Exploring and introducing dynamics into de novo proteins by design

The Woolfson group has developed a series of de novo designed peptides that assemble into unusual protein structures called alpha-helical barrels. This project will explore the dynamic properties of these structures along with how they can be altered and developed for further functionality.

* Kinetics of coiled-coil disassembly
Peptides labelled with self-quenching fluorescent dyes will be synthesised and used in studies to gain a greater understanding of the dynamic behaviour of coiled coils in solution, and particularly their rates of dissociation and peptide exchange.

* Post-translational modifications as "switches" for barrels
I will synthesise alpha-helical barrels with sites that can be modified by natural enzymes, such as phosphorylation sites, and analyse how modification affects the structure and stability of the barrels. Further work will be done to develop this into a switchable system where the assembly and disassembly of the barrels can be controlled enzymatically. After in vitro work, the aim would be to develop these systems into biological assays. The barrels will be delivered into cells and undergo a modification leading to a detectable change.

The students will be the key beneficiaries of this research as they will be exposed to and be able to exploit a new form of
PhD training in the chemical sciences. In particular they will be able to input to and shape their project before embarking on
it - this will make a key impact on the science compared to the normal PhD route and will produce students who are
motivated and engaged from the start. Aspects of the course such as Brainstorming, regular problem sessions, Outreach
and Public Engagement, and the organization and delivery of the CDT-Syngenta Award to a world-leading academic will
produce students who are more confident in their own abilities. This in turn will have a real impact on their future careers
when making presentations or when interviewed, as well as fast tracking their leadership skills. Other aspects of the
training such as IP, Entrepreneurship and Commercialisation, will help stimulate and prepare these students for developing
their own Start-up ventures based around their science skills. Science and Technology SMEs are increasingly vital to the
UK's economy and if we are to make an impact on the world stage our next generation of scientists must be empowered to
move quickly and flexibly in that direction. At an academic level the science that these students will produce will make an
impact right across the chemical synthesis landscape and will train a new generation of academic unafraid to cross
chemical boundaries. These students promise to contribute to vitally important areas of society such as healthcare,
medicine, energy and food production - all requiring new molecular entities to be produced efficiently and effectively. The
nations health both financially (eg GDP) and physically (eg antibiotics) desperately need innovative new directions. For
example, the Pharmaceutical industry requires a new direction for drug discovery. One ripe area is to explore new 3D
molecular space, a space that just a few years ago would have been avoided due to complexity and expense. If new drug
IP is to be created, and tax revenue thereof, then we must train a new generation of molecule makers who are unafraid to
take on the challenges of this unexplored space and, more importantly, be able to exploit it commercially. We believe that
our Centre will be able to train PhD students with this level of scientific skill and commercial aspiration.
Our industrial stakeholders are invaluable to the the patronage and direction of the Centre and will benefit greatly from
direct interaction with the various cohorts during their tenure in the Centre. For example, by providing the CDT students
with industrial placements, an effective two way knowledge and skills exchange will operate: students will get invaluable
insight into small, medium and large industries; industry will see first hand the highly motivated and skilled students the
Centre produces as well as get access to much of the unique electronic teaching material that the Centre has developed.
Finally the CDT will have a positive impact on supervisor behavior by ensuring collaboration under conditions that are not
forced or artificial. All potential PhD projects submitted for Brainstorming must have at least two supervisors. This can be
either academic -academic (home/away) or academic-industrial. We have found with the current CDT that these proposals
must describe real collaborations or the students are unlikely to select them. This provides the right encouragement for
collaborators to generate strong proposals that will interest all parties, which in turn is leading to high quality publications in
high impact journals.