A Supervised Molecular Dynamics Approach to Unbiased Ligand-Protein Unbinding
A Supervised Molecular Dynamics Approach to Unbiased Ligand-Protein Unbinding
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DOI：
10.1021/acs.jcim.9b01094
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发表时间：
2020-03-23
影响因子：
5.6
通讯作者：
Reynolds, Christopher A.
中科院分区：
文献类型：
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作者：
Deganutti, Giuseppe;Moro, Stefano;Reynolds, Christopher A.
最近使用动力学参数代替热力学常数的范式转变正在引导计算化学社区开发研究药物结合和解除结合机制的方法。从这个角度来看，分子动力学（MD）在提供分子尺度的洞察力方面发挥着重要作用。然而，MD的一个已知限制是时间尺度通常与配体-受体解结合事件所涉及的时间尺度相距甚远。在这里，我们证明了监督MD （SuMD）背后的算法可以模拟类药物小分子的解离机制，同时避免了任何能量偏差的输入，以促进过渡。SuMD在七种不同的分子间复合物上进行了测试，包括四种G蛋白偶联受体：A（2A）和A(1)腺苷受体，食欲素2和毒蕈碱2受体，以及可溶性球形环氧化物水解酶。SuMD很好地描述了配体-受体解离的多步骤性质，合理化了先前的实验数据，并为结构-动力学关系提出了有价值的工作假设。
The recent paradigm shift toward the use of the kinetics parameters in place of thermodynamic constants is leading the computational chemistry community to develop methods for studying the mechanisms of drug binding and unbinding. From this standpoint, molecular dynamics (MD) plays an important role in delivering insight at the molecular scale. However, a known limitation of MD is that the time scales are usually far from those involved in ligand-receptor unbinding events. Here, we show that the algorithm behind supervised MD (SuMD) can simulate the dissociation mechanism of druglike small molecules while avoiding the input of any energy bias to facilitate the transition. SuMD was tested on seven different intermolecular complexes, covering four G protein-coupled receptors: the A(2A) and A(1) adenosine receptors, the orexin 2 and the muscarinic 2 receptors, and the soluble globular enzyme epoxide hydrolase. SuMD well-described the multistep nature of ligand-receptor dissociation, rationalized previous experimental data and produced valuable working hypotheses for structure-kinetics relationships.