Tipping the balance: theoretical interrogation of divergent extended heterolytic fragmentations

Laconsay, Croix; Tsui, Ka Yi; Tantillo, Dean J.

doi:10.1039/c9sc05161a

Cited by 16 publications

(12 citation statements)

References 90 publications

(102 reference statements)

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“…Recent studies have shown that the internal electric fields along the reaction coordinate in small molecules and enzymes can be an important factor that defines the reaction mechanism and specificity. − , To evaluate how the conformational changes involved in HAT can influence the electric field, we performed calculations of the local electric field along the direction of FeO bond in the ferryl complex reactant geometries using TITAN . The results, as shown in Table S4, reveal that in all of the five snapshots used for the WT calculations, the value of the electric field intensity exhibits slight variations as a function of the conformational changes in RCs.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The energies of the optimized stationary points were recalculated via single-point energy calculation using a larger basis set, def2-TZVP (labeled as B2) for all of the atoms. Electric field calculations were done using TITAN code as in other studies. , Energy decomposition analysis (EDA) , calculations were then carried out on the optimized reactants and transition state geometries to determine the nonbonded interactions of all of the residues.…”

Section: Methodsmentioning

confidence: 99%

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Catalytic Mechanism of Human Ten-Eleven Translocation-2 (TET2) Enzyme: Effects of Conformational Changes, Electric Field, and Mutations

Waheed

Chaturvedi

Karabencheva‐Christova

et al. 2021

ACS Catal.

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Ten-eleven translocation (TET) family of enzymes are non-heme Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases that perform oxidation of the methyl group of the 5-methylcytosine (5mC) on DNA. TET enzymes play a crucial role in epigenetic modifications and have been linked to malignant transformation and various forms of cancer such as prostate, lung, and breast cancer. In this study, molecular dynamic (MD) and combined quantum mechanic/molecular mechanic (QM/MM) approaches were used to explore the catalytic mechanism, conformational dynamics, and the effects of mutations during the first oxidation from 5mC substrate to 5hmC by human TET2 enzyme. The studies reveal that a correlated motion between the main structural elements in TET2, the glycine–serine (GS) linker and the Cys-rich N-terminal (Cys-N) subdomain, plays a key role in the orientation of the DNA substrate in the wild-type (WT) TET2. This correlated motion is affected in the mutant forms of TET2. The conformational changes in the WT TET2 influence the rate of the hydrogen atom abstraction (HAT) step; however, its mechanism via σ-channel remains unchanged. The results enabled us to identify key residues that are crucial for HAT and to delineate their crucial energy contributions and long-range correlated interactions. Notably, several remote mutations, far away from the TET2 enzymes’ active site, unexpectedly exercise a substantial effect on the HAT step by (i) increasing the required activation barrier and (ii) switching the electron transfer mechanism from σ- to π-channel. Remarkably, mutations alter the internal electric fields along the FeO bond that in synergy with changes in the geometric factors (e.g., the hydrogen abstraction distance and the angle) influence the reactivity of the TET2 mutant forms. The kinetic isotope effect (KIE) calculations indicate weak tunneling contributions in the WT, with variations in the mutant forms. The double-mutant form K1299E-S1303N, which has clinical implications in patients with refractory anemia, exercises a substantial effect on the activation barrier, electric field, and the KIE. This study offers a novel insight into molecular biophysics and pathology of the human TET2 enzyme and asserts the vital effects of the protein residues in the second sphere and beyond on the catalytic process.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Catalytic Mechanism of Human Ten-Eleven Translocation-2 (TET2) Enzyme: Effects of Conformational Changes, Electric Field, and Mutations

Waheed

Chaturvedi

Karabencheva‐Christova

et al. 2021

ACS Catal.

