Molecular recognition by beta-cyclodextrin derivatives: FEP vs MM/PBSA study

Area of Science:

• Supramolecular Chemistry
• Computational Chemistry
• Host-Guest Chemistry

Background:

• Cyclodextrins are widely used in host-guest complexation due to their unique structures.
• Novel cyclodextrin derivatives with modified linkers offer tunable binding properties.
• Accurate computational methods are crucial for predicting complexation behavior.

Purpose of the Study:

• To computationally investigate the complexation of specific guest molecules with a novel bis-cyclodextrin derivative.
• To compare the accuracy of free energy perturbation (FEP) and Molecular Mechanics/Poisson Bolzmann Surface Area (MM/PBSA) methods in predicting binding affinities.
• To evaluate the binding affinity of a bisadamantyl-phosphate derivative relative to ester and amide guests.

Main Methods:

• Free energy perturbation (FEP) calculations.
• Molecular Mechanics/Poisson Bolzmann Surface Area (MM/PBSA) calculations.
• Study of guest molecules: p-tert-butylphenyl p-tert-butylbenzoate (ester), N-(p-tert-butylphenyl)-p-tert-butylbenzamide (amide), and a bisadamantyl-phosphate derivative.
• Host molecule: a beta-cyclodextrin dimer linked by a disulfide bridge.

Main Results:

• MM/PBSA calculations showed good agreement with experimental relative free energies for the amide and ester guests.
• FEP calculations did not achieve good agreement with experimental data for the amide and ester guests.
• MM/PBSA predicted the association free energy of the bisadamantyl-phosphate complex to be similar to the ester, consistent with experimental observations.

Conclusions:

• MM/PBSA is a reliable computational method for predicting the complexation of guest molecules with this novel bis-cyclodextrin derivative.
• The binding affinity of the bisadamantyl-phosphate derivative is comparable to that of the ester guest.
• Computational studies provide valuable insights into host-guest interactions, aiding in the design of new supramolecular systems.