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 selfassembly 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.

β‐sheet breakers with consecutive phenylalanines: Insights into mechanism of dissolution of β‐amyloid fibrils

“…However, in our opinion CHC will remain as the most probable target of BSBs and within it both phenylalanines 19 and 20 are supposedly crucial for the action of inhibitor molecules. This notion is also substantiated by the results obtained by use of different fibril models and small non‐peptide molecule inhibitors 52‐56 …”

Destabilization potential of beta sheet breaker peptides on Abeta fibril structure: an insight from molecular dynamics simulation study

“…The major factors that were considered by most of the researchers for evaluating the destabilization potential of the ligands are secondary structure content especially beta and coil content, salt bridge distance between Asp23-Lys28 (especially in U-shaped model), inter-chain hydrogen and hydrophobic interaction. 64,65,[81][82][83][84][85][86][87] In the current work, it was observed that binding of peptides with Abeta protobril has resulted in the loss of beta structure and gain of coil structure. This is in accordance with previous studies showing increase of coil and decrease of beta structures.…”

“…The U-shaped model (2BEG) has been part of most of the previously reported molecular simulation studies. [64][65][66][67][68][69][70] Thus, 2BEG model was selected for the study.…”

Origin of stronger binding of ionic pair (IP) inhibitor to Aβ42 than the equimolar neutral counterparts: synergy mechanism of IP in disrupting Aβ42 protofibril and inhibiting Aβ42 aggregation under two pH conditions

“…1 Ab peptides are prone to misfolding, producing b-folded structures that ultimately lead to the self-association of peptides to form toxic substances. 2 The two most abundant Ab isoforms are Ab1-42 (Ab42 for short) and Ab1-40 (Ab40 for short), both of which are proteolytically cleaved by b-and g-secretases from the amyloid precursor protein (APP), a transmembrane precursor protein. 3,4 Ab42 has higher neurotoxicity and aggregation capacity than Ab40.…”