X-ray Absorption Spectroscopy Combined with Time-Dependent Density Functional Theory Elucidates Differential Substitution Pathways of Au(I) and Au(III) with Zinc Fingers

Author(s)

Abbehausen, Camilla ^[1] ; Ferraz de Paiva, Raphael Enoque ^[1] ; Bjornson, Ragnar ^[2] ; Gomes, Saulo Quintana ^[1] ; Du, Zhifeng ^[3] ; Corbi, Pedro Paulo ^[1] ; Lima, Frederico Alves ^{[4, 5]} ; Farrell, Nicholas ^[3]

Affiliation

^[1] Univ Estadual Campinas, Inst Chem, POB 6154, BR-13083970 Campinas, SP - Brazil

^[2] Univ Iceland, Sci Inst, Dunhagi 3, IS-107 Reykjavik - Iceland

^[3] Virginia Commonwealth Univ, Dept Chem, 1001 W Main St, Richmond, VA 23284 - USA

^[4] Ctr Nacl Pesquisa Energia & Mat, Brazilian Synchrotron Light Lab LNLS, CP 6192, BR-13084971 Campinas, SP - Brazil

^[5] European XFEL GmbH, Holzkoppel 4, D-22869 Schenefeld - Germany

• Document type: Journal article
• Source: Inorganic Chemistry; v. 57, n. 1, p. 218-230, JAN 1 2018.
• Web of Science Citations: 8

Abstract

A combination of two elements' (Au, Zn) X-ray absorption spectroscopy (XAS) and time-dependent density functional theory (TD-DFT) allowed the elucidation of differential substitution pathways of Au(I) and Au(III) compounds reacting with biologically relevant zinc fingers (ZnFs). Gold L-3-edge XAS probed the interaction of gold and the C-terminal Cys(2)HisCys finger of the HIV-1 nucleocapsid protein NCp7, and the Cys(2)His(2) human transcription factor Sp1. The use of model compounds helped assign oxidation states and the identity of the gold-bound ligands. The computational studies accurately reproduced the experimental XAS spectra and allowed the proposition of structural models for the interaction products at early time points. The direct electrophilic attack on the ZnF by the highly thiophilic Au(I) resulted in a linear P-Au-Cys coordination sphere after zinc ejection whereas for the Sp1, loss of PEt3 results in linear Cys-Au-Cys or Cys-Au-His arrangements. Reactions with Au(III) compounds, on the other hand, showed multiple binding modes. Prompt reaction between {[}AuCl(dien)](2+) and {[}Au(dien)(DMAP)(3+) with Sp1 showed a partially reduced Au center and a final linear His-Au-His coordination. Differently, in the presence of NCp7, {[}AuCl(dien)](2+) readily reduces to Au(I) and changes from square-planar to linear geometry with Cys-Au-His coordination, while {[}Au(dien)(DMAP)](3+) initially maintains its Au(III) oxidation state and square-planar geometry and the same first coordination sphere. The latter is the first observation of a ``noncovalent{''} interaction of a Au(III) complex with a zinc finger and confirms early hypotheses that stabilization of Au(III) occurs with N-donor ligands. Modification of the zinc coordination sphere, suggesting full or partial zinc ejection, is observed in all cases, and for {[}Au(dien)(DMAP)](3+) this represents a novel mechanism for nucleocapsid inactivation. The combination of XAS and TD-DFT presents the first direct experimental observation that not only compound reactivity, but also ZnF core specificity, can be modulated on the basis of the coordination sphere of Au(III) compounds. (AU)

• FAPESP's process: 13/20334-0 - Systematic studies of zinc ejection of NCp7 HIV-1 protein by gold(I) complexes.
• Grantee: Camilla Abbehausen
• Support Opportunities: Scholarships in Brazil - Post-Doctoral