Modeling zinc in biomolecules with the self consistent charge‐density functional tight binding (SCC‐DFTB) method: Applications to structural and energetic analysis

Elstner, Marcus; Cui, Qiang; Munih, Petra; Kaxiras, Efthimios; Frauenheim, Thomas; Karplus, Martin

doi:10.1002/jcc.10201

Cited by 162 publications

(258 citation statements)

References 114 publications

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“…At pH 10.50 the bridging water molecule is fully ionized; therefore, a single proton is transferred but cannot come from the deprotonation of the bridging water/hydroxide moiety. Formation of a bridging hydroxide is favored by ϳ200 kcal/mol, as shown by theoretical calculations, which results in a more rigid environment around the metal ions (18). Therefore, the Zn(II) ions appear to be responsible for the proper positioning of the hydroxyl group, as proposed in the catalytic mechanism (2), and this hydroxyl group interacts with Glu-151.…”

Section: Temperature Dependence Of K Cat and K M For E151d-aap-mentioning

confidence: 87%

“…8). Deprotonation of the metal-bound water molecule to form a nucleophilic hydroxide moiety is particularly important at pH values lower than 7.0, the postulated pK a of the bridging water molecule, yet appears not to be the ratelimiting step based on higher stability of the -hydroxo bridge (18). Once the metal-bound hydroxide is formed, it can attack the activated carbonyl carbon of the peptide substrate forming a gem-diolate transition state complex that is stabilized by coordination of both oxygen atoms to the dizinc(II) center, consistent with the x-ray crystal structure of [ZnZn(AAP)] bound by L-leucine phosphonic acid (21).…”

Section: Temperature Dependence Of K Cat and K M For E151d-aap-mentioning

confidence: 99%

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The Catalytic Role of Glutamate 151 in the Leucine Aminopeptidase from Aeromonas proteolytica

Bzymek

Holz

2004

Journal of Biological Chemistry

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Glutamate 151 has been proposed to act as the general acid/base during the peptide hydrolysis reaction catalyzed by the co-catalytic metallohydrolase from Aeromonas proteolytica (AAP). However, to date, no direct evidence has been reported for the role of Glu-151 during catalytic turnover by AAP. In order to elucidate the catalytic role of Glu-151, altered AAP enzymes have been prepared in which Glu-151 has been substituted with a glutamine, an alanine, and an aspartate. The Michaelis constant (K m ) does not change upon substitution to aspartate or glutamine, but the rate of the reaction changes drastically in the following order: glutamate (100% activity), aspartate (0.05%), glutamine (0.004%), and alanine (0%). Examination of the pH dependence of the kinetic constants k cat and K m revealed a change in the pK a of a group that ionizes at pH 4.8 in recombinant leucine aminopeptidase (rAAP) to 4.2 for E151D-AAP. The remaining pK a values at 5.2, 7.5, and 9.9 do not change. Proton inventory studies indicate that one proton is transferred in the rate-limiting step of the reaction at pH 10.50 for both rAAP and E151D-AAP, but at pH 6.50 two protons and general solvation effects are responsible for the observed effects in the reaction catalyzed by rAAP and E151D-AAP, respectively. Based on these data, Glu-151 is intrinsically involved in the peptide hydrolysis reaction catalyzed by AAP and can be assigned the role of a general acid and base.

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Section: Temperature Dependence Of K Cat and K M For E151d-aap-mentioning

confidence: 87%

Section: Temperature Dependence Of K Cat and K M For E151d-aap-mentioning

confidence: 99%

The Catalytic Role of Glutamate 151 in the Leucine Aminopeptidase from Aeromonas proteolytica

Bzymek

Holz

2004

Journal of Biological Chemistry

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“…DFTB calculations of Zn active sites give relatively good agreement with B3LYP for distances and most reaction energies. 59 Modeling of substrate binding in a dinuclear Zn-β-lactamase show relatively similar Zn-ligand distances for DFTB/MM simulations compared to B3LYP calculations (usually within 0.1 Å for reactants and intermediates).…”

Section: B Zn-β-lactamase -Various Active Site Modelsmentioning

confidence: 93%

Case Studies of ONIOM(DFT:DFTB) and ONIOM(DFT:DFTB:MM) for Enzymes and Enzyme Mimics

Lundberg

Sasakura

Zheng

et al. 2010

J. Chem. Theory Comput.

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The replacement of standard molecular mechanics force fields by inexpensive molecular orbital (QM') methods in multi-scale models has many advantages, e.g., a more straightforward description of mutual polarization and charge transfer between layers. The ONIOM(QM:QM') scheme with mechanical embedding can combine any two methods without prior parameterization or significant coding effort. In this scheme the environmental effect is evaluated fully at the QM' level and the accuracy therefore depends on how well the low-level QM' method describes the changes in electron density of the reacting region. To examine the applicability of the QM:QM' approach we perform case studies with density- Polarization effects are fairly well described using DFTB, but in some cases QM and QM' methods converge to different electronic states. We discuss when the QM:QM' approach is appropriate and the possibilities of estimating the quality of the ONIOM extension without having to make explicit benchmarks of the entire system. 3

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“…Recent work in the development of SCC-DFTB has focused on the pragmatic advancement of the model, and has resulted in new, efficient, and ever-improving methods, 4,[12][13][14] parameters, 9,[15][16][17][18] and computer codes. 2,19,20 The approach we have chosen is quite different, in that we start from an ab initio-like model that reproduces DFT results very well without the use of parameters, and then identify where and quantify by how much the model breaks down when various approximations are introduced.…”

Section: Introductionmentioning

confidence: 99%

Density-functional expansion methods: Generalization of the auxiliary basis

Giese¹,

York²

2011

The Journal of Chemical Physics

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The formulation of density-functional expansion methods is extended to treat the second and higherorder terms involving the response density and spin densities with an arbitrary single-center auxiliary basis. The two-center atomic orbital products are represented by the auxiliary functions centered about those two atoms, and the mapping coefficients are determined from a local constrained variational procedure. This two-center variational procedure allows the mapping coefficients to be pretabulated and splined as a function of internuclear separation for efficient look up. The splines of mapping coefficients have a range no longer than that of the overlap integrals, and the auxiliary density appears as a single point-multipole expansion to all nonoverlapping atoms, thus allowing for the trivial implementation of a linear-scaling algorithm. The method is tested using Gaussian multipole expansions, and the effect of angular and radial completeness is explored. Several auxiliary basis sets are parametrized and compared to an auxiliary basis analogous to that used in the selfconsistent-charge density-functional tight-binding model, and the method is demonstrated to greatly improve the representation of the density response with respect to a reference expansion model that does not use an auxiliary basis.

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Modeling zinc in biomolecules with the self consistent charge‐density functional tight binding (SCC‐DFTB) method: Applications to structural and energetic analysis

Cited by 162 publications

References 114 publications

The Catalytic Role of Glutamate 151 in the Leucine Aminopeptidase from Aeromonas proteolytica

The Catalytic Role of Glutamate 151 in the Leucine Aminopeptidase from Aeromonas proteolytica

Case Studies of ONIOM(DFT:DFTB) and ONIOM(DFT:DFTB:MM) for Enzymes and Enzyme Mimics

Density-functional expansion methods: Generalization of the auxiliary basis

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