Flavin reduction potential tuning by substitution and bending

Abstract

Computations on a series of flavin derivatives with the B3LYP hybrid density functional and 6-311G(2d,2p) basis set indicate that the ionization potentials (IPs) of the anionic semiquinone and hydroquinone states serve as accurate predictors of the flavin one- and two-electron reduction potentials. The relation between the semiquinone IPs and the two-electron reduction potentials, E m, is ΔIP sq − /Δ E m=3.69±0.18 meV/mV, with a very similar relation obtained for the flavin derivatives' Kohn–Sham highest occupied molecular orbital (KS-HOMO) energies, E KS-HOMO vs. E m. Interestingly, these good correlations between vertical IPs and E ms are observed even though the second reduction step, Fl sq⇌Fl red − involves significant conformational changes for a number of the derivatives. In fact, the flavin derivatives can be divided roughly into two categories. Those derivatives with high E ms are either planar in the anionic reduced state, or else a negligible amount of energy (<kT) is required for planarizing them. Flavin derivatives of low potential however possess significant conformational energy (>kT), and tend to have larger butterfly bends. The flavin parent compound, lumiflavin, represents the dividing point between these two categories, a result with possibly interesting biological implications for the conformational control of flavin redox potentials by enzymes. B3LYP/6-311G(2d,2p) calculations on lumiflavin constrained to various butterfly bend angles show that the oxidized and semiquinone states (both anionic and protonated at N 5) resist bending, with the oxidized state being by far the stiffest. On the other hand, the optimum geometry of the fully reduced state is bent by 15.9° in the anionic state and 24.4° in the neutral state. Full MP2 geometry optimizations confirm the reduced flavin butterfly bend, however the bend angles are larger than the DFT results: 28.7° and 32.6° for the anionic and neutral states, respectively. The relation of the N 5 and N 10 pyramidalization to the flavin butterfly bend is discussed. The results indicate that a protein-enforced flavin conformation should have significant and differing effect on each of the one electron reduction steps.