In Silico Binding Affinities of Methanobactin Analogs oo First Row Transition Metal Ions

Document Type


Degree Name

Master of Science (MS)



Date of Award

Fall 2013


Methanobactins (Mbns) are a family of copper-binding natural products involved incopper uptake by methanotrophic bacteria. The Mbns that have been structurally characterized feature copper coordination by two nitrogen-containing heterocycles next to thioamide groupsembedded in a peptidic backbone of varying composition. The zinc-finger Zif268 binds toneurological genes through three repeated zinc finger motifs which are stabilized by the specificcoordination of Zn2+ via Cys2-His2 ligation, which provides the structural functionality of Zif268.The metal ion binding properties of the three oligopeptides Ac-His-Cys-Gly-Pro-His-Cys, Ac-His-Cys-Tyr-Pro-His-Cys and methylbutanol-oxazolone-enethiol-Gly-Pro-oxazolone-enethiol-Gly peptide that reproduce some of the sequence properties of Mbns and Zif268 were studiedusing the B3LYP hybrid functional and LanL2DZ basis set with the SMD aqueous solventmodel. The goal of the research is to design peptides that exhibit Cu+ or Zn2+ metal ionivselectivity and can be used at potential therapeutics for maintaining Zn and Cu homeostasis. Thebinding properties of Ac-His-Cys-Gly-Pro-His-Cys and Ac-His-Cys-Tyr-Pro-His-Cys havebeen examined for their binding affinity towards a series of important biologically active metalions Mn2+ , Fe2+ , Fe3+ Ni2+ , Cu2+, Cu+ and Zn2+. The B3LYP geometry optimization andfrequency calculations predict that Ac-His-Cys-Gly-Pro-His-Cys binds to the metal ions, in theaqueous-phase, in the order of Ni2+ >Fe3+ > Fe2+ >Cu2+>Cu+> Zn2+>Mn2+ and Ac-His-Cys-Tyr-Pro-His-Cys and methylbutanol-oxazolone-enethiol-Gly-Pro-oxazolone-enethiol-Gly binds tometal ions in the order of Ni2+ >Fe3+ > Cu2+> Cu+ >Zn2+ >Fe2+ > Mn2+ . Tetrahedral andsquare pyramidal coordination were observed predominantly depending on the charge state ofAc-His-Cys-Gly-Pro-His-Cys.Molecular modeling of the species observed in the ion mobility mass spectrometry(IMMS) analysis of Ac-His-Cys-Gly-Pro-His-Cys provides the likely structures of the peptidemetalcomplexes. These models appropriately fitted the charge state and mass of the ioniccomplexes. Visualization of the conformations gave a deeper insight into the binding sites and coordination structures of Cu2+ and Zn2+ complexes.


Laurence A. Angel

Subject Categories

Chemistry | Physical Sciences and Mathematics