Welcome to the Theobald Lab!

Most biochemical reactions take from hundreds to billions of years to occur spontaneously. However, life depends on highly organized networks of catalyzed chemical reactions that proceed not only rapidly, but specifically and with high fidelity. Biological catalysts are enzymes, complicated molecular nanomachines that massively accelerate reactions by positioning specific substrate molecules with such precision that they are compelled to react. The molecular mechanism by which an enzyme executes this remarkable feat involves an exquisitely orchestrated sequence of steps. The structures, mechanisms, and functions of enzymes are all products of millions of years of evolution. Yet despite their fundamental biological importance, we have only a rudimentary understanding of the atomistic basis of the evolutionary changes that create novel enzymes.

Hence a precise molecular understanding of macromolecular assemblies ultimately must be informed by evolutionary mechanisms. For knowledge of the macromolecular structure-function relationship, we consider it essential to explicitly incorporate modern developments in population genetics, phylogenetics, and probability theory. Conversely, biochemical and biophysical principles also inform evolutionary inferences.