On Transition Structures for Hydride Transfer Step in Enzyme Catalysis. A Comparative Study on Models of Glutathione Reductase Derived from Semiempirical, HF, and DFT Methods

Andrés, Juán; Moliner, Vicent; Safont, Vicent S.; Domingo, Luís R.; Picher, M. Teresa

doi:10.1021/jo960803y

Cited by 25 publications

(18 citation statements)

References 122 publications

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“…This conformation is conserved among all the tDBDFs, further supporting the experimental evidence indicating similarity in the reductive half-reaction, especially when viewed in the context of the broad variations they exhibit in both substrates and interaction partners (Figure 5). A number of studies provide evidence that this conserved orientation is optimal for hydride transfer from the pro-S position [24, 25]. Molecular orbital calculations on model compounds show that an endo configuration between the hydride donor and hydride acceptor minimizes the transition state energy [25].…”

Section: Resultsmentioning

confidence: 99%

Evolution of Function in the “Two Dinucleotide Binding Domains” Flavoproteins

2007

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Structural and biochemical constraints force some segments of proteins to evolve more slowly than others, often allowing identification of conserved structural or sequence motifs that can be associated with substrate binding properties, chemical mechanisms, and molecular functions. We have assessed the functional and structural constraints imposed by cofactors on the evolution of new functions in a superfamily of flavoproteins characterized by two-dinucleotide binding domains, the “two dinucleotide binding domains” flavoproteins (tDBDF) superfamily. Although these enzymes catalyze many different types of oxidation/reduction reactions, each is initiated by a stereospecific hydride transfer reaction between two cofactors, a pyridine nucleotide and flavin adenine dinucleotide (FAD). Sequence and structural analysis of more than 1,600 members of the superfamily reveals new members and identifies details of the evolutionary connections among them. Our analysis shows that in all of the highly divergent families within the superfamily, these cofactors adopt a conserved configuration optimal for stereospecific hydride transfer that is stabilized by specific interactions with amino acids from several motifs distributed among both dinucleotide binding domains. The conservation of cofactor configuration in the active site restricts the pyridine nucleotide to interact with FAD from the re-side, limiting the flow of electrons from the re-side to the si-side. This directionality of electron flow constrains interactions with the different partner proteins of different families to occur on the same face of the cofactor binding domains. As a result, superimposing the structures of tDBDFs aligns not only these interacting proteins, but also their constituent electron acceptors, including heme and iron-sulfur clusters. Thus, not only are specific aspects of the cofactor-directed chemical mechanism conserved across the superfamily, the constraints they impose are manifested in the mode of protein–protein interactions. Overlaid on this foundation of conserved interactions, nature has conscripted different protein partners to serve as electron acceptors, thereby generating diversification of function across the superfamily.

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Section: Resultsmentioning

confidence: 99%

Evolution of Function in the “Two Dinucleotide Binding Domains” Flavoproteins

2007

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“…Such structural changes have been noted in ab initio model studies on hydride transfer between two nicotinamide rings (21). In contrast to the previous calculations on model systems (9)(10)(11), our calculations are able to identify the important role of the enzyme on transition state structure and energetics. Thus, the human enzyme yields a lower barrier and earlier transition state than the e.coli enzyme (Table I), which is reflected in the smaller KIE calculated for the human enzyme (Table II).…”

Section: Hydride Transfer and Kinetic Isotope Effects In Glutathione mentioning

confidence: 54%

“…These reactions have traditionally been studied theoretically using a range of quantum mechanical methods, applied to considerably simplified models of the actual biological system (9)(10)(11). Both the degree of realism of the model system and the level of sophistication of the quantum mechanical treatment have progressively advanced, with a recent study involving the use of density functional theory (DFT) methods (10). Such calculations are often directed towards interpretation of the measured kinetic isotope effects (KIE) associated with the hydride transfer.…”

Section: The Hybrid Modelmentioning

confidence: 99%

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Modelling of Transition States in Condensed Phase Reactivity Studies

Burton

Harrison

Hillier

et al. 1999

ACS Symposium Series

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In this Chapter we describe the calculation of transition states for condensed phase reactions involving catalysis by an enzyme and by a titanosilicate. Transition structures for hydride transfer between NADPH and FAD in the enzyme glutathione reductase have been determined using a QM/MM potential, for two forms of the enzyme, e. coli and human. Both the transition state structures and energies, and the associated kinetic isotope effects are found to differ for the two enzymes. A cluster has been used to model the transition state for alkene epoxidation by hydrogen peroxide, catalysed by titanosilicates, predicting attack of the oxygen atom of the titanium(IV)-hydroperoxide intermediate that is closer to the metal centre.The majority of chemical processes and all biochemical ones occur in the condensed, rather than the gas phase. Methods for modelling the potential energy surfaces associated with gas phase reactions are well established and widely available in quantum chemistry packages. Here, for small and medium size systems results of a "chemical" accuracy may be obtained using widely available distributed computational resources. There is now increasing effort to achieve this degree of realism for condensed phase systems, particularly to understand reactivity and catalysis and hence to aid molecular design across a range of important chemical areas. It is to solve these problems that the traditional methods of both computational chemistry and solid state physics are now being focused. In the latter area, periodic calculations based upon a plane wave pseudopotential (PWP) approach, incorporating the work of Car and Parrinello to permit dynamical simulations to be performed, have been used to study solid state structure and

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“…Ab initio studies have been performed to understand the enzyme activity of carboxypeptidase A (e.g., Refs. [36,54]) and alcohol dehydrogenase [55,56]. In general, these studies have focused on models for the active site [57] while neglecting the role of the remainder of the protein.…”

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confidence: 99%

Models for protein–zinc ion binding sites. II. The catalytic sites*

Deerfield

Carter

Pedersen

2001

Int J of Quantum Chemistry

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ABSTRACT:The first and selected members of the second coordination shells for four model protein-Zn(II) ion catalytic sites have been studied using ab initio computational methodology. The influence of deprotonation on the structure and relative energetics of model complexes was examined. Significant lengthening of the Zn(II)-S, Zn(II)-O, and Zn(II)-N ionic distance is observed as the negative charge about the Zn(II) ion increases. In a model Escheridia coli cytidine deaminase site, we find a substantial lengthening of the Zn-SH 2 ionic distance in the active site, which corresponds to the lengthening found for transition state analogs in X-ray crystal structures. The lowest energy complex of a sulfur-containing ligand was found to be singly deprotonated, with the complex having an overall charge of +1. The deprotonation of any ligand in a model complex for thermolysin, on the other hand, was found to be endothermic. The influence of other ligands of the metal ion, along with second-shell ligands, on the energy requirement for deprotonation was also examined for other model systems.

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On Transition Structures for Hydride Transfer Step in Enzyme Catalysis. A Comparative Study on Models of Glutathione Reductase Derived from Semiempirical, HF, and DFT Methods

Cited by 25 publications

References 122 publications

Evolution of Function in the “Two Dinucleotide Binding Domains” Flavoproteins

Evolution of Function in the “Two Dinucleotide Binding Domains” Flavoproteins

Modelling of Transition States in Condensed Phase Reactivity Studies

Models for protein–zinc ion binding sites. II. The catalytic sites*

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