Achieving Chemical Accuracy in Cyclodextrin Host-Guest Binding via Integrative Atomistic Modelling

Area of Science:

• Supramolecular Chemistry
• Computational Chemistry
• Chemical Physics

Background:

• Cyclodextrins (CDs) are versatile amphiphilic hosts with broad applications.
• Accurate computational modeling of CD host-guest interactions remains a significant challenge.
• Existing methods struggle with complex dynamics and flexible CDs like gamma-CD.

Purpose of the Study:

• To develop and validate an integrative computational protocol for accurate CD host-guest binding strength calculation.
• To address limitations of conventional force fields in modeling flexible CDs.
• To enable high-throughput screening and rational design of macrocyclic host systems.

Main Methods:

• Integrative computational protocol combining force-field recalibration, enhanced sampling, and nonequilibrium methods.
• Work convolution algorithm and finite-size corrections for accurate free energy calculations.
• Energy decomposition analysis to identify binding driving forces.

Main Results:

• The protocol accurately and rapidly calculates binding strengths for 222 CD host-guest systems.
• Unbiased capture of CD dynamics and multi-modal coordination patterns.
• Consistent accuracy across diverse systems, outperforming conventional force fields for flexible CDs.

Conclusions:

• The developed protocol offers a robust solution for accurate and efficient modeling of cyclodextrin host-guest complexes.
• It overcomes limitations of traditional methods, particularly for flexible macrocycles.
• Enables new avenues for high-throughput screening and rational design in host-guest chemistry.