Protein design: from fundamental understanding, through entirely de novo structure and assemblies, to real-life applications
The principal aims of the Woolfson lab are (1) to understand the links between protein sequence, structure and function, i.e., the informatics aspect of the protein-folding problem; (2) to apply this knowledge to design entirely new protein structures and assemblies from scratch; and (3) to use these de novo proteins as components for applications in biotechnology, cell biology and synthetic biology.
To do this, we garner sequence-to-structure/function relationships and structural principles through bioinformatics studies of natural protein structures deposited in the various protein databases. We then use the understanding gained as sequence rules and geometric guides to construct de novo protein sequences that adopt 3D protein structures and assemblies, which either mimic those of natural proteins or entirely new ones in what is termed the dark matter of protein space. We characterise these de novo proteins using a wide variety of biophysical methods and through to high-resolution NMR or X-ray crystal structures. Where possible, we employ the new proteins in applications for cell and synthetic biology, and particular as novel biomaterials.
Recent examples of our work include: deciphering rules for carbohydrate-protein recognition1 and for miniprotein stability2; the construction of a basis set of de novo coiled coils for applications in synthetic biology and biomaterials designs3; the development of easy-to-use software for generating in silico models of coiled-coil proteins4 and the parametric design of protein structures more generally5; the design and characterisation of a largely new class of protein assembly called alpha-helical barrels6; the use of coiled-coil helical bundles as building blocks for the assembly of new types of biomaterials7,8; the installation of binding and catalytic functions into the alpha-helical barrels 9,10; the engineering of peptides that span lipid bilayers11; and the assembly of hybrid natural-designed proteins to form novel cytoscaffolds in bacterial cells12.
Current research themes in the lab include: parametric protein design; engineering new types of protein-based sensors; and protein design in the cell. If you are interested in these themes or any of the above work and you would like to explore possibilities of joining the group please contact Dek Woolfson.
The banner image was created by Claudia Stoker at Vivid Biology upon commission by the Bristol BioDesign Institute.
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(2) Baker et al., (2017) Nat Chem Biol 13 764
(3) Fletcher et al., (2012) ACS Synth Biol 1 240
(4) Wood et al., (2018) Protein Sci 27 103
(5) Wood et al., (2017) Bioinformatics 33 3043
(6) Thomson et al., (2014) Science 346 485
(7) Fletcher et al., (2013) Science 340 595
(8) Burgess et al., (2015) J Am Chem Soc 137 10554
(9) Burton et al., (2016) Nat Chem 8 837
(10) Thomas et al., (2016) Angewandte Chemie 55 987
(11) Mahendran et al., (2017) Nat Chem 9 411
(12) Lee et al., (2018) Nat Chem Biol 14 142
(13) Ross et al., (2017) ACS Nano 11 7901;
(14) Galloway et al., (2018) ACS Nano 12 1420
(15) Thomas et al., (2018) ACS Syn Biol 7 1808