Structure and behaviour of magnetic enzymes.

Summary

This project will investigate how magnetic fields influence the behaviour of complex magnetic molecules using experimental and modelling techniques.

Molecular magnets are complex molecular systems that can exhibit ferromagnetic behaviour. The huge variety of magnetic molecular systems that have been synthesised, and the complexity of their interactions, means that they can exhibit a range of exotic and tuneable magnetic behaviours that are relevant to a range of technologies. In addition, many magnetic molecules play important biological functions. Molecules that have active sites containing two or more coupled magnetic ions can be made to change their symmetry in response to magnetic fields, due to spin-crossover and charge transfer effects. A key example of this behaviour is the magnetic enzyme Urease, which metabolises urea into ammonia, and is a leading cause of stomach ulcers and stomach cancer. While it is well known that the magnetic state of the active site of Urease is important in this reaction, the mechanism for this is not understood. It is also not clear whether magnetic fields might be able to influence the activity of Urease, and other bioactive magnetic molecules. This project will use a combination of Density Functional Theory and advanced magnetometry to investigate the structure of magnetic molecules, including Urease, in strong magnetic fields and investigate how this alters their activity. The successful student will be trained in the use of cutting edge modelling techniques to uncover the mechanism by which magnetic fields can influence the structure of magnetic molecules, pairing this with experiments in the multi-disciplinary Bragg centre which will uncover new routes toward magnetic therapies that take advantage of these effects.

Jack Bean Urease is a unique metal dependent enzyme which plays an important role in hydrolysis of urea to ammonia. [1] Controlling the hydrolysis of urea can inhibit the growth of H. Pylori bacteria in the stomach, which is a class 1 carcinogen associated with the formation of peptic ulcers and gastric cancer. [2] Urea hydrolysis involves the binding of the molecule to a nickel ion in one of six active sites in the urease enzyme. Each active site contains two nickel ions bridged by a hydroxide ion. [3] Due to the presence of magnetic ions in this enzyme and their critical role in the hydrolysis reaction, there have been several attempts to perform magnetic characterization on crystalline Jack Bean Urease (JBU) which have determined that binding of urea to the active site is accompanied by a change in paramagnetic susceptibility due to the different role of high and low spin Ni sites in the reaction. [4]

This project will expand on initial work, where we have observed a blocking like transition in the crystalline JBU, and vibrational modes which become Raman active in a magnetic field. The successful candidate will learn cutting edge methods for simulating the behaviour of the Urease active site using DFT, in particular, learning to simulate the effects of different spin states on the structure and vibrational spectrum of the molecule. They will combine this with cutting edge magnetometry and spectroscopy techniques, to experimentally confirm theoretical predictions. Finally, they will assist in designing and building a reaction chamber within a high field magnet, with which they will study the effects of large magnetic fields on the reactivity of Urease and related magnetic molecules. We anticipate that, in the long term, this work might inform whether magnetic therapies are possible, whereby the behaviour of this enzyme and its carcinogenic risk can be mitigated using magnetic fields.

[1] H L T Mobley, Helicobacter pylori: Physiology and Genetics, Chapter 16, pg 179 – 188, ASM Press, 2001.

[2] H L T Mobley et al, Microbiol Rev, 59, 451-480, 1995.

[3] A Balasubramanian et al, Jour Mol Bio, 400, 3, 2010.

[4] M G Finnega et al, J Am Chem Soc, 113, 10, 1991.

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