First and second one-​electron reduction of lumiflavin in water - A first principles molecular dynamics study

Flavins are ubiquitously found in nature as cofactors in proteins that regulate electron and proton transfer reactions. The electron and proton affinities of flavins are modulated by their molecular environment. Using density functional theory based molecular dynamics simulations, we have studied the first and second reduction reactions of the prototypical flavin named lumiflavin in aqueous solution. We find that the reduction potential, calculated using free energy perturbation simulations, has the typical parabolic shape as predicted by Marcus’ theory of electron transfer. The water solvent structure undergoes significant changes within the first coordination shell upon lumiflavin reduction. These structural changes account largely for the reorganization free energy term in the measured redox potential. However, in the second reduction reaction, from semiquinone to fully reduced lumiflavin, also the inner-sphere reorganization contributes significantly via the increased "butterfly" bending of the flavin. This butterfly bending causes a deviation from the linear response approximation that underlies Marcus’ theory of electron transfer