Simulation Reveals the Chameleonic Behavior of Macrocycles

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Chemical physics

Background:

• Conformational analysis is key for designing bioactive molecules, but challenging for macrocycles due to coupled interactions.
• Standard molecular mechanics force fields often fail to accurately predict macrocycle behavior in different environments.

Purpose of the Study:

• To simulate and verify macrocycle conformations in various solvents.
• To investigate environment-dependent intramolecular interactions and conformational adaptability.
• To establish a computational platform for designing 'molecular chameleons'.

Main Methods:

• Molecular dynamics simulations with explicit solvent models were employed.
• Conformations were refined using ab initio calculations.
• Results were validated against Nuclear Magnetic Resonance (NMR) spectroscopy in chloroform and dimethyl sulfoxide.

Main Results:

• Explicit solvent molecular dynamics accurately predicted macrocycle conformations in both tested solvents.
• Ab initio refinement was essential for reproducing experimental observations, surpassing standard force fields.
• An unprecedented solvent-induced conformational switch in the macrocyclic ring was identified.

Conclusions:

• Advanced computational methods, including explicit solvent molecular dynamics and ab initio refinement, are crucial for accurate macrocycle conformational analysis.
• The study demonstrates the ability to predict and design molecules that adapt their conformation to environmental changes.
• This work provides a foundation for the rational design of responsive and adaptable bioactive compounds.