Prof. Dek Woolfson, Professor of Chemistry and Biochemistry & Director, Bristol BioDesign Institute (University of Bristol), will give a talk entitled: “Augmenting biology through de novo protein design”.

About the talk

Protein design—i.e., the construction of entirely new protein sequences that fold into prescribed structures—has come of age: it is possible now to generate a wide variety stable protein folds from scratch using rational and/or computational approaches. A challenge for the field is to move from what have been largely in vitro exercises to protein design in living cells and, in so doing, to augment biology. This talk will illustrate what is currently possible in this nascent field using de novo α-helical coiled-coil peptides as building blocks.

Coiled coils are bundles of 2 or more α helices that wrap around each other to form rope-like structures. They are one of the dominant structures that direct natural protein-protein interactions. Our understanding of coiled coils provides a strong basis for building new proteins from the bottom up. The first part of this talk will survey this understanding, our design methods, and our current “toolkit” of de novo coiled coils.

Next, the speaker will describe how the toolkit can be used to direct protein-protein interactions and build complex protein assemblies in bacterial cells. First, in collaboration with the Savery lab (Bristol), they have used homo- and hetero-oligomeric coiled coils as modules in engineered and de novo transcriptional activators and repressors. Secondly, with the Warren (Kent) and the Verkade (Bristol) labs, they have engineered hybrids of a de novo heterodimer and a natural component of bacterial microcompartments to form a “cytoscaffold” that permeates E. coli cells. This can be used to support the co-localisation of functional enzymes.

About Dek Woolfson

Dek Woolfson is Professor of Chemistry and Biochemistry, Principal Investigator of BrisSynBio (a BBSRC/EPSRC-funded Synthetic Biology Research Centre), Director of the Bristol BioDesign Institute at the University of Bristol, and Founder of Rosa Biotech.

Dek took his first degree in Chemistry at the University of Oxford, UK in 1987.  In 1991, he gained a PhD in Chemistry and Biochemistry at the University of Cambridge.  He then did post-doctoral research at University College London (1991 – 92) and the University of California, Berkeley (1992 – 94).  He returned to the UK to take up a Lectureship in Biochemistry at the University of Bristol (1994 – 95).  From 1996 – 2005 he was Lecturer through to Professor of Biochemistry at the University of Sussex.  He moved back Bristol in 2005 to a joint chair in Chemistry and Biochemistry.

Dek’s research has always been at the interface between chemistry and biology, applying chemical methods and principles to understand biological phenomena such as protein folding and stability.  He has a long-standing interest in the challenge of rational protein design, and how this can be applied in synthetic biology and biotechnology. His particular emphasis is on making completely new protein structures not known to natural biology using a combination of rational and computational design.  The current focuses of his group are in the parametric design of protein structures, assemblies and materials; and in porting these into living cells to augment natural biology.

In 2011, Dek became the first recipient of the Medimmune Protein and Peptide Science Award of the Royal Society of Chemistry; in 2014, he received a Royal Society Wolfson Research Merit Award, and he gained an ERC Advanced Grant; and in 2016 he won the Interdisciplinary Prize of the Royal Society of Chemistry.

References

• “Coiled-coil design: updated and upgraded“, DN Woolfson. Subcellular Biochemistry 82, 35-61 (2017).
• “CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil-protein assemblies“, CW Wood et al. Bioinformatics 30, 3029-3035 (2014).
• “ISAMBARD: an open-source computational environment for biomolecular analysis, modelling and design“, CW Wood et al. Bioinformatics 33, 3043–3050 (2017).
• “A basis set of de novo coiled-coil peptide oligomers for rational protein design and synthetic biology“, JM Fletcher et al. ACS Synth Biol 1, 240-250 (2012).
• “A set of de novo designed parallel heterodimeric coiled coils with quantified dissociation constants in the micromolar to sub-nanomolar regime“, F Thomas et al. J Am Chem Soc 135, 5161-5166 (2013).
• “Computational design of water-soluble a-helical barrels“, AR Thomson et al., Science 346, 485-488 (2014).
• “Guiding biomolecular interactions in cells using de novo protein-protein interfaces“, AJ Smith et al. bioRxiv 486902; doi: https://doi.org/10.1101/486902.
• “Engineered synthetic scaffolds for organizing proteins within the bacterial cytoplasm“, MJ Lee et al., Nature Chem Biol 14, 142-147 (2018).