Primary vs secondary: Directionalized guest coordination in β-cyclodextrin derivatives

Area of Science:

• Computational chemistry
• Supramolecular chemistry
• Molecular modeling

Background:

• Cyclodextrin (CD) host-guest binding is crucial in various applications.
• Accurate computational modeling requires accounting for asymmetric guest binding faces (primary vs. secondary).
• Existing models often simplify binding modes, neglecting directional preferences.

Purpose of the Study:

• To comprehensively analyze fixed-charge modeling of beta-cyclodextrin (β-CD) host-guest complexes.
• To evaluate the accuracy of different force field parameter sets and charge schemes.
• To investigate the impact of enhanced sampling on capturing binding equilibria.

Main Methods:

• Fixed-charge molecular dynamics simulations of β-CD host-guest systems.
• Force field evaluation using GAFF2 parameter set and RESP charge scheme.
• Enhanced sampling techniques to accelerate guest diffusion and explore binding modes.

Main Results:

• GAFF2 shows promise, but accurate reproduction of electrostatics remains challenging.
• Enhanced sampling successfully captured binding/unbinding events and diverse binding modes.
• Predicted binding affinities had intermediate errors; primary-secondary preferences matched experiments only partially.

Conclusions:

• Force field limitations, especially electrostatic inaccuracies, hinder precise prediction of CD host-guest binding affinities and preferences.
• Further refinement of force fields is necessary for reliable computational modeling of asymmetric host-guest interactions.
• This study highlights the need for advanced sampling methods to explore complex binding landscapes.