Using approaches from molecular biology, bioinformatics, enzymology, and structural biology, this research program aims to expand the natural diversity of ribosomally synthesized and post-translationally modified peptides (RiPPs) and to elucidate their biosynthetic pathways and mechanisms. Unlike non-ribosomal peptides and polyketides—whose biosynthetic gene clusters (BGCs) contain several conserved enzymes and can be readily identified in sequenced genomes—RiPPs are produced by a highly diverse set of primary modification enzymes. Consequently, the number of yet-undiscovered RiPP classes, differing in their core structures and biosynthetic machineries, remains unknown. The current focus is on expanding the chemical space of peptide scaffolds, including aryl–aryl cross-linkages, oxidative decarboxylation, and multiple ester/amide bond formations.

Another research program is to develop a new approach of directed evolution of proteins. By mimicking the process of the natural protein evolution, in which DNA diversification and clonal selection are the central processes, directed evolution allows to obtain in laboratory protein variants that have better properties. However, traditional directed evolution relies on in vitro DNA diversification, and thus is limited by labor-intensive discrete steps and relatively low size of DNA library. The in vivo mutagenesis methods that have been recently reported greatly facilitate the continuous directed evolution, in which the gene diversification and selection are simultaneously performed inside cells. However, the simple and fast in vivo mutagenesis methods with better targeting abilities (e.g. target only desired genes) are yet to be developed. This research aims at developing novel in vivo mutagenesis methods with high target-specificity and applying them to the evolution of enzymes of practical value. These studies will ultimately help to explore novel structural and functional space of biomolecules with implications in biotechnology and medicine.