The RutA enzyme catalyzes a first step of uracil degradation in hydroxypropionate, ammonia, and carbon dioxide, allowing bacteria to use pyrimidine rings as nitrogen source and belongs to a large family of flavoprotein monooxygenases (FMOs) widely spread across all kingdoms of life. Mammalian FMOs are indispensable as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. Growing evidence points to implication of FMOs in aging, several deceases and metabolic pathways. FMOs activate molecular oxygen and insert a single oxygen atom in small organic substrates containing heteroatoms and convert the second oxygen atom in a water molecule. The chemical formulae of the reactants in the monooxygenation reaction of uracil by RutA are shown in Fig. . According to the current knowledge, the reduced form of flavin mononucleotide (FMN), which is non-covalently bound to the RutA macromolecule, activates the dioxygen molecule by transferring an electron from FMN. The reactive oxygen is capable to bind chemically to one of the atoms of the isoalloxazine ring of FMN, and this intermediate flavin-based species is involved in the chain of transformations of the uracil molecule. There are unresolved puzzles in this plausible mechanism; one of them is specification of a target atom in the isoalloxazine ring (C4a, N5, C6) for the attack of the reactive oxygen. Detailed consideration of the reaction mechanism is far beyond the scope of this work; here, we focus on computational characterization of reactants, namely, on how the ligands, FMN, uracil and O2, are accommodated inside the protein favoring possible reaction pathways. The work of Matthews et al. reported atomic coordinates of the RutA-FMN-O2uracil complex deposited to the Protein Data Bank (the structure PDB ID 6TEG). This complex was obtained as the O2-pressurized crystal at 15 bars O2; however, low occupancies of the ligands were observed. From the theoretical side, it should be noted that methods of describing protein-ligand interaction using customary force field parameters may fail in such project, even if some hints are provided by results of crystallography studies. It is not an essential problem to accommodate FMN in the protein cavity, despite location of this ligand close to the solvent accessible area. A small organic molecule, uracil, can also be localized in the active site; however, with more uncertainties, given the disparity in the FMN and uracil sizes. The greatest problem presents the dioxygen molecule because no reliable classical force field parameters are available to describe polarization and a partial charge transfer to this species when it approaches the negative charged FMN and the protein groups. Needless to remind that the localization of dioxygen in protein cavities is a nontrivial experimental task. Thus, quantum-based computer simulations are the indispensable tools to characterize complexes of proteins with small organic molecules and dioxygen.