Wu Emilia L, Mei Ye, Han KeLi, Zhang John Z H
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Biophys J. 2007 Jun 15;92(12):4244-53. doi: 10.1529/biophysj.106.099150. Epub 2007 Mar 23.
Molecular dynamics simulations followed by quantum mechanical calculation and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis have been carried out to study binding of proline- and pyrazinone-based macrocyclic inhibitors (L86 and T76) to human alpha-thrombin. Detailed binding interaction energies between these inhibitors and individual protein fragments are calculated using DFT method based on a new quantum mechanical approach for computing protein-ligand interaction energy. The analysis of detailed interaction energies provides insight on the protein-ligand binding mechanism. Study shows that T76 and L86 bind to thrombin in a very similar "inhibition mode" except that T76 has relatively weaker binding interaction with Glu(217). The analysis from quantum calculation of binding interaction is consistent with the MM-PBSA calculation of binding free energy, and the calculated free energies for L86/T76-thrombin binding agree well with the experimental data.
通过分子动力学模拟，随后进行量子力学计算和分子力学泊松-玻尔兹曼表面积（MM-PBSA）分析，以研究脯氨酸和吡嗪酮基大环抑制剂（L86和T76）与人α-凝血酶的结合。基于一种计算蛋白质-配体相互作用能的新量子力学方法，使用密度泛函理论（DFT）方法计算了这些抑制剂与单个蛋白质片段之间的详细结合相互作用能。详细相互作用能的分析为蛋白质-配体结合机制提供了深入了解。研究表明，T76和L86以非常相似的“抑制模式”与凝血酶结合，只是T76与Glu(217)的结合相互作用相对较弱。结合相互作用的量子计算分析与结合自由能的MM-PBSA计算一致，并且L86/T76-凝血酶结合的计算自由能与实验数据吻合良好。
