Quantifying the limits of transition state theory in enzymatic catalysis

Zinovjev, Kirill; Tuñón, Iñaki

doi:10.1073/pnas.1710820114

Cited by 31 publications

(31 citation statements)

References 61 publications

(85 reference statements)

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“…The friction concept is a convenient way to express the effect of enzymatic degrees of freedom on a given reaction coordinate, by viewing it as an effective friction acting against the advancing of the system past the coordinate. In our treatment, for enzymes acting on their natural substrates under physiological conditions, this effect can be seen as a small perturbation of the equilibrium description assumed in transition state theory . In nature, an enzyme's active site is preorganised to work with specific substrates at a given temperature.…”

Section: Dihydrofolate Reductasesupporting

confidence: 89%

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Heavy Enzymes and the Rational Redesign of Protein Catalysts

Scott

Luk

Tuñón³

et al. 2019

ChemBioChem

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An unsolved mystery in biology concerns the link between enzyme catalysis and protein motions. Comparison between isotopically labelled “heavy” dihydrofolate reductases and their natural‐abundance counterparts has suggested that the coupling of protein motions to the chemistry of the catalysed reaction is minimised in the case of hydride transfer. In alcohol dehydrogenases, unnatural, bulky substrates that induce additional electrostatic rearrangements of the active site enhance coupled motions. This finding could provide a new route to engineering enzymes with altered substrate specificity, because amino acid residues responsible for dynamic coupling with a given substrate present as hotspots for mutagenesis. Detailed understanding of the biophysics of enzyme catalysis based on insights gained from analysis of “heavy” enzymes might eventually allow routine engineering of enzymes to catalyse reactions of choice.

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Section: Dihydrofolate Reductasesupporting

confidence: 89%

“…The active site reorganisation needed to accommodate the charge distribution of the chemical step takes place on a different timescale from the transition state crossing. Hence, protein motions will have their greatest impact before or after the chemical step …”

Section: Dihydrofolate Reductasesupporting

confidence: 88%

Heavy Enzymes and the Rational Redesign of Protein Catalysts

Scott

Luk

Tuñón³

et al. 2019

ChemBioChem

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“…Note, for example that in Section 2.1 we pointed out that the ideal location for the dividing surface was guaranteed to be identical to the location of the conventional TS only in one dimension. It has been proven that the inclusion of solvent coordinates in the calculation of the PMF can give a more complete picture of the reaction and even improve the definition of the TS dividing surface to the point where the transmission coefficient is close to unity . This means that, while most PMF use only the solute coordinates (i.e.…”

Section: Limits Of the Frameworkmentioning

confidence: 99%

Re‐Evaluating the Transition State for Reactions in Solution

García-Meseguer

Carpenter

2018

Eur J Org Chem

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In this microreview we revisit the early work in the development of Transition State Theory, paying particular attention to the idea of a dividing surface between reactants and products. The correct location of this surface is defined by the requirement that trajectories not recross it. When that condition is satisfied, the true transition state for the reaction has been found. It is commonly assumed for solution‐phase reactions that if the potential energy terms describing solvent‐solute interactions are small, the true transition state will occur at a geometry close to that for the solute in vacuo. However, we emphasize that when motion of solvent molecules occurs on a time scale similar or longer than that for structural changes in the reacting solute the true transition state may be at an entirely different geometry, and that there is an important inertial component to this phenomenon, which cannot be described on any potential energy surface. We review theories, particularly Grote‐Hynes theory, which have corrected the Transition State Theory rate constant for effects of this kind by computing a reduced transmission coefficient. However, we argue that searching for a true dividing surface with near unit transmission coefficient may sometimes be necessary, especially for the common situation in which the rate‐determining formation of a reactive intermediate is followed by the branching of that intermediate to several products.

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“…11,12 We then explored the reaction mechanism for the formation of the covalent acylenzyme complex (E-I, see equation 1) using QM/MM simulation methods at the hybrid B3LYP/MM level, 13,14 including D3 dispersion corrections, 15 with the 6-31G* and 6-31+G* basis set, as explained in Methods section. The string-method 16,17 was employed to find the reaction minimum free energy paths (MFEP) on multidimensional free energy surfaces defined by a set of Collective Variables (CVs) in which we included those geometrical parameters (bond lengths) suffering noticeable changes during the process. A path-CV (s) was then defined to trace the corresponding free energy profiles.…”

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confidence: 99%

A Microscopic Description of SARS-CoV-2 Main Protease Inhibition with Michael Acceptors. Strategies for Improving Inhibitors Design

Ramos-Guzmán¹,

Ruiz‐Pernía²,

Tuñón

2020

Preprint

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The irreversible inhibition of the main protease of SARS-CoV-2 by a Michael acceptor compound known as N3 has been investigated using multiscale simulation methods. The noncovalent enzyme-inhibitor complex was simulated using classical Molecular Dynamics techniques and the pose of the inhibitor in the active site was compared to that of the natural substrate, a peptide containing the Gln-Ser scissile bond. The formation of the covalent enzyme-inhibitor complex was then simulated using hybrid QM/MM free energy methods. After binding, the reaction mechanism was found to be composed of two steps: i) the activation of the catalytic dyad (Cys145 and His41) to form an ion pair and ii) a Michael addition where the attack of the Sg atom of Cys145 to the Cb atom of the inhibitor precedes the water-mediated proton transfer from His41 to the Ca atom. The microscopic description of protease inhibition by N3 obtained from our simulations is strongly supported by the excellent agreement between the estimated activation free energy and the value derived from kinetic experiments. Comparison with the acylation reaction of a peptide substrate suggest that that N3-based inhibitors could be improving adding chemical modifications that could facilitate the formation of the catalytic dyad ion pair.

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Quantifying the limits of transition state theory in enzymatic catalysis

Cited by 31 publications

References 61 publications

Heavy Enzymes and the Rational Redesign of Protein Catalysts

Heavy Enzymes and the Rational Redesign of Protein Catalysts

Re‐Evaluating the Transition State for Reactions in Solution

A Microscopic Description of SARS-CoV-2 Main Protease Inhibition with Michael Acceptors. Strategies for Improving Inhibitors Design

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