From peptides to proteins to functions by design
_{CHEM GUEST Talks}

I will start my presentation with a short introduction to the CPD and our plans to foster collaborative, multidisciplinary protein design at KU and across Scandinavia.  I will then turn to the science that my group does in peptide and protein chemistry and design.

It is now possible to generate many stable peptide assemblies and proteins from scratch using rational and computational design approaches.¹  One challenge in this field of de novo protein design is to move past structures found in nature and target the ‘dark matter of protein space’; that is, structures that should be possible in terms of chemistry and physics, but which biology seems to have overlooked.  This talk will illustrate what is currently possible in this nascent area using de novo designed coiled-coil peptides and proteins.

I will describe our “toolkit” of de novo coiled-coil peptide assemblies,² and how we are converting these oligomeric bundles and barrels into single-chain proteins through rationally seeded computational protein design.³  Then, I will describe how we are functionalising these using a combination of rational and physics-based computational methods.4 Finally, I will turn to subcellular applications, and specifically to some recent and unpublished work on de novo designed systems that undergo phase-separation in bacterial and eukaryotic cells (⁵, and unpublished). 

1. A brief history of de novo protein design: minimal, rational, and computational
   Derek N. Woolfson
   J Mol Biol 443, ARTN: 167160 (2021). DOI:10.1016/j.jmb.2021.167160
   
   
2.  Understanding a protein fold: The physics, chemistry, and biology of alpha-helical coiled coils
   DN Woolfson
   J Biol Chem 299, ARTN: 104579 (2023). DOI: 10.1016/j.jbc.2023.104579
   
   
3.  Rationally seeded computational protein design of α-helical barrels
   KI Albanese, R Petrenas, F Pirro, EA Naudin, U Borucu, WM Dawson, DA Scott, GJ Leggett, OD Weiner, TAA Oliver, DN Woolfson
   Nature Chem Biol 20, 991-9 (2024). DOI: 10.1038/s41589-024-01642-0
   
   
4.  Rapid Assessment of Size, Shape, and Chemical Complementarity of Ligands for Computational Protein Design
   R Petrenas, K Ożga, JJ Chubb, AV Romanyuk, JJ McManus, GJ Leggett, NS Scrutton, TAA Oliver, DN Woolfson
   bioRxiv 2025.06.30.662286; doi: https://doi.org/10.1101/2025.06.30.662286
   
   
5.  Assembling membrane-less organelles from de novo designed proteins.
   AT Hilditch, A Romanyuk, SJ Cross, R Obexer, JJ McManus, DN Woolfson
   Nature Chem 16, 89-97 (2024).  DOI: 10.1038/s41557-023-01321-y
   
   

Dek is Professor of Protein Design in the Department of Biology at the University of Copenhagen, and Director and Principal Investigator of the CPD.  He also holds a position at the University of Bristol as Professor of Chemistry and Biochemistry, and he splits his time between Copenhagen and Bristol.

He graduated from the University of Oxford with a degree in Chemistry (1987), and from the University of Cambridge with a PhD (1992).  He did post-doctoral research at University College London (1991 – 92) and the University of California, Berkeley (1992 – 94).   He has held positions as Lecturer in Biochemistry (University of Bristol, 1994 – 95), Lecturer through to Professor of Biochemistry (University of Sussex, 1996 – 2005), and Professor of Chemistry and Biochemistry (University of Bristol, since 2005).  He took up the position in Copenhagen in August 2025. 

Dek’s research is at the interface between chemistry and biology.  He applies chemical methods and principles to understand biological phenomena such as protein folding, stability, and interactions. To do this, his group focuses on the design of completely new protein structures and functions from scratch, using the resulting synthetic proteins directly in cells to study biological processes. 

Dek’s work has been recognised by the Protein and Peptide Science Award (2011) and Interdisciplinary Prize (2016) of the Royal Society of Chemistry; a Humboldt Research Award (2020); the Vincent du Vigneaud Award of the American Peptide Society (2025); and election to the Fellowship of the Royal Society (2025).