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 beta protein (A beta) 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 A beta self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with A beta peptides spanning the regions of residues 12-28 and 17-42, none of these studies were conducted on the full-length A beta 1-42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of beta 1-42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and A beta 1-42, which change the A beta 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 silica experiments with NQTrp with shorter A beta fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of A beta 1-42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting A beta 1-42 dimer against AD.