Investigating of the structural characteristicsand aggregation of amyloid beta oligomer usingmolecular dynamics simulation

• Main Authors: Kuo-Wei Chih, 池國維
• Other Authors: Chi-Chuan Hwang
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/10817481301623123203

碩士 === 國立成功大學 === 工程科學系碩博士班 === 97 === At present there are considerable literatures indicated that amyloid-β (Aβ) peptides play a major critical role caused the Alzheimer’s disease (AD). The Aβ is a 39 to 43 amino acid peptide that is a major component in the senile plaques of AD. These monomer Aβ peptides could aggregate the plaque form and further hinder the nervous transmission. Thus, the aggregation behavior of Aβ peptides is a rather significant event for treating the AD. On the other hand, from the atom force microscopy (AFM) observations, the monomer Aβ peptides form the sphere oligomers before they form the amyloid fibrils. Motivated by these findings, at present study attempts to investigate the structural stability and possible aggregation behavior including the wild-type and it’s analogues of Aβ oligomers using molecular dynamics (MD) simulations. The detailed study contents are as follows: (1) Wild-type Aβ17-42 pentamer. The simulated results reveal that the pentamer aggregating the stable sphere form; (2) Ile41-to-Asn mutation within the coding sequence of wild-type Aβ17-42 pentamer disrupts the hydrophobic core. That is, C-terminus forms relatively weak hydrophobic interaction, as reflected by the hydrophilic residue 41Asn. As a result, residue 41Asn tends to close with residue 34-36; subsequently, the case of Ile41-to-Arg mutation was also studied. Our results indicate the appearance of salt bridge was increased with mutations than wild-type Aβ17-42. Besides, the radius of gyration (Rg) was also examined. The results display that the Rg value exhibit the same tendency between mutation and wild-type Aβ17-42; (3) The absence of residue 41-42 destabilize the conformation in wild-type Aβ17-42 pentamer because of the lack of the hydrophobic interaction in C-terminus; However, the absence of residue 42 in wild-type Aβ17-42 pentamer enhance aggregation. This result is supported by the same distribution of secondary structure with wild-type, but smaller value for Rg. (4) Because of the structural heterogeneity in N-terminus of Aβ, the exact structure of Aβ oligomer is still incomplete. Here we performed MD simulation to investigate the formation of Aβ1-42 pentamer. The results show that the distribution of secondary structure in this case differs from the case of N-terminus truncated pentamer as mentioned above.