Overcharging of zinc ion in the structure of zinc finger protein is needed for DNA binding stability

TL;DR

This study uses molecular dynamics simulations to demonstrate that the overcharged zinc ion in zinc finger proteins is crucial for stabilizing their structure and DNA binding, providing insights into their molecular function.

Contribution

The paper reveals that the deprotonated, negatively charged cysteine residues and the overcharged zinc ion are essential for zinc finger stability and DNA interaction, advancing understanding of zinc finger mechanisms.

Findings

Deprotonated cysteines stabilize zinc finger structure.

Overcharged zinc ion enhances DNA binding stability.

DNA influences zinc finger conformation upon complexation.

Abstract

The zinc finger structure where a Zn2+ ion binds to 4 cysteine or histidine amino acids in a tetrahedral structure is very common motif of nucleic acid binding proteins. The corresponding interaction model is present in 3% of the genes of human genome. As a result, zinc finger has been shown to be extremely useful in various therapeutic and research capacities, as well as in biotechnology. In stable configuration, the cysteine amino acids are deprotonated and become negatively charged. This means the Zn2+ ion is overscreened by 4 cysteine charges (overcharged). It is question of whether this overcharged configuration is also stable when such negatively charged zinc finger binds to negatively charged DNA molecule. Using all atom molecular dynamics simulation up to microsecond range of an androgen receptor protein dimer, we investigate how the deprotonated state of cysteine influences its structure, dynamics, and function in binding o DNA molecules. Our results show that the deprotonated state of cysteine residues are essential for mechanical stabilization of the functional, folded conformation. Not only this state stabilizes the protein structure, it also stabilizes the protein-DNA binding complex. The differences in structural and energetic properties of the two (sequence-identical) monomers are also investigated showing the strong influence of DNA on the structure of zinc fingers upon complexation. Our result has potential impact on better molecular understanding of one of the most common classes of zinc fingers