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 or
dered 鈥渁myloid鈥?oligomers formed by the mo
del un
decapepti
de of amyloid 尾-pepti
de 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) pepti
des. The conformational transition, that leads to the formation of 尾-sheet fibrils from soluble unor
dered structures, was found to
depend on the environmental conditions, whereas the presence of myricetin
destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed 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 un
derstanding the mechanism of action of well-known inhibitors and the pepti
de amino acid residues involved in the interaction leading to a rational drug
design of more potent new molecules able to antagonize the self-assembly process.
Keywords:
de+25%E2%88%9235&qsSearchArea=searchText">Amyloid 尾-peptide 25鈭?5; self-aggregation; circular dichroism spectroscopy; ThT fluorescence spectroscopy; myricetin; curcumin; (鈭?-tetracycline