Bioinorganic chemistry of metalloproteins and tetrapyrroles

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The foundation of our research programme is the bioinorganic chemistry of metalloproteins and synthetic analogs. Metal-containing proteins dominate Life. A wide range of essential metals fulfill roles from ionic balance, nerve, and muscle action to structural stability (often zinc) to catalytic activity (for example iron). These metals must be inserted into the apoprotein and the structural integrity of the resulting holoprotein assured for optimal, physiological activity. A key cellular aspect is the storage of metals following absorption from nutritional sources. Transition and d-block metals must be bound to chaperones to avoid unwanted and potentially toxic cellular-based reactivity. The metalation pathways, binding constants, reaction mechanisms and the structural impact of metallation on proteins are our focus. These studies are supported by expertise with a wide range of instrumental resources to probe the underlying properties of the biologically demanding molecular systems. Our research makes use of computational data to predict optical and redox properties of the metal-binding sites. Three technologies dominate our studies: (i) Quantitative analytical measurements primarily from equilibrium-, time- and temperature-dependent properties determined by electrospray-ionization mass spectrometry (ESI-MS). (ii) Detailed optical spectroscopic measurements that identify metalated speciation, ligand coordination and spin and oxidation states. (iii) Computational studies of the geometric and electronic structures of complexes involving molecular dynamics for metalloprotein structures and docking, and DFT and TD-DFT methods for coordination geometries and excited state properties. Two classes of metalloprotein and the tetrapyrroles form the core focus of our programme. (i) Proteins that are dependent on metals for activity (specifically, transferrin, heme proteins, carbonic anhydrase, and superoxide dismutase). (ii) Metallothionein, a copper and zinc cellular storage protein that subsequently transfers these metals to metalloenzymes, but in addition this protein scavenges for toxic metals, and, finally, can act as a gate-keeper for the cell, guarding against intrusion by xenobiotic metals (such as metal-containing drugs). Our proposed studies are directly applicable to the protein misfolding currently the focus in catastrophic neurological diseases. We will use computational studies of metal-binding sites to understand the specific chemistries involved during folding. (iii) Tetrapyrroles are the cofactors of heme proteins, and synthetically, as porphyrins and phthalocyanines, offer remarkably diverse properties from the chlorins in chlorophylls, to the porphyrins in the P450 cytochromes and in the oxygen processing apparatus. The synthetic chlorophyll analogs are key to devices that can act as photon collectors in solar cells. Our computationally-guided synthesis will highlight key molecular factors to enhance photosensitizer activity.