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.

Topology of the ancient Rossmann fold

The de novo emergence of proteins

The answer to: How did protein X evolve, is typically, via sequences changes in protein Y whose structure and function are closely related. But how did Y, and Y’s precursor, and Y’s precursor’s precursor, emerge? Some proteins emerged de novo, namely from a fundamentally different precursor, for example from a short segment grafted from a different fold. We are examining routes leading from relatively short polypeptides (25 -50 amino acids) 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 protein(s).

“Niche” enzymology

Our knowledge of how enzyme work and how they evolved is mostly based on explorations of model organisms such as E. coli. However, life goes far beyond model organisms. The oceans, where life began, and about a third of this planet’s biomass resides, in a largely unexplored enzyme territory. Here, our interest lies primarily in the enzymes that produce the ‘smell of sea’ – dimethyl sulfide (DMS), and its precursor dimethylsulfoniopropionate (DMSP). These metabolites that may seem esoteric are produced at a rate of over 109 tons per year.

Enzyme and metabolic engineering

We apply state-of-the art approaches towards the engineering of new enzymes, including computational design, ‘smart’ library designs and high-throughput selection strategies. We have engineered, for example, enzymes that can efficiently degrade and thus prevent intoxication by the most toxic nerve agent, VX. We are currently engineering enzymes for new applications in cell- and neuro-biology, and in engineering novel metabolic pathways for improving crop efficiency