Efficient sampling of ligand orientations and conformations in free energy calculations using the λ-dynamics method
Efficient sampling of ligand orientations and conformations in free energy calculations using the λ-dynamics method
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DOI：
10.1021/jp001177i
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发表时间：
2000-07-27
影响因子：
3.3
通讯作者：
Brooks, CL
中科院分区：
文献类型：
--
作者：
Banba, S;Guo, ZY;Brooks, CL
利用最新发展的基于波长动力学自由能的模拟方法，研究了10个五元环杂环衍生物与细胞色素c过氧化物酶内诱变形成的人工空腔的结合。将拉姆达动力学应用于该体系，对配体的结合亲和力给出了合理的估计。这种方法还提供了一种比传统MD更好地探索结合口袋内配体的结合方向和构象的方法。这是由于it动力学方法中固有的力的比例，它降低了分隔不同结合模式和构象的障碍。对配体的拉姆达动力学轨迹的检查发现了不同的结合方向和构象，这是结晶学没有检测到的。此外，从随机初始取向出发的Lambda动力学模拟，其中一些Li配体的取向与X射线结构的取向明显不同，成功地采样了所有配体的X射线晶体取向。由传统MD从相同的初始结构开始的配体采样仍然困在它们开始的局部极小值。这种对配体取向和构象的有效采样有望减少这样的限制，即初始配体结构必须接近其真实结合方向，才能产生合理的结合自由能估计。
The recently developed lambda-dynamics free-energy based simulation method was used to study the binding of 10 five-member ring heterocycle derivatives to an artificial cavity created by mutagenesis inside cytochrome c peroxidase. Application of lambda-dynamics to this system gives a reasonable estimate of the binding affinity of the ligands. This methodology also provides a means to explore the binding orientations and conformations of the ligands inside the binding pocket much better than does conventional MD. This is due to the scaling of forces inherent in the it-dynamics method, which lowers the barriers separating different binding modes and conformations. Examination of the lambda-dynamics trajectory of the ligands revealed alternative binding orientations and conformations not detected by crystallography. Furthermore, a lambda-dynamics simulation starting from random initial orientations, in which some li,ligands take significantly different orientations as compared with those from the X-ray structure, successfully samples the X-ray crystallographic orientations in all ligands. Ligand sampling by conventional MD starting from same initial structures remains trapped in the local minima from which they start. Such efficient sampling of ligand orientations and conformations is expected to diminish the limitation that an initial ligand structure must be close to its true bound orientation in order to yield a reasonable estimate of the binding free energy.