海藻糖抑制淀粉质多肽42构象转变的分子动力学模拟

Molecular Dynamics Simulation of the Conformational Transition of Amyloid Peptide 42 Inhibited by Trehalose

应用分子动力学模拟方法研究了海藻糖抑制淀粉质多肽42(Aβ42)构象转变的分子机理.结果表明,海藻糖溶液浓度对Aβ42构象转变具有非常重要的影响.在水和低浓度海藻糖溶液(0.18mol·L-1)中,Aβ42可由初始的α-螺旋结构转变成β-折叠的二级结构;但海藻糖浓度为0.37mol·L-1时即可有效抑制Aβ42的构象转变.这是因为海藻糖利用其优先排阻作用使水分子在多肽周围0.2nm内富集,而其自身却在距离多肽0.4nm的位置附近团聚.另外,海藻糖还可通过降低多肽间的疏水相互作用,减少多肽分子内远距离的接触,有效抑制多肽的疏水塌缩和构象转变.上述分子模拟的结果对于进一步合理设计阿尔茨海默病的高效抑制剂具有非常重要的理论指导意义.

The molecular mechanism of the conformational transition of amyloid peptide 42（Aβ42） inhibited by trehalose was studied using molecular dynamics simulation.It is confirmed that the conformational transition of Aβ42 is prevented by trehalose in a dose-dependent manner.In water and low-concentration trehalose（0.18 mol·L-1） solutions,Aβ42 transforms from its initial α-helix to a β-sheet.In 0.37 mol·L-1 trehalose,however,the conformational transition of Aβ42 is prevented.It is obvious that there is a hydration shell within about 0.2 nm from the closest atoms of Aβ42 on the peptide surface,which is caused by the preferential exclusion of trehalose.Trehalose molecules cluster around the peptide at a distance of 0.4 nm.In addition,the intra-peptide hydrophobic interactions are weakened and the number of long range contacts of Aβ42 is decreased by trehalose.Therefore,the hydrophobic collapse of the peptide is alleviated and the conformational transition is inhibited.These findings are important for the rational design of a highly efficient inhibitor for Alzheimer＇s disease.