotropic hyperfine coupling constant, the agreement between the calculated and experimental values was quite good, but the good agreement was determined to be a result of a cancellation of errors due to the neglect of spin-orbit coupling and an underestimation of core spin polarization. The anisotropic components of the hyperfine coupling constant calculated with the scalar-relativistic spin-restricted open-shell Kohn Sham (SO + SR ROKS) method provided the best agreement with experimental values.