Investigation of the misfolding of [3-amyloid induced by phenyl pyridinium derivatives and heavy metals : A Computational Study

Abstract

The intention of this work is to understand the structural changes occurring in P-amyloids at the early stages of misfolding. The study uses molecular dynamics (MD) simulations to describe specific observations made in published, experimental and theoretical work. A series of MD simulations were carried out to study the structural changes in the P-amyloid 1-42 protein, which is implicated in the pathology of Alzheimer’s disease. The P-amyloid 1-42 is known to go through structural changes (misfold) and aggregate. The proteins aggregate into a soluble proteinaceous aggregate called amyloid oligomers, which are toxic to the human brain. The molecule l-Methyl-4- phenylpyridinium and its derivatives are known to induce structural changes in proteins and four phenylpyridinium derivatives were chosen to study their effect on the misfolding of P-amyloid 1-42 monomer with respect to their inhibition kinetics. According to the results the 4'-trifluromethylphenyl pyridinium derivative can induce structural changes that trigger misfolding of P-amyloid 1- 42 protein. Heavy metals play a vital role in amyloid toxicity. Thus a single heavy metal ion (Cu2+) was first chosen and the effect of the Cu2+ ion on amyloid misfolding is also studied. The Cu2+ is bound to Pamyloid 1-42 protein at the methionine residue (position 35 of the P-amyloid 142 sequence) and structural changes in the complete protein is studied through MD simulations. This study has identified a new binding site for Cu2+ at MET-35. Furthermore the effect of Cu2+ on amyloid oligomers is also studied by simulating penta-peptide systems of P-amyloid 142. This part of the study indicated physiological conditions where Cu2'r can initiate p-sheet formations in p-amyloid oligomers.