Molecular properties and tautomeric equilibria of isolated flavins

Flavins are employed as redox cofactors and chromophores in a plethora of flavoenzymes. Their versatility is an outcome of intrinsic molecular properties of the isoalloxazine ring modulated by the protein scaffold and surrounding solvent. Thus, an investigation of isolated flavins with high-level electronic-structure methods and with error assessment of the calculated properties will contribute to building better models of flavin reactivity. Here, we benchmarked ground-state properties such as electron affinity, gas-phase basicity, dipole moment, torsion energy, and tautomer stability for lumiflavins in all biologically relevant oxidation and charge states. Overall, multiconfigurational effects are small and chemical accuracy is achieved by coupled-duster treatments of energetic properties. Augmented basis sets and extrapolations to the complete basis-set limit are necessary for consistent agreement with experimental energetics. Among DFT functionals tested, M06-2X shows the best performance for most properties, except gas-phase basicity, in which M06 and CAM-B3LYP perform better. Moreover, dipole moments of radical flavins show large deviations for all functionals studied. Tautomers with noncanonical protonation states are significantly populated at normal temperatures, adding to the complexity of modeling flavins. These results will guide future computational studies of flavoproteins and flavin chemistry by indicating the limitations of electronic-structure methodologies and the contributions of multiple tautomeric states.

Automated summary

Flavins play important roles as redox cofactors and chromophores in flavoenzymes. Understanding their properties is crucial for modeling flavin reactivity. In this study, high-level electronic-structure methods were used to investigate the ground-state properties of lumiflavins in different oxidation and charge states. The results show that M06-2X is the most accurate functional for most properties, except gas-phase basicity. Additionally, the presence of noncanonical protonation states adds complexity to modeling flavins. These findings will guide future computational studies of flavoproteins and flavin chemistry.