Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms
Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms
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DOI：
10.1021/acs.jpcb.6b04012
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发表时间：
2016-06-23
影响因子：
3.3
通讯作者：
Lotz, Samuel D.
中科院分区：
文献类型：
--
作者：
Dickson, Alex;Lotz, Samuel D.
配体与其分子受体的结合在生物学中具有巨大的重要性。虽然已经把重点放在表征结合位点和结合姿态，确定结合热力学，配体结合的途径重要地决定了结合动力学。整个无偏配体结合和释放途径的计算研究仍然是一个新兴的领域，最近才有可能在计算硬件和采样方法的进步。我们已经开发了一个这样的方法（WExplore），它是基于加权合奏的轨迹，我们适用于配体释放的第一次，使用一组三个先前表征的低亲和力配体和蛋白质FKBP-12（FK-506结合蛋白）之间的相互作用。发现WExplore比传统采样更有效，即使对于这里观察到的纳秒级解绑事件也是如此。从一个非平衡系综的未绑定的轨迹，我们得到配体的停留时间和释放途径，而不使用偏置力或马尔可夫假设区域之间的过渡。我们介绍了一套分析工具的非结合过渡途径，包括使用冯米塞斯费舍尔分布模型云的配体出口点，这提供了一个定量代理配体表面扩散。过渡途径合奏的三个配体之间的差异进行了识别和讨论。
The binding of ligands with their molecular receptors is of tremendous importance in biology. Although much emphasis has been placed on characterizing binding sites and bound poses that determine the binding thermodynamics, the pathway by which a ligand binds importantly determines the binding kinetics. The computational study of entire unbiased ligand binding and release pathways is still an emerging field, made possible only recently by advances in computational hardware and sampling methodologies. We have developed one such method (WExplore) that is based on a weighted ensemble of trajectories, which we apply to ligand release for the first time, using a set of three previously characterized interactions between low-affinity ligands and the protein FKBP-12 (FK-506 binding protein). WExplore is found to be more efficient that conventional sampling, even for the nanosecond-scale unbinding events observed here. From a nonequilibrium ensemble of unbinding trajectories, we obtain ligand residence times and release pathways without using biasing forces or a Markovian assumption of transitions between regions. We introduce a set of analysis tools for unbinding transition pathways, including using von Mises Fisher distributions to model clouds of ligand exit points, which provide a quantitative proxy for ligand surface diffusion. Differences between the transition pathway ensembles of the three ligands are identified and discussed.