本論文利用平行淬煉分子動態法 (Replica-Exchange molecular dynamics, REMD) 模擬類澱粉蛋白(Aβ)片段- Aβ25-35及其突變物N27A- Aβ25-35折疊及穿膜的機制。Aβ是阿茲海默症的主要病源，Aβ25-35保有和全長A???????類似的特性?具細胞毒性及amphipathicity (N?端具親水性，C?端具疏水性)。模擬中，Aβ25-35是以全原子的方式進行，水相及膜是以implicit model的方式進行，搭配REMD，以達到有效率的空間搜尋效果。 模擬結果顯示，Aβ25-35以疏水性的C?端插入膜的疏水區域，並形成穩定的α-helix構形 (Ala30- Leu34); N?端(Gly25 -Lys28)具極性，分佈在水相及頭基的區域，沒有明顯的二級結構; 結果和NMR決定的結構吻合。此外有一小部份的Aβ25-35越過了能量障礙深入膜的疏水核心區域，但並不是穩定結構。 N27A-Aβ25-35 是將Aβ25-35中極性的Asn取代成疏水性Ala，此一改變使得N27A-Aβ25-35毒性下降。模擬結果顯示，N27A-Aβ25-35 和Aβ25-35具有相似的構形及性質，但N27A-Aβ25-35 的C?端較Aβ25-35更深入膜的疏水區域，α-helix構形往N?端延長且較穩定。 膜變薄效應也會影響Aβ25-35及N27A-Aβ25-35的構形，當膜逐漸變薄時，Aβ25-35及N27A-Aβ25-35會更容易深入膜內，形成較長且穩定的α-helix構形。 The folding and membrane insertion of the Alzheimer’s amyloid-β(25-35) peptide and the mutate N27A-Aβ(25-35) peptide are explored using replica exchange molecular dynamics(REMD). All the peptide use all atom model and the solvent region (water and water-membrane region) are implicit solvent model This amphiphilic peptide (hydrophilicity in N-terminus , hydrophobicity in C-terminus) is a natural by-product of the Alzheimer’s amyloid-β(1-40) peptide and retains the toxicity of its full-length counterpart as the ability to aggregate into β-sheet rich fibrils. The simulation result show that Aβ(25-35) insert into the membrane and form the helix structure in C-terminus (Ala30-Leu34);and N-terminus(Gly25-Lys28) are disordered at the water region.Our simulation result agree with the NMR structure.A little portion of structures inser into membrane but the structures are unstable. N27A-Aβ(25-35) peptide,where Asn27 is repliced by Ala. The mutate peptide shows lower neurotoxicity than the wild type despite its increased hydrophobicity. The simulation result shows N27A-Aβ(25-35) peptide and Aβ(25-35) peptide have similar structure and property, but N27A-Aβ(25-35) peptide can insert into membrane more deeper than Aβ(25-35) and the helix structure form more complete than Aβ(25-35).The membrane thining effect also affect the structure of Aβ(25-35) and N27A-Aβ(25-35). When the membrane become thin,two kind of peptide can insert into membrane easily and form stable α-helix structure.
