School of Chemistry & Biochemistry, Thapar Institute of Engineering & Technology, Patiala, 147004, Punjab, India.
School of Chemistry & Biochemistry, Thapar Institute of Engineering & Technology, Patiala, 147004, Punjab, India.
J Mol Graph Model. 2023 Nov;124:108558. doi: 10.1016/j.jmgm.2023.108558. Epub 2023 Jun 24.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly characterized by extracellular accumulation of amyloid-β (Aβ) peptide. Previous studies reported pentapeptide RIIGL as an effective inhibitor of Aβ aggregation and neurotoxicity induced by Aβ aggregates. In this work, a library of 912 pentapeptides based on RIIGL has been designed and assessed for their efficacy to inhibit Aβ aggregation using computational techniques. The top hit pentapeptides revealed by molecular docking were further assessed for their binding affinity with Aβ monomer using MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method. The MM-PBSA analysis identified RLAPV, RVVPI, and RIAPA, which bind to Aβ monomer with a higher binding affinity -55.80, -46.32, and -44.26 kcal/mol, respectively, as compared to RIIGL (ΔG = -41.29 kcal/mol). The residue-wise binding free energy predicted hydrophobic contacts between Aβ monomer and pentapeptides. The secondary structure analysis of the conformational ensembles generated by molecular dynamics (MD) depicted remarkably enhanced sampling of helical and no β-sheet conformations in Aβ monomer on the incorporation of RVVPI and RIAPA. Notably, RVVPI and RIAPA destabilized the D23-K28 salt bridge in Aβ monomer, which plays a crucial role in Aβ oligomer stability and fibril formation. The MD simulations highlighted that the incorporation of proline and arginine in pentapeptides contributed to their strong binding with Aβ monomer. Furthermore, RVVPI and RIAPA prevented conformational conversion of Aβ monomer to aggregation-prone structures, which, in turn, resulted in a lower aggregation tendency of Aβ monomer.
阿尔茨海默病（AD）是一种多因素神经退行性疾病，主要特征是细胞外淀粉样β（Aβ）肽的积累。先前的研究报道五肽 RIIGL 是 Aβ 聚集和 Aβ 聚集诱导的神经毒性的有效抑制剂。在这项工作中，设计了一个基于 RIIGL 的 912 个五肽文库，并使用计算技术评估其抑制 Aβ 聚集的效果。分子对接显示的顶级命中五肽进一步使用 MM-PBSA（分子力学泊松-玻尔兹曼表面面积）方法评估其与 Aβ 单体的结合亲和力。MM-PBSA 分析确定 RLAPV、RVVPI 和 RIAPA 与 Aβ 单体的结合亲和力更高，分别为-55.80、-46.32 和-44.26 kcal/mol，而 RIIGL 为-41.29 kcal/mol。残基结合自由能预测了 Aβ 单体与五肽之间的疏水接触。分子动力学（MD）生成的构象系综的二级结构分析表明，在 RVVPI 和 RIAPA 的掺入下，Aβ 单体中螺旋和无β-折叠构象的采样得到了显著增强。值得注意的是，RVVPI 和 RIAPA 使 Aβ 单体中 D23-K28 盐桥失稳，该盐桥在 Aβ 寡聚物稳定性和纤维形成中起关键作用。MD 模拟强调了五肽中脯氨酸和精氨酸的掺入有助于它们与 Aβ 单体的强结合。此外，RVVPI 和 RIAPA 阻止了 Aβ 单体向聚集倾向结构的构象转换，从而降低了 Aβ 单体的聚集倾向。
