Reducible sulfur and selenium (r-S/Se) compounds eject Zn2+ from zinc-sulfur proteins such as zinc fingers (ZFs) and metallothionein. Zn-S centers are important to different biological processes such as DNA transcription and repair, biochemical recognition and protein regulation. Zn2+ ejection from ZFs leads to the loss of tertiary structure to inhibit the protein’s ability to recognize DNA. In the current work, the mechanism of Zn2+ release from ZFs by ebselen, diselenides and disulfides is explored through a series of QM/MM studies within AMBER. Molecular dynamics simulations of ZFs of the Cys2His2, Cys3His and Cys4 types show that the charge and the solvent accessibility of all ZF Cys S atoms relate to the most favorable site for the attack of the electrophilic r-S/Se compound. Activation barriers will be compared to previous small-molecule gas-phase calculations.

QM/MM MD simulations of zinc finger proteins and their reactivity with reducible sulfur and selenium compounds

2019 Spring National Meeting

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