Linking Electrostatic Effects and Protein Motions in Enzymatic Catalysis. A Theoretical Analysis of Catechol <i>O</i>-Methyltransferase

García-Meseguer, Rafael; Zinovjev, Kirill; Roca, Maite; Ruiz‐Pernía, J. Javier; Tuñón, Iñaki

doi:10.1021/jp505746x

Cited by 19 publications

(18 citation statements)

References 79 publications

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“…In particular, the methyl transfer reaction catalyzed by catechol O-methyl transferase (COMT) proceeds from charged reactants (catecholate and S-adenosyl methionine) to neutral products. In that case it was found that the transmission coefficient for the enzymatic TS defined using a simple antisymmetric transfer coordinate was quite high ( 52 ). In addition, the quality of the RC, determined from the committor histogram, was not noticeably improved when optimized, including also a collective environmental coordinate.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the limits of transition state theory in enzymatic catalysis

Zinovjev

Tuñón

2017

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceTransition state theory (TST) is the most popular theory to calculate the rates of enzymatic reactions. However, in some cases TST could fail due to the violation of the nonrecrossing hypothesis at the transition state. In the present work we show that even for one of the most controversial enzymatic reactions—the hydride transfer catalyzed by dihydrofolate reductase—the error associated to TST represents only a minor correction to the reaction rate. Moreover, this error is actually larger for the reaction in solution than in the enzymatic active site. Based on this finding and on previous studies we propose an “enzymatic shielding” hypothesis which encompasses various aspects of the catalytic process.

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Section: Discussionmentioning

confidence: 99%

Quantifying the limits of transition state theory in enzymatic catalysis

Zinovjev

Tuñón

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The activation barriers of the methyl transfer reaction for COMT and its Y68A mutant were evaluated by the empirical valence bond (EVB) method . This method, which is described in details elsewhere and in the Supporting Information, provides a powerful way of obtaining reliable activation free energies, while taking into account the full protein flexibility and configuration space. All the simulations were carried out by the MOLARIS package using the ENZYMIX force field.…”

Section: Methods and Computational Approachesmentioning

confidence: 99%

“…who have proposed that electrostatic preorganization has an important contributions to the rate enhancement in the reaction catalyzed by COMT (see also recent work in Ref. ). Although this study was not done at a sufficiently quantitative level it has provided a reasonable analysis.…”

Section: Introductionmentioning

confidence: 96%

Methyltransferases do not work by compression, cratic, or desolvation effects, but by electrostatic preorganization

et al. 2015

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The enzyme catechol O-methyltransferase (COMT) catalyzes the transfer of a methyl group from S-adenosylmethionine to dopamine and related catechols. The search for the origin of COMT catalysis has led to different proposals and hypothesis, including the entropic, the NAC and the compression proposals as well as the more reasonable electrostatic idea. Thus it is important to understand the catalytic power of this enzyme and to examine the validity of different proposals and in particularly the repeated recent implication of the compression idea. The corresponding analysis should be done by well-defined physically based analysis that involves computations rather than circular interpretations of experimental results. Thus we explore here the origin of the catalytic efficiency of COMT by using the empirical valence bond and the linear response approximation approaches. The results demonstrate that the catalytic effect of COMT is mainly due to electrostatic preorganization effects. It is also shown that the compression, NAC and entropic proposals do not account for the catalytic effect.

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“…S2). Numerous computational studies have attempted to understand the origin of the experimentally measured inverse KIE (15)(16)(17)(18)(27)(28)(29)(30)(31)(32)(33). Using the available X-ray structures for the soluble form of COMT, Lau and Bruice (16) applied classical molecular dynamics (MD) to identify a small subset of ground state structures that bring the donor and acceptor atoms closer than van der Waals distances.…”

mentioning

confidence: 99%

Mediation of donor–acceptor distance in an enzymatic methyl transfer reaction

Zhang

Kulik

Martı́nez

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

147

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Enzymatic methyl transfer, catalyzed by catechol-O-methyltransferase (COMT), is investigated using binding isotope effects (BIEs), time-resolved fluorescence lifetimes, Stokes shifts, and extended graphics processing unit (GPU)-based quantum mechanics/molecular mechanics (QM/MM) approaches. The WT enzyme is compared with mutants at Tyr68, a conserved residue that is located behind the reactive sulfur of cofactor. Small (>1) BIEs are observed for an S-adenosylmethionine (AdoMet)-binary and abortive ternary complex containing 8-hydroxyquinoline, and contrast with previously reported inverse (<1) kinetic isotope effects (KIEs). Extended GPU-based computational studies of a ternary complex containing catecholate show a clear trend in ground state structures, from noncanonical bond lengths for WT toward solution values with mutants. Structural and dynamical differences that are sensitive to Tyr68 have also been detected using time-resolved Stokes shift measurements and molecular dynamics. These experimental and computational results are discussed in the context of active site compaction that requires an ionization of substrate within the enzyme ternary complex.ethyltransferases are widely distributed in nature, playing critical roles in metabolic transformations, natural product biosynthesis (1, 2), and cellular regulation via the reversible methylation of proteins and nucleic acids (3-5). The ability to understand the origin of catalysis within this class of reactions is crucial to any efforts at protein redesign (6, 7) or inhibition (5,8,9). Catechol-O-methyltransferase (COMT), a drug target for a number of neurological diseases, emerged early as a prototype for mechanistic investigations (8,10,11). A compelling and unusual feature of COMT catalysis is the presence of a large inverse kinetic isotope effect (KIE) during transfer of the methyl group from the cofactor S-adenosylmethionine (AdoMet) to catechol acceptor. Comparison of the enzymatic behavior with a model reaction in solution led to the proposal of a role for transition state compression in enzymatic rate acceleration (12-18).Over the past decade, there has been a major shift in focus away from a historical interpretation of enzyme catalysis within the context of static 3D protein structures. Increasingly, protein motions are seen as integral to protein function at every level, from ligand binding to allosteric control and enzyme catalysis (19)(20)(21)(22). Models for catalysis that depend on such protein motions have been particularly important in the area of C-H activation, where the transfer of hydrogen by tunneling mechanisms implicates a critical dependence of the reaction rate on barrier width, and not just barrier height (23,24). Achievement of the tunneling-ready state requires a transient sampling of enzymatic ground states that achieves a reduced distance between the H-donor and acceptor (25). This feature raises the question of whether the reported inverse KIE in COMT could result from ground state interactions that bring about catalytically re...

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Linking Electrostatic Effects and Protein Motions in Enzymatic Catalysis. A Theoretical Analysis of Catechol O-Methyltransferase

Cited by 19 publications

References 79 publications

Quantifying the limits of transition state theory in enzymatic catalysis

Quantifying the limits of transition state theory in enzymatic catalysis

Methyltransferases do not work by compression, cratic, or desolvation effects, but by electrostatic preorganization

Mediation of donor–acceptor distance in an enzymatic methyl transfer reaction

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