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(BBSRC DTP) Biofuel synthesis from enzymes: how do charge distributions affect product control?

Project Description

One of this project ‘s strengths is the novel computational technology it introduces to the paramount field of biocatalysis. Any quantum mechanical insight into enzymes is initially holistic in character, that is, energies and electron densities are calculated for the whole systems. The introduction of a sophisticated partitioning method called IQA delivers atomic insight into enzymes, which is vital to gain a deeper understanding in how they work. Cutting-edge bioscience is indeed critically dependent on the availability of modern research infrastructure and the adoption of new ways of working; this project very much complies with this requirement. IQA originates from the world of small molecules (~20 atoms) but will now be applied to system of ~150 atoms. By using IQA in combination with the University’s powerful computer infrastructure called CSF, the student will thus fulfil BBSRC’s goal for researchers to routinely apply computational and mathematical techniques to high-quality quantitative biological data.

With dwindling resources of fossil fuels there is an urgent need for alternative energy sources. Biofuels constitute a possible source, which has not yet been extensively exploited. Several natural enzymes catalyse the decarboxylation reaction of fatty acids leading to terminal olefins that could be used as biofuels. One such enzyme with huge potential for the synthesis of biofuels, and thus to the biotechnology industry, is the cytochrome P450 peroxygenase OleTJE [1]. This enzyme utilizes hydrogen peroxide on an iron(III)-heme center and converts long chain (C12-C20) fatty acids into terminal olefins. However, by-products for - and -hydroxylation and desaturation are observed as well. To gain insight into the bifurcation processes leading to these various products detailed mechanistic and computational studies are important, in order to rationally engineer these enzymes for optimal biotechnological functions [2].

First principle calculations provide a wealth of valuable information, independent of experiment, but initially only for the whole system. The next challenge is to extract chemical insight from these calculations, most importantly, at atomic level [3]. Indeed, the quantum physics governing a chemical system is complex: each atom interacts with every other, according to various energy types: electrostatic, exchange and electron correlation. Despite this underlying physical complexity, a chemist routinely singles out a few atoms in a given system in order for them to explain the behaviour of the total system. The question is how this can be done rigorously, ideally by computation, and most excitingly, how novel insight may emerge from previously unseen patterns. In particular, a very recent study [4] on peptide hydrolysis in HIV-1 protease shows the importance of O…O and O…N through-space (exchange) interactions, where one oxygen belongs to the reactive water. These are revealed by the newly developed Relative Energy Gradient (REG) method [5], which automatically ranks atomic energy contributions according to their similarity in behaving like the total system. In the case of HIV-1 protease (represented by 133 atoms) there were more than 17,000 energy contributions. The in-house program ANANKE (which implements the REG method) correctly disclosed a concerted cascade of bond strengthening (or forming) and bond weakening (or breaking) atomic interactions. By analysing and studying the catalytic mechanism of fatty acid decarboxylation by peroxygenases, novel bioengineered enzymes can be created for optimal reactant conversion leading to biofuel products.

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Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.


[1] "Quantum Chemical Topology”, P.L.A. Popelier, in “The Chemical Bond – 100 years old and getting stronger”, Ed. M. Mingos, Chapter 2, pp. 71-117, Springer, Switzerland (2016); [2] M. A. Blanco, A. Martín Pendás and E. Francisco, J.Chem.Theor.Comput. , 1, 1096 (2005); [3] J.C.R. Thacker and P.L.A. Popelier, Theor.Chem.Accs., 136, 86 (2017).

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