Studying the role of protein dynamics in an SN2 enzyme reaction using free-energy surfaces and solvent coordinates

García-Meseguer, Rafael; Martí, Sérgio; Ruiz‐Pernía, J. Javier; Moliner, Vicent; Tuñón, Iñaki

doi:10.1038/nchem.1660

Cited by 52 publications

(60 citation statements)

References 54 publications

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“…Because this is a fully atomistic calculation, it is capable of including the effects of possible fast protein motions coupled to the reactive event with a time scale similar to the chemical barrier crossing, an effect that (if it exists) would have been omitted in computational studies that treat the protein as an ensemble average. For example, a recent study 34 that suggests that protein dynamics play no important part in the reaction projects the protein system, with many thousand degrees of freedom, onto a two-dimensional surface. Our group has found indications of direct coupling of protein dynamics to reaction in horse liver alcohol dehydrogenase (HLADH) 35 and felt it likely that similar dynamics occurs in YADH as well.…”

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confidence: 99%

Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling

Dzierlenga

Antoniou

Schwartz

2015

J. Phys. Chem. Lett.

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The mechanisms involved in enzymatic hydride transfer have been studied for years, but questions remain due, in part, to the difficulty of probing the effects of protein motion and hydrogen tunneling. In this study, we use transition path sampling (TPS) with normal mode centroid molecular dynamics (CMD) to calculate the barrier to hydride transfer in yeast alcohol dehydrogenase (YADH) and human heart lactate dehydrogenase (LDH). Calculation of the work applied to the hydride allowed for observation of the change in barrier height upon inclusion of quantum dynamics. Similar calculations were performed using deuterium as the transferring particle in order to approximate kinetic isotope effects (KIEs). The change in barrier height in YADH is indicative of a zero-point energy (ZPE) contribution and is evidence that catalysis occurs via a protein compression that mediates a near-barrierless hydride transfer. Calculation of the KIE using the difference in barrier height between the hydride and deuteride agreed well with experimental results.

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confidence: 99%

Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling

Dzierlenga

Antoniou

Schwartz

2015

J. Phys. Chem. Lett.

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“…[13][14][15] To model chemical reactions in enzymes, hybrid QM/MM methods combining a quantum description of the active-site region with a classical description of the rest of the enzyme and of the solvent are widely employed. However, a series of recent studies [16][17][18][19] have underlined the need for a proper sampling of the protein configurations, since different conformations may lead to different catalytic rates.…”

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confidence: 99%

Coupled Valence-Bond State Molecular Dynamics Description of an Enzyme-Catalyzed Reaction in a Non-Aqueous Organic Solvent

et al. 2017

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Enzymes are widely used in nonaqueous solvents to catalyze non-natural reactions. While experimental measurements showed that the solvent nature has a strong effect on the reaction kinetics, the molecular details of the catalytic mechanism in nonaqueous solvents have remained largely elusive. Here we study the transesterification reaction catalyzed by the paradigm subtilisin Carlsberg serine protease in an organic apolar solvent. The rate-limiting acylation step involves a proton transfer between active-site residues and the nucleophilic attack of the substrate to form a tetrahedral intermediate. We design the first coupled valence-bond state model that simultaneously describes both reactions in the enzymatic active site. We develop a new systematic procedure to parametrize this model on high-level ab initio QM/MM free energy calculations that account for the molecular details of the active site and for both substrate and protein conformational fluctuations. Our calculations show that the reaction energy barrier changes dramatically with the solvent and protein conformational fluctuations. We find that the mechanism of the tetrahedral intermediate formation during the acylation step is similar to that determined under aqueous conditions, and that the proton transfer and nucleophilic attack reactions occur concertedly. We identify the reaction coordinate to be mostly due to the rearrangement of some residual water molecules close to the active site.

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“…In the context of enzymatic catalysis, the mechanisms by which protein fluctuations are coupled to the reactive events are still under debate [14][15][16], but it is becoming increasingly evident that characteristic motions of the protein, present in the native state, preferentially follow the pathways that create the configuration optimum for catalysis [11]. Some of these pathways can be analysed by classical molecular dynamics (MD) simulations [13], whereas subtle motions of active site residues, often coupled to electronic rearrangements, can be captured by quantum chemical and ab initio MD approaches [17] such as the Car-Parrinello (CP) method.…”

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confidence: 99%

Car-Parrinello Simulations of Chemical Reactions in Proteins

Rovira

2014

Protein Modelling

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Studying the role of protein dynamics in an SN2 enzyme reaction using free-energy surfaces and solvent coordinates

Cited by 52 publications

References 54 publications

Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling

Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling

Coupled Valence-Bond State Molecular Dynamics Description of an Enzyme-Catalyzed Reaction in a Non-Aqueous Organic Solvent

Car-Parrinello Simulations of Chemical Reactions in Proteins

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