1 PhD thesis proposal : Development of new approaches for studying conformational dynamics of biological macromolecular complexes by X - ray free electron lasers

Biological macromolecular complexes are of great interest for molecular biology and structure-based drug design as they are involved in core biological functions such as protein synthesis or cellular transport. They undergo large conformational transitions to achieve these functions. Therefore, characterization of structure and conformational flexibility of these macromolecular complexes is crucial to understand their functional mechanisms, and plays an important role in drug development. X-ray crystallography has been the primary tool to provide high-resolution structures, but crystallization can be difficult in the case of large complexes with conformational flexibility. We are specialized in development of image analysis methods and their applications in single particle cryo electron microscopy (cryo-EM). Cryo-EM is currently more and more used to study conformational transitions of biomolecular complexes. Conformational dynamics has been studied by single particle cryo-EM in our team (Jin et al., Structure 2014) and in other teams (Simonetti et al., Nature 2008; Dashti et al., PNAS 2014; Katsevich et al., SIAM J Imaging Sci 2015). Single particle X-ray freeelectron laser (XFEL) experiments in solution are currently under development because of their potential to allow studying structure and conformational dynamics of biological systems under physiological conditions. This PhD thesis aims at developing analytical and computational approaches for characterizing macromolecular structure and dynamics using single particle XFEL.