Binding of 12-Crown-4 with Alzheimer's Aβ40 and Aβ42 Monomers and Its Effect on Their Conformation: Insight from Molecular Dynamics Simulations

Alzheimer's disease is the most common form of dementia and is considered to be caused by the conformational change of A beta monomers, from their native monomeric states, to form A beta oligomers/aggregates in the brain. Turn formation in A beta monomer has been suggested to be the nucleation step for A beta misfolding. In the present work, we have performed a series of all-atom molecular dynamics simulations, a total time of 11.4 mu s, to elucidate factor that contributes for early stage misfolding of A beta 40 and A beta 42 monomers and reveals the binding modes of 12-crown-4 on A beta 40 and A beta 42 monomer and effect of its binding on structural stability. Our simulation data revealed that the region around Va124-Lys28 is most prevalent for turn formation and a gain of water molecules around Lys28 side chains occurs at the same time as a significant gain in conformational entropy of the side chain. The initiation steps lead a greater number of water molecules available and enhancement of the conformational entropy of the backbone atoms; this leads to greater probability of breaking Lys28 backbone intrapeptide H-bonds, and consequently turns formation. Simulations of A beta 40 and A beta 42 monomers with 12 crown-4 showed that the molecule is highly specific toward positively charged Lys16, Lys28 residues, and N-terminal Aspl. Lys16 and Aspl have been previously reported to make A beta peptide toxic. Our secondary structure analysis revealed that in the absence of 12-crown-4 there was a beta-sheet formed in the. A beta 640 peptide. In case of A beta 42 monomer, in the absence of 12-crown-4, we observed that the second helix region converted into a coil and turn; however, in the presence of 12-crown-4 it remained stable. Observed pharmacophore features of, 12-crown-4 will not only help in designing new candidate drug molecules, which are specific to A beta peptides but could also be used to design new imaging probe molecules, which could be used for labeling A beta peptide