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-/beta (A beta(40)/A beta(42)) peptide with a length of 40 or 42 residues is naturally secreted as cleavage product of the amyloid precursor protein, and formation of A beta 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 A beta aggregation. The disaggregation/inhibition effect of the inhibitors applies generally to both A beta(40) and A beta(42) aggregations. Here we capture the atomic-level details of the interaction between A beta(40)/A beta(42) and either natural tanshinone compound TS1 or its derivative TS0, and observe novel results by using moleular dynamics simulations. We observe that the natural TS1 indeed inhibits the monomolecular A beta(42) (mA beta(42)) aggregation and disaggregates A beta(42) amyloid fibrils, being in good agreement with the experimental results. TS1 is favorable to stabilize mA beta(40) and even A beta(40) fibril, playing an opposite role to that in the A beta(42) counterpart, however. TS0 can inhibit the misfolding of either mA beta(40) or mA beta(42) and disaggregate A beta(42) fibril but stabilize the A beta(40) 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 A beta(42) fibril, as well as twist the A beta(42) fibril seriously. It turns out to destabilize the A beta(42) fibril and enable the conversion of U-shaped A beta(42) 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.