Simulation Reveals the Environment-dependent Conformational Switching of Macrocycles

In the future, computer-supported molecular design will be the rule rather than the exception. Conformational analysis is central to design, but is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. In this report, six simulation protocols are verified against NMR measurements, in chloroform and DMSO, for five macrocycles designed to express a progression of increasing complexity in molecular interactions. The protocols use the Monte Carlo method with an implicit solvation model, or molecular dynamics with an explicit solvent model, respectively. Only molecular dynamics handled both solvents correctly, whereas both methods were accurate for chloroform. Generation 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 intramolecular interactions between side-chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring.