Barrier passage and protein dynamics in enzymatically catalyzed reactions

Antoniou, Dimitri; Caratzoulas, Stavros; Kalyanaraman, Chakrapani; Mincer, Joshuas S.; Schwartz, Steven D.

doi:10.1046/j.1432-1033.2002.03021.x

Cited by 142 publications

(170 citation statements)

References 68 publications

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“…Several phenomenological models were developed in recent years that fall under the title Marcus-like models (e.g. Borgis et al 1989;Borgis & Hynes 1993, 1996Antoniou et al 2002;Sutcliffe & Scrutton 2002;Kohen 2003Kohen , 2005). All these models were constructed assuming that rates and KIEs can be measured for a single kinetic step (the chemical step), and thus are relevant to the experimental measurements described here.…”

Section: Results and Discussion (A) Competitive Primary Kinetic Isotomentioning

confidence: 99%

The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductase

Wang

Goodey

Benkovic

et al. 2006

Phil. Trans. R. Soc. B

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Residues M42 and G121 of Escherichia coli dihydrofolate reductase (ecDHFR) are on opposite sides of the catalytic centre (15 and 19 Å away from it, respectively). Theoretical studies have suggested that these distal residues might be part of a dynamics network coupled to the reaction catalysed at the active site. The ecDHFR mutant G121V has been extensively studied and appeared to have a significant effect on rate, but only a mild effect on the nature of H-transfer. The present work examines the effect of M42W on the physical nature of the catalysed hydride transfer step. Intrinsic kinetic isotope effects (KIEs), their temperature dependence and activation parameters were studied. The findings presented here are in accordance with the environmentally coupled hydrogen tunnelling. In contrast to the wild-type (WT), fluctuations of the donor-acceptor distance were required, leading to a significant temperature dependence of KIEs and deflated intercepts. A comparison of M42W and G121V to the WT enzyme revealed that the reduced rates, the inflated primary KIEs and their temperature dependences resulted from an imperfect potential surface prearrangement relative to the WT enzyme. Apparently, the coupling of the enzyme's dynamics to the reaction coordinate was altered by the mutation, supporting the models in which dynamics of the whole protein is coupled to its catalysed chemistry.

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Section: Results and Discussion (A) Competitive Primary Kinetic Isotomentioning

confidence: 99%

The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductase

Wang

Goodey

Benkovic

et al. 2006

Phil. Trans. R. Soc. B

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“…Using this framework, it is possible to return to studies of several different systems [91][92][93] that were used to argue for the mode coupling idea. In this respect we like to clarify that having correlated motions does not present a new view on catalysis because even in solutions we have highly correlated structural changes.…”

Section: Mode Coupling Dynamical Effects and Compressionmentioning

confidence: 99%

Perspective: Defining and quantifying the role of dynamics in enzyme catalysis

Warshel

Bora

2016

The Journal of Chemical Physics

190

168

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Enzymes control chemical reactions that are key to life processes, and allow them to take place on the time scale needed for synchronization between the relevant reaction cycles. In addition to general interest in their biological roles, these proteins present a fundamental scientific puzzle, since the origin of their tremendous catalytic power is still unclear. While many different hypotheses have been put forward to rationalize this, one of the proposals that has become particularly popular in recent years is the idea that dynamical effects contribute to catalysis. Here, we present a critical review of the dynamical idea, considering all reasonable definitions of what does and does not qualify as a dynamical effect. We demonstrate that no dynamical effect (according to these definitions) has ever been experimentally shown to contribute to catalysis. Furthermore, the existence of non-negligible dynamical contributions to catalysis is not supported by consistent theoretical studies. Our review is aimed, in part, at readers with a background in chemical physics and biophysics, and illustrates that despite a substantial body of experimental effort, there has not yet been any study that consistently established a connection between an enzyme’s conformational dynamics and a significant increase in the catalytic contribution of the chemical step. We also make the point that the dynamical proposal is not a semantic issue but a well-defined scientific hypothesis with well-defined conclusions.

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“…There has also been considerable recent debate over the role of protein dynamics in the mediation of enzyme reaction and tunnelling events, and a number of related theories have been proposed to explain the experimental kinetic data (Antoniou et al 2002;Sutcliffe & Scrutton 2002;Kim & Hammes-Schiffer 2003;Klinman 2003;Knapp & Klinman 2003;Schwartz 2003;Warshel & Villa-Freixa 2003;Mincer & Schwartz 2004). Both molecular simulation and experimental kinetics have been used to study the role of promoting vibrations in a range of enzymes, mainly concentrating on liver alcohol dehydrogenase, dihydrofolate reductase and soybean lipoxygenase, and to ask if key amino acid residues may be involved to enhance catalysis (Billeter et al 2001;; Mincer & Schwartz 2003;Sikorski et al 2004).…”

Section: Introductionmentioning

confidence: 99%

An analysis of reaction pathways for proton tunnelling in methylamine dehydrogenase

Núñez

Tresadern

Hillier

et al. 2006

Phil. Trans. R. Soc. B

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Computational methods have now become a valuable tool to understand the way in which enzymes catalyse chemical reactions and to aid the interpretation of a diverse set of experimental data. This study focuses on the influence of the condensed-phase environment structure on proton transfer mechanisms, with an aim to understand how C-H bond cleavage is mediated in enzymatic reactions. We shall use a combination of molecular simulation, ab initio or semi-empirical quantum chemistry and semi-classical multidimensional tunnelling methods to consider the primary kinetic isotope effects of the enzyme methylamine dehydrogenase (MADH), with reference to an analogous application to triosephosphate isomerase. Analysis of potentially reactive conformations of the system, and correlation with experimental isotope effects, have highlighted that a quantum tunnelling mechanism in MADH may be modulated by specific amino acid residues, such as Asp428, Thr474 and Asp384.Keywords: proton tunnelling; methylamine dehydrogenase; enzyme catalysis; kinetic isotope effects; triosephosphate isomerase; quantum mechanical and molecular mechanical computational methods

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Barrier passage and protein dynamics in enzymatically catalyzed reactions

Cited by 142 publications

References 68 publications

The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductase

The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductase

Perspective: Defining and quantifying the role of dynamics in enzyme catalysis

An analysis of reaction pathways for proton tunnelling in methylamine dehydrogenase

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