In this conference, we will present our most recent theoretical results on the aggregation of Amyloid-β(1-42) and Aβ(25-35). The peptides were optimized at the theoretical levels PM6 and Hartree-Fock, respectively. The Aβ(1-42) monomer presents the same structural remarks pointed by Gremer experimental geometry, including a stable L-S topology. Aβ(1-42) shows a highly localized electric dipole moment partially oriented perpendicular to the peptide plane. The dipole enhances the aggregation rate by dipole-dipole interactions, a property that was not uncovered until now. The protofibril arrangement is conformed by two monomers bounded by salt bridges and exhibits a dipole moment utterly align with the fibril axis. The axial dipole moment facilitates the aggregation of protofibrils, yielding to fibrils with a significant dipole moment. The dipole acts as a self-catalyst following a sustained cascade of dipole-dipole aggregation, growing protofibrils into fibrils, and ultimately into plaques. We have demonstrated that the Aβ(25-35) monomer presents a dipole moment entirely perpendicular to the fibril plane. The Latter is capable of forming protofibrils, but with dipole moments considerably larger than in the case of Aβ(1-42). The latter explains its high cytotoxicity and aggregation rate. The stabilization energies, as well as the dipole moment orientation in both amyloids, suggest that the Aβ(25-35) peptide does not require nucleation to accomplish fast aggregation. The aggregation mechanism of the latter is contrary to the Aβ(1-42) peptide that follows a nucleated polymerization aggregation route. Additionally, we will show outcomes indicating that the localized electric dipole moment in both amyloids is fundamental for the formation of ion channels. The latter explains the excessive neurotoxicity of these peptides in comparison with others.

Dipole moment dependent aggregation and cytotoxicity of amyloid-beta peptides in Alzheimer's disease

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.