Predicting substituent effects on activation energy changes by static catalytic fields

Chojnacka, Martyna; Feliks, Mikołaj; Beker, Wiktor; Sokalski, W. Andrzej

doi:10.1007/s00894-017-3559-6

Cited by 3 publications

(4 citation statements)

References 20 publications

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“…The demonstration that true catalytic enhancement can be achieved by incorporating electric field optimization in the design process of enzymes is an important future direction in a range of catalytic systems . While Head-Gordon and co-workers have created a top-down approach for optimizing electrostatics of an existing enzyme scaffold through mutations, Sokalski and co-workers − have developed a bottom-up strategy of proposing what would be the optimal electric field environment for a given active site chemistry. Motivated by the role of electric fields in biocatalysis, Coote and co-workers have taken electrostatic design in exciting new directions ranging from synthetic chemistry illustrated by the Diels–Alder reaction to electrocatalysis .…”

Section: Beyond the Standard Model For Enzyme Designmentioning

confidence: 99%

“…104 While the Head-Gordon lab has created a top-down approach for optimizing electrostatics of an existing enzyme scaffold through mutations 175 , Sokalski and co-workers have developed a bottom-up strategy of proposing what would be the optimal electric field environment for a given active site chemistry. [176][177][178] Motivated by the role of electric fields in biocatalysis, Coote and co-workers have taken electrostatic design in exciting new directions ranging from synthetic chemistry illustrated by the Diels Alder reaction 179 to electrocatalysis 180 .…”

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confidence: 99%

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Computational Design of Synthetic Enzymes

2018

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We review the standard model for de novo computational design of enzymes, which primarily focuses on the development of an active site geometry composed of protein functional groups in orientations optimized to stabilize the transition state for a novel chemical reaction not found in nature. Its emphasis is placed on the structure and energetics of the active site embedded in an accommodating protein that serves as a physical support that shields the reaction chemistry from solvent, which is typically improved upon using laboratory directed evolution. We also provide a review of design strategies that move beyond the standard model, by placing more emphasis on the designed enzyme as a whole catalytic construct. Starting with complete de novo enzyme design examples, we consider additional design factors such as entropy of individual residues, correlated motion between side chains (mutual information), dynamical correlations of the enzyme motions that could aid the reaction, reorganization energy, and electric fields as a way to exploit the entire protein scaffold to improve upon the catalytic rate, thereby providing directed evolution with better starting sequences for increasing the biocatalytic performance.

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Section: Beyond the Standard Model For Enzyme Designmentioning

confidence: 99%

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confidence: 99%

Computational Design of Synthetic Enzymes

2018

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“…Although the catalytic field technique has been derived in our laboratory 24 − 26 using the theory of intermolecular interactions, it could be also applied to systems involving intramolecular interactions. The ability to predict catalytic effects resulting from hydrogen to fluorine (H → F) substitutions has been illustrated for two simple model organic reactions, 32 which demonstrates qualitative applicability of this technique to model substrate-assisted catalysis. 33 …”

Section: Introductionmentioning

confidence: 99%

Bottom-Up Nonempirical Approach To Reducing Search Space in Enzyme Design Guided by Catalytic Fields

Beker

Sokalski

2020

J. Chem. Theory Comput.

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Currently developed protocols of theozyme design still lead to biocatalysts with much lower catalytic activity than enzymes existing in nature, and, so far, the only avenue of improvement was the in vitro laboratory-directed evolution (LDE) experiments. In this paper, we propose a different strategy based on “reversed” methodology of mutation prediction. Instead of common “top-down” approach, requiring numerous assumptions and vast computational effort, we argue for a “bottom-up” approach that is based on the catalytic fields derived directly from transition state and reactant complex wave functions. This enables direct one-step determination of the general quantitative angular characteristics of optimal catalytic site and simultaneously encompasses both the transition-state stabilization (TSS) and ground-state destabilization (GSD) effects. We further extend the static catalytic field approach by introducing a library of atomic multipoles for amino acid side-chain rotamers, which, together with the catalytic field, allow one to determine the optimal side-chain orientations of charged amino acids constituting the elusive structure of a preorganized catalytic environment. Obtained qualitative agreement with experimental LDE data for Kemp eliminase KE07 mutants validates the proposed procedure, yielding, in addition, a detailed insight into possible dynamic and epistatic effects.

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“…In another recent work along the same vein, Sokalski and his co-workers used a simple atomic multipole electrostatic model to evaluate the effects of mutation on enzyme activity and tested its performance on several variants of the ketosteroid isomerase (KSI). , In agreement with Boxer’s experimental works, they showed computationally the importance of electrostatic interaction due to the mutations in the active site during catalysis.…”

Section: Designed Local Electric Fields (D-lef)mentioning

confidence: 65%

Local Electric Fields: From Enzyme Catalysis to Synthetic Catalyst Design

Dubey

Stuyver

Shaik³

2022

J. Phys. Chem. B

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This Mini-Review Article outlines recent advances in the study of local electric field (LEF) governed enzyme catalysis and the application of the LEF principle in synthetic catalyst design. We start by discussing the electrostatics principles that drive enzyme catalysis, and its experimental verifications through vibrational Stark spectroscopy. Subsequently, we describe aspects of LEFs other than catalysis, i.e., induction of mechanistic crossovers, among others. Here, we focus on the early work done using computational tools, along with some recent contributions. Following an in-depth discussion of the role of LEFs in enzyme catalysis, we then highlight some recent works on designed local electric fields (D-LEF) and their applications in organic synthesis. Subsequently, we turn to D-LEFs in synthetic enzymes and supramolecular systems (cf. the work by the Head-Gordon group). We end by discussing some of the software packages that have been developed to analyze local electric fields computationally. Overall, the present Mini-Review Article paints an insightful picture of the current state of the art using LEF in enzyme catalysis and its application for further bioengineering and synthetic organic frameworks in a broad perspective.

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Predicting substituent effects on activation energy changes by static catalytic fields

Cited by 3 publications

References 20 publications

Computational Design of Synthetic Enzymes

Computational Design of Synthetic Enzymes

Bottom-Up Nonempirical Approach To Reducing Search Space in Enzyme Design Guided by Catalytic Fields

Local Electric Fields: From Enzyme Catalysis to Synthetic Catalyst Design

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