Influence of Stacking on Hydrogen Bonding:  Quantum Chemical Study on Pyridine−Benzene Model Complexes

Mignon, Pierre; Loverix, Stefan; Proft, Frank De; Geerlings, Pau̧l

doi:10.1021/jp049240h

Cited by 122 publications

(119 citation statements)

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“…Although TvNH lacks a general acid, it is equally catalytically proficient to nucleoside hydrolases from other sources (17). We have previously shown that, instead of employing general acid catalysis, TvNH activates the leaving purine base by increasing the N7 basicity (hence favoring its protonation) via a parallel aromatic stacking interaction with the indole side chain of Trp-260 (8,24). The high level ab initio calculations presented here rule out a previously presumed stabilizing catalytic interaction between 5ЈO and 4ЈO.…”

Section: Discussionmentioning

confidence: 63%

Substrate-assisted Leaving Group Activation in Enzyme-catalyzed N-Glycosidic Bond Cleavage

Loverix

Geerlings

McNaughton

et al. 2005

Journal of Biological Chemistry

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In enzymatic depurination of nucleosides, the 5-OH group of the ribose moiety of the substrate is often shown to contribute substantially to catalysis. The purine-specific nucleoside hydrolase from Trypanosoma vivax (TvNH) fixes the 5-OH group in a gauche,trans orientation about the C4-C5 bond, enabling the 5-oxygen to accept an intramolecular hydrogen bond from the C8-atom of the purine leaving group. High level ab initio quantum chemical calculations indicate that this interaction promotes protonation of the purine at N7. Steady state kinetics comprising engineered substrates confirm that a considerable fraction of the catalytic 5-OH effect can be attributed to leaving group activation.In enzyme-catalyzed ribosyl transfer reactions on nucleosides (e.g. hydrolysis, phosphorolysis), the 5Ј-hydroxyl group of the substrate has often been implicated in catalysis (1-4). Inverse 4Ј-3 H and normal 5Ј-3 H kinetic isotope effects are commonly observed, contrary to the non-enzymatic reactions, and have been invoked to account for a strained conformation of the 5Ј-OH group in the transition state (5). However, care must be taken in the interpretation of these kinetic isotope effects because they may be caused by binding rather then catalysis (6). The present study on the purine-specific nucleoside hydrolase (EC 3.2.2.1) of Trypanosoma vivax (TvNH) 1 aims to elucidate the catalytic role of the 5Ј-OH group, which contributes 5.4 kcal/mol to k cat /K m (1).The putative transition state for enzymatic cleavage of Nglycosidic bonds is generally highly dissociative with substantial lengthening of the scissile bond but no bond formation to the incoming nucleophile (5, 7). The transition state has a high ribo-oxocarbenium character with sp 2 hybridization at C1Ј and a C3Ј-exo pucker. In purine nucleosides, departure of the leaving group is facilitated by protonation at N7 prior to reaching the transition state. In the base aspecific 2 NH of Crithidia fasciculata a histidine residue has been identified as the general acid to accomplish this. However, a remarkable feature of the TvNH enzyme is the apparent lack of an acidic group to protonate the leaving purine. In this enzyme, x-ray crystallography and mutagenic scanning analysis did not reveal a suitable general acid candidate (1). Rather, a tryptophan (Trp-260) was found to be the only catalytic residue in the vicinity of the purine leaving group. A previous study combining quantum chemical calculations, mutagenesis, and presteady state kinetics revealed that an aromatic stacking interaction between Trp-260 and the purine ring contributes to catalysis by raising the basicity of the latter (8). Because enhanced basicity facilitates protonation by solvent, it appears that the TvNH enzyme employs specific, rather than general, acid catalysis.Depurination by TvNH is further catalyzed by interactions with the three hydroxyls of the ribose moiety of the substrate, because the 2Ј-, 3Ј-, and 5Ј-deoxy nucleosides are severely impaired in binding and catalysis (1). The inosine bound in t...

