Binding energies of five molecular pincers calculated by explicit and implicit solvent models

Area of Science:

• Supramolecular Chemistry
• Computational Chemistry
• Molecular Modeling

Background:

• Molecular tweezers are designed to bind and release molecules, with applications in drug delivery and environmental technologies.
• Accurate theoretical modeling of complexation energies is challenging but crucial for optimizing molecular tweezer design.
• Van der Waals forces typically dominate the binding interactions in these systems.

Purpose of the Study:

• To compare the accuracy of Density Functional Theory (DFT) and molecular dynamics (MD) simulations in predicting the binding energies of molecular tweezers.
• To evaluate the performance of different computational methods against experimental Nuclear Magnetic Resonance (NMR) data.
• To assess the utility of computational modeling as a tool for designing novel molecular tweezers.

Main Methods:

• Density Functional Theory (DFT) computations with a dielectric continuum solvent model.
• Potential of Mean Force (PMF) approach using umbrella sampling and Weighted Histogram Analysis Method (WHAM) with Molecular Dynamics (MD) simulations.
• Comparison of computational results with experimental NMR spectroscopic data for five synthesized Tröger's base tweezers.

Main Results:

• DFT computations accurately predicted trends in complex stability but overestimated binding energies compared to experimental data.
• The semiempirical PM6-DH2X method provided better binding energy magnitudes than DFT but not the correct stability order.
• MD-WHAM simulations yielded the most realistic Gibbs binding energies, though slight discrepancies in relative stability ordering were observed compared to NMR.

Conclusions:

• While DFT struggles with quantitative accuracy for binding energies, it captures stability trends in molecular tweezers.
• MD-WHAM simulations offer a more reliable approach for calculating Gibbs binding energies, providing valuable insights for tweezer design.
• Computational modeling, particularly MD-WHAM, is a useful tool for understanding molecular tweezer complex geometry, flexibility, and guiding future design efforts.