Calculation of standard binding free energies: Aromatic molecules in the T4 lysozyme L99A mutant
Calculation of standard binding free energies: Aromatic molecules in the T4 lysozyme L99A mutant
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DOI：
10.1021/ct060037v
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发表时间：
2006-09-12
影响因子：
5.5
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Deng, Yuqing;Roux, Benoit
本文介绍了利用分子动力学（MD）模拟计算各种非极性芳香族配体与T4溶菌酶L99A突变体的结合自由能。为了确保更好的收敛性，当配体在结合口袋中与其环境解耦时，使用偏置势来限制配体相对于结合位点的取向和质心运动。一旦配体与系统的其余部分充分相互作用，且计算出的结合自由能与所施加的限制无关，就去除限制势引入的偏差。为了降低计算成本，模拟是在一个简化的系统中进行的，其中明确包含配体周围15埃半径球体内的蛋白质和水分子，而系统的其余部分则用广义溶剂边界势（GSBP）处理。对于所有配体，计算出的自由能精度小于0.5千卡/摩尔。对于苯、甲苯和乙苯等小的非极性配体，计算出的结合自由能与实验值相差在1.1千卡/摩尔以内。对于较大的配体，计算出的结合自由能比实验值略有利。非结合极性分子苯酚的计算结合自由能为 -0.88千卡/摩尔。这里介绍的模拟方案提供了一种以适中的计算成本计算小分子与受体结合自由能的方法。
Calculations of the binding free energy of various nonpolar aromatic ligands with the L99A mutant of T4 lysozyme using molecular dynamics (MD) simulation are presented. To ensure better convergence, biasing potentials are used to restrain the ligand orientation and center-of-mass movement relative to the binding site when the ligand is decoupled from its environment in the binding pocket. The bias introduced by the restraint potentials is removed once the ligand fully interacts with the rest of the system and the calculated binding free energy is independent of the applied restraints. To decrease the computational cost, the simulations are generated with a reduced system in which protein and water atoms within a 15 angstrom-radius sphere around the ligand are included explicitly, while the rest of the system is treated with the generalized solvent boundary potential (GSBP). For all the ligands, the precision of the calculated free energy is less than 0.5 kcal/mol. For small nonpolar ligands such as benzene, toluene, and ethylbenzene, the calculated binding free energies are within 1.1 kcal/mol of the experimental values. For larger ligands, the computed binding free energies are slightly more favorable than the experimental values. The nonbinding polar molecule, phenol, has a calculated binding free energy of -0.88 kcal/mol. The simulation protocol presented here provides a way to calculate the binding free energy of small molecules to receptors at moderate computational cost.