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Energetic portrait of the amyloid beta nucleation transition state.

Anna ArutyunyanMireia SeumaAndre J FaureBenedetta BolognesiBen Lehner
Published in: bioRxiv : the preprint server for biology (2024)
Amyloid protein aggregates are pathological hallmarks of more than fifty human diseases including the most common neurodegenerative disorders. The atomic structures of amyloid fibrils have now been determined, but the process by which soluble proteins nucleate to form amyloids remains poorly characterised and difficult to study, even though this is the key step to understand to prevent the formation and spread of aggregates. Here we use massively parallel combinatorial mutagenesis, a kinetic selection assay, and machine learning to reveal the transition state of the nucleation reaction of amyloid beta, the protein that aggregates in Alzheimer's disease. By quantifying the nucleation of >140,000 proteins we infer the changes in activation energy for all 798 amino acid substitutions in amyloid beta and the energetic couplings between >600 pairs of mutations. This unprecedented dataset provides the first comprehensive view of the energy landscape and the first large-scale measurement of energetic couplings for a protein transition state. The energy landscape reveals that the amyloid beta nucleation transition state contains a short structured C-terminal hydrophobic core with a subset of interactions similar to mature fibrils. This study demonstrates the feasibility of using mutation-selection-sequencing experiments to study transition states and identifies the key molecular species that initiates amyloid beta aggregation and, potentially, Alzheimer's disease.
Keyphrases
  • machine learning
  • single cell
  • cognitive decline
  • protein protein
  • crispr cas
  • genome wide
  • artificial intelligence
  • single molecule
  • mild cognitive impairment