Florian Hollfelder

Chemical biology: from mechanism to droplet microfluidics (and back).

Nature has evolved the most amazing functional biomolecules, and as researchers we want to understand how they work. Enzymes are the all-purpose catalysts that make the chemistry of life run smoothly and efficiently, under the mildest, 'greenest' conditions, and protein binders are involved in governing many biological processes.

The Hollfelder Group is interested in gaining a fundamental understanding of the principles responsible for molecular recognition processes in chemistry and biology. We probe whether these principles enable us to describe, manipulate and ultimately make functional molecules. Using an eclectic mix of techniques we extend the mechanistic lessons learned to potential applications in biotechnology, synthetic chemistry and medicine.

Research objectives

• How does protein evolution work and where do functional proteins come from?

• Can we explain biological catalysis and molecular recognition in chemical and biophysical terms?

• Where does extreme miniaturisation of experiments (into picoliter droplets made in microfluidic devices) help to answer chemical and biological questions?

Key publications

van Loo B, Bayer CD, Fischer G, Jonas S, Valkov E, Mohamed MF, Vorobieva A, Dutruel C, Hyvönen M, Hollfelder F (2019). Balancing specificity and promiscuity in enzyme evolution: Multidimensional activity transitions in the alkaline phosphatase superfamily. J. Am. Chem. Soc., 141(1):370-387. doi: 10.1021/jacs.8b10290

Miton CM, Jonas S, Fischer G, Duarte F, Mohamed MF, van Loo B, Kintses B, Kamerlin SCL, Tokuriki N, Hyvönen M, Hollfelder F (2018). Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset. Proc. Natl. Acad. Sci. U.S.A., 115(31):E7293-E7302. doi: 10.1073/pnas.1607817115

Gielen F, Hours R, Emond S, Fischlechner M, Schell U, Hollfelder F (2016). Ultrahigh-throughput-directed enzyme evolution by absorbance-activated droplet sorting (AADS). Proc. Natl. Acad. Sci. U.S.A., 113(47):E7383-E7389. doi: 10.1073/pnas.1606927113

Colin PY, Kintses B, Gielen F, Miton CM, Fischer G, Mohamed MF, Hyvönen M, Morgavi DP, Janssen DB, Hollfelder F (2015). Ultrahigh-throughput discovery of promiscuous enzymes by picodroplet functional metagenomics. Nat. Commun., 6:10008. doi: 10.1038/ncomms10008

Fischlechner M, Schaerli Y, Mohamed MF, Patil S, Abell C, Hollfelder F (2014). Evolution of enzyme catalysts caged in biomimetic gel-shell beads. Nat. Chem., 6(9):791-796. doi: 10.1038/nchem.1996