Simulation Reveals the Chameleonic Behavior of Macrocycles

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 ab initio 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（conformational analysis）是生物活性分子（bioactive molecules）设计的核心研究内容。对于大环化合物（macrocycles）而言，由于其往往同时存在相互耦合的非共价跨环相互作用（noncovalent transannular interactions）、空间位阻效应（steric interactions）与环张力（ring strain），构象分析极具挑战性。本研究中，我们针对五个大环化合物开展构象模拟，这些大环被设计为呈现出环境依赖型分子内相互作用复杂度逐步提升的变化趋势，并以氯仿与二甲基亚砜中的核磁共振（NMR）测量结果为参照，对模拟结果进行了验证。采用显式溶剂模型（explicit solvent model）的分子动力学（molecular dynamics）方法可正确适配两种溶剂体系，而采用隐式溶剂化（implicit solvation）的蒙特卡洛（Monte Carlo）方法则无法实现这一点。在从头算（ab initio）层面开展构象精修，是重现实验观测结果的核心前提——当前最先进的分子力学力场（molecular mechanics force fields）均无法满足这一要求。本次模拟不仅正确预测了侧链与大环之间的分子内相互作用，还揭示了一种前所未有的溶剂诱导型大环构象转换现象。本研究结果为可适配环境特性的分子变色龙（molecular chameleons）的理性、前瞻性设计提供了可靠的研究平台。