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

Abstract

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 Aβ42 aggregation and disaggregates preformed Aβ42 fibrils significantly. Moreover, 4v 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 4v 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 4v. The MD simulations highlighted that 4v 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 4v 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 ΔGbinding = −44.9 ± 3.3 kcal/mol for the Aβ42 monomer–4v complex. The free energy landscape analysis highlighted that the Aβ42 monomer–4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aβ42 monomer alone (17%). Compound 4v 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 4v indicate destabilization of the Aβ42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v 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.