A new extremely promising class of ligand-induced fluorescent protein (LIFP) has been discovered  in June 2013. The UnaG protein emits intense and bright green light once the bilirubin (BR) ligand is bound to the protein. BR is an indirect marker of various human liver functions and has an antioxidant role. UnaG is therefore a promising direct medical tool to track liver disease as well as a probe to detect cardiovascular diseases. The InducedFluo proposal aims to model this new LIFP class for the very first time, to understand its, electronic, spectral and conformational properties as well as to design new ligands or mutants able to enlarge the panel of possible applications.

The InducedFluo goals will be fulfil thanks to the state-of-the-art multi-scaling computational tools including: i) robust and/or refined quantum mechanics methods to model the BR antioxidant and excited-states properties; ii) hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) schemes to account for surroundings; iii) molecular dynamics to assess the impact of conformational changes; iv) free energies calculations to estimate the binding energy of BR to the protein; and v) docking to explore new ligands, and so enhanced UnaG applications.

More precisely within the QM/MM methods we will use a very recent method to explicitly account for electronic polarization of the surrounding of the ligand. After a careful exploration of UnaG properties, we will suggest modifications of crucial neighbouring residues around BR to tune its response in order to enlarge the spectral activity of the BR once bound to the protein, e.g., going to the red will induce less cell damage. Eventually we should be able to associate UnaG to other human fatty acids compounds similar to BR that do not target the liver but other human functions.

Thomas PAPINEAU

Master 1