Biosensing using arrays of de novo designed proteins

In de novo protein design entirely new proteins structures and functions are built from scratch. This is basic science that
tests our understanding of sequence-to-structure/function relationships of natural proteins. It also presents possibilities
for generating protein structures not yet observed in nature (Woolfson et al., (2015) Curr Opin Struct Biol 33 16). In
applied science, it offers routes to hyperstable proteins with functions not performed by natural proteins.
Over the past 5 - 10 years, protein designers have
delivered increasingly complex stable de novo proteins
that fold and assemble as prescribed. This has come
through improvements in our understanding of
sequence-to-structure relationships in proteins,
advances in computational design methods, the
reduced cost of synthetic peptides and genes, and
increased speeds of high-throughput screening of
protein libraries. These advances set new targets for
the field of de novo protein design. One of these
challenges is to make functional de novo proteins with
potential applications in biotechnology and medicine.
Recently, the Woolfson group has discovered and developed an entirely new class of de novo proteins called alpha-helical
barrels (aHBs; Thomson et al., (2014) Science 346 485). These have central cavities that recognise and bind small
molecules, e.g. biomarkers of disease including cancers. aHBs resemble receptor proteins of the mammalian olfactory
system. However, unlike these natural receptors, which are membrane proteins, aHBs are water soluble, hyperstable and
easy to produce and manipulate. In collaboration with a University of Bristol spin-out company, Rosa Biotech, we are
developing aHBs as components of a novel biosensor to mimic the sense of smell; essentially, we are trying to construct a
biochemical nose from scratch. This is necessarily interdisciplinary science, as it has to bring together chemistry, structural
biology and photophysics to make it work.
The proposed PhD project builds on our foregoing work and the academia-biotech collaboration. It aims to train the
student at these interfaces specifically in rational and computational protein design, X-ray crystallography, and the
development of diagnostic devices. In addition, the project brings in a new academic collaboration in chemical physics and
spectroscopy through the Oliver group. In this way, the student will not only be able to design and characterise new
proteins biochemically and structurally, they will also be able examine how these proteins interact with fluorescent dyes
that Rosa Biotech uses in its innovative technology.