How Does the Mono-Triazole Derivative Modulate A?42 Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations.

ABSTRACT: Clinical studies have identified that abnormal self-assembly of amyloid-? (A?) 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 ?-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 A?42 aggregation and disaggregates preformed A?42 fibrils significantly. Moreover, 4v strongly averts the Cu2+-induced A?42 aggregation and disaggregates the preformed Cu2+-induced A?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 A?42 aggregation by 4v and disaggregation of preformed A?42 fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the A?42 monomer and a pentameric protofibril structure of A?42 in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the A?42 monomer and chains D and E of the A?42 protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the A?42 monomer into the aggregation-prone ?-sheet conformation. The binding free energy calculated by the molecular mechanics Poisson-Boltzmann surface area method revealed an energetically favorable process with ?G binding = -44.9 ± 3.3 kcal/mol for the A?42 monomer-4v complex. The free energy landscape analysis highlighted that the A?42 monomer-4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the A?42 monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and ?-? interactions with Phe19 (chain D) of the A?42 protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the A?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 A?42 protofibril in the presence of 4v indicate destabilization of the A?42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the A?42 monomer and persuades a destabilization in the protofibril structure of A?42. The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.

SUBMITTER: Kaur A 

PROVIDER: S-EPMC7331201 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature