Oral Presentation 12th Australian Peptide Conference 2017

From rational to computational peptide design and back again (#53)

Dek Woolfson 1
  1. Schools of Chemistry and Biochemistry, & Bristol BioDesign Institute University of Bristol, UK

The vast majority of peptide designs have been based on heuristics or simple rules of thumb learnt from natural proteins or derived empirically through experiment.  The de novo a-helical coiled-coil assemblies provide a good example of this.1 The rules relate sequence to structure to guide the specification of coiled-coil oligomerization state, strand orientation, partner selection, and, to some extent, stability.  This has been extremely informative and productive, and design and engineering is probably more advanced for coiled coils than for any other protein structure.2  However, to move past the low-hanging fruit of peptide and coiled-coil design, and into the dark matter of protein structures, we will all have to learn new tricks.  To address this we and others—notably the André, Baker, DeGrado, Grigoryan and Harbury groups—have begun to tackle coiled-coil design parametrically using computational methods.3  For our part, we have developed CCBuilder, which is an easy-to-use web-based GUI;4 and ISAMBARD, which is a more-versatile Python-based API that is free to download from GitHub and has been written for protein design more generally.5 

I will describe how a serendipitous discovery of a 6-stranded a-helical barrel,6 which are rare in nature, led us to develop our computational methods; and how we used these to deliver a-helical barrels predictably.7  The talk will demonstrate the utility of this approach to make water-soluble protein-like barrels and pores, which we have engineered to form materials, bind small molecules, and catalyse simple reactions.8,9 Most recently in collaboration with the Bayley lab (Oxford), we have engineered membrane-soluble variants of these a-helical barrels that insert into lipid bilayers and conduct ions in a voltage-dependent manner.10  I will touch on how the barrels and related structures that we have built are improving our general understanding of coiled coils and peptide design more generally.

  1. The design of coiled-coil structures and assemblies. DN Woolfson. Adv Prot Chem 70, 79-112 (2005)
  2. Coiled-coil design: updated and upgraded. DN Woolfson. Subcellular Biochemistry 82, 35-61 (2017)
  3. De novo protein design: how do we expand into the universe of possible protein structures? DN Woolfson et al. Curr Opin Struct Biol 33, 16-26 (2015)
  4. CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil-protein assemblies. CW Wood et al. Bioinformatics 30, 3029-3035 (2014)
  5. ISAMBARD: an open-source computational environment for biomolecular analysis, modelling and design CW Wood et al. Bioinformatics In press (2017)
  6. A de novo peptide hexamer with a mutable channel. NR Zaccai et al. Nature Chem Biol 7, 935-941 (2011)
  7. Computational design of water-soluble helical barrels. AR Thomson et al., Science 346, 485-488 (2014)
  8. Modular design of self-assembling peptide-based nanotubes. NC Burgess et al. J Am Chem Soc 137, 10554-10562 (2015)
  9. Installing hydrolytic activity into a completely de novo protein framework. AJ Burton et al., Nature Chem 8, 837-844 (2016)
  10. A monodisperse helical peptide barrel. KR Mahendran et al., Nature Chem 9, 411-419, (2017)