Molecular insights into A[beta]42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

• Published in: Journal of molecular recognition Vol. 30; no. 12
• Main Authors: Saini, Rajneet Kaur, Shuaib, Suniba, Goyal, Bhupesh
• Format: Journal Article
• Language: English
• Published: Nutley Wiley Subscription Services, Inc 01.12.2017
• Subjects: Agglomeration; Alzheimer's disease; Binding energy; Biocompatibility; Chains; Chemical bonds; Coils; Destabilization; Dismantling; Fluorination; Free energy; Hydrogen bonds; Molecular docking; Molecular dynamics; Molecular structure; Oligomers; Simulation; Toxicity
• ISSN: 0952-3499; 1099-1352
• DOI: 10.1002/jmr.2656

The aggregation of amyloid [beta]-peptide (A[beta]42) into toxic oligomers, fibrils, has been identified as a key process in Alzheimer's disease (AD) progression. The role of halogen-substituted compounds have been highlighted in the disassembly of A[beta] protofibril. However, the underlying inhibitory mechanism of A[beta]42 protofibril destabilization remains elusive. In this regard, a combined molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a fluorinated compound, D744, which has been reported previously for potential in vitro and in vivo inhibitory activity against A[beta]42 aggregation and reduction in the A[beta]-induced cytotoxicity. The molecular docking analysis highlights that D744 binds and interacts with chain A of the protofibril structure with hydrophobic contacts and orthogonal multipolar interaction. MD simulations reveal destabilization of the protofibril structure in the presence of D744 due to the decrease in [beta]-sheet content and a concomitant increase of coil and bend structures, increase in the interchain D23-K28 salt bridge distance, decrease in the number of backbone hydrogen bonds, increase in the average distance between C[alpha] atoms, and decrease in the binding affinity between chains A and B of the protofibril structure. The binding free-energy analysis between D744 and the protofibril structure with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) reveal that residues Leu17, Val18, Phe19, Phe20, Ala21, Glu22, Asp23, Leu34, Val36, Gly37, and Gly38 of chain A of the protofibril structure contribute maximum towards binding free energy ([Delta]Gbinding = -44.87 kcal/mol). The insights into the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against A[beta]42 will be beneficial for the current and future AD therapeutic studies.