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(BBSRC DTP) A computational model for improving catalytic rate in enzymes.


Faculty of Biology, Medicine and Health

Manchester United Kingdom Biochemistry Bioinformatics Biophysics Computational Chemistry Structural Biology

About the Project

Directed evolution of enzyme activity is an established methodology, generating biocatalysts that are of benefit for biotechnology, for example in bioenergy production [Turner 2009]. Such work typically involves mutation of amino acids lining an active site, with random traversal of this restricted sequence space coupled to experimental screening for activity. We would like to understand better the relationships between sequence, structure, and enzyme activity. Considering the influence of mutations on both substrate specificity and catalytic rate, in very simple terms, steric and charge complementarity in the ground state map to specificity, whereas complementarity in the transition state influences rate. Relatively little work has been carried out to support models for rate variation as compared to those for modulation of specificity. An interesting feature is that rate (kcat) can be altered by changes at some distance from the active site [Currin et al 2015], laying down a challenge for the construction of predictive models. Since charge often plays a major role in transition state stabilisation [Singh et al 2014], it makes sense to ask whether measured activity data correlate with calculated charge interactions in a chemical model for transition and ground states. A precedent for this approach lies in the observation that redox potentials of heme groups correlate with computed charge interactions with the protein environment [Zheng & Gunner 2009]. Thus physicochemical modelling allows us to understand variation in key biological and biotechnological properties. This computational PhD project will combine the expertise of 3 groups within the MIB to develop a predictive model for enzyme rate change upon engineering and redesign. It will focus on charge interactions, but include other effects where appropriate, such as flexibility. Briefly, and noting expertise within the supervisory team, developing chemical models for ground and transition states is key for this work (Sam de Visser), informed by docking of substrates (Sam Hay), followed by calculations of enzyme – ground/transition state interactions over a wide range of engineered sequences and modelled structures (Jim Warwicker) [Ivanov et al 2017]. In practical terms there is cross-over in the expertise of the team, a central theme is that we aim to better understand enzyme action through the use of both focussed studies on well-characterised enzymes and more broadly across enzyme families. The project will make predictive models available at our http://www.protein-sol.manchester site. An early task, for web delivery, is to develop more simple visualisations of electric field than are available currently.

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, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

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 http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

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 View Website

References


Currin A, Swainston N, Day PJ, Kell DB (2015) Chem Soc Rev 44:1172.
Ivanov SM, Cawley A, Huber RG, Bond PJ, Warwicker J (2017) PLoS One 12:e0185928.
Singh MK, Chu ZT, Warshel A (2014) J Phys Chem B 118:12146.
Turner NJ (2009) Nat Chem Biol 5:567.
Zheng Z, Gunner MR (2009) Proteins 75:719.

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