How Does the Mono-Triazole Derivative Modulate Aβ(42) Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations

[Image: see text] 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 4(a–x), where compound 4v was identified as the most potent inhibitor of Aβ(42) aggregation and disaggregates preformed Aβ(42) fibrils significantly. Moreover, 4v strongly averts the Cu(2+)-induced Aβ(42) aggregation and disaggregates the preformed Cu(2+)-induced Aβ(42) fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aβ(42) aggregation by 4v and disaggregation of preformed Aβ(42) fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aβ(42) monomer and a pentameric protofibril structure of Aβ(42) in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the Aβ(42) monomer and chains D and E of the Aβ(42) protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the Aβ(42) 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 ΔG(binding) = −44.9 ± 3.3 kcal/mol for the Aβ(42) monomer–4v complex. The free energy landscape analysis highlighted that the Aβ(42) monomer–4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aβ(42) monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and π–π interactions with Phe19 (chain D) of the Aβ(42) protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aβ(42) 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 Aβ(42) protofibril in the presence of 4v indicate destabilization of the Aβ(42) protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the Aβ(42) monomer and persuades a destabilization in the protofibril structure of Aβ(42). The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.