Modeling Secondary Coordination Sphere Interactions in Heme Proteins: From Small Molecule Ligands to Macromolecular Porphyrin-cored Polymer Nanoparticles

Joel Kyle Rodriguez, University of New Hampshire, Durham


Heme proteins are responsible for a wide variety of functions throughout biology. These functions range from electron transfer, catalysis, small molecule sensing, and transport. While the primary coordination sphere of the heme cofactor predominately dictates function, the hydrogen-bonding rich, secondary coordination sphere heavily influences the reactivity of these proteins. To investigate these interactions, synthetic model complexes have been designed to provide insight on how these secondary coordination spheres affect the structure and function of these proteins. These models range from small molecule ligands to macromolecular polymers. This dissertation describes the design and synthesis of small molecule ligands and macromolecular polymer nanoparticles that incorporate aspects of the proteins’ secondary coordination spheres to help elucidate the role of these secondary interactions. New synthetic routes to a series of intramolecular hydrogen-bond donating, thiophenolate derived ligands were designed in order to generate models that mimic the protein environment around the axial cysteinate in heme-thiolate proteins. The ligand design is based on 2-(acetylamino)thiophenol and 2,6-bis(acetylamino)thiophenol derivatives. While further work needs to be completed on the optimization of these syntheses, these models can provide a way to probe how the iron center is affected by secondary interactions through a small molecule ligand design. Porphyrin-cored polymer nanoparticles (PCPNs) were synthesized and characterized as heme protein models. Created using novel collapsible porphyrin-cored star polymers (PCSPs) containing pendant groups susceptible to intramolecular cross-linking, these systems afford model heme cofactors buried within similar macromolecular environments found in native proteins. Unlike traditional heme protein models, PCPNs offer tunable macromolecular backbones which can further incorporate secondary coordination sphere microenvironments around the porphyrin-core. Through reversible addition-fragmentation chain transfer (RAFT) polymerizations, these polymers were generated at high molecular weights similar to native proteins with uniformed chain lengths. PCPNs were formed through the photodimerization of 9-anthracenylmethyl methacrylate (AMMA) monomer units. Using orthogonally reactive pentafluorophenyl methacrylate (PFPMA) and 2-vinyl-4,4-dimethylazlactone (VDMA) monomers, post-polymerization modifications allowed for site-specific functionalization of the PCPNs. These modifications permit access to various microenvironments (hydrophobic, hydrophilic, hydrogen-bonding rich, etc.) to study their effects on heme iron reactivity.