Titanium, although being undeniably abundant, relatively cheap, and meeting all criteria necessary for biological activity, has been assumed to be irrelevant in biological systems and underused in biological roles due to its susceptibility to hydrolytic precipitation. Outside of aqueous solution, however, titanium has demonstrated various uses, such as solar energy, catalysis, and TiO2 materials – which are used as coloring and fillers in various products. Nature has found ways to work around this hydrolysis by utilizing ligands that bind and stabilize these metals, which keeps them soluble in aqueous solutions. Titanium has also been shown to interact with many biological molecules, such as vitamin C and transferrin. Although many proteins have been shown to bind to titanium compounds, no native titanium binding protein or enzyme is known. However, these uses show that there is a multitude of possible applications for titanium in aqueous solutions, if control can be maintained. For example, the development of titanium biocatalysts has potential to eliminate the necessity for harsh solvent conditions that are currently used in industrial titanium catalysis. The coordination residues in the binding sites of naturally occurring metal binding proteins offer insight for studying how they can prevent hydrolysis. Through this insight, known de novo designed proteins based on the G4DFsc scaffold were modified in order to mimic the binding sites of naturally occurring metal binding proteins. These modified proteins feature a tyrosine residue, which has been shown to be a good ligand for titanium. These proteins were bound to titanium complexes, including titanium citrate or titanium tetrachloride. Circular dichroism (CD) spectroscopy has shown that, independently, our proteins show alpha-helical character, and some constructs, upon addition of titanium, show an increase in alpha-helical character, consistent with metal binding. Experiments are underway to test the capability of these Ti bound proteins to function as hydrolytic mini-metalloenzymes (MMEs). Initial tests show modest hydrolytic cleavage of both small molecules and DNA with these titanium MMEs. Further exploration of this activity will confirm the development of the first homogenous titanium enzyme.

Hydrolytic titanium mini-metalloenzymes

2019 Spring National Meeting

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