Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, CH-8093 Zürich, Switzerland.
J Comput Chem. 2011 Jul 15;32(9):1801-12. doi: 10.1002/jcc.21761. Epub 2011 Apr 12.
An understanding at the atomic level of the driving forces of inhibitor binding to the protein plasmepsin (PM) II would be of interest to the development of drugs against malaria. To this end, three state of the art computational techniques to compute relative free energies-thermodynamic integration (TI), Hamiltonian replica-exchange (H-RE) TI, and comparison of bound versus unbound ligand energy and entropy-were applied to a protein-ligand system of PM II and several exo-3-amino-7-azabicyclo[2.2.1]heptanes and the resulting relative free energies were compared with values derived from experimental IC(50) values. For this large and flexible protein-ligand system, the simulations could not properly sample the relevant parts of the conformational space of the bound ligand, resulting in failure to reproduce the experimental data. Yet, the use of Hamiltonian replica exchange in conjunction with thermodynamic integration resulted in enhanced convergence and computational efficiency compared to standard thermodynamic integration calculations. The more approximate method of calculating only energetic and entropic contributions of the ligand in its bound and unbound states from conventional molecular dynamics (MD) simulations reproduced the major trends in the experimental binding free energies, which could be rationalized in terms of energetic and entropic characteristics of the different structural and physico-chemical properties of the protein and ligands.
在原子水平上理解抑制剂与蛋白胞浆素（PM）II 结合的驱动力，对于开发抗疟疾药物将具有重要意义。为此，我们应用了三种最先进的计算技术来计算相对自由能——热力学积分（TI）、哈密顿复制交换（H-RE TI）和比较结合与未结合配体的能量和熵——来研究 PM II 和几种外消旋 3-氨基-7-氮杂双环[2.2.1]庚烷的蛋白-配体体系，并且将得到的相对自由能与实验得出的 IC50 值进行了比较。对于这个大型且灵活的蛋白-配体体系，模拟无法正确地对结合配体的构象空间的相关部分进行采样，导致无法重现实验数据。然而，与标准热力学积分计算相比，使用哈密顿复制交换与热力学积分相结合的方法可以提高收敛性和计算效率。从传统分子动力学（MD）模拟中仅计算配体在结合和未结合状态下的能量和熵贡献的更近似方法，重现了实验结合自由能的主要趋势，可以根据蛋白和配体的不同结构和物理化学性质的能量和熵特征进行合理化解释。
