Computational design of biological catalysts

Martí, Sérgio; Andrés, Juán; Moliner, Vicent; Silla, Estanislao; Tuñón, Iñaki; Bertrán, Juan

doi:10.1039/b710705f

Cited by 43 publications

(36 citation statements)

References 36 publications

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“…It can probe enzymatic mechanisms at the atomic level which is generally hard to be experimentally explored [1,2,3,4,5]. Ever since the pioneer study by Warshel and Levitt on a realistic enzyme system in 1976 [6], the QM/MM technique has been improved and widely applied.…”

Section: Introductionmentioning

confidence: 99%

How Many Conformations of Enzymes Should Be Sampled for DFT/MM Calculations? A Case Study of Fluoroacetate Dehalogenase

Zhang

et al. 2016

IJMS

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The quantum mechanics/molecular mechanics (QM/MM) method (e.g., density functional theory (DFT)/MM) is important in elucidating enzymatic mechanisms. It is indispensable to study “multiple” conformations of enzymes to get unbiased energetic and structural results. One challenging problem, however, is to determine the minimum number of conformations for DFT/MM calculations. Here, we propose two convergence criteria, namely the Boltzmann-weighted average barrier and the disproportionate effect, to tentatively address this issue. The criteria were tested by defluorination reaction catalyzed by fluoroacetate dehalogenase. The results suggest that at least 20 conformations of enzymatic residues are required for convergence using DFT/MM calculations. We also tested the correlation of energy barriers between small QM regions and big QM regions. A roughly positive correlation was found. This kind of correlation has not been reported in the literature. The correlation inspires us to propose a protocol for more efficient sampling. This saves 50% of the computational cost in our current case.

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Section: Introductionmentioning

confidence: 99%

How Many Conformations of Enzymes Should Be Sampled for DFT/MM Calculations? A Case Study of Fluoroacetate Dehalogenase

Zhang

et al. 2016

IJMS

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“…7 Random mutations or recombination can be done to evolve proteins in the laboratory identifying the successful variants by screening or by selection. New proteins with new desired functions can be obtained after some mutations or recombining protein fragments.…”

Section: Introductionmentioning

confidence: 99%

“…In a review published in 2008, we already distinguished between “structure-based strategies” and “reaction analysis-based strategies”. 7 Enzyme designs based in a ‘theozyme’ would fall in the first category while the limitations pointed out in current strategies could be overcome with methods that make use of the analysis of reaction profiles. Obviously the computational cost of this second strategy, which is based in the use of Molecular Dynamics (MD) with hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) potentials, is much higher and then it has to be used in combination with the first one.…”

Section: Introductionmentioning

confidence: 99%

“…5,7,9,11,38,39,40,41,42,43,44,45 This review will focus mainly on the advances obtained in the field of the de novo design during the last years, emphasizing the new achievements of the different computational strategies employed in the design process. The three aforementioned reactions, Kemp, Diels-Alder and retro-aldolase, will be used to illustrate these points.…”

Section: Introductionmentioning

confidence: 99%

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Computational strategies for the design of new enzymatic functions

Świderek

Tuñón

Moliner

et al. 2015

Archives of Biochemistry and Biophysics

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In this contribution, recent developments in the design of biocatalysts are reviewed with particular emphasis in the de novo strategy. Studies based on three different reactions, Kemp elimination, Diels-Alder and retro-aldolase, are used to illustrate different success achieved during the last years. Finally, a section is devoted to the particular case of designed metalloenzymes. As a general conclusion, the interplay between new and more sophisticated engineering protocols and computational methods, based on molecular dynamics simulations with Quantum Mechanics/Molecular Mechanics potentials and fully flexible models, seems to constitute the bed rock for present and future successful design strategies.

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“…As commented in a previous review, the knowledge of the differences between RC and TS could be used as a guide the design bio-catalysts. 44 …”

Section: Introductionmentioning

confidence: 99%

Computational Studies of Candida Antarctica Lipase B to Test Its Capability as a Starting Point To Redesign New Diels–Alderases

Świderek

Moliner

2015

J. Phys. Chem. B

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The design of new biocatalysts is a target that is receiving increasing attention. One of the most popular reactions in this regard is the Diels-Alder cycloaddition due to its applications in organic synthesis and the absence of efficient natural enzymes that catalyze it. In this paper, the possibilities of using the highly promiscuous Candida Antarctica lipase B (CALB) as a protein scaffold to re-design a Diels-Alderase has been explored by means of theoretical quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Free energy surfaces have been computed for two reactions in the wild-type and in several mutants with hybrid AM1/MM potentials with corrections at M06-2X/MM level. The study of the counterpart reactions in solution has allowed performing comparative analysis that render interesting conclusion. Since the dienophile anchors very well in the oxyanion hole of all tested protein variants, the slight electronic changes from reactant complex to the transition state suggest that mutations should be focused in favoring the formation of reactive conformations of reactant complex that, in turn, would reduce the energy barrier.

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Computational design of biological catalysts

Cited by 43 publications

References 36 publications

How Many Conformations of Enzymes Should Be Sampled for DFT/MM Calculations? A Case Study of Fluoroacetate Dehalogenase

How Many Conformations of Enzymes Should Be Sampled for DFT/MM Calculations? A Case Study of Fluoroacetate Dehalogenase

Computational strategies for the design of new enzymatic functions

Computational Studies of Candida Antarctica Lipase B to Test Its Capability as a Starting Point To Redesign New Diels–Alderases

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