RESUMO
Uranium is routinely handled in various stages of nuclear fuel cycle and its association with human serum albumin (HSA) has been reported in literature, however, their binding characteristics still remains obscure. The present study aims to understand interaction of uranium with HSA by employing all atom molecular dynamics simulation of the HSA-metal ion complex. His67, His247 and Asp249 residues constitute the major binding site of HSA, which capture the uranyl ion (UO22+). A total of six sets of initial coordinates are used for Zn2+-HSA and UO22+-HSA system at pH = 4, 7.4 and 9, respectively. Enhance sampling method, namely, well-tempered meta-dynamics (WT-MtD) is employed to study the binding and un-binding processes of UO22+ and Zn2+ ions. Potential of mean force (PMF) profiles are generated for all the six sets of complexes from the converged WT-MtD run. Various basins and barriers are observed along the (un)binding pathways. Hydrogen bond dynamics and short-range Coulomb interactions are evaluated from the equilibrium run at each basins and barriers for both the ions at all pH values. The binding of UO22+ ion with HSA is the result of the dynamical balance between UO22+-HSA and UO22+-water short range Coulomb interactions. Zn2+ ion interact more strongly than UO22+ at all pH through short range Coulomb interactions. PMF values further concludes that UO22+ cannot associate to the Zn2+ bound HSA protein but can be captured by free HSA at all pH values i.e. endosomal, alkaline and physiological pH.Communicated by Ramaswamy H. Sarma.
RESUMO
In the context of the mitigation of the biological effects of internal radionuclide contamination and for efficient decorporation, the design and development of efficient chelators for lanthanide and actinide metal ions has become a central issue. The pioneering work of Raymond and coworkers (Chem. Rev., 2003, 103, 4207-4282) led to the development of siderophore-related hydroxypyridinonate ligands for possible treatment of internalized radionuclides. However, the structure-function relationship of Ln/An bound to these ligands, particularly the bonding and coordination aspects are not clearly understood at the atomic level. Here, we have investigated the structure, binding and energetics of trivalent and tetravalent Ln/An (Sm3+, Eu3+, Am3+, Cm3+, Th4+, Pu4+) ions with spermine-based octadentate hydroxypyridinonate chelators, namely 3,4,3-LI(1,2-HOPO) and its 3,3,3 variant, using relativistic density functional theory (DFT). Furthermore, we have performed orbital and density based analyses to elucidate the nature of bonding in these complexes. In accordance with the experimental stability constant, we found the maximum binding free energy for An4+ (Pu4+, Th4+) as compared to trivalent metal ions. CDA and ECDA analyses along with orbital-based population analyses confirmed the higher ligand to metal charge transfer for An4+ than for trivalent metal ions. Furthermore, the aromaticity index analysis suggested the presence of crucial chelatoaromatic stabilization for all these metal ions with the maximum for An4+. QTAIM descriptors indicated that the binding of An/Ln with the hard oxygen donor of the ligands is of the donor-acceptor type but a higher degree of covalency exists for actinides as compared to lanthanides. Furthermore, QTAIM and molecular orbital analysis confirmed that such covalency is of the energy-driven type and strictly originates from the orbital mixing event of An-5f orbitals with the ligand orbitals.