QM/MM MD Simulations Selective ZF Proteins and Molecular Docking Studies with Reducible Sulfur and Selenium Compounds

QM/MM MD Simulations Selective ZF Proteins and Molecular Docking Studies with Reducible Sulfur and Selenium Compounds

College

College of Sciences

Program

Ph.D. Chemistry

Publication Date

3-28-2019

Abstract

Reducible sulfur and selenium (r-S/Se) compounds eject Zn2+ from zinc-sulfur proteins such as zinc fingers (ZFs) and metalothionein. The Zn2+ ejection leads to the loss of the tertiary and quaternary structure of the protein and therefore the loss of its functions. Zn-S centers are important to different biological processes such as DNA transcription and repair, biochemical recognition and protein regulation. The underlying mechanism is poorly understood and a fully characterization is required to design and use specific sulfur- and selenium-based inhibitors of the therapeutic potential. In the current work, the mechanism of Zn2+ release from ZFs by sulfur analog of ebselen and dithiones are explored through a series of QM/MM studies that addresses both the energetics and the sterics of the interactions. Both the charge and the solvent accessibility of all ZF Cys S atoms are calculated to determine the most favorable site for the attack of the electrophilic r-S/Se compound. The results are compared with the experimental data, when available. In addition, we investigate the structural changes due to oxidation of the Zn-S centers of a fragment of transcription factor TFIIIA that contains three ZF domains in the presence or absence of 5S RNA.

QM/MM MD Simulations Selective ZF Proteins and Molecular Docking Studies with Reducible Sulfur and Selenium Compounds


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