Implications of Metal Coordination in Damage and Recognition of Nucleic Acids and Lipid Bilayers

Metal ions have a myriad of biological functions from structural stability to enzymatic (de)activation and metabolic electron transfer. Redox-active metals also mediate the formation of reactive oxygen species which may either cause oxidative damage or protect cellular components. Computational modeling is used here to investigate the role of (1) metal-ion binding to antimicrobial peptides, (2) metal-ion removal and disulfide formation on zinc finger (ZF) proteins, and (3) coordination of thiones/selones for the prevention of metal-mediated redox damage. Piscidins, natural-occurring antimicrobial peptides, efficiently kill bacteria by targeting their membranes. Their efficacy is enhanced in vitro by metal-binding and the presence of membrane-destabilizing oxidized phospholipids (oxPLs). Molecular dynamics (MD) simulations are used to model insertion of Ni2+-bound piscidins 1 (P1:Ni2+) and 3 (P3:Ni2+) into lipid bilayers in the presence and absence of oxPLs. Metallation promotes deeper peptide insertion in the membrane, and P1:Ni2+ is suggested to interact more with anionic lipid headgroups in the presence of oxPLs. The release of Zn2+ from ZF proteins through oxidation of the cysteine thiolates is associated with inhibition of viral replication, disruption of cancer gene expression, and DNA repair preventing tumor growth. Multi-microsecond MD simulations were performed to examine the effect of cysteine oxidation on the ZF456 fragment of transcription factor IIIA and its complex with 5S RNA. Upon oxidation in the absence of RNA, the individual ZF domains unfold yielding a globular ZF456 peptide. Oxidation of the RNA-bound ZF456 peptide disrupts key hydrogen bonding interactions between ZF5/ZF6 and 5S RNA. The antioxidant properties of sulfur and selenium compounds prevent metal-mediated (i.e., Fenton chemistry) oxidative damage. The effect of the coordination of sulfur/selenium derivatives of imidazolidinone (thiones/selones) on the electronic structure and reduction potential of Fe2+ ions solvated or coordinated to guanine are examined using density functional theory. The highest occupied molecular orbital (HOMO) for the Fe(II)-aqua complex is metal-centered but localized on the nucleobase in the Fe2+-guanine complex. Complexation of the thione/selone shifts the HOMO to the sulfur/selenium center suggesting a mechanism for protection of DNA by sacrificial oxidation of the sulfur/selenium ligand

The Effect of Metalation on Antimicrobial Piscidins Imbedded in Normal and Oxidized Lipid Bilayers

Metalation of the N-terminal Amino Terminal Cu(II)- and Ni(II)-binding (ATCUN) motif may enhance the antimicrobial properties of piscidins. Molecular dynamics simulations of free and nickelated piscidins 1 and 3 (P1 and P3) were performed in 3 : 1 POPC/POPG and 2.6 : 1 : 0.4 POPC/POPG/aldo-PC bilayers (POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine: POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol; aldo-PC, 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholine) bilayer models. Nickel(II) binding decreases the conformation dynamics of the ATCUN motif and lowers the charge of the N-terminus to allow it to embed deeper in the bilayer without significantly changing the overall depth due to interactions of the charged half-helix of the peptide with the headgroups. Phe1⋯Ni2+ cation–π and Phe2–Phe1 CH–π interactions contribute to a small fraction of structures within the nickelated P1 simulations and may partially protect a bound metal from metal-centered chemical activity. The substitution of Phe2 for Ile2 in P3 sterically blocks conformations with cation–π interactions offering less protection to the metal. This difference between metalated P1 and P3 may indicate a mechanism by which peptide sequence can influence antimicrobial properties. Any loss of bilayer integrity due to chain reversal of the oxidized phospholipid chains of aldo-PC may be enhanced in the presence of metalated piscidins

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

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.https://digitalcommons.odu.edu/sciences_achievement/1006/thumbnail.jp