Exhaustive Search of Ligand Binding Pathways via Volume-Based Metadynamics
Exhaustive Search of Ligand Binding Pathways via Volume-Based Metadynamics
复制标题
DOI：
10.1021/acs.jpclett.9b01183
复制
发表时间：
2019-06-20
影响因子：
5.7
通讯作者：
Parrinello, Michele
中科院分区：
文献类型：
--
作者：
Capelli, Riccardo;Carloni, Paolo;Parrinello, Michele
确定完整的配体结合-解除结合途径对于药物发现和突变数据的合理解释非常重要。在这里，我们开发了一种基于元动力学的技术来解决这个问题，并允许在存在多个逃逸路径的情况下估计亲和力。我们的方法展示了与苯分子复合的溶菌酶 T4 变体。计算的结合自由能与实验数据一致。值得注意的是，我们不仅能够找到所有先前鉴定的配体结合途径，而且还鉴定了三种先前未鉴定的途径。这些结果是以很小的计算成本获得的，使得这种方法对于实际应用很有价值，例如筛选小型化合物库。
Determining the complete set of ligands' binding-unbinding pathways is important for drug discovery and for rational interpretation of mutation data. Here we have developed a metadynamics-based technique that addresses this issue and allows estimating affinities in the presence of multiple escape pathways. Our approach is shown on a lysozyme T4 variant in complex with a benzene molecule. The calculated binding free energy is in agreement with experimental data. Remarkably, not only were we able to find all the previously identified ligand binding pathways, but also we identified three pathways previously not identified as such. These results were obtained at a small computational cost, making this approach valuable for practical applications, such as screening of small compound libraries.