化学学报 ›› 2009, Vol. 67 ›› Issue (9): 1019-1025. 上一篇    下一篇

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

  

  1. (山东师范大学物理与电子科学学院 济南 250014)

  • 收稿日期:2008-04-30 修回日期:2008-11-24 出版日期:2009-05-14 发布日期:2009-05-14
  • 通讯作者: 张少龙

Molecular Dynamics Simulations and Free Energy Calculation of FKBP12 Protein and Its Inhibitors

Hu, Guodong Zhang, Shaolong* Zhang, Qinggang   

  1. (College of Physics and Electronics, Shandong Normal University, Jinan 250014)
  • Received:2008-04-30 Revised:2008-11-24 Online:2009-05-14 Published:2009-05-14
  • Contact: Zhang, Shaolong

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

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 mechanism. The results show that the three inhibitors bind to FKBP12 in very similar binding models, the inhibitors form hydrogen bonds with Ile56 and Tyr82, and the hydrophobic pocket is formed by Tyr26, Phe46, Val55, Ile56, Trp59, Tyr82, Tyr87 and Phe99. The calculated data agree well with the experimental ones.

Key words: molecular dynamics, MM-GBSA, binding free energy, FKBP12, inhibitor