Understanding flavin electronic structure and spectra

Abstract

Flavins have emerged as central to electron bifurcation, signaling, and countless enzymatic reactions. In bifurcation, two electrons acquired as a pair are separated in coupled transfers wherein the energy of both is concentrated on one of the two. This enables organisms to drive demanding reactions based on abundant low‐grade chemical fuel. To enable incorporation of this and other flavin capabilities into designed materials and devices, it is essential to understand fundamental principles of flavin electronic structure that make flavins so reactive and tunable by interactions with protein. Emerging computational tools can now replicate spectra of flavins and are gaining capacity to explain reactivity at atomistic resolution, based on electronic structures. Such fundamental understanding can moreover be transferrable to other chemical systems. A variety of computational innovations have been critical in reproducing experimental properties of flavins including their electronic spectra, vibrational signatures, and nuclear magnetic resonance (NMR) chemical shifts. A computational toolbox for understanding flavin reactivity moreover must be able to treat all five oxidation and protonation states, in addition to excited states that participate in flavoprotein's light‐driven reactions. Therefore, we compare emerging hybrid strategies and their successes in replicating effects of hydrogen bonding, the surrounding dielectric, and local electrostatics. These contribute to the protein's ability to modulate flavin reactivity, so we conclude with a survey of methods for incorporating the effects of the protein residues explicitly, as well as local dynamics. Computation is poised to elucidate the factors that affect a bound flavin's ability to mediate stunningly diverse reactions, and make life possible. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Electronic Structure Theory > Combined QM/MM Methods Theoretical and Physical Chemistry > Spectroscopy

Comparing ultrafast excited state quenching of flavin 1,N6-ethenoadenine dinucleotide and flavin adenine dinucleotide by optical spectroscopy and DFT calculations

“…As a test of computed radical spectra, the calculated lumiflavin radical anion spectrum is shown in blue. Characteristic bands at 439, 385, and 362 nm are observed in experimental [6,56] and computational [57][58][59] studies. Experimental comparisons are difficult because Lf •− is not stable in water, but can be estimated from the spectroelectrochemical work [60] of Niemz et al on N(3)-methyl-N( 10)isobutylflavin in CH 2 Cl 2 by comparing the absorbance of the oxidized flavin at 450 nm with the anionic semiquinone at 360 nm.…”

Tuning the Quantum Chemical Properties of Flavins via Modification at C8

“…37 The B3LYP functional has been routinely employed for the ground state (GS) geometry optimization in flavin systems because of its accuracy. 33 Several studies have quantified the theoretical errors in GS bond lengths. 50−55 Furche and Ahlrichs 50 showed that DFT methods in conjunction with B3LYP can reproduce experimental bond lengths with a maximum deviation of 0.02 Å, whereas Liu et al 51 reported TD-DFT (B3LYP) to have mean absolute errors of 0.014 Å.…”

“…TD-DFT methods are ubiquitous in studies of electronic structure; however, they come with theoretical errors associated with energies and equilibrium geometries, which are particularly suspect in cases involving charge transfer . The B3LYP functional has been routinely employed for the ground state (GS) geometry optimization in flavin systems because of its accuracy . Several studies have quantified the theoretical errors in GS bond lengths. − Furche and Ahlrichs showed that DFT methods in conjunction with B3LYP can reproduce experimental bond lengths with a maximum deviation of 0.02 Å, whereas Liu et al reported TD-DFT (B3LYP) to have mean absolute errors of 0.014 Å.…”

“…Recent successes have been comprehensively reviewed. 33 The objective of this work is to provide a detailed analysis of how flavin electronic structure responds to different substituents at the C8 position. The data set comprises seven lumiflavin variants, including the parent molecule with methyl at that position (LF), and variants where methyl is replaced by chloro, cyano, formyl, amino, mercapto, or hydroxyl (Scheme 1).…”

“…Moreover, identification of accurate methods of calculating vertical excitation energy, and thereby optical spectra, remains one of the more challenging aspects of computational chemistry because the methods need to accurately describe both the ground state (GS) and low-lying excited states as well. Recent successes have been comprehensively reviewed …”