(BBSRC DTP) Improving catalysis and selectivity of cytochrome P450 enzymes through electric field effects and charge distributions. at The University of Manchester on FindAPhD.com

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Dr S De Visser, Prof Jim Warwicker, Prof Sam Hay No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Manchester United Kingdom Biochemistry Bioinformatics Biophysics Chemical Engineering Computational Chemistry Inorganic Chemistry

About the Project

Enzymes reacts with high selectivity and reaction rates with substrates as compared to analogous homogeneous catalysts. Recent work of our groups has shown that electric field perturbations in proteins can guide and direct chemical selectivity in enzymes. These local electric field effects are generated by charged groups in the protein, such as the binding of cations, e.g. Na⁺/K⁺, or anions or from charged amino acid residues. The long-range electrostatic and dipole interactions perturb rate-determining transition states in enzymes and guide a reaction to a wanted selectivity. The details on these electric field effects are still unknown, but they may be used in biotechnology to engineer proteins and give them novel functions. We aim to explore this further by (a) understanding the selectivity patterns of natural enzymes and (b) by selective engineering of proteins to direct the reactions to novel pathways and enhance reactivities, i.e. k_cat. The work will involve a combination of computational and experimental studies on enzymes and engineered variants. In particular, models will be set-up to understand the details of chemical reaction mechanisms of enzymes and electric charge distributions of proteins using a combination of density functional theory modelling, quantum mechanics/molecular mechanics and electrostatic modelling. In addition, a set of experimental studies using vibrational Stark spectroscopy and UV-vis absorption studies on selective systems will be done in parallel.

http://personalpages.manchester.ac.uk/staff/j.warwicker/

http://www.manchester.ac.uk/research/sam.devisser/research

https://www.research.manchester.ac.uk/portal/sam.hay.html

Entry Requirements

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

How To Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Funding Notes

Funding will cover tuition fees and stipend only. This scheme is open to both UK and international applicants. However, we are only able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Lin, Y.-T.; Ali, H.S.; de Visser, S.P. Electrostatic perturbations from the protein affect C-H bond strengths of the substrate and enable negative catalysis in the TmpA biosynthesis enzyme. Chem. Eur. J. 2021, 27, 8851-8864.
2. de Visser, S.P.; Lin, Y.-T.; Ali, H.S.; Bagha, U.K.; Mukherjee, G.; Sastri, C.V. Negative catalysis or non-Bell-Evans-Polanyi reactivity by metalloenzymes: Examples from mononuclear heme and non-heme iron oxygenases. Coord. Chem. Rev. 2021, 439, 213914.
3. Dixit, V.A.; Warwicker, J.; de Visser, S.P. How do metal ions modulate the rate-determining electron transfer step in cytochrome P450 reactions? Chem. Eur. J. 2020, 26, 15270-15281.