Computational strategies for the design of new enzymatic functions

Świderek, Katarzyna; Tuñón, Iñaki; Moliner, Vicent; Bertrán, Juan

doi:10.1016/j.abb.2015.03.013

Cited by 49 publications

(41 citation statements)

References 163 publications

(209 reference statements)

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“…These flexible models are now possible thanks to advances in quantum chemistry methods and QM/MM in particular, which provide a more accurate potential for enzymatic complexes. 83 This also unlocks new possibilities and access to novel protein folds.…”

Section: Recognized Limitations and Improvement Strategymentioning

confidence: 95%

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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: Recognized Limitations and Improvement Strategymentioning

confidence: 95%

“…Standard Model for de novo enzyme design 83. The theozyme is built around thetransition state geometry resolved by quantum chemistry methods and matched to a pre-existing scaffold.…”

mentioning

confidence: 99%

Computational Design of Synthetic Enzymes

2018

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“…The Kemp elimination reaction is also catalyzed in different environments, such as amino-cyclodextrins, cationic micelles, synzymes, serum albumins and antibodies. [2,29] It is worth mentioning the large dependence of the reaction rate on the solvent when one uses acetate as the base B (see Scheme 1). Aprotic organic solvents dramatically catalyze the reaction.…”

Section: Introductionmentioning

confidence: 99%

Kemp Elimination Reaction Catalyzed by Electric Fields

et al. 2020

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The Kemp elimination reaction is the most widely used in the de novo design of new enzymes. The effect of two different kinds of electric fields in the reactions of acetate as a base with benzisoxazole and 5‐nitrobenzisoxazole as substrates have been theoretically studied. The effect of the solvent reaction field has been calculated using the SMD continuum model for several solvents; we have shown that solvents inhibit both reactions, the decrease of the reaction rate being larger as far as the dielectric constant is increased. The diminution of the reaction rate is especially remarkable between aprotic organic solvents and protic solvents as water, the electrostatic term of the hydrogen bonds being the main factor for the large inhibitory effect of water. The presence of an external electric field oriented in the direction of the charge transfer (z axis) increases it and, so, the reaction rate. In the reaction of the nitro compound, if the electric field is oriented in an orthogonal direction (x axis) the charge transfer to the NO2 group is favored and there is a subsequent increase of the reaction rate. However, this increase is smaller than the one produced by the field in the z axis. It is worthwhile mentioning that one of the main effects of external electric fields of intermediate intensity is the reorientation of the reactants. Finally, the implications of our results in the de novo design of enzymes are discussed.

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“…In the review of Alexandra Vardi-Kilshtain, Neta Nitoker and Dan Major, [3] progresses in the development of multi-scale simulation methods for the calculation of nuclear quantum effects (NQE) and accurate computation of kinetic isotope effects and Juan Bertran. [7] Based on three different reactions, Kemp elimination, Diels-Alder and retro-aldolase, the different success achieved during the last years are illustrated. As a general conclusion, the authors conclude that the interplay between new and more sophisticated engineering protocols and computational methods, based on molecular dynamics simulations with multi-scale methods and fully flexible models, seems to constitute the bed rock for present and future successful design strategies.…”

Section: Special Issue In Computational Modelingmentioning

confidence: 99%

Special issue in computational modeling on biological systems

Moliner

2015

Archives of Biochemistry and Biophysics

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(Spain)This Special Issue is centered on questions concerning the difficulties and recent advances in the computational modeling of biological systems. Despite the expression "biological system" can enroll many different phenomena, it is focused on biochemical processes related with living organisms and, more specifically, in the foundations and applications achieved by the use of the computational chemistry on enzymatic processes and functional proteins. Enzymes are biological catalysts that speed up chemical reactions making them compatible with life. Apart from this catalytic power, often these catalysts show important advantages with respect to non-natural catalysts such as their chemo-, regio-and stereoselectivity, or the ability to work under mild conditions of temperature and pressure, which makes them the best environmental friendly catalysts to speed up the rate of chemical reactions. Nevertheless, although there have been numerous studies that have provided a solid understanding about some of the key factors of these biocatalysts, the knowledge about the origin of enzymatic efficiency to catalyze chemical reactions is still not complete. Advances in this field will contribute for their application in industry but, in order to extend their applicability to different purposes, we need a deeper understanding of their way of action. In this regard, the combination of experimental techniques and computer simulations pave the way to a quicker development in the field. The more we learn about the foundations of processes governing chemical processes in living organisms (including our bodies and cells), the better position we will have to control them with the corresponding benefits in fields such as biomedicine, biotechnology, pharmacy, etc. Thus, we could say that the developments and advances on computer simulations are closely linked to the improvements in quality of live in our planet.This special issue contains contributions from leading experts on different sub-themes of computer simulations of enzyme related problems, starting with a review by Martin

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Computational strategies for the design of new enzymatic functions

Cited by 49 publications

References 163 publications

Computational Design of Synthetic Enzymes

Computational Design of Synthetic Enzymes

Kemp Elimination Reaction Catalyzed by Electric Fields

Special issue in computational modeling on biological systems

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