Human degenerative diseases, such as Alzheimer’s, Parkinson’s disease, and Huntington's diseases, are attributed to the aggregation of soluble peptides or proteins under specific physiological conditions. Among amyloid-forming peptides/proteins, human beta2-microglobulin (b2m) tends to aggregate into insoluble amyloid fibrils which cause dialysis-associated amyloidosis in chronic dialysis patients. The mechanism of b2m amyloid formation has been extensively investigated for more than few decades, however, the detailed mechanisms are still unclear and under intense debate. Remarkably, recent experiments suggest that transition metal ions play a crucial role in alternating the aggregation process of b2m. To reveal the ion induced amyloid formation mechanism, we performed quantum chemistry calculations and molecular dynamics simulations to provide insights into ion binding sites and how they initiate protein conformational changes. We found that several intermolecular salt bridges play an important role in stabilizing b2m dimer and tetramer structures when ions are bound. The major motions of b2m oligomers are highly associated with the cooperation between these intermolecular salt bridges. By mutating the key residues which participate in these intermolecular salt bridges, b2m oligomers tend to dissociate in our simulations. This suggests that, by designing a proper salt bridge blocker, a promising treatment for b2m related amyloidosis will be established in a near future.

Revealing the amyloid formation mechanism of human beta2-microglobulin induced by transition metal ions

256th National Meeting (2018)

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