Interactions of Curcumin’s Degradation Products with the Aβ₄₂ Dimer: A Computational Study

Abstract

Amyloid-β (Aβ) dimers are the smallest toxic species along the amyloid-aggregation pathway and among the most populated oligomeric accumulations present in the brain affected by Alzheimer’s disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aβ into higher-order structures is to develop molecules that inhibit the early stages of aggregation, i.e., dimerization. Under physiological conditions, the Aβ dimer is highly dynamic and does not attain a single well-defined structure but is rather characterized by an ensemble of conformations. In a recent study, a highly heterogeneous library of conformers of the Aβ dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aβ dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomistic detail of the interactions between the curcumin degradation products and the Aβ dimer. The simulations show that the aromatic residues of Aβ, and in particular 19FF20, interact with ferulic aldehyde and vanillin through π–π stacking. The binding of these small molecules induces significant changes on the 16KLVFF20 region.

Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

“…For small molecule docking, snapshots from molecular dynamics simulations of the Aβ 42 monomer, 134 dimer 50 or multimers 52,135 have been clustered to generate representative ensembles to be prepared for docking, which can be experimentally validated. 62 Briefly, curcumin and a set of curcumin derivatives were docked onto Aβ 42 multimeric conformations generated with molecular dynamics simulations.…”

“…62 Briefly, curcumin and a set of curcumin derivatives were docked onto Aβ 42 multimeric conformations generated with molecular dynamics simulations. 50,52 Results revealed that the small molecules interact with high probability with the amyloidogenic driving domains 16 KLVFF 20 and 29 GAIIG 33 of Aβ 42 and disrupt their secondary structure in the hexameric 52 and dimeric arrangements. 50 Interestingly, Silybin A (Sil A) and Silybin B (Sil B), two diasteroisomers of silibinin were shown to have different interaction preferences to Aβ 40 and distinct biological response.…”

How oxidized EGCG remodels α-synuclein fibrils into non-toxic aggregates: insights from computational simulations

“…To circumvent this problem, some studies employed heterogeneous conformational ensembles of monomers and dimers of IDPs for docking studies. 53,54 On the other hand, in studies with a-syn fibrils, fragments of the Greek-key-like core of fulllength a-syn were investigated. 44,45,55,56 Notably, the core of the a-syn fibril comprises about 70 amino acids in the repeat region, organized in parallel, in-register b-sheets in a wellstructured Greek key topology.…”

Identification of Catechins’ Binding Sites in Monomeric Aβ42 through Ensemble Docking and MD Simulations

“…Several studies have revealed that a large number of natural compounds derived from plants, animals and 2 of 20 microorganisms have the potential to inhibit oligomerization [11,12,[18][19][20]. For example, several computational and experimental observations have shown that polyphenolic plant compounds which occur naturally in fruit, vegetables, chocolate, and tea are capable of inhibiting IDP aggregation [12,13,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38].…”

“…However, IDPs display high conformational heterogeneity, and ligand binding causes large structural changes in the IDP conformations. To circumvent this problem, heterogeneous conformational ensembles of IDPs have been used for docking studies [27,38,42,50,51]. Nevertheless, challenges associated with generating and choosing a set of suitable conformations for docking still remain.…”