OO080 - AMYLOID-Β OLIGOMERIZATION STUDY USING NOVEL COMPUTATIONAL PROTOCOLS (ID 838)
Abstract
Aims
The oligomerization of amyloid-β (Aβ) peptides is a major neuropathological hallmark of Alzheimer’s disease (AD). Although Aβ oligomerization has been intensively investigated in both theoretical and experimental studies, its kinetics and molecular mechanism remain mysterious to us. In this study, we developed and applied novel computational protocols to investigate the oligomerization of Aβ peptides at different conditions including monomer concentrations, mutations, and the presence of ligands.
Methods
We utilized molecular dynamics (MD) simulations of Aβ oligomerization. We estimated the oligomerization time of dimer, trimer, and tetramer; we tracked oligomerization pathways; we characterized the structures of the Aβ oligomers; we analyzed intermolecular residue-residue interactions in the different oligomers.
Results
We have established for the first time derived equations that could quantitatively describe the relationship between the oligomerization time and the monomer concentration. We’ve found that the Aβ42 oligomerization time depends on the monomer concentration by a power of -2.4. The residue-residue interaction analysis showed that K28 residues play an important role in the formation of Aβ42 oligomers. K16F/E22F mutations speeded up the oligomerization process of Aβ16-22 peptides.
Conclusions
Our established equations quantitatively can estimate the risk score of AD, which is a function of age. It also indicated that Aβ42 tetramer is the critical nucleus of the early Aβ42 oligomerization. Additionally, we have identified the most dominant pathway of forming Aβ tetramers, probably the most important and toxic Aβ oligomer. The increase of the peptide hydrophobicity speeds up the oligomerization process.
