Quantum classical simulations of the retinal chromophore photoisomerization event in newly discovered rhodopsins

The research presented and discussed in this thesis aims to enhance our understanding of how the spectroscopy and photochemical reactivity of conjugated double-bonds can be controlled at the supramolecular level (i.e. by incorporating the substrate in a specific macromolecular environment). This is achieved through the study of two recently discovered natural light-responsive proteins within the rhodopsin family. In fact, rhodopsins, together with phytochromes and xanthopsins, utilize an "elementary" light-induced double-bond isomerization reaction to catch, store, and subsequently leverage, the energy of light to trigger a multitude of biological functions across all the kingdoms of life. The research objective is, therefore, the mechanistic investigation of the photoisomerization taking place inside two different protein environments. This objective represents a meaningful goal for two main reasons. Firstly, it could provide novel insights into how nature exploits photoisomerization to incorporate light-sensitivity in proteins. Secondly, it could serve as a source of inspiration for bio-inspired technological applications, as the ability, invariably linked to this reaction, of these proteins to sense and respond to light has broad applications in various technological fields, such as optogenetics or synthetic biology. More specifically, this thesis reports on the computational investigation of two rhodopsins called Neorhodopsin (NeoR) and thermoplasmatales archaeon rhodopsin (TaHeR). NeoR was discovered in 2020 in the fungi spores produced by certain members of the phylum chytridiomycota and exhibits a set of extreme spectral properties that are particularly desirable in optogenetic tools. On the other hand, TaHeR is a rhodopsin expressed in the archea thermoplasmatales archaeon and belongs to the novel and elusive heliorhodopsin (HeR) family, only discovered in 2018. For both proteins, an in silico study of the photoisomerization event was carried out through the construction of two analogous hybrid quantum mechanics / molecular mechanics (QM/MM) models.