Mechanistic Insights into Au(I)(NHC)Cl Targeting of the HIV-NCp7 Zinc Finger via Metadynamics Simulations

Zinc fingers (ZFs) regulate important metabolic pathways. Their inhibition in cancer cells or pathogenic viruses and protozoa can be achieved with transition metal-based compounds, including gold complexes. However, selectively targeting specific ZFs can be challenging, due also to the structural diversity of ZFs and to the lack of mechanistic details. Here, metadynamics simulations were employed to investigate the mechanism of interaction between the [Au(I)(NHC)Cl] complex and the zinc finger region of HIV-NCp7, which comprises two zinc finger domains essential for the protein’s function and the viral life cycle. The simulations revealed that the two zinc finger cores exhibit markedly different reactivities. Specifically, the C-terminal zinc finger, with Cys49 as the target residue, was identified as the primary site for Au(I) binding. Additionally, the simulations uncovered acid-base steps, induced by the [Au(I)(NHC)]+ species, that facilitate thiolate coordination of Cys39 to the Au(I)(NHC) complex. These events also promote conformational changes, including widening of the zinc finger core, enabling water access to the zinc centre.