Flavins
are central to countless enzymes but display different
reactivities depending on their environments. This is understood to
reflect modulation of the flavin electronic structure. To understand
changes in orbital natures, energies, and correlation over the ring
system, we begin by comparing seven flavin variants differing at C8,
exploiting their different electronic spectra to validate quantum
chemical calculations. Ground state calculations replicate a Hammett
trend and reveal the significance of the flavin π-system. Comparison
of higher-level theories establishes CC2 and ACD(2) as methods of
choice for characterization of electronic transitions. Charge transfer
character and electron correlation prove responsive to the identity
of the substituent at C8. Indeed, bond length alternation analysis
demonstrates extensive conjugation and delocalization from the C8
position throughout the ring system. Moreover, we succeed in replicating
a particularly challenging UV/Vis spectrum by implementing hybrid
QM/MM in explicit solvents. Our calculations reveal that the presence
of nonbonding lone pairs correlates with the change in the UV/Vis
spectrum observed when the 8-methyl is replaced by NH2,
OH, or SH. Thus, our computations offer routes to understanding the
spectra of flavins with different modifications. This is a first step
toward understanding how the same is accomplished by different binding
environments.
Flavin‐based electron bifurcation accomplishes the feat of producing highly‐reducing electrons at the expense of a less reactive source. By consuming two modestly‐reducing electrons from NADH for each one electron transferred to the more reducing ferredoxin acceptor, the process conforms to the laws of thermodynamics. Critical mechanistic ingredients include coupling between two separate electron transfer reactions, a protein conformation change preventing the high‐energy electron from exploiting the more exergonic path, and high‐efficiency transfer of that electron to the more reducing acceptor instead. All of this is accomplished based on the dynamic structure of the protein, in conjunction with the distinctive electrochemical reactivity of flavins. We are combining QM/MM approaches with site‐directed mutagenesis and electrochemistry to clarify how the protein enforces one‐electron chemistry at the electron transfer site but bifurcation at the other. Complementary studies seek to identify covalent modifications that accumulate on one of the two flavins, especially at high pH.
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