Unveiling the inhibitory mechanism of peptidomimetic inhibitor against Aβ42 aggregation and protofibril disaggregation by molecular dynamics

Abstract

Alzheimer’s disease (AD) is an irreversible, progressive, and degenerative brain disorder characterized by the aggregation and deposition of amyloid-β (Aβ) oligomers in the brain of patients. A recent study highlighted the peptidomimetic compound (C1) as an inhibitor of Aβ42 aggregation and disassembly of Aβ42 oligomeric structures. However, its molecular mechanism of inhibition remains poorly understood. In this regard, the inhibitory mechanism of C1 against Aβ42 aggregation and disassembly of S-shaped protofibril structure was investigated using molecular docking and molecular dynamics (MD) simulations. MD simulations highlighted that C1 preserved the non-aggregation-prone helical conformation of Aβ42 monomer. C1 destabilized the salt bridge interaction between Asp23 and Lys28 in Aβ42 monomer, which plays a critical role in the formation of the self-assembly prone conformation of Aβ42 monomer. C1 binds with Aβ42 protofibril structure with favourable binding free energy (△Gbinding = –78.2 ± 4.04 kcal/mol) and caused destabilization of the S-shaped protofibril structure. A lower binding affinity between chains C and D of Aβ42 protofibril structure was observed in the presence of C1, which highlighted the destabilization of the Aβ42 protofibril structure. The study provided a complete picture of the inhibitory mechanism of peptidomimetic inhibitor against Aβ42 aggregation and fibril disassembly, which is in accordance with the observed potential in vitro anti-aggregation activity of C1 against Aβ42. The study will be beneficial in the design of potential inhibitors against Aβ42 aggregation and S-shaped protofibril disassembly.