Atomic and dynamic insights into the beneficial effect of the 1,4-naphthoquinon-2-yl-L-tryptophan inhibitor on Alzheimer's Aβ1-42 dimer in terms of aggregation and toxicity.

Aggregation of the amyloid β protein (Aβ) peptide with 40 or 42 residues is one key feature in Alzheimer's disease (AD). The 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12-28 and 17-42, none of these studies were conducted on the full-length Aβ1-42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1-42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1-42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1-42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1-42 dimer against AD.