QM/MM study of<scp>l</scp>-lactate oxidation by flavocytochrome b<sub>2</sub>

Gillet, Natacha; Ruiz‐Pernía, J. Javier; Lande, Aurélien de la; Levy, Bernard C.; Lederer, Florence; Demachy, Isabelle; Moliner, Vicent

doi:10.1039/c6cp00395h

Cited by 10 publications

(7 citation statements)

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“…Conceptual DFT calculations and topological analysis of electron density, which have been applied to P450 and other enzymes [ 174 , 175 ], could provide unprecedented insight into the chemical properties of NOSox active site during oxidation [ [176] , [177] , [178] ]. Use of QM/MM and DFTB-QM/MM metadynamics might also be considered for studying electron transfer from the reductase to the oxygenase domain and identifying the key players involved in this process [ [179] , [180] , [181] ]. Overall, there is a wide range of possibilities for the study of NOS molecular mechanisms with molecular modeling and simulations, opening perspectives that could lead to important breakthroughs on this topic.…”

Section: Discussionmentioning

confidence: 99%

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Bignon

Rizza

Filomeni

et al. 2019

Computational and Structural Biotechnology Journal

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Nitric oxide (NO) is an essential signaling molecule in the regulation of multiple cellular processes. It is endogenously synthesized by NO synthase (NOS) as the product of L-arginine oxidation to L-citrulline, requiring NADPH, molecular oxygen, and a pterin cofactor. Two NOS isoforms are constitutively present in cells, nNOS and eNOS, and a third is inducible (iNOS). Despite their biological relevance, the details of their complex structural features and reactivity mechanisms are still unclear. In this review, we summarized the contribution of computational biochemistry to research on NOS molecular mechanisms. We described in detail its use in studying aspects of structure, dynamics and reactivity. We also focus on the numerous outstanding questions in the field that could benefit from more extensive computational investigations.

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Section: Discussionmentioning

confidence: 99%

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Bignon

Rizza

Filomeni

et al. 2019

Computational and Structural Biotechnology Journal

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“…Oxidation of amines has been analyzed using deuterium and nitrogen isotope effects, and the results are consistent with hydride transfer from the neutral amine [6]. A number of computational studies support these mechanisms [7–12]. …”

mentioning

confidence: 93%

13C kinetic isotope effects on the reaction of a flavin amine oxidase determined from whole molecule isotope effects

Tormos

Suarez

Fitzpatrick

2016

Archives of Biochemistry and Biophysics

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A large number of flavoproteins catalyze the oxidation of amines. Because of the importance of these enzymes in metabolism, their mechanisms have previously been studied using deuterium, nitrogen, and solvent isotope effects. While these results have been valuable for computational studies to distinguish among proposed mechanisms, a measure of the change at the reacting carbon has been lacking. We describe here the measurement of a 13C kinetic isotope effect for a representative amine oxidase, polyamine oxidase. The isotope effect was determined by analysis of the isotopic composition of the unlabeled substrate, N, N'-dibenzyl-1,4-diaminopropane, to obtain a pH-independent value of 1.025. The availability of a 13C isotope effect for flavoproteincatalyzed amine oxidation provides the first measure of the change in bond order at the carbon involved in this carbon-hydrogen bond cleavage and will be of value to understanding the transition state structure for this class of enzymes.

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“…In order to achieve time scales relevant to biological processes, a classical interaction potential, or force field, is typically used. Although approximate, these models are a vital part of developing the mechanistic, thermodynamic, and kinetic understanding of biological phenomena including but not limited to enzyme catalysis, − protein folding, − protein–ligand binding, − and protein conformational change. − The results of these studies strongly depend on the accuracy of the underlying force field. While there have been noteworthy simulations on protein dynamics using a quantum chemical potential energy surface, − these are still incapable of realizing dynamics on the biologically relevant time scales (ns and beyond) for larger proteins (200 residues and beyond).…”

Section: Introductionmentioning

confidence: 99%

Building a More Predictive Protein Force Field: A Systematic and Reproducible Route to AMBER-FB15

et al. 2017

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The increasing availability of high-quality experimental data and first-principles calculations creates opportunities for developing more accurate empirical force fields for simulation of proteins. We developed the AMBER-FB15 protein force field by building a high-quality quantum chemical data set consisting of comprehensive potential energy scans and employing the ForceBalance software package for parameter optimization. The optimized potential surface allows for more significant thermodynamic fluctuations away from local minima. In validation studies where simulation results are compared to experimental measurements, AMBER-FB15 in combination with the updated TIP3P-FB water model predicts equilibrium properties with equivalent accuracy, and temperature dependent properties with significantly improved accuracy, in comparison with published models. We also discuss the effect of changing the protein force field and water model on the simulation results.

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QM/MM study ofl-lactate oxidation by flavocytochrome b₂

Abstract: Free energy surfaces calculated from a state-of-the-art computational methodology highlight the role of active site residues in l-lactate oxidation by flavocytochrome b2.

Cited by 10 publications

References 57 publications

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

13C kinetic isotope effects on the reaction of a flavin amine oxidase determined from whole molecule isotope effects

Building a More Predictive Protein Force Field: A Systematic and Reproducible Route to AMBER-FB15

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QM/MM study ofl-lactate oxidation by flavocytochrome b2

Abstract: Free energy surfaces calculated from a state-of-the-art computational methodology highlight the role of active site residues in l-lactate oxidation by flavocytochrome b2.

Cited by 10 publications

References 57 publications

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

13C kinetic isotope effects on the reaction of a flavin amine oxidase determined from whole molecule isotope effects

Building a More Predictive Protein Force Field: A Systematic and Reproducible Route to AMBER-FB15

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Product

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QM/MM study ofl-lactate oxidation by flavocytochrome b₂