No abstract

Highlights-Oxidation is clue to induce protein misfolding -Natural mutation does not seem critical as a sole reason to determine pathogenicity -Atherosclerosis and amyloidosis are closely related -Intramolecular crosslinking restrains protein flexibility and function

Aggregation-prone region 1 (APR1), comprising residues 14-19, is consistently conserved during the evolutionary history of Apolipoprotein A-I. • APR1 contributes to thermal stability of the ɑ-helix bundle in the full-length Apolipoprotein A-I model. • Amyloid variants introduce a destabilizing effect on the monomer structure of Apolipoprotein A-I, in contrast to HDL-deficiency and naturally-occurring variants, which are nearly neutral. • During molecular dynamics simulations, G26R amyloidogenic mutant lead to the partial unfolding of ɑ-helix bundle and exposure of APR1..