1 Biomolecular Sciences, Department of Biology, Faculty of Science, Københavns Universitet2 Lund University3 Administration, Department of Computer Science, Faculty of Science, Københavns Universitet4 Administration, Department of Computer Science, Faculty of Science, Københavns Universitet
Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated disordered 1-93 fragment of this protein, in wild-type and mutated (G26R, S36A, K40L, W50R) forms. In atomic-level Monte Carlo simulations of the free monomer, validated by circular dichroism spectroscopy, we observe changes in the position-dependent β-strand probability induced by mutations. We find that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I.
Protein Science, 2014, Vol 23, Issue 11, p. 1559-1571