FKBP12蛋白与其抑制剂结合的分子动力学模拟与结合自由能计算.pdfVIP

2009 年第67 卷 化 学 学 报 Vol. 67, 2009 第9 期, 1019～1025 ACTA CHIMICA SINICA No. 9, 1019～1025 ·研究论文· FKBP12 蛋白与其抑制剂结合的分子动力学模拟和结合自由能计算 扈国栋 张少龙* 张庆刚 ( 山东师范大学物理与电子科学学院 济南 250014) 摘要 FKBP12 (FK506-binding protein-12)是一种具有神经保护和促神经再生作用的蛋白. 采用分子动力学模拟取样, 运用MM-GBSA 方法计算了FKBP12 和3 个抑制剂(GPI-1046, 308 和107) 的绝对结合自由能, GPI-1046 的结合能最小, 308 小于107 的结合能. 通过能量分解的方法考察了FKBP12 蛋白的主要残基与抑制剂之间的相互作用和识别, 计算结 果表明: 3 个抑制剂具有相似的结合模式, Ile56 和Tyr82 主要表现为氢键作用, Tyr26, Phe46, Val55, Ile56, Trp59, Tyr82, Tyr87 和Phe99 形成疏水作用区. 计算结果和实验结果吻合. 关键词 分子动力学; MM-GBSA; 结合自由能; FKBP12; 抑制剂 Molecular Dynamics Simulations and Free Energy Calculation of FKBP12 Protein and Its Inhibitors Hu, Guodong Zhang, Shaolong* Zhang, Qinggang (College of Physics and Electronics, Shandong Normal University, Jinan 250014) Abstract FKBP12 (FK506-binding protein-12) plays important roles in the treatment of nerve injuries and neurodegenerative disorders. In the paper, the absolute binding free energies of FKBP12 with three potent inhibitors (GPI-1046, 308 and 107) were calculated by molecular dynamics simulations with an MM-GBSA method, finding that GPI-1046 has the weakest binding energy, and 308 has weaker binding energy than 107. The analysis of detailed interaction energies provides insight into the protein-ligand binding mecha- nism. The results show that the three inhibitors bind to FKBP12 in very similar binding models, the inhibi- tors form hydrogen bonds with Ile56 and Tyr82, and the hydrophobic pocket is formed by Tyr26, Phe46, Val55, Ile56, Trp59, Tyr82, T