Prof M S P Sansom
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
Membrane proteins are of immense importance to all aspects of biology (they account for ca. 20% of genes) and play a major function as drug targets (ca. 40% of drug targets are membrane proteins). However, structural biology of membrane proteins has progressed relatively slowly due to the challenges of crystallisation and structure determination. Recent developments in single particle cryoelectron microscopy (cryoEM) are proving to be a ‘game changer’ in membrane protein structural biology, as crystals are no longer required. A number of recent structures (e.g. TRPV channels, glycine receptors, γ-secretase) have demonstrated that this method will lead to a rapid growth in the number of membrane protein structures determined over the next 5-10 years. However, structures determined by cryoEM are often at modest resolutions (typically ca. 3.5 Å), and may be determined not in the presence of a lipid bilayer but with an ‘annulus’ of detergent to enable solubilisation and dispersion of the membrane proteins as single particles. Molecular simulations allow us to ‘extend’ and ‘repair’ such structures, by enabling us: (i) to refine the structures of surface loops & characterise their dynamics; (ii) to add the protein structure back to a lipid bilayer environment; (iii) to include water molecules in and around ligand binding sites. All of these refined features are essential if a membrane protein structure is to be used in a drug discovery study. Molecular simulations also allow us to model clustering and/or oligomerisation of membrane proteins. This reveals membrane protein-protein interactions (mPPIs) as potential drug targets. Overall, by using advanced multiscale simulations, we are able to go from a ‘raw’ cryoEM structure to a refined model suitable for a drug discovery study. The current project will develop and apply methods to provide a ‘raw to refined’ pipeline for cryoEM and related structures of membrane proteins. It will build upon our expertise in multiscale simulation and modelling of membrane proteins, in developing the MemProtMD database (http://sbcb.bioch.ox.ac.uk/memprotmd/) and in modelling complex mammalian cell membranes. The project will address fundamental challenges in simulation studies of cryoEM structures of membrane proteins and their lipid interactions, in addition to developing computational tools for pipelining, and high throughput MD simulations. It will result in robust protocols for use by experimentalists and industry. These methods will be applied to selected receptors, channels, and transporters as new structures emerge, with an especial focus on potential CNS drug targets.
The project will be undertaken within the SBCB unit of the Biochemistry Department, which provides a first-rate environment and facilities for computational studies of membranes and their proteins (see http://sbcb.bioch.ox.ac.uk/). The successful applicant will also undertake a placement with UCB (of no less than 12 weeks duration).
This project is supported through the Oxford Interdisciplinary Bioscience Doctoral Training Partnership (DTP) BBSRC Industrial CASE (iCASE) studentship programme. The student recruited to this project will join a cohort of students enrolled in the DTP’s interdisciplinary training programme, and will be able to take full advantage of the training and networking opportunities available through the DTP. For further details please visit www.biodtp.ox.ac.uk.
Prospective applicants should contact the project supervisor Professor Mark Sansom ([Email Address Removed]) prior to submitting an application.
Applications for this project will be made via the Oxford Interdisciplinary Bioscience DTP. For further details please visit www.biodtp.ox.ac.uk.
Attributes of suitable applicants:
A background in Biochemistry or Chemistry with some experience of molecular simulations and/or structural biology is desirable.
Funding Notes
This project is funded for four years by the Biotechnology and Biological Sciences Research Council BBSRC. BBSRC eligibility criteria apply (http://www.bbsrc.ac.uk/documents/studentship-eligibility-pdf/). EU nationals who do not meet BBSRC residence criteria are encouraged to contact the programme administrator to check their eligibility for BBSRC funding before submitting a formal application. Successful students will receive a stipend of no less than the standard RCUK stipend rate, currently set at £14,296 per year, which will usually be supplemented by the industrial partner.