Biomedical subjects

Adriana Dinescu

Publications and source records attributed to Adriana Dinescu.

7 recordsLinked to original sources

PubMed2006

Catalytic loop motion in human glutathione synthetase: A molecular modeling approach.

Conformational changes of three flexible loops (G, A, and S) in human glutathione synthetase (hGS) arise to accommodate the substrates inside the active site. The crystal structure of hGS, a member of the ATP-grasp superfamily, has been reported only for the product-enzyme complex. To study the function of the hGS loops, molecular dynamics simulations are performed on three different conformational models: unbound enzyme, reactant-enzyme, and product-enzyme complex of hGS. The conformational changes among the three models are analyzed and the roles of the loops during the catalytic process are described. The modeled structures of hGS show that the central portions of the G- and A-loop have a double role in the reactant complex conformation: they bind the substrates and simultaneously interact with each other through an extensive network of hydrogen bonds. The present study proposes that these favorable loop-ligand and loop-loop interactions are required for opening and closing of the active site of hGS. Additionally, this research identifies important amino acid residues and explains their function within the catalytic loops of hGS.

Amino Acid Sequence↗

PubMed2006

The correlation-consistent composite approach: application to the G3/99 test set.

The correlation-consistent composite approach (ccCA), an ab initio composite technique for computing atomic and molecular energies, recently has been shown to successfully reproduce experimental data for a number of systems. The ccCA is applied to the G3/99 test set, which includes 223 enthalpies of formation, 88 adiabatic ionization potentials, 58 adiabatic electron affinities, and 8 adiabatic proton affinities. Improvements on the original ccCA formalism include replacing the small basis set quadratic configuration interaction computation with a coupled cluster computation, employing a correction for scalar relativistic effects, utilizing the tight-d forms of the second-row correlation-consistent basis sets, and revisiting the basis set chosen for geometry optimization. With two types of complete basis set extrapolation of MP2 energies, ccCA results in an almost zero mean deviation for the G3/99 set (with a best value of -0.10 kcal mol(-1)), and a 0.96 kcal mol(-1) mean absolute deviation, which is equivalent to the accuracy of the G3X model chemistry. There are no optimized or empirical parameters included in the computation of ccCA energies. Except for a few systems to be discussed, ccCA performs as well as or better than Gn methods for most systems containing first-row atoms, while for systems containing second-row atoms, ccCA is an improvement over Gn model chemistries.

Journal Article↗

PubMed2006

Oxygen atom transfer energetics: assessment of the effect of method and solvent.

Several density functional methods, the semiempirical methods AM1 and PM3, Hartree-Fock, and Gaussian3 theories were applied to compute the oxygen atom transfer enthalpies for 14 X/XO couples (inorganic and organic systems, charged and neutral species, light and heavy main group element containing molecules). The calculated reaction enthalpies were compared to available experimental data. The G3 method alone was found to perform within the experimental error, while the popular B3LYP and BLYP functionals provided inadequate results. Solvent effects were estimated for 19 neutral and anionic X/XO couples by using the conductor-like polarizable continuum model and several cavity models coupled with the B3LYP/6-31++G(2d,2p) level of theory. Surprisingly, the magnitude of the aqueous solvent correction was found to vary significantly for different solute cavity models, occasionally giving larger errors than the gas-phase calculation.

Computer Simulation↗

PubMed2006

The butterfly dimer [(tBu3SiO)Cr]2(mu-OSitBu3)2 and its oxidative cleavage to (tBu3SiO)2Cr(=N-N=CPh2)2 and (tBu3SiO)2Cr=N(2,6-Ph2-C6H3).

