Revealing the relationship between photophysics and biochemistry in metabolic redox cofactors

Project ID: 2228cd1331 (You will need this ID for your application)

UCL Lead department: Division of Biosciences

Project Summary:

Nicotinamide adenine dinucleotide (NAD) and flavin act as redox cofactors inside biological cells, facilitating key steps in metabolic pathways by accepting and donating electrons. Intriguingly, these molecules are also intrinsically fluorescent. As dysfunction in metabolism is a hallmark of a wide range of diseases, and the fluorescence characteristics of a molecule are highly sensitive to its local environment, this emission offers a potential diagnostic biomarker or intrinsic probe for biomedical research. However, we must first understand how the array of biochemical interactions experienced by these molecules can differentially alter their photophysics.

Spectroscopy experiments have revealed that the redox state of NAD and flavin and their binding to enzymes significantly perturb their fluorescence. However, it is difficult to relate these results to precise molecular mechanisms. Quantum mechanics/molecular mechanics (QM/MM) techniques allow quantum mechanical elements (fluorescence) to be computationally simulated as part of a larger biomolecular system (the enzyme). This PhD project will establish the use of QM/MM to study the excited state behaviour of these cofactors on high performance computing platforms. You will apply this approach to investigate how diverse binding configurations of NAD and the dynamic quenching of flavin by nearby amino acid residues perturb their fluorescence in different redox states and in different metabolic enzymes.

You will work across the groups of Dr. Thomas Blacker (Structural & Molecular Biology) and Prof. Edina Rosta (Physics & Astronomy). Dr. Blacker develops optical techniques for probing the metabolism of living tissues based on time-correlated single photon counting techniques. Prof. Rosta uses computational methods to understand the molecular mechanisms of enzymes. This project would therefore suit applicants with enthusiasm to work at the interface between the physical and life sciences, and theory and experiment. In return, you would develop a distinct interdisciplinary skillset upon which to build a future career in scientific research.