Metal Coupled Folding of Cys2His2 Zinc-Finger

TL;DR

This study uses molecular dynamics simulations to explore how zinc ions influence the folding process of Cys2His2 zinc-finger proteins, revealing zinc's stabilizing role and its impact on secondary structure formation.

Contribution

It provides the first detailed computational analysis of zinc-coupled folding mechanisms in zinc-finger motifs, highlighting zinc's early binding and its effect on hydrophobic packing and ligand coordination.

Findings

Zinc stabilizes the native structure and participates early in folding.

Zinc binding directs folding and stabilizes secondary structures.

Zinc influences water behavior and ligand exchange during folding.

Abstract

Zinc-fingers, which widely exist in eukaryotic cell and play crucial roles in life processes, depend on the binding of zinc ion for their proper folding. To computationally study the zinc coupled folding of the zinc-fingers, charge transfer and metal induced protonation/deprotonation effects have to be considered. Here, by attempting to implicitly account for such effects in classical molecular dynamics and performing intensive simulations with explicit solvent for the peptides with and without zinc binding, we investigate the folding of the Cys2His2 type zinc-finger motif and the coupling between the peptide folding and zinc binding. We find that zinc ion not only stabilizes the native structure, but also participates in the whole folding process. It binds to the peptide at early stage of folding, and directs or modulates the folding and stabilizations of the component beta-hairpin and alpha-helix. Such a crucial role of zinc binding is mediated by the packing of the conserved hydrophobic residues. We also find that the packing of the hydrophobic residues and the coordination of the native ligands are coupled. Meanwhile, the processes of zinc binding, mis-ligation, ligand exchange and zinc induced secondary structure conversion, as well as the water behaviour, due to the involvement of zinc ion are characterized. Our results are in good agreement with related experimental observations, and provide significant insight into the general mechanisms of the metal-cofactor dependent protein folding and other metal induced conformational changes of biological importance.