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Determination of the conformational states of strychnine using NMR residual dipolar couplings in a tensor-free approach
Methods ( IF 4.8 ) Pub Date : 2018-09-01 , DOI: 10.1016/j.ymeth.2018.07.005
Giulia Tomba , Carlo Camilloni , Michele Vendruscolo

Small molecules with rotatable bonds can occupy different conformational states in solution as a consequence of their thermal fluctuations. The accurate determination of the structures of such states, as well as of their statistical weights, has been challenging because of the technical difficulties in extracting information from experimental measurements, which are normally averaged over the conformational space available. Here, to achieve this objective, we present an approach based on a recently proposed tensor-free method for incorporating NMR residual dipolar couplings as structural restraints in replica-averaged molecular dynamics simulations. This approach enables the information provided by the experimental data to be used in the spirit of the maximum entropy principle to determine the structural ensembles of small molecules. Furthermore, in order to enhance the sampling of the conformational space we incorporated the metadynamics method in the simulations. We illustrate the method in the case of strychnine, determining the three major conformational states of this small molecule and their associated occupation probabilities.

中文翻译:

在无张量方法中使用 NMR 残余偶极耦合测定士的宁的构象状态

由于热波动,具有可旋转键的小分子可以在溶液中占据不同的构象状态。由于从实验测量中提取信息存在技术困难,这些信息通常在可用的构象空间上进行平均,因此准确确定此类状态的结构及其统计权重一直具有挑战性。在这里,为了实现这一目标,我们提出了一种基于最近提出的无张量方法的方法,该方法将 NMR 残余偶极耦合作为复制平均分子动力学模拟中的结构限制。这种方法使实验数据提供的信息能够本着最大熵原理的精神来确定小分子的结构集合。此外,为了增强对构象空间的采样,我们在模拟中加入了元动力学方法。我们举例说明了士的宁的方法,确定了这个小分子的三个主要构象状态及其相关的占据概率。
更新日期:2018-09-01
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