Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Methods. 2018 Sep 15;148:4-8. doi: 10.1016/j.ymeth.2018.07.005. Epub 2018 Jul 21.
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.
小分子由于热波动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的技术困难，这些构象状态的准确确定及其统计权重一直具有挑战性，因为实验测量通常是在可用构象空间上进行平均的。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张量自由方法的方法，将 NMR 残差偶极耦合作为结构约束纳入复制品平均分子动力学模拟中。该方法能够根据最大熵原理的精神利用实验数据提供的信息来确定小分子的结构集合。此外，为了增强构象空间的采样，我们在模拟中加入了元动力学方法。我们以士的宁为例说明了该方法，确定了这种小分子的三种主要构象状态及其相关的占据概率。
