Zinc finger (ZF) proteins interact with nucleic acids and proteins which plays an important role in DNA transcription and repair, biochemical recognition, and protein regulation. The release of Zn2+ through oxidation of cysteine thiolates is associated with inhibition of viral replication, disruption of cancer gene expression, and DNA repair preventing tumor growth. Molecular dynamics (MD) simulations were carried out to examine the effect of cysteine oxidation on the ZF456 fragment of transcription factor III A (TFIIIA) and its complex with 5S RNA at the atomistic level. In the absence of 5S RNA, the reduced ZF456 peptide undergoes conformational changes in the secondary structure due to the reorientation of the intact ZF domains. Upon oxidation, the individual ZF domains unfold to various degrees, yielding a globular ZF456 peptide with ZF4 and ZF6 losing their ββα-folds. ZF5, on the other hand, participates in nonspecific interactions through its α-helix that conditionally unravels early in the simulation. In the presence of RNA, oxidation of the ZF456 peptide disrupts the key hydrogen bonding interactions between ZF5/ZF6 and 5S RNA. However, interactions with ZF4 are dependent on the protonation state of His119. Therefore, disulfide formation and Zn2+ loss diminish the ability of the oxidized ZF456 peptides to recognize RNA. This loss of key protein – RNA interactions and the conformational flexibility of the oxidized peptide demonstrate the structural importance of Zn2+ to the ZF secondary structure and ZF recognition mechanisms.