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Section: Discussionmentioning

confidence: 63%

Substrate-assisted Leaving Group Activation in Enzyme-catalyzed N-Glycosidic Bond Cleavage

Loverix

Geerlings

McNaughton

et al. 2005

Journal of Biological Chemistry

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“…In addition, both BH&H and MP2/6-31G(0.25)* perform much better than the MP2/ aug-cc-pVDZ calculations reported in ref. 24, where binding energy is overestimated on average by of 5.27 kJ mol Ϫ1 . Sinnokrot and Sherrill ascribed the trends in binding energy along this series to the subtle interplay of electrostatic, dispersion, and exchange forces.…”

Section: Resultsmentioning

confidence: 96%

“…Geerlings and coworkers 24 have achieved similar results, analysing the stacking of substituted benzene-pyridine complexes to study the interplay of stacking and hydrogen bonding. In particular, they showed that the H-bond capacity of pyridine is closely related to the electron-donating/withdrawing character of substituents on the benzene ring, while the stacking energy is less dependent on those properties.…”

Section: Introductionmentioning

confidence: 77%

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Hybrid density functional theory for π‐stacking interactions: Application to benzenes, pyridines, and DNA bases

et al. 2006

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The suitability of a hybrid density functional to qualitatively reproduce geometric and energetic details of parallel pi-stacked aromatic complexes is presented. The hybrid functional includes an ad hoc mixture of half the exact (HF) exchange with half of the uniform electron gas exchange, plus Lee, Yang, and Parr's expression for correlation energy. This functional, in combination with polarized, diffuse basis sets, gives a binding energy for the parallel-displaced benzene dimer in good agreement with the best available high-level calculations reported in the literature, and qualitatively reproduces the local MP2 potential energy surface of the parallel-displaced benzene dimer. This method was further critically compared to high-level calculations recently reported in the literature for a range of pi-stacked complexes, including monosubstituted benzene-benzene dimers, along with DNA and RNA bases, and generally agrees with MP2 and/or CCSD(T) results to within +/-2 kJ mol(-1). We also show that the resulting BH&H binding energy is closely related to the electron density in the intermolecular region. The net result is that the BH&H functional, presumably due to fortuitous cancellation of errors, provides a pragmatic, computationally efficient quantum mechanical tool for the study of large pi-stacked systems such as DNA.

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“…The minimum Fukui function principle captures the irrelevance of the frontier orbitals but misses the fact that electrostatic interactions normally dominate hard-hard interactions. [67,68,72] In contrast to the well studied local softness, few studies of the local hardness are reported in the literature, mainly by our group using the local hardness as an indicator for charge concentration in studies on zeolite-catalyzed reactions, [73][74][75] noncovalent intermolecular interactions, [76][77][78][79][80] and local HSAB. [81] Then, one of the goals of this work is to see if the local hardness is able to locate the hardest reactive sites in a molecule.…”

Section: Introductionmentioning

confidence: 99%

Do the Local Softness and Hardness Indicate the Softest and Hardest Regions of a Molecule?

Torrent‐Sucarrat¹,

Proft²,

Geerlings³

et al. 2008

Chemistry A European J

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In this work, we will show that the largest values of the local softness and hardness do not necessarily correspond to the softest and hardest regions of the molecule, respectively. Based on our results, we will argue that it is more useful to interpret the local softness and the local hardness as functions that measure the "local abundance" or "concentration" of the corresponding global properties. This new point of view helps reveal how and when these local reactivity indices are most useful.

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Influence of Stacking on Hydrogen Bonding: Quantum Chemical Study on Pyridine−Benzene Model Complexes

Cited by 122 publications

References 115 publications

Substrate-assisted Leaving Group Activation in Enzyme-catalyzed N-Glycosidic Bond Cleavage

Substrate-assisted Leaving Group Activation in Enzyme-catalyzed N-Glycosidic Bond Cleavage

Hybrid density functional theory for π‐stacking interactions: Application to benzenes, pyridines, and DNA bases

Do the Local Softness and Hardness Indicate the Softest and Hardest Regions of a Molecule?

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