Redox Properties of Flavin in BLUF and LOV Photoreceptor Proteins from Hybrid QM/MM Molecular Dynamics Simulation

Flavins play an important role in many oxidation and reduction processes in bio- logical systems. For example, flavin adenine dinucleotide (FAD) and flavin mononu- cleotide (FMN) are common cofactors found in enzymatic proteins that use the special redox properties of these flavin molecules for their catalytic or photoactive functions. The redox potential of the flavin is strongly affected by its (protein) environment, however the underlying molecular interactions of this effect are still unknown. Using hybrid Quantum Mechanics / Molecular Mechanics (QM/MM) simulation techniques, we have studied the redox properties of flavin in the gas phase, aqueous solution and two different protein environments, in particular a BLUF and a LOV photoreceptor domain. By mapping the changes in electrostatic potential and solvent structure, we gain insight in how specific polarization of the flavin by its environment tunes the re- duction potential. We find also that accurate calculation of the reduction potentials of these systems by using the hybrid QM/MM approach is hampered by a too limited sampling of the counter ion configurations and by artifacts at the QM/MM boundary. We make suggestions on how these issues can be overcome.