N-Terminus Binding Preference for Either Tanshinone or Analogue in Both Inhibition of Amyloid Aggregation and Disaggregation of Preformed Amyloid Fibrils-Toward Introducing a Kind of Novel Anti-Alzheimer Compounds.

Amyloid-β (Aβ/Aβ) peptide with a length of 40 or 42 residues is naturally secreted as cleavage product of the amyloid precursor protein, and formation of Aβ aggregates in a patient's brain is a hallmark of Alzheimer's disease (AD). Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aβ aggregation. The disaggregation/inhibition effect of the inhibitors applies generally to both Aβ and Aβ aggregations. Here we capture the atomic-level details of the interaction between Aβ/Aβ and either natural tanshinone compound TS1 or its derivative TS0, and observe novel results by using molecular dynamics simulations. We observe that the natural TS1 indeed inhibits the monomolecular Aβ (mAβ) aggregation and disaggregates Aβ amyloid fibrils, being in good agreement with the experimental results. TS1 is favorable to stabilize mAβ and even Aβ fibril, playing an opposite role to that in the Aβ counterpart, however. TS0 can inhibit the misfolding of either mAβ or mAβ and disaggregate Aβ fibril but stabilize the Aβ fibril. Using a combination of secondary structural analysis, MM-PBSA binding energy calculations, and radial distribution functions computations, we find that both TS0 and TS1, especially the former, prefer to bind at the charged residues within disordered N-terminus with a scarce positive binding energy and disappear the characteristic C-terminal bend region of Aβ fibril, as well as twist the Aβ fibril seriously. It turns out to destabilize the Aβ fibril and enable the conversion of U-shaped Aβ fibril from the onefold to the twofold morphologies. The N-terminal binding preference helps us to identify N-terminal region as the specific epitope for specific inhibitors/drugs (such as TS0 and analogues), heralding unusual inhibition/disaggregation or stabilization mechanisms, and offering an alternative direction in engineering new inhibitors to treat AD.