Combined results of theoretical molecular dynamic simulations and
in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the 尾-sheet ordered 鈥渁myloid鈥?oligomers formed by the model undecapeptide of amyloid 尾-peptide 25鈥?5 [A尾(25鈥?5)]. A尾(25鈥?5) was chosen because it is the shortest fragment capable of forming large 尾-sheet fibrils and retaining the toxicity of the full length A尾(1鈥?0/42) peptides. The conformatio
nal transition, that leads to the formation of 尾-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformatio
nal shift. In parallel, we a
nalyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (鈭?-tetracycline), found to be stronger and weaker A尾(1鈥?2) aggregation inhibitors, respectively, were also studied. The combined
in vitro and theoretical studies of the A尾(25鈥?5) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a ratio
nal drug design of more potent new molecules able to antagonize the self-assembly process.
Keywords:
Amyloid 尾-peptide 25鈭?5; self-aggregation; circular dichroism spectroscopy; ThT fluorescence spectroscopy; myricetin; curcumin; (鈭?-tetracycline