Novel Disassembly Mechanisms of Sigmoid Aβ₄₂ Protofibrils by Introduced Neutral and Charged Drug Molecules

Alzheimer's disease (AD) is characterized by fibrillar deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles of Tau proteins. Aβ peptides are composed of 37-49 residues, among which the Aβ₄₂ isoform is particularly toxic and aggregation-prone and is enriched in the plaques of AD brains and thus considered central to the development of AD. Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aβ aggregation. Here we capture the atomic-level details of the interactions between sigmoid Aβ₄₂ fibril 2MXU or 5KK3 and either natural tanshinone compounds TS1 or TS0 or negatively charged ER, proposing two unprecedented disassembly mechanisms. Natural TS1 or TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation, destroying the ordered growth of subsequent monomers along the fibril axis. For the more compact two-fold 5KK3 , attachment of TS1 or TS0 at the surface including some inserted in cavity results in the separation of the two folds. In the two sigmoid fibril systems, it is no longer applicable for the routine criteria to assess Aβ₄₂ fibril disassembly by introduction of these drugs, such as either reduced H-bond number, decreased β-sheet contents, or both. ER, like-charged to Aβ₄₂ fibril, is especially exceptional, and departs utterly from the neutral ones to disassemble Aβ₄₂ fibril. Besides the inapplicable routine criteria, positive binding energy between ER and Aβ₄₂ fibril also deviates from the hypotheses of "ligands exhibiting greater affinity for the β-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity" ( Cairo et al. , Biochemistry 2002 , 41 , 8620 - 8629 ) but results in stronger disassembly effect on the two kinds of sigmoid Aβ₄₂ fibrils than neutral TS0 or TS1. The disassembly power of charged ER molecules derives from its stronger deformation ability to the conformation of Aβ₄₂ fibril than the neutral ones, twisting the one-fold 2MXU into tapered-shape and separating two-fold 5KK3 in two parts further, which is in great agreement with experimental observations ( Irwin et al. Biomacromolecules 2013 , 14 ( 1 ), 264 - 274 ). The unusual disassembly mechanisms fill the gaps and offer an alternative direction in engineering new inhibitors to treat AD.