Directed Evolution and Synthetic Biology

We apply state-of-the art approaches to evolve new enzymes and metabolic pathways. For example, enzyme systems can efficiently degrade and thus prevent intoxication by the most toxic nerve agent, VX. New metabolic pathways have been used to improve carbon fixation for eventual implementation in plants. Engineering methods include computational design, ‘smart’ library designs and high-throughput selection strategies.

Topology of the ancient Rossmann fold

The de novo emergence of proteins

How do new proteins evolve? The typical answer is: from other proteins. But where did the precursors for these proteins come from?

Proteins may have emerged emerge de novo, from short, functional polypeptides. For example, we recently showed that the P-loop motif of only 55 amino acids had nucleotide binding activity. We are examining routes leading from these short polypeptides to globular, functional proteins.  We are particularly interested in ancient motifs that are common to many different enzyme families (e.g. enzymes belonging to the Rossmann fold) and that led to the emergence of the very first proteins.

Conformational freedom permits evolution of new functions, while conformational disorder causes evolutionary dead-ends.

Principles of protein evolvability

We explore the fundamental principles of protein evolution. We unravel, at atomic detail, features of proteins that promote the rapid acquisition of new functions such as conformational diversity (one sequence adopting multiple structures), promiscuity (latent, coincidental functions), structural stability, and the potential of neutral mutations to promote adaptation. Our reconstructions of the ancestors and intermediates that led of today’s proteins are providing crucial insights as to how evolution shapes protein properties such as stability and folding, or enzyme catalytic efficiency and specificity.


A "lab review" by Tyler Hampton.