Network of hotspot interactions cluster tau amyloid folds

Vishruth Mullapudi, Jaime Vaquer-Alicea, Vaibhav Bommareddy, Anthony R. Vega, Bryan D. Ryder, Charles L. White, Marc I. Diamond, Lukasz A. Joachimiak

Research output: Contribution to journalArticlepeer-review


Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method to estimate the relative energetic contribution of each amino acid in an amyloid assembly. We apply our method to twenty-seven ex vivo and in vitro fibril structural polymorphs of the microtubule-associated protein tau. We uncover networks of energetically important interactions involving amyloid-forming motifs that stabilize the different fibril folds. We evaluate our predictions in cellular and in vitro aggregation assays. Using a machine learning approach, we classify the structures based on residue energetics to identify distinguishing and unifying features. Our energetic profiling suggests that minimal sequence elements control the stability of tau fibrils, allowing future design of protein sequences that fold into unique structures.

Original languageEnglish (US)
Article number895
JournalNature communications
Issue number1
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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