We report on the evolution and function of the pair of amide-hydrolases: urease and �-lactamase. Nature's choice for the functional metals in these structurally and mechanisticallysimilar enzymes is perplexing: urease, hydrolyzing urea, employs two Ni cations, whereas �-lactamase, hydrolyzing the �-lactam ring of antibiotics, employs two Zn cations. Our work istwo-fold. Protein-substrate binding modes were identified via mixed quantum-classicalmolecular dynamics. In particular, for �-lactamases, we elaborated on the role of the �-hairpinloop above the active site in the enzyme's ability to bind a diverse set of substrates. Further, toexplicate the origin of the aforementioned evolutionary effect, we investigated the structuraland electronic effects in the reaction mechanisms of the two enzymes, using ab initiomethods and Density Functional Theory. Our results infer that the most likely reason forNature's choice for the metals is rooted in the bioavailability of Ni versus that of Zn.

Elucidation of nature's choice for catalytic metals: A comparative study of di-nickel urease and di-zInc β−lactamase

243rd National Meeting (2012)

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