DecipheRing Early steps of self-assembly of AMYloid forming peptides – DREAMY

The DREAMY project aims at deciphering the early steps of the self-assembly process of amyloid peptides, which is key to several biomolecular processes among which uncurable diseases such as Alzheimer Disease. Several studies have already brought information on the aggregation of this class of peptides, using different theoretical or experimental approaches, yet independently and only in a partial way. Our goal is to combine synergistically NMR and Molecular Modeling to study the dynamic supramolecular interaction process at stake. To that end, we will use a recent lanthanide complex, crystallophore (Xo4), as a tool to interfere with the self-assembly process under study and as a local probe of structural and dynamic changes at play.
First, we will implement state-of-the-art methods in physical chemistry to explore the interaction of Xo4 with the fragment Ab1-28 for characterizing the supramolecular interaction process. Then, the effect of Xo4 on the self-assembly of Ab1-28 will be studied using well-established biophysical methods to describe the interaction and get early multimeric species that will be suitable for a study by NMR. Second, we will investigate the dynamic supramolecular interaction between monomeric Ab1-28 and Xo4 using a set of NMR methods implementing suitably chosen paramagnetic lanthanide centers in Xo4 to extract structural and dynamic informations. Third, we will probe the oligomers that are involved in the early steps of the self-assembly process triggered by Xo4. We will use state-of-the-art approaches in the field of relaxometry and exploit the electron-nucleus relaxation to get information on the early oligomeric species. Finally, we will implement Molecular Dynamics simulations to describe in silico the interaction between peptides and Xo4. The results from this Molecular Modelling approach will be combined with our experimental data to help building a complete and detailed dynamic picture of the early steps of the self-assembly process