Department of Chemical Engineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
Center for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
J Mol Model. 2021 Nov 18;27(12):356. doi: 10.1007/s00894-021-04968-x.
The amyloid-β peptide exists in the form of fibrils in the plaques found in the brains of patients with Alzheimer's disease. One of the therapeutic strategies is the design of molecules which can destabilize these fibrils. We present a designed peptide KLVFFP with two segments: the self-recognition sequence KLVFF and a β-sheet breaker proline pentamer. Molecular dynamics simulations and docking results showed that this peptide could bind to the protofibrils and destabilize them by establishing hydrophobic contacts and hydrogen bonds with a higher affinity than the KLVFF peptide. In the presence of the KLVFFP peptide, the β-sheet content of the protofibrils was reduced significantly; the hydrogen bonding network and the salt bridges were disrupted to a greater extent than the KLVFF peptide. Our results indicate that the KLVFFP peptide is an effective β-sheet disruptor which can be considered in the therapy of Alzheimer's disease.
淀粉样蛋白-β肽以纤维的形式存在于阿尔茨海默病患者大脑中的斑块中。一种治疗策略是设计可以使这些纤维不稳定的分子。我们提出了一种带有两个片段的设计肽 KLVFFP：自我识别序列 KLVFF 和 β-折叠破坏脯氨酸五聚体。分子动力学模拟和对接结果表明，这种肽可以与原纤维结合，并通过与原纤维建立疏水接触和氢键以比 KLVFF 肽更高的亲和力来使其不稳定。在 KLVFFP 肽存在的情况下，原纤维的β-折叠含量显著降低；氢键网络和盐桥被破坏的程度比 KLVFF 肽更大。我们的结果表明，KLVFFP 肽是一种有效的β-折叠破坏剂，可考虑用于阿尔茨海默病的治疗。
