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.