Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23Uppsala, Sweden.
J Chem Inf Model. 2023 Jan 9;63(1):138-146. doi: 10.1021/acs.jcim.2c01093. Epub 2022 Dec 23.
Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the level was fundamental to reproducing the experimental observations─standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.
构象分析是设计生物活性分子的核心。由于非共价的跨环相互作用、立体相互作用和环应变通常是耦合的，因此对于大环化合物来说，这是一项极具挑战性的任务。在此，我们模拟了五个大环化合物的构象，这些化合物旨在表达环境依赖性分子内相互作用的逐渐增加的复杂性，并将结果与氯仿和二甲基亚砜中的 NMR 测量值进行了验证。使用显式溶剂模型的分子动力学，而不是具有隐式溶剂化的蒙特卡罗方法，可以正确处理这两种溶剂。在 水平上对构象进行细化对于重现实验观察至关重要——标准的最先进的分子力学力场是不够的。我们的模拟正确预测了侧链与大环之间的分子内相互作用，并揭示了大环环前所未有的溶剂诱导构象转变。我们的结果为合理的、有前瞻性的分子变色龙设计提供了一个平台，这些变色龙可以适应环境的性质。