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“…The Grimme's D3 dispersion correction [49a] is applied in single‐point calculations and the energy profile is presented in the Supporting Information. The external electric fields (EEFs) were applied for the QM/MM calculations using TITAN code [49b] as in other studies [50,51] . The TITAN code was used to generate uniform electric fields on the entire model of the enzyme used for the QM/MM calculations [Figures S5‐S6].…”

Section: Methodsmentioning

confidence: 99%

What Is the Catalytic Mechanism of Enzymatic Histone N‐Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

Ramanan

Waheed

Schofield

et al. 2021

Chemistry A European J

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Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2‐oxoglutarate dependent Jumonji‐C (JmjC) Nϵ‐methyl lysine histone demethylases also have N‐methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N‐methyl arginine demethylation by human KDM4E and compare the results with those reported for N‐methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen‐bond between the substrate Ser1 and Tyr178. The calculations imply that in either C−H or N−H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N‐methyl arginine demethylation, electron transfer occurs via a σ‐channel; the transition state for the N−H pathway is ∼10 kcal/mol higher than for the C−H pathway due to the higher bond dissociation energy of the N−H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier‐lowering effect on the C−H pathway, by contrast, such EEFs inhibit the N−H activation rate. The overall results imply that KDM4 catalyzed N‐methyl arginine demethylation and N‐methyl lysine demethylation occur via similar C−H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates.

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“…The possibility to control catalysis, regio-, stereo-, and enantioselectivity (as well as the product selectivity in divergent fragmentation reactions) 32 with the help of OEEFs is a very appealing prospect, which could potentially revolutionize chemical synthesis as we know it today. However, an important impediment to the wide-scale adoption of the principles outlined in the previous section is the current difficulty to harness these electrostatic effects in an experimental setting since a meticulous control over the microscopic alignment between the molecule or molecular complex and the oriented field is an essential prerequisite to this end.…”

Section: Practical Implementations Of Oeefsmentioning

confidence: 99%

Electric-Field Mediated Chemistry: Uncovering and Exploiting the Potential of (Oriented) Electric Fields to Exert Chemical Catalysis and Reaction Control

Shaik¹,

Joy²,

Wang³

et al. 2020

J. Am. Chem. Soc.

250

248

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This Perspective discusses oriented external-electric-fields (OEEF), and other electric-field types, as “smart reagents”, which enable in principle control over wide-ranging aspects of reactivity and structure. We discuss the potential of OEEFs to control nonredox reactions and impart rate-enhancement and selectivity. An OEEF along the “reaction axis”, which is the direction whereby electronic reorganization converts reactants’ to products’ bonding, will accelerate reactions, control regioselectivity, induce spin-state selectivity, and elicit mechanistic crossovers. Simply flipping the direction of the OEEF will lead to inhibition. Orienting the OEEF off the reaction axis enables control over stereoselectivity, enantioselectivity, and product selectivity. For polar/polarizable reactants, the OEEF itself will act as tweezers, which orient the reactants and drive their reaction. OEEFs also affect bond-dissociation energies and dissociation modes (covalent vs ionic), as well as alteration of molecular geometries and supramolecular aggregation. The “key” to gaining access to this toolbox provided by OEEFs is microscopic control over the alignment between the molecule and the applied field. We discuss the elegant experimental methods which have been used to verify the theoretical predictions and describe various alternative EEF sources and prospects for upscaling OEEF catalysis in solvents. We also demonstrate the numerous ways in which the OEEF effects can be mimicked by use of (designed) local-electric fields (LEFs), i.e., by embedding charges or dipoles into molecules. LEFs and OEEFs are shown to be equivalent and to obey the same ground rules. Outcomes are exemplified for Diels–Alder cycloadditions, oxidative addition of bonds by transition-metal complexes, H-abstractions by oxo-metal species, ionic cleavage of halogen bonds, methane activation, etc.

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Tipping the balance: theoretical interrogation of divergent extended heterolytic fragmentations

Abstract: We interrogate a type of heterolytic fragmentation called a ‘divergent fragmentation’ using density functional theory (DFT), natural bond orbital (NBO) analysis, ab initio molecular dynamics (AIMD), and external electric field (EEF) calculations.

Cited by 16 publications

References 90 publications

Catalytic Mechanism of Human Ten-Eleven Translocation-2 (TET2) Enzyme: Effects of Conformational Changes, Electric Field, and Mutations

Catalytic Mechanism of Human Ten-Eleven Translocation-2 (TET2) Enzyme: Effects of Conformational Changes, Electric Field, and Mutations

What Is the Catalytic Mechanism of Enzymatic Histone N‐Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

Electric-Field Mediated Chemistry: Uncovering and Exploiting the Potential of (Oriented) Electric Fields to Exert Chemical Catalysis and Reaction Control

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