Zhang Huitu, Sang Jingcheng, Li Li, Jiang Luying, Lu Fuping, He Shan, Cui Wei, Zhang Xiaoqing, Liu Fufeng
State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology of Ministry of Education; Tianjin Key Laboratory of Industrial Microbiology; College of Biotechnology, Tianjin University of Science & Technology, Tianjin, P. R. China.
College of Marine and Environmental Sciences, Tianjin University of Science & Technology, Tianjin, P. R. China.
J Biomol Struct Dyn. 2021 Oct;39(17):6440-6451. doi: 10.1080/07391102.2020.1799863. Epub 2020 Jul 29.
Previous studies have indicated that 5-hydroxycyclopenicillone (HCP), an active compound derived from marine sponge, could inhibit oligomerization of amyloid β-protein (Aβ). However, the molecular basis for the interaction between HCP and Aβ remains unclear. Herein, all-atom molecular dynamics (MD) simulations were used to explore the conformational conversion of an Aβ monomer at different concentrations (0-40 mM) of HCP at the atomic level. It is confirmed that the conformational transition of the Aβ monomer is prevented by HCP in a concentration-dependent manner . In 40 mM HCP solution, the initial α-helix-rich conformation of Aβ monomer is kept under the action of HCP. The intra-peptide hydrophobic collapse and D23-K28 salt bridge are prevented by HCP. Moreover, it is indicated that the non-polar binding energy dominates the binding between HCP and Aβ monomer as evaluated by molecular mechanics Poisson-Boltzmann surface area method. And, the residues of F4, Y10, V12, L17 and L34 in Aβ might contribute to the binding energy in HCP-Aβ complex. All these results elucidate the molecular mechanism underlying the inhibitory effects of HCP against the conformational transformation of Aβ, providing a support that HCP may be developed as a potential anti-Aβ compound for the treatment of Aβ-related diseases.Communicated by Ramaswamy H. Sarma.
先前的研究表明，5-羟基环青霉素（HCP）是一种源自海洋海绵的活性化合物，能够抑制淀粉样β蛋白（Aβ）的寡聚化。然而，HCP与Aβ之间相互作用的分子基础仍不清楚。在此，通过全原子分子动力学（MD）模拟在原子水平上探索了不同浓度（0-40 mM）HCP作用下Aβ单体的构象转换。证实HCP以浓度依赖性方式阻止Aβ单体的构象转变。在40 mM HCP溶液中，Aβ单体最初富含α-螺旋的构象在HCP作用下得以保持。HCP阻止了肽内疏水塌缩和D23-K28盐桥的形成。此外，通过分子力学泊松-玻尔兹曼表面积法评估表明，非极性结合能在HCP与Aβ单体的结合中起主导作用。并且，Aβ中的F4、Y10、V12、L17和L34残基可能对HCP-Aβ复合物中的结合能有贡献。所有这些结果阐明了HCP对Aβ构象转变抑制作用的分子机制，为HCP可能被开发成为治疗Aβ相关疾病的潜在抗Aβ化合物提供了支持。由拉马斯瓦米·H·萨尔马通讯。
