Computational Study on the Effects of Halogenated Compounds on Amyloid-Beta 40 Monomer Aggregation in Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is one of the most common types of degenerative dementia. Investigation into the mechanism of aggregation of the most potential Alzheimer’s protein, amyloid-beta (Aβ40) peptide suggested that the initial α-helical Aβ monomer structured transformed into an intermediate state of aggregation. Erythrosine B (ER) is a component of FDA-approved red food dye. Dr. Kwon at University of Virginia observed that the halogenated structure of ER inhibited the formation of Aβ fibril via in vitro experiments. Our group used computational molecular modeling such as AutoDock docking and molecular dynamics simulations to test the effect of ER and its modified version, EOY, on Aβ40 monomer. The drug candidates were modeled using Cerius2, and initial Aβ40 structure was obtained from the protein data bank (ID: 1BA4). AutoDock was used to perform molecular docking, and then molecular dynamics (MD) simulations were conducted using GROMACS 4.6.1 software package. An approximate binding site for each system was found using AutoDock. When the MD simulations were run, the drug molecules were located in the binding sites. Four analysis methods were used to investigate the interactions between Aβ40 and the drug candidates: comparison of the protein structures, secondary structure analysis, root mean square deviation (RMSD) of the protein’s position, and distance calculation between Aβ40 and the drug candidates. According to our analyses, ER was effective in preventing the conformational change of Aβ40, whereas EOY was a relatively poor inhibitor due to weak binding with Aβ40.