Evolution is an autonomous, all-purpose problem solver. In nature, employing recursive cycles of diversification, selection and amplification has resulted in a plethora of biomolecules with remarkable functions. My group aspires to employ the Darwinian algorithm in the laboratory and employ selections for the creation of made-to-order biomolecules and to obtain a molecular understanding of the underlying evolutionary processes. In our efforts, make use of innovative molecular evolution approaches to:
(1) process catalytic information in bacteria to engineer efficient biocatalysts and map their structure-function relationships
(2) interface synthetic chemistry with phage display protocols to select natural-product-like macrocyclic peptides that combine the favorable traits of small-molecule and peptide-based drugs.
In a first step toward these goals, we have established an in vivo selection strategy that can elicit biotechnologically-relevant biocatalysts with vastly improved activities through serial passaging of populations harboring enzyme libraries. Requiring minimal human intervention and no specialized equipment, our strategy lends itself readily to automation and parallelization, thus making it ideal to efficiently navigate a complex sequence space. For the generation and selection of natural-product-like macrocyclic peptides, we have developed strategies to employ modified privileged scaffolds – common building blocks for small-molecule libraries – as non-peptidic cyclization units on the surface of bacteriophages. These strategies enable us to simultaneously generate billions of natural-product-like compounds that fall into a previously inaccessible chemical space, and select high-affinity binders from these libraries by phage display.