Determinants for Sub-Stoichiometric Inhibition of Amyloid Aggregations of both IAPP and Aβ by Bri2 BRICHOS

Bri2 BRICHOS, a folded domain of the transmembrane protein Bri2 expressed in both the brain and pancreas, is an experimentally known sub-stoichiometric inhibitor of amyloid aggregation. The molecular chaperon effectively delays fibrillization at low molar ratios for both beta-amyloid (Aβ) in Alzheimer’s disease (AD) and islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). While discovering effective anti-amyloid inhibitors that work at low doses is an appealing strategy to mitigate amyloid toxicity, the molecular mechanism underlying the broad and efficient anti-amyloid activity of Bri2 BRICHOS remains unknown. Here, we computationally demonstrated that Bri2 BRICHOS exhibits a stronger binding affinity to fibril seeds than to monomers, using atomistic discrete molecular dynamic simulations. By competing with monomers to bind the active elongation sites on newly nucleated, weakly populated fibril seeds, a small amount of Bri2 BRICHOS could block rapid fibril growth via monomer addition. The experimentally observed differential inhibition efficiency against IAPP and Aβ aggregation was found to depend on the relative fibril-binding affinities of the inhibitor compared to those of self-seeding monomers. Our computationally derived determinants for sub-stoichiometric inhibition against amyloid aggregation by Bri2 BRICHOS may inform the future design of potent anti-amyloid therapies for AD, T2D and other amyloid diseases.