Prediction of solution phase association constants by mapping contact points in intermolecular complexes

Area of Science:

• Computational chemistry
• Molecular modeling
• Biophysics

Background:

• Non-covalent interactions are crucial for molecular recognition and binding.
• Quantifying these interactions in solution is essential for understanding biological processes and designing new molecules.
• Existing methods may struggle with complex interaction types or solvent effects.

Purpose of the Study:

• To develop and validate a computational method for calculating pairwise molecular interactions using Atomic Surface Site Interaction Points (AIPs).
• To assess the accuracy of the SSIMPLE algorithm in predicting solution phase binding free energies and association constants.
• To provide a tool for identifying key intermolecular contacts driving binding affinity.

Main Methods:

• Utilizing Atomic Surface Site Interaction Points (AIPs) to represent molecular interaction sites.
• Employing the Surface Site Interaction Model for the Properties of Liquids at Equilibrium (SSIMPLE) algorithm to calculate pairwise interaction free energies.
• Developing computational and visualization tools to analyze intermolecular contacts in molecular complexes.

Main Results:

• The SSIMPLE algorithm successfully reproduces solution phase association constants within an order of magnitude for host-guest complexes.
