Revisiting amyloid aggregation across diseases: Mechanistic insights driven by histidine tautomerism

Abstract Protein misfolding and aggregation are critical in amyloidogenic diseases such as Alzheimer's disease, diabetes, and prion disorders. While aggregation has been widely studied in terms of extrinsic factors, the influence of intrinsic molecular features, particularly histidine tautomerism, remains poorly understood. In this mini‐review, we summarize recent computational studies elucidating how histidine tautomeric states regulate the structural changes, aggregation propensity, and intermolecular interactions of major amyloidogenic proteins, including amyloid‐β (Aβ40/42), Tau, amylin, prion protein, and profilin‐1, as well as their disease‐associated variants. We discuss tautomer‐dependent effects on monomer conformations, early oligomerization, fibril formation, and cross‐seeding behavior, and highlight the integration of molecular dynamics simulations and computational two‐dimensional infrared spectroscopy for resolving tautomer‐specific signatures. These findings emphasize histidine tautomerism as a critical but underestimated factor in amyloid aggregation mechanisms.