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 beta-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid beta-peptide 25-35 [Abeta(25-35)]. Abeta(25-35) was chosen because it is the shortest fragment capable of forming large beta-sheet fibrils and retaining the toxicity of the full length Abeta(1-40/42) peptides. The conformational transition, that leads to the formation of beta-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 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 (-)-tetracycline), found to be stronger and weaker Abeta(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Abeta(25-35) 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 rational drug design of more potent new molecules able to antagonize the self-assembly process
Amyloid beta-Peptide 25-35 Self Assembly and Its Inhibition: A Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of the Alzheimer's Disease Process and Treatment
De Simone A.;
2012-01-01
Abstract
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 beta-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid beta-peptide 25-35 [Abeta(25-35)]. Abeta(25-35) was chosen because it is the shortest fragment capable of forming large beta-sheet fibrils and retaining the toxicity of the full length Abeta(1-40/42) peptides. The conformational transition, that leads to the formation of beta-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 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 (-)-tetracycline), found to be stronger and weaker Abeta(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Abeta(25-35) 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 rational drug design of more potent new molecules able to antagonize the self-assembly process
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