The Project

A defining characteristic of life is the requirement of energy from an external source; we eat, plants absorb light. To maximize the energy gained from the food that we and all oxygen-breathing organisms consume, oxygen is converted to water as a final step and carbon dioxide is released. The oxygen in this equation arises from plants as they convert water, carbon dioxide and light, into oxygen and fuel. This cycle is not merely an auspicious result of billions of years of evolution. The molecular events that allow the processes of respiration and photosynthesis to happen are connected in deep ways, down to shared structures, molecules, and mechanisms.

Natural modular oxidoreductases support electron transfer over long distances and catalysis

At their most basic, respiration and photosynthesis are Nature’s way to capture and convert energy from one form to another. To do this, Nature has evolved complex structures, termed oxidoreductases, that bind molecules that aid in this conversion. These molecules can both absorb light, imparting plants with their colours, and take and give electrons. The oxidoreductases have evolved to take energy from external sources and convert it into forms that can be used by living organisms to grow and survive. The evident complexity of this process belies a central feature of the oxidoreductases involved: evolution has yielded structures that are built from repeats of relatively simple modules. All of respiration and photosynthesis are built on these repeating modules. But despite nearly a century of investigation, where we have outlined how respiration and photosynthesis work in fine detail, we remain unable to construct our own models of these processes. This naturally leads to a question of whether we really understand how these processes occur.

Here we have assembled a team of researchers from multiple academic institutions and disciplines to address deficiencies in our knowledge, with the unified target of building completely new oxidoreductases from scratch. Through this work we will fill holes in our understanding of how Nature captures and converts energy.

Our work begins by combining powerful computational techniques that allow us to design and construct oxidoreductases with tailor made functions. Within a virtual reality framework that we are developing for this project, we will work together in a shared digital space to construct molecular binding sites, alter how molecules take and give electrons or catalyse reactions, and create oxidoreductase modules that, taking inspiration from Nature, we will join to produce more complex functions. With these designs, we will use an iterative ‘build-test-learn’ approach to construct new oxidoreductases that match the activities and actions of those Nature uses in respiration and photosynthesis. By pulling together our expertise in computational biophysical methods, oxidoreductase engineering, modular structure creation, molecular binding site assembly and their chemistry, and the analysis of very fast oxidoreductase functions, our team stands to make a substantial leap in our understanding of how to construct new oxidoreductases that has, so far, remained beyond our grasp.

The principles we establish through this work will help us to better understand the oxidoreductases of respiration and photosynthesis, finally clarifying architectural features that are essential for their assembly and function that have remained opaque for over a century. With our new sets of design principles, we will be able to create oxidoreductases that fulfil our needs in bioscience and biotechnology, from the creation of single structures that produce fuels from light, water and carbon dioxide akin to photosynthesis to biosensors that detect toxins in the environment or signs of disease.

The Team

University of Bristol

J. L. Ross Anderson
Project Lead, and PI
Paulina Dubiel (PDRA With JLRA)
Adrian J. Mulholland
Protein Dynamics Lead, and Co-I
Paul Curnow
Membrane Protein Design Lead, and Co-I
Ben Hardy (PDRA With PC)
Thomas A. A. Oliver
Multi-dimentional Spectroscopy Lead, and Co-I
Ziyi (Eric) Hu (PDRA with TAAO)
Fabio Parmeggiani
Computational Design Lead, and Co-I
Sofia Oliveira
Computational Protein Analysis, and Res-Co-I

University of Portsmouth

Bruce R. Lichtenstein
Protein Chemistry and Design Lead, and Co-I

University of East Anglia

Julea Butt
Electron Transport Lead, and Co-I

University College London/Birkbeck

Amadine Marechal
PCET Lead, and Co-I

The Positions

University of Portsmouth

Postdoctoral Research Associate (Chemical Biology) — Protein Chemistry and Design Group (Bruce Lichtenstein Lead)

A postdoctoral research position working at the interface of chemical biology and de novo design is available for 36 months within the Centre for Enzyme Innovation (CEI) at the University of Portsmouth (UoP). This position is supported by the BBSRC Grant BB/W003449/1, Creating and comprehending the circuitry of life: precise biomolecular design of multi-centre redox enzymes for a synthetic metabolism, and the project is a deep collaboration between teams at Universities across the UK, including the University of Bristol, University of East Anglia, and the University College of London.

This multidisciplinary project aims to clarify the rules governing the natural engineering of biological circuits. Our work at UoP will focus on synthesising artificial cofactors to extend the function of de novo designed proteins. By using this approach, we will gain a measure of control over the cofactors to direct the transfer of electrons, energy, and protons in our non-natural proteins towards applications in light harvesting, photocatalysis, and chemo-electronic sensing.

Job Role:
The work will focus on the creation of synthetic, non-natural redox or photo-active compounds and the computational de novo design of protein modules that employ these moieties as functional cofactors for electron transfer, light harvesting and catalysis. The senior research associate (SRA) will use organic synthesis to create the cofactors, and experimentally characterise these using electrochemical and spectroscopic techniques. These cofactors will be built into protein modules that the SRA will design using new computational tools, including machine learning and VR-based approaches, with a focus on binding and the control of the cofactors’ properties. Biophysical methods will be used to clarify how the designed environment has affected the cofactor chemistry.

The SRA will also work collaboratively with other researchers on the team who have complimentary expertise in membrane protein design, biomolecular simulation, and spectroscopy with the aim of constructing multi-cofactor assemblies designed as non-natural electron transport chains and catalytic oxidoreductases.

You should apply if:
This position would best suit a talented and motivated early career researcher with a PhD in Chemistry or related field, with experience in small molecule organic synthesis and who is interested in applying synthetic techniques to extend the function of designed proteins. The following skills would be additionally advantageous: experience with organic synthesis of redox cofactors; bioenergetics and spectroscopy; cofactor-containing proteins and enzymes, and protein design. The ability to communicate complex information clearly and accurately in English, both in written and oral forms is essential, as well as the ability to work independently and as part of a team.

Informal enquiries are actively encouraged and should be made to Dr Bruce Lichtenstein, (, in the first instance.

Funding Provided By: