Structural Insights into the Binding of Uranyl with Human Serum Protein Apotransferrin Structure and Spectra of Protein−Uranyl Interactions

Abstract

Ab initio quantum mechanical computational studies for the structure and IR spectra of the uranyl complex with human serum apotransferrin (TF) protein are carried out to model uranyl intake into the human cell through endocytosis and formation of a coordination complex with the protein binding sites. The computed IR spectra and structure of the uranyl-protein complex facilitate interpretation of the observed spectra and confirm the primary binding sites of the transferrin protein with the uranyl ion. Our computed equilibrium geometry and the IR spectra of the uranyl-TF complex reveal that uranyl ion is bound to two tyrosines, one aspartate group, and one carbonate ion. Our IR spectra indicate that histidine is not involved in binding to uranyl with transferrin protein. Our computations reveal a short, strong hydrogen bond, which could play an important role in the stabilization and formation of the uranyl-TF complex. Computed Laplacian charge plots indicate high chemical reactivity on this complex as both an electrophile and a nucleophile, facilitating binding to different receptors and thus entry into a number of target organs and the blood-brain barrier. The Mulliken charge density plots and the three-dimensional charge density plots suggest a donor-acceptor mechanism in the complex formation.

Extracellular reduction of uranium via Geobacter conductive pili as a protective cellular mechanism

“…Despite differences in the mechanism and yields of U reduction, the strains with the lowest levels of periplasmic mineralization (WT P+ , pRG5::pilA, and WT P− ) produced similar U L III -edge EXAFS spectra that were modeled as mostly U(IV) coordinated by C-containing ligands in bidentate and monodentate fashion and that lacked any Fe-or P-containing ligands. The bidentate C1-C3 ligand is likely biological in nature, as reported for the carboxyl coordinations involving amino acids and lipolysaccharide sugars (30)(31)(32). In contrast, the PilA − mutant, which had the highest degree of periplasmic mineralization, required an additional monodentate P ligand.…”

“…It is also unlikely that the low levels of U(VI) reduced by the PilA − strain contributed to the distinct spectra, because WT P− cells reduced less U(VI) and did not require a P ligand for U coordination. The P coordination and the generalized periplasmic mineralization observed in the PilA − mutant cells suggest that U(VI) permeated deep and fast into the cell envelope, where it formed carboxyl and phosphoryl-coordinated complexes with periplasmic proteins and the peptidoglycan layer (30,31) and membrane phospholipids (33), respectively. The formation of a mononuclear U(IV) phase has also been reported for other bacteria of relevance to U bioremediation (34,35), yet contrasts with earlier reports of uraninite formation by Geobacter spp.…”

Uranyl Binding to Proteins and Structural-Functional Impacts

“…Tf was also found to form a uranyl-Tf complex, and Vidaud et al suggested that the UO 2 2+ ions may occupy the Fe 3+ binding site with similar coordination ligands, except for His249 (Figure 3a, right), as indicated by the FTIR data [61]. The uranyl coordination was late on confirmed by ab inito quantum mechanical computational studies [62]. It should be noted that although Tf is capable of binding a uranyl ion to each of N-lobe and C-lobe, Tf was predicted to form only~2.4% of the protein-bound uranyl in blood, due to its low binding affinity Tf (K D = 2.8 µM) and relatively low concentration (2-4 g/L) [22].…”

Electron transfer at the cell–uranium interface in Geobacter spp.

“…Furthermore, approximately 50% of the uranium atoms in the PilA − mutant cells required an additional monodentate phosphorus ligand in the uranium L III -edge EXAFS models [24]. The phosphorus co-ordination is consistent with the permeation of uranium into the cell envelope, where it forms carboxyl-and phosphoryl-coordinated complexes with periplasmic proteins and the peptidoglycan layer [27,28] and with membrane phospholipids [42] respectively. This also compromised the respiratory functions of the cell envelope and decreased the survival rates [24].…”

“…There is also a carbon ligand-bonded to one oxygen atom in a monodentate co-ordination with uranium and attached to a distant oxygen atom [24]. The bidentate C1-C3 ligand is likely to be biological in nature as reported for the carboxyl co-ordinations involving amino acids and lipolysaccharide sugars [27][28][29]. Furthermore, the measured spectra did not produce a uranium signal corresponding to the uranium-uranium distance in uraninite at 3.87 Å (1 Å = 0.1 nm) [24].…”