Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Graduate School of Simulation Studies, University of Hyogo, 7-1-28 Minatojima Minami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
Sci Rep. 2020 Jan 29;10(1):1406. doi: 10.1038/s41598-020-58320-z.
Antibody based bio-molecular drugs are an exciting, new avenue of drug development as an alternative to the more traditional small chemical compounds. However, the binding mechanism and the effect on the conformational ensembles of a therapeutic antibody to its peptide or protein antigen have not yet been well studied. We have utilized dynamic docking and path sampling simulations based on all-atom molecular dynamics to study the binding mechanism between the antibody solanezumab and the peptide amyloid-β (Aβ). Our docking simulations reproduced the experimental structure and gave us representative binding pathways, from which we accurately estimated the binding free energy. Not only do our results show why solanezumab has an explicit preference to bind to the monomeric form of Aβ, but that upon binding, both molecules are stabilized towards a specific conformation, suggesting that their complex formation follows a novel, mutual population-shift model, where upon binding, both molecules impact the dynamics of their reciprocal one.
抗体类生物分子药物作为一种替代传统小分子化合物的新型药物开发途径，令人兴奋。然而，治疗性抗体与其肽或蛋白质抗原的结合机制及其对构象集合体的影响尚未得到很好的研究。我们利用基于全原子分子动力学的动态对接和路径采样模拟来研究抗体 solanezumab 与肽淀粉样蛋白-β（Aβ）之间的结合机制。我们的对接模拟再现了实验结构，并为我们提供了代表性的结合途径，从中我们准确估计了结合自由能。我们的结果不仅表明了为什么 solanezumab 明显偏爱与 Aβ 的单体形式结合，而且在结合后，两个分子都朝着特定构象稳定，这表明它们的复合物形成遵循一种新颖的、相互的种群转移模型，在结合后，两个分子都影响彼此的动态。
