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

Abstract

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 fulllength 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.

Self-assembly of the full-length amyloid Aβ42 protein in dimers

“…47–49 We utilized a hybrid REMD simulation approach, in which proteins are defined using united atom parameters, and Martini water is used as the solvent. The energy landscape plot is shown in Fig.…”

Inhibition of protein aggregation and amyloid formation by small molecules

“…For example, Zhu suggests 35 binding pockets for Ab1-42 monomer/curcumin [38]. Zhang suggests 100 pockets for Ab1-42 dimer/2NQTrp and even within a transient pocket there are multiple binding modes [40 ]. While the Ab12-28 or Ab16-21/22 fragments can rank compounds, results are not transposable to Ab40/42 because both the N-terminal and C-terminal contribute to binding.…”

Synthesis of chemically-tethered amyloid-β segment trimer possessing amyloidogenic properties

“…Curcumin, 29,30 EGCG,18,31 NQTrp (1,4-naphthoquinon-2-yl-L-tryptophan), 32,33 and thionin 34 had strong inhibitory effects on aggregation of 1, whereas tetracycline 35 and D-H-KLVFF-OH 36 had no inhibitory activity ( Table 1). As curcumin 30 and EGCG 18 is known to inhibit the aggregation of Ab [25][26][27][28][29][30][31][32][33][34][35] , these inhibitions on 1 imply that the aggregation pattern of the original Ab 25-35 is preserved in 1. In addition, as EGCG and thionin did not exhibit such high inhibitory activities on Ab 1-42 , these two compounds might have the potential to specifically inhibit aggregation of the trimers.…”

“…2). As the Ab chain, we used the pathogenic segment Ab [25][26][27][28][29][30][31][32][33][34][35] , which has been used in both in vitro [16][17][18] and in vivo [19][20][21] experiments, and which retains the same toxic effect in rat hippocampal compared to Ab To synthesize 1, we prepared the following two peptides by Fmoc chemistry-based solid phase peptide synthesis: cyclic peptide 2 and azide functionalized Ab 25-35 3 (for their structures, see Fig. S1).…”

“…25 To compare the amount of cross b-sheet structures between 1 and the corresponding monomers Ab [25][26][27][28][29][30][31][32][33][34][35] (6), we performed a thioflavin-T (ThT) fluorescence assay; cross b-sheet structures are recognized by ThT, leading to an increase in its fluorescence intensity (FI) (Fig. 4a).…”