中文摘要：

应用分子动力学模拟和结合自由能计算方法研究了多肽抑制剂KLVFF、VVIA和LPFFD抑制淀粉质多肽42 （Aβ42）构象转换的分子机理. 结果表明, 三种多肽抑制剂均能够有效抑制Aβ42的二级结构由α-螺旋向β-折叠的构象转换. 另外, 多肽抑制剂降低了Aβ42分子内的疏水相互作用, 减少了多肽分子内远距离的接触, 有效抑制了Aβ42的疏水塌缩, 从而起到稳定其初始构象的作用. 这些抑制剂与Aβ42之间的疏水和静电相互作用（包括氢键）均有利于它们抑制Aβ42的构象转换. 此外, 抑制剂中的带电氨基酸残基可以增强其和Aβ42之间的静电相互作用（包括氢键）, 并降低抑制剂之间的聚集, 从而大大增强对Aβ42构象转换的抑制能力. 但脯氨酸的引入会破坏多肽的线性结构, 从而大大降低其与Aβ42 之间的作用力. 上述分子模拟的结果揭示了多肽抑制剂KLVFF、VVIA和LPFFD抑制Aβ42构象转换的分子机理, 对于进一步合理设计Aβ的高效短肽抑制剂具有非常重要的理论指导意义.

英文摘要：

The molecular mechanisms of the conformational transition of amyloid β-peptide （Aβ） 42 inhibited by the peptide inhibitors KLVFF, VVIA, and LPFFD were studied by using molecular dynamics simulations and binding free energy calculations. These studies confirmed that the conformational transition of Aβ42 from its initial α-helix to β-sheet structure is prevented by these three peptide inhibitors. The calculations also demonstrated that the intra-peptide hydrophobic interactions of Aβ42 are weakened, and its quantity of long range contacts decreased by these inhibitors. Consequently, the hydrophobic collapse of Aβ42 is alleviated and its initial structure is maintained well. Both hydrophobic and electrostatic interactions, including hydrogen bonding, were found to favor the binding of these peptide inhibitors to Aβ42. Moreover, the charged residues of the inhibitors were shown to enhance the electrostatic interactions including hydrogen bonding, decreasing the capacity of the peptide for self-assembly, and increasing the inhibition effect. It was also determined that interactions between the inhibitors and Aβ42 are reduced when proline residue is introduced into the peptide inhibitor, since its linear structure is disrupted. In general, this work has allowed a better understanding of the molecular mechanisms of the effects of the peptide inhibitors KLVFF, VVIA, and LPFFD on the conformational transition of Aβ42 and will assist in the systematic design of high efficiency peptide inhibitors of Aβ aggregation.