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Decoding ‘protein-small molecule’ interactions by quantitative STD NMR spectroscopic techniques (ANGULOU16SF

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  • Full or part time
    Dr Angulo
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

The specific interactions between biomolecules by non-covalent forces in solution represent the fundamental basis of molecular recognition processes in biology. The specificity comes from structural and functional complementarities between the chemical groups of the participant molecules. NMR spectroscopy has demonstrated its suitability to provide such structural information at atomic level and many experiments have been developed and applied. Among the NMR techniques based on the observation of ligand signals, saturation transfer difference (STD) NMR has become one of the most powerful and versatile, with growing applications both in academic research as well as in pharma industry in drug discovery, design and optimization.

“Quantitative STD NMR” refers to the accurate correlation of NMR results with the 3D structure and the kinetics of a given protein-ligand intermolecular complex. The current approaches involve collecting different sets of NMR experiments and using 3D molecular models (from modeling, X-ray diffraction, etc…) to compute theoretical outcomes, by employing the so-called full relaxation matrix calculation approach. This project will involve the development of new implementations and protocols for reducing significantly the amount of experimental data to be collected, as well as the computational level required, to pave the way for “fast” quantitative STD NMR studies, to be carried out in a much shorter time.

This PhD project is offered to an enthusiastic candidate with a first class or 2.1 degree in Physics, Chemistry, Biology, or Pharmacy. The selected candidate will work in well-equipped laboratories, with access to state of the art High Performance Computing Cluster (302 node cluster providing a total of 4148 cores) and powerful NMR equipment (800 MHz, 2x 500 MHz, 2x 400 MHz, and 300 MHz spectrometers, equipped with different liquid-, solid-state, and HR-MAS probe heads), in a highly stimulating scientific environment that includes collaboration with internationally distinguished scientists at UEA and the Norwich Research Park (NRP).

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at http://www.uea.ac.uk/pgresearch/pgrfees.

A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.

References

i) Mayer, M.; Meyer, B., Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angewandte Chemie-International Edition 1999, 38 (12), 1784-1788.
ii) Angulo, J.; Rademacher, C.; Biet, T.; Benie, A. J.; Blume, A.; Peters, H.; Palcic, M.; Parra, F.; Peters, T., NMR Analysis of Carbohydrate–Protein Interactions. In Methods in Enzymology, Minoru, F., Ed. Academic Press: 2006; Vol. Volume 416, pp 12-30.
iii) Angulo, J.; Díaz, I.; Reina, J. J.; Tabarani, G.; Fieschi, F.; Rojo, J.; Nieto, P. M., Saturation Transfer Difference (STD) NMR Spectroscopy Characterization of Dual Binding Mode of a Mannose Disaccharide to DC-SIGN. Chembiochem 2008, 9 (14), 2225-2227.
iv) Angulo, J.; Enriquez-Navas, P. M.; Nieto, P. M., Ligand-Receptor Binding Affinities from Saturation Transfer Difference (STD) NMR Spectroscopy: The Binding Isotherm of STD Initial Growth Rates. Chem-Eur J 2010, 16 (26), 7803-7812.
v) Angulo, J.; Nieto, P., STD-NMR: application to transient interactions between biomolecules—a quantitative approach. Eur Biophys J 2011, 40 (12), 1357-1369.

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