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Establishing NMR chemical shifts as reliable reporters of atomic charge distributions in enzymes

Project Description

Enzymes are not only central to life but also to the growing need to harness elements of the natural world to the benefit of mankind. While knowledge of enzymes is ever-expanding, fundamental questions still limit the ability to predict their catalytic behaviour. The distribution of charge in enzyme active sites, and how it changes during the catalytic cycle, is of critical importance to this level of understanding. Currently, access to this information at the accuracy required to understand and predict catalytic rate enhancements reliably, requires a combination of very high resolution structural biology and very high level quantum calculations, along with accurate methods to partition the calculated electron densities to individual atoms. The required resolution is only seldomly available in experimentally determined protein structures, and current computational capabilities dictate that relatively few atoms (<200) can be accommodated in the appropriate quantum calculations, meaning that the generated picture is necessarily limited. The primary objective of this studentship is to establish how NMR measurements can be used in a reliable manner as a surrogate reporter of the charges associated with all atoms in enzymes. Our preliminary work has established that charge partitioning using the QTAIM method derived from the Quantum Chemical Topology approach can deliver proof of a quantitative predictable framework linking NMR chemical shifts to atomic charges. The focus is now to take this exciting preliminary data and extend QTAIM derived predictions to a wide variety of enzymes. We have the necessary experimental NMR and X-ray data available for various complexes of enzymes from different classes, and appropriate QM models for many of these. The derived understanding of atomic charges at different stages of the catalytic cycle has far reaching consequences for the future exploitation of biocatalysis.

Academic background of candidates:
Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in Chemistry or Biophysics. A Masters degree in a relevant subject and/or experience in Structural Biology / Quantum Chemistry is desirable.

Contact for further Information

Funding Notes

This is a 3.5 year EPSRC DTG funded studentship covering fees and stipend (£15,009 in 2019-20)

Open to UK/EU applicants only due to funding restrictions.

We expect the programme to commence in September 2020.


1] Griffin JL, Bowler MW, Baxter NJ, Leigh KN, Dannatt HRW, Hounslow AM, Blackburn GM, Webster CE, Cliff MJ, Waltho JP. Proc. Nat. Acad. Sci. USA 2012, 109, 6910-6915.
2] Jin Y, Bhattasali D, Pellegrini E, Forget SM, Baxter NJ, Cliff MJ, Bowler MW, Jakeman DL, Blackburn GM, Waltho JP. Proc. Nat. Acad. Sci. USA 2014, 111, 12384-12389.
3] Popelier P. In The Chemical Bond - 100 years old and getting stronger; Mingos, M., Ed.; Springer, 2016, p 71
4] Johnson LA, Robertson AJ, Baxter NJ, Trevitt CR, Bisson C, Jin Y, Wood HP, Hounslow AM, Cliff MJ, Blackburn GM, Bowler MW, Waltho JP. ACS Catalysis 2018, 8, 8140-8153.
5] Czarnota S, Johannissen LO, Baxter NJ, Rummel F, Wilson A, Cliff MJ, Levy CW, Scrutton NS, Waltho JP, Hay S. ACS Catalysis 2019, 9, 4394-4401

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