Noncovalent interactions that tune the reactivities of the flavins in bifurcating electron transferring flavoprotein

María González-Viegas, Rajiv K. Kar, Anne Frances Miller, Maria Andrea Mroginski

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Bifurcating electron transferring flavoproteins (Bf-ETFs) tune chemically identical flavins to two contrasting roles. To understand how, we used hybrid quantum mechanical molecular mechanical calculations to characterize noncovalent interactions applied to each flavin by the protein. Our computations replicated the differences between the reactivities of the flavins: the electron transferring flavin (ETflavin) was calculated to stabilize anionic semiquinone (ASQ) as needed to execute its single-electron transfers, whereas the Bf flavin (Bfflavin) was found to disfavor the ASQ state more than does free flavin and to be less susceptible to reduction. The stability of ETflavin ASQ was attributed in part to H-bond donation to the flavin O2 from a nearby His side chain, via comparison of models employing different tautomers of His. This H-bond between O2 and the ET site was uniquely strong in the ASQ state, whereas reduction of ETflavin to the anionic hydroquinone (AHQ) was associated with side chain reorientation, backbone displacement, and reorganization of its H-bond network including a Tyr from the other domain and subunit of the ETF. The Bf site was less responsive overall, but formation of the Bfflavin AHQ allowed a nearby Arg side chain to adopt an alternative rotamer that can H-bond to the Bfflavin O4. This would stabilize the anionic Bfflavin and rationalize effects of mutation at this position. Thus, our computations provide insights on states and conformations that have not been possible to characterize experimentally, offering explanations for observed residue conservation and raising possibilities that can now be tested.

Original languageEnglish
Article number104762
JournalJournal of Biological Chemistry
Issue number6
StatePublished - Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors


  • FAD
  • QM/MM
  • conformational change
  • electron bifurcation
  • electron density
  • electron transfer
  • electron transfer flavoprotein
  • flavoprotein
  • hydrogen bond
  • redox tuning

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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