Insight into the kinetics and thermodynamics of the hydride transfer reactions between quinones and lumiflavin: a density functional theory study

Abstract

The kinetics and equilibrium of the hydride transfer reaction between lumiflavin and a number of substituted quinones was studied using density functional theory. The impact of electron withdrawing/donating substituents on the redox potentials of quinones was studied. In addition, the role of these substituents on the kinetics of the hydride transfer reaction with lumiflavin was investigated in detail under the transition state (TS) theory assumption. The hydride transfer reactions were found to be more favorable for an electron-withdrawing substituent. The activation barrier exhibited a quadratic relationship with the driving force of these reactions as derived under the formalism of modified Marcus theory. The present study found a significant extent of electron delocalization in the TS that is stabilized by enhanced electrostatic, polarization, and exchange interactions. Analysis of geometry, bond-orders, and energetics revealed a predominant parallel (Leffler-Hammond) effect on the TS. Closer scrutiny reveals that electron-withdrawing substituents, although located on the acceptor ring, reduce the N-H bond order of the donor fragment in the precursor complex. Carried out in the gas-phase, this is the first ever report of a theoretical study of flavin's hydride transfer reactions with quinones, providing an unfiltered view of the electronic effect on the nuclear reorganization of donor-acceptor complexes.

Cyclic Changes in Active Site Polarization and Dynamics Drive the “Ping-pong” Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations

“…14–16 The dimethylisoalloxazine ring (flavin) of FAD oscillates between two oxidation states allowing the active site to facilitate the opposing hydride transfer reactions catalyzed with a single set of active site residues. 15–20 In these enzymes, the general catalysis follows a ‘ping-pong’ mechanism, where one substrate binds to the active site and serves as a hydride donor to the flavin during the reduction half-cycle. The exit of the product is followed by binding of another substrate (in the oxidative half-cycle) serving as a hydride acceptor (Scheme 1).…”

“…NRH: quinone oxidoreductase 2 (NQO2) and its paralog NADPH: quinone oxidoreductase 1 (NQO1) are flavin-dependent cellular defense enzymes, − which catalyze the reduction of a wide variety of quinone derivatives, − including melatonin, menadione (vitamin K3), and estrogen quinones. ,− Using the flavin adenine dinucleotide (FAD) cofactor, they reduce quinones to hydroquinones in an obligatory 2e – /H + (i.e., hydride) transfer process. − The dimethylisoalloxazine ring (flavin) of FAD oscillates between two oxidation states allowing the active site to facilitate the opposing hydride transfer reactions catalyzed with a single set of active site residues. − In these enzymes, the general catalysis follows a “ping-pong” mechanism, where one substrate binds to the active site and serves as a hydride donor to the flavin during the reduction half-cycle. The exit of the product is followed by binding of another substrate (in the oxidative half-cycle) serving as a hydride acceptor (Scheme ).…”

“…In addition, it could help designing inhibitors targeting a specific redox state of the enzyme. As a sequel to our previous study of the interplay of redox chemistry of flavin and NQO2 enzymology, − , herein presented is an investigation of the geometric and energetic changes of the “ping-pong” kinetics. As illustrated in Scheme , the hydride donor, N -methyldihydronicotinamide (abbreviated here after as NMH), and the hydride acceptor p- benzoquinone (abbreviated here after as PBQ) were used in this study.…”

Writing a literature review as a class project in an upper‐level undergraduate biochemistry course

“…undergraduates as coauthors resulted from in-class research projects. [8][9][10][11][12] These low-cost initiatives are important for providing research opportunities to undergraduates, where a lack of resources and opportunities limit the exposure to undergraduate collaborative research for all students. 13 Thus, this literature review writing and research training are important for our undergraduates, who are the researchers and workforce of the future.…”

Virtual Screening of Molecules via Neural Fingerprint-based Deep Learning Technique

“…In our lab, computational chemistry has been used for over a decade in elucidating the chemistry of enzymes that are drug targets [18][19][20][21][22][23][24][25][26][27]. Using classical and quantum physics-based models, these studies explored intermolecular interactions [18,20,22].…”