Self-complementary Heterofunctional and Chiral Artificial Oligopeptides Substituted with Metal Binding Ligands

Open Access
Author:
Coppock, Matthew Bradford
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
May 08, 2012
Committee Members:
  • Mary Elizabeth Williams, Dissertation Advisor
  • Thomas E Mallouk, Committee Member
  • John H Golbeck, Committee Member
  • Alexander Thomas Radosevich, Committee Member
Keywords:
  • artificial oligopeptide
  • ligandoside
  • self-assembly
  • PNA
Abstract:
The design and synthesis of molecules that mimic the assembly and molecular recognition properties of natural systems is a strategy that can be utilized to make sizeable structures from small modular units that would otherwise be difficult to synthesize. The combination of peptide coupling chemistry and transition metal chemistry to create these mimetic molecules has the potential to construct exceptionally intricate supramolecular structures for applications in molecular wiring, catalysis, and sensing. This thesis describes synthetic modifications to ligand-substituted oligopeptide sequences for the creation of selective strands that interact with transition metals to form specific duplex structures, and introduces analytical techniques that could be exploited to study the formation and structure of the resulting metallated complexes. All of the experiments are aimed towards the conception of more elaborate, metal containing constructs in solution. The solution phase synthesis of artificial self-complementary di and tri peptides composed of ligand substituted aminoethylglycine (aeg) was achieved to produce anti-parallel metallated duplexes in the presence of tetracoordinate metals. Studies of the dipeptides, which consist of a monodentate pyridine (py) and tridentate terpyridine (tpy) or phenyl terpyridine (Φ-tpy) ligand in series on the aeg backbone, exhibit a 2:2 Cu:dipeptide binding stoichiometry during spectrophotometric titrations with Cu2+, indicative of the predicted metallated duplex. The single strands and the Cu-linked complexes are characterized by NMR, mass spectrometry, elemental analysis, HPLC, and absorbance spectroscopy. An artificial tripeptide has also been synthesized that consists of py, dimethyl bipyridine (bpy), and tpy in series on the aeg backbone. Characterization and formation of the duplex with three metal centers is investigated by various techniques such as EPR and spectrophotometric titrations. As an additional synthetic modification that could potentially impact the selectivity between strands, self-complementary chiral artificial oligopeptides composed of N-heterocyclic bpy ligands tethered on an aminoethylvaline (aev) backbone have been made. These strands are also designed to self-assemble in solution upon addition of a tetracoordinate metal, forming metallated duplexes. Metal complexation between the oligopeptides forms coordinative crosslinks (i.e. Cu(bpy)22+ or Zn(bpy)22+), which is monitored by circular dichroism (CD) spectroscopy. The chiral single strands and complexes are characterized by NMR, mass spectrometry, CD, elemental analysis, and HPLC. The thermodynamic properties and binding stoichiometries of metal to ligand-substituted oligopeptide interactions can be quantitatively determined using isothermal titration calorimetry (ITC). These data can help in the fabrication of much longer, heterofunctional structures. High resolution NMR is an analytical tool that can be utilized to gain essential information about the formation and resulting structure of metal crosslinked oligopeptides. A titration of paramagnetic Cu(II) into a solution of the heterofunctional Fmoc-aeg(py)-aeg(bpy)-aeg(tpy)-OtBu tripeptide has been followed by NMR spectroscopy, affording a qualitative insight into the multidentate ligand saturation dependence on the concentration of added metal ions. Substitution of a diffusion probe in the spectrometer allows the computation of the diffusion coefficient for isolated metallated duplex structures as a method to confirm successful duplex formation and estimate the size of the molecules.