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.
