Understanding flavin electronic structure and spectra

Rajiv K. Kar, Anne Frances Miller, Maria Andrea Mroginski

Research output: Contribution to journalReview articlepeer-review

20 Scopus citations


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.

Original languageEnglish
Article numbere1541
JournalWiley Interdisciplinary Reviews: Computational Molecular Science
Issue number2
StatePublished - Mar 1 2022

Bibliographical note

Funding Information:
R.K.K. and A.‐F. M. thank the Einstein Foundation of Berlin for support. This work is based upon work supported by the National Science Foundation, Chemistry of Life Processes CHE‐1808433, the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DE‐SC0021283, as well as EPSCoR PON2 6,352,000,003,148. M.A.M. thanks the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy—EXC 2008‐390540038‐UniSysCat for funding. The authors acknowledge Prof. Dr. P. Hildebrandt for ground‐breaking applications of spectroscopy to bio‐catalytic systems and recognition of the power of computational chemistry in this connection.

Funding Information:
Division of Chemistry, U.S. National Science Foundation, Grant/Award Number: CHE 1808433 ‐ to A.‐F. Miller; Einstein Stiftung Berlin, Einstein Visiting Fellow ‐ to A.‐F. Miller; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy, Grant/Award Number: EXC 2008‐390540038‐UniSyscCat ‐ to M.‐A. Mroginski; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Grant/Award Numbers: DE‐SC0021283, EPSCoR PON2 635 2000003148 ‐ to A.‐F. Miller Funding information

Publisher Copyright:
© 2021 The Authors. WIREs Computational Molecular Science published by Wiley Periodicals LLC.


  • computational methodology
  • electronic structure
  • flavin
  • flavoprotein
  • hybrid QM/MM

ASJC Scopus subject areas

  • Biochemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Computational Mathematics
  • Materials Chemistry


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