Aggregation And Inhibition Mechanisms Of Beta-Amyloid Peptides Simulated By Molecular Dynamics

Alzheimer’s disease is a common neurodegenerative disease,characterized by the accumulation of extracellular amyloid deposits composed of amyloid β-protein(Aβ),intracellular neurofibrillary tangles,and neuronal loss.It threatens human’s health seriously.However,the pathogenic mechanism of Alzheimer’s disease is still in the state of the study,and the specific pathogenesis is unclear currently.Aβ40/42 peptide is a major component of the Aβpeptides aggregation plaque.According to many researches,the interaction between metal ions and Aβp peptides focuses on Aβ1-16 peptide area.The interaction of Aβ1-16 peptide and metal ions indicate that metal ions are easily to have a coordination reaction with HIS6 and HIP 13/14.Some researchers also found that the aggregation process of Aβ40/42 peptide was great different under different external pH value conditions,indicating that both protonated residues and residue numbers is dependent on pH values,The differentiated behaviors of Aβ1-16 in different acidic conditions is a focal point in our present work.In addition,researchers also found that the rodents would not suffer from Alzheimer’ s disease under normal environment,but under conditions of a large number of metal ions involved,they can catch the AD.Thus metal ions should be associated closely with AD,it also imply that metal ions can induce to aggregation of Aβ peptide.There were only three amino acids mutations in the rodent Aβ1-16 peptide compared with human Aβ1-16 peptide.The three mutated amino acids characterize of rodent Aβ1-16 peptides,and offer strong theoretical significance to study the differences and aggregation mechanism of Aβ1-16 peptide under different external conditions,which greatly help ones to understand the interaction between the metal ions and Aβ1-16 peptide under different external conditions further.According to the above problems and interest points,I first studied the structure and the aggregation mechanism of human Aβ1-16 peptide under different external conditions(under defferent protonated status),and then studied the rodent Aβ1-16 using the same method to compare with each other.Research results show that the Aβ1-16 monomers of both rodent and human can change from disorderly state to orderly state under low pH condition,and theβ-sheet structure can be appeared indirect,indicating that the Aβ1-16 peptide monomers of both rodent and human is prone to aggregate at a low pH conditions,which can be further confirmed by the analysis of free energy.However,the change process from disorderly state to orderly state is unstable.What’s more,the mutated amino acid sites are just which the metal ion will coordinated with.Thus,it can be predicted that when these key amino acid sites is protonated in a acidic conditions,it would also induce the Aβ1-16 peptide further curled and dense,inhibiting the metal ions to further interact with them.This may be one of the important reasons that the combination sites and ligands between metal ions and Aβ1-16 change greatly at different pH conditions.In order to further study the effect of protonation on aggregation of Aβ1-16 peptide,the structure behaviors of rodents’s Aβ1-16 peptide dimer were studied under pH 6.3 environmental condition.The results showed that the structures of β-sheet and β-bridge are stably appeared on the rodents Aβ1-16 peptide dimer,indicating that the dimer aggregation from each other can be occurred under this condition.From the analysis of the hydrogen bonds,we can find that protonated HIS6 plays an important role on the aggregation of dimer.In addition,the Aβ1-12 peptide and the absorption of Aβ1-12 peptide dimers and tetramers on the single-walled surface of carbon nanotubes(SWCNT)were also preparatory studied in this article.The results show that because of the strong hydrophobic effect of single-walled carbon nanotubes,peptides would first be adsorbed onto the surface of the carbon nanotubes,and then wind and parcel to the SWCNT.This results is similar to the β-barrel structures of Aβ25-35,studied by Zhaoming Fu groups.We holp this study can help ones to to understand the pathogenesis of Alzheimer’s disease and provide the valuable information for the development of new drugs as well as preventing and controlling the disease.