Treatment of CrCl2(THF)2 with NaOSitBu3 afforded the butterfly dimer [(tBu3SiO)Cr]2(mu-OSitBu3)2 (1(2)), whose d(CrCr) of 2.658(31) A and magnetism were indicative of strong antiferromagnetic coupling. A Boltzmann distribution of low-energy 1A1, 3B1, 5A1, 7B1, and 9A1 states obtained from calculations on [(HO)2Cr]2(muOH)2 (1'(2)) were used to provide a reasonable fit of the mu(eff) vs T data. Cleavage of 1(2) with various L (L = 4-picoline, p-tolunitrile, tBuCN, tBuNC, Ph2CO, and PMe3) generated (tBu3SiO)2CrL2 (1-L2). The dimer was oxidatively severed by Ph2CN2 to give (tBu3SiO)2Cr(N2CPh2)2 (2) and by RN3 at 23 degrees C to afford (silox)2Cr=NR (3-R) for bulky R (adamantyl (Ad), 2,6-iPr2-C6H3, 2,4,6-Me3-C6H2 = Mes, 2,6-Ph2-C6H3) and (tBu3SiO)2Cr(=NR)2 (4-R) for smaller substituents (R = 1-Naph, 2-Anth). X-ray structural studies were conducted on 1(2), square planar 1-(OCPh2)2, pseudo-Td 2 and pseudo-trigonal 3-(2,6-Ph2-C6H3), whose S = 1 ground state was discussed on the basis of calculations of (H3SiO)2Cr=NPh (3' '-Ph).

Journal Article↗

PubMed2005

A T-shaped three-coordinate nickel(I) carbonyl complex and the geometric preferences of three-coordinate d9 complexes.

A three-coordinate diketiminate-nickel(I) complex with a carbonyl ligand has been characterized using EPR and IR spectroscopies and X-ray crystallography. The T geometry (bending from the sterically favored C(2)(v)() structure) contrasts with that of isosteric d(9) copper(II) complexes. DFT calculations on a truncated model reproduce experimental geometries, implying that the geometric differences are electronic in nature. Analysis of the charge distribution in the complexes shows that the geometry of the three-coordinate d(9) complexes is affected by differential charge donation of the ligands to the metal center.

Journal Article↗

PubMed2004

Function of conserved residues of human glutathione synthetase: implications for the ATP-grasp enzymes.

Glutathione synthetase is an enzyme that belongs to the glutathione synthetase ATP-binding domain-like superfamily. It catalyzes the second step in the biosynthesis of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner. Glutathione synthetase has been purified and sequenced from a variety of biological sources; still, its exact mechanism is not fully understood. A variety of structural alignment methods were applied and four highly conserved residues of human glutathione synthetase (Glu-144, Asn-146, Lys-305, and Lys-364) were identified in the binding site. The function of these was studied by experimental and computational site-directed mutagenesis. The three-dimensional coordinates for several human glutathione synthetase mutant enzymes were obtained using molecular mechanics and molecular dynamics simulation techniques, starting from the reported crystal structure of human glutathione synthetase. Consistent with circular dichroism spectroscopy, our results showed no major changes to overall enzyme structure upon residue mutation. However, semiempirical calculations revealed that ligand binding is affected by these mutations. The key interactions between conserved residues and ligands were detected and found to be essential for enzymatic activity. Particularly, the negatively charged Glu-144 residue plays a major role in catalysis.

Adenosine Triphosphate↗

PubMedDate not supplied

Stability studies of transition-metal linkage isomers using quantum mechanical methods. Groups 11 and 12 transition metals.

Several hypotheses to elucidate the linkage isomer preference of the thiocyanate (SCN(-)) ion have been offered. For complexes with small coordination numbers (i.e., 1 and 2) and groups 11 (Cu-triad) and 12 (Zn-triad) metals, different levels of theory and a variety of basis sets have been employed to study linkage isomerism. Similar results are obtained for all density functionals tested, pure and hybrid. Overall, good agreement, vis-à-vis experimentally identified linkage isomers, is achieved for ab initio techniques, whereas semiempirical quantum mechanical methods show a bias toward S-ligated isomers. Despite the seeming ease for the a priori prediction of the most stable thiocyanate isomers using acid/base principles, this research highlights the sensitivity of quantitative calculations of transition-metal linkage isomerism to the choice of basis set and electron correlation, particularly with post-Hartree-Fock treatments.

Journal Article↗