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  • 1
    Electronic Resource
    Electronic Resource
    The coordination chemistry of the structural zinc ion in alcohol dehydrogenase studied by ab initio quantum chemical calculations (1996)
    Springer
    European biophysics journal 24 (1996), S. 213-221 
    Details
    ISSN: 1432-1017
    Keywords: Combined quantum chemical and molecular geometry optimisations ; Solvent cavity models ; Protein strain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract The coordination chemistry of the structural zinc ion in horse liver alcohol dehydrogenase has been examined by quantum chemical geometry optimisations. It is shown that all four cysteine ligands are deprotonated in the enzyme, not only two of them as has been suggested. The Zn-S bond lengths are very sensitive to the theoretical treatment; in vacuum they are predicted to be 15 pm longer than in the crystal structure. Half of this discrepancy is due to electronic correlation, the rest can be attributed to screening of the negative sulphide charges by the enzyme, in particular by N-H-S hydrogen bonds. The potential surface is rather flat, so the large difference in geometry between the crystal and the vacuum structure corresponds to an energy change of less than 35 kJ/mol. The experimental bond lengths can be reproduced only with methods that account explicitly for the enzyme. A dielectric continuum model gives bond lengths which are too long, indicating that the enzyme solvates the coordination sphere better than water. Thus, the structural zinc ion can be used as a sensitive test of methods which try to model the surrounding medium in quantum chemical computations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00205102
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  • 2
    Electronic Resource
    Electronic Resource
    On the role of strain in blue copper proteins (2000)
    Springer
    JBIC 5 (2000), S. 565-574 
    Details
    ISSN: 1432-1327
    Keywords: Blue copper proteins Quantum chemical calculations Entatic state theory Induced-rack theory Protein strain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract. Theoretical investigations of the structure and function of the blue copper proteins are described. We have studied the optimum vacuum geometry of oxidised and reduced copper sites, the relative stability of trigonal and tetragonal Cu(II) structures, the relation between the structure and electronic spectra, the reorganisation energy, and reduction potentials. Our calculations give no support to the suggestion that strain plays a significant role in the function of these proteins; on the contrary, our results show that the structures encountered in the proteins are close to their optimal vacuum geometries (within 7 kJ/mol). We stress the importance of defining what is meant by strain and of quantifying strain energies or forces in order to make strain hypotheses testable.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007750000147
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  • 3
    Electronic Resource
    Electronic Resource
    On the significance of the trigger reaction in the action of the calicheamicin γ1I anti-cancer drug (1997)
    Springer
    Theoretical chemistry accounts 97 (1997), S. 203-210 
    Details
    ISSN: 1432-2234
    Keywords: Key words: Bergman reaction ; Calicheamicin ; Integral-direct MP2 ; Parallel MP2 ; Trigger reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract. The significance of the so-called trigger reaction in the reaction mechanism of the calicheamicin γ1 I anti-cancer drug has been studied with ab initio quantum chemical methods. The structures of four fragments of calicheamicin γ1 I , consisting of either 39 or 41 atoms, have been fully optimized using the Becke-Perdew86 density functional method and the 6-31G* basis sets. The four structures constitute members of an isodesmic reaction for which the reaction energy is a direct measure of the change in activation energy of the Bergman reaction, caused by the structural rearrangements of the preceding trigger reaction. This difference in activation energy has been calculated with density functional theory, using the exchange-correlation functional mentioned above, and with second-order Møller-Plesset perturbation theory (MP2), employing an ANO-type basis set. In both cases a value of 12 kcal/mol is obtained. The study firmly supports the hypothesis that the significance of the trigger reaction is to saturate a double bond in the vicinity of the enediyne group, which counteracts the formation of the biradical state of the drug. The MP2 computations became feasible by a novel implementation of an integral-direct, distributed-data, parallel MP2 algorithm.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002140050254
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  • 4
    Electronic Resource
    Electronic Resource
    The coordination of the catalytic zinc ion in alcohol dehydrogenase studied by combined quantum-chemical and molecular mechanics calculations (1996)
    Springer
    Journal of computer aided molecular design 10 (1996), S. 153-164 
    Details
    ISSN: 1573-4951
    Keywords: Geometry optimisation ; Five-coordination ; Reaction mechanism ; Geometry imposed by enzyme ; Protein strain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The coordination number of the catalytic zinc ion in alcohol dehydrogenase has been studied by integrated ab initio quantum-chemical and molecular mechanics geometry optimisations involving the whole enzyme. A four-coordinate active-site zinc ion is 100–200 kJ/mol more stable than a five-coordinate one, depending on the ligands. The only stable binding site for a fifth ligand at the zinc ion is opposite to the normal substrate site, in a small cavity buried behind the zinc ion. The zinc coordination sphere has to be strongly distorted to accommodate a ligand in this site, and the ligand makes awkward contacts with surrounding atoms. Thus, the results do not support proposals attributing an important role to five-coordinate zinc complexes in the catalytic mechanism of alcohol dehydrogenase. The present approach makes it possible also to quantify the strain induced by the enzyme onto the zinc ion and its ligands; it amounts to 42–87 kJ/mol for four-coordinate active-site zinc ion complexes and 131–172 kJ/mol for five-coordinate ones. The four-coordinate structure with a water molecule bound to the zinc ion is about 20 kJ/mol less strained than the corresponding structure with a hydroxide ion, indicating that the enzyme does not speed up the reaction by forcing the zinc coordination sphere into a structure similar to the reaction intermediates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402823
