Forces and energetics of hapten-antibody dissociation:: A biased molecular dynamics simulation study
Forces and energetics of hapten-antibody dissociation:: A biased molecular dynamics simulation study
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DOI：
10.1006/jmbi.2001.5103
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发表时间：
2001-11-30
影响因子：
5.6
通讯作者：
Karplus, M
中科院分区：
文献类型：
--
作者：
Paci, E;Caflisch, A;Karplus, M
用偏置分子动力学方法研究了荧光素与4D 5流感抗体单链Fv片段的解离。为了获得统计上有意义的结果，大量的非绑定轨迹计算，他们涉及的总模拟时间超过200纳秒。模拟进行了与时间相关的扰动，并在存在一个恒定的力。这两种技术提供了互补的信息，通过有利于增加配体和抗体之间的距离来诱导解结合。这个距离是一个适当的进度变量的解离反应，并允许直接比较的解束缚力的模拟与原子力显微镜（AFM）的数据。依赖于时间的扰动产生接近平衡的展开路径，并且可以用于重建平均力;即，平均力的势的导数，沿着反应坐标。这是支持的分析的整体解绑配置文件和平均力的大小，这是类似的解绑力（即外力，由于随时间变化的扰动）平均超过几个unbindingevents.The多个模拟表明，解绑收益沿着一个相当明确的路径为广泛的有效拉动速度。最初，存在定位于C-末端区域的蛋白质的变形，随后荧光素从结合位点离开。这发生在涉及破坏特定静电和货车范德华相互作用的步骤中。似乎模拟没有探索与AFM实验中测量的相同的障碍，因为前者的展开速度要高得多。的力的对数上的加载速率的依赖性是线性的，斜率是高于在AFM中，在其他系统中，其中不同的斜率观察到不同的制度与实验一致。基于解结合事件，预测4D 5 Flu抗原结合位点的突变会导致解结合力的显著变化。(C)北京：科学出版社.
The unbinding of fluorescein from the single-chain Fv fragment of the 4D5Flu antibody is investigated by biased molecular dynamics with an implicit solvation model. To obtain statistically meaningful results, a large number of unbinding trajectories are calculated; they involve a total simulation time of more than 200 ns. Simulations are carried out with a time-dependent perturbation and in the presence of a constant force. The two techniques, which provide complementary information, induce unbinding by favoring an increase in the distance between the ligand and the antibody. This distance is an appropriate progress variable for the dissociation reaction and permits direct comparison of the unbinding forces in the simulations with data from atomic force microscopy (AFM). The time-dependent perturbation generates unfolding pathways that are close to equilibrium and can be used to reconstruct the mean force; i.e. the derivative of the potential of mean force, along the reaction coordinate. This is supported by an analysis of the overall unbinding profile and the magnitude of the mean force, which are similar to those of the unbinding force (i.e. the external force due to the time-dependent perturbation) averaged over several unbinding events.The multiple simulations show that unbinding proceeds along a rather well-defined pathway for a broad range of effective pulling speeds. Initially, there is a distortion of the protein localized in the C-terminal region followed by the fluorescein exit from the binding site. This occurs in steps that involve breaking of specific electrostatic and van der Waals interactions. It appears that the simulations do not explore the same barriers as those measured in the AFM experiments because of the much higher unfolding speed in the former. The dependence of the force on the logarithm of the loading rate is linear and the slope is higher than in the AFM, in agreement with experiment in other systems, where different slopes were observed for different regimes. Based on the unbinding events, mutations in the 4D5Flu antigen binding site are predicted to result in significant changes in the unbinding force. (C) 2001 Academic Press.