How Does the Mono-Triazole Derivative Modulate Aβ₄₂ Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations

Clinical studies have identified that abnormal self-assembly of amyloid-β (Aβ) peptide into toxic fibrillar aggregates is associated with the pathology of Alzheimer’s disease (AD). The most acceptable therapeutic approach to stop the progression of AD is to inhibit the formation of β-sheet-rich structures. Recently, we designed and evaluated a series of novel mono-triazole derivatives <b>4­(a</b>–<b>x)</b>, where compound <b>4v</b> was identified as the most potent inhibitor of Aβ₄₂ aggregation and disaggregates preformed Aβ₄₂ fibrils significantly. Moreover, <b>4v</b> strongly averts the Cu²⁺-induced Aβ₄₂ aggregation and disaggregates the preformed Cu²⁺-induced Aβ₄₂ fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aβ₄₂ aggregation by <b>4v</b> and disaggregation of preformed Aβ₄₂ fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aβ₄₂ monomer and a pentameric protofibril structure of Aβ₄₂ in the presence of <b>4v</b>. The MD simulations highlighted that <b>4v</b> binds preferentially at the central hydrophobic core region of the Aβ₄₂ monomer and chains D and E of the Aβ₄₂ protofibril. The dictionary of secondary structure of proteins analysis indicated that <b>4v</b> retards the conformational conversion of the helix-rich structure of the Aβ₄₂ monomer into the aggregation-prone β-sheet conformation. The binding free energy calculated by the molecular mechanics Poisson–Boltzmann surface area method revealed an energetically favorable process with <i>ΔG</i>_binding = −44.9 ± 3.3 kcal/mol for the Aβ₄₂ monomer–<b>4v</b> complex. The free energy landscape analysis highlighted that the Aβ₄₂ monomer–<b>4v</b> complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aβ₄₂ monomer alone (17%). Compound <b>4v</b> displayed hydrogen bonding with Gly37 (chain E) and π–π interactions with Phe19 (chain D) of the Aβ₄₂ protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aβ₄₂ protofibril showed the maximum contribution in the binding free energy. The decreased binding affinity and residue–residue contacts between chains D and E of the Aβ₄₂ protofibril in the presence of <b>4v</b> indicate destabilization of the Aβ₄₂ protofibril structure. Overall, the structural information obtained through MD simulations indicated that <b>4v</b> stabilizes the native helical conformation of the Aβ₄₂ monomer and persuades a destabilization in the protofibril structure of Aβ₄₂. The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.