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  • 5
    Electronic Resource
    Electronic Resource
    The coordination chemistry of the catalytic zinc ion in alcohol dehydrogenase studied by ab initio quantum chemical calculations (1994)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 52 (1994), S. 1229-1243 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The coordination chemistry of the zinc ion in the active site of alcohol dehydrogenase has been studied by the ab initio Hartree-Fock method. Geometry optimizations were performed using analytical gradients and basis sets of double-zeta quality. Correlation effects were included at the MP2 level. The active site was modeled by Zn(HS)2XL(H2O)0-2, where X denotes ammonia or imidazole and L denotes water, methanol, ethanol, or the corresponding aldehydes or anions. It is shown that with uncharged L-ligands the four-coordinate complexes are about 20, 17, and 40kJ/mol more stable than are the corresponding three-, five-, and six-coordinate complexes, respectively. If the L-ligand is negatively charged, only the four-coordinate complexes are stable. These results suggest that the active-site zinc ion in alcohol dehydrogenase prefers a coordination number of four during the catalytic reaction, especially when the nonprotein ligand is negatively charged. Ligand exchange at the zinc ion is likely to proceed by an associative mechanism with intermittent formation of a five-coordinate complex. The results lend no support to mechanistic proposals attributing an important catalytic role to a negatively charged five-coordinate hydroxide or alkoxide ligand. © 1994 John Wiley & Sons, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560520508
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  • 6
    Electronic Resource
    Electronic Resource
    Comparison of methods for deriving atomic charges from the electrostatic potential and moments (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 19 (1998), S. 377-395 
    Details
    ISSN: 0192-8651
    Keywords: atomic charges ; copper complexes ; electrostatic potential charges ; molecular simulation ; rank-deficiency problems ; Chemistry ; Theoretical, Physical and Computational Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: Four methods for deriving partial atomic charges from the quantum chemical electrostatic potential (CHELP, CHELPG, Merz-Kollman, and RESP) have been compared and critically evaluated. It is shown the charges strongly depend on how and where the potential points are selected. Two alternative methods are suggested to avoid the arbitrariness in the point-selection schemes and van der Waals exclusion radii: CHELP-BOW, which also estimates the charges from the electrostatic potential, but with potential points that are Boltzmann-weighted after their occurrence in actual simulations using the energy function of the program in which the charges will be used, and CHELMO, which estimates the charges directly from the electrostatic multipole moments. Different criteria for the quality of the charges are discussed. The CHELMO method gives the best multipole moments for small and medium-sized polar systems, whereas the CHELP-BOW charges reproduce best the total interaction energy in actual simulations. Among the standard methods, the Merz-Kollman charges give the best moments and potentials, but they show an appreciable dependence on the orientation of the molecule.We have also examined the recent warning that charges derived by a least-squares fit to the electrostatic potential normally are not statistically valid. It is shown that no rank-deficiency problems are encountered for molecules with up to 84 atoms if the least-squares fit is performed using pseudoinverses calculated by singular value decomposition and if constraints are treated by elimination.   © 1998 John Wiley & Sons, Inc.   J Comput Chem 19: 377-395, 1998
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Molecular dynamics simulations of alcohol dehydrogenase with a four- or five-coordinate catalytic zinc ion (1995)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 21 (1995), S. 40-56 
    Details
    ISSN: 0887-3585
    Keywords: zinc parameterization ; effective force-field ; four-coordination ; five-coordination ; reaction mechanism ; ligand exchange ; bond length constraint ; ligand dynamics ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A detailed parameterization is presented of a zinc ion with one histidine and two cysteinate ligands, together with one or two water, hydroxide, aldehyde, alcohol, or alkoxide ligands. The parameterization is tailored for the active site of alcohol dehydrogenase and is obtained entirely from quantum chemical computations. The force-field reproduces excellently the geometry of quantum chemically optimized zinc complexes as well as the crystallographic geometry of the active site of alcohol dehydrogenase and small organic structures. The parameterization is used in molecular dynamics simulations and molecular mechanical energy minimizations of alcohol dehydrogenase with a four- or five-coordinate catalytic zinc ion. The active-site zinc ion seems to prefer four-coordination over five-coordination by at least 36 kJ/mol. The only stable binding site of a fifth ligand at the active-site zinc ion is opposite to the normal substrate site, in a narrow cavity behind the zinc ion. Only molecules of the size of water or smaller may occupy this site. There are large fluctuations in the geometry of the zinc coordination sphere. A four-coordinate water molecule alternates frequently (every 7 ps) between the substrate site and the fifth binding site and even two five coordinate water molecules may interchange ligation sites without prior dissociation. Ligand exchange at the zinc ion probably proceeds by a dissociative mechanism. The results show that it is essential to allow for bond stretching degrees of freedom in molecular dynamics simulations to get a correct description of the dynamics of the metal coordination sphere; bond length constraints may restrict the accessible part of the phase space and therefore lead to qualitatively erroneous results. © 1995 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340210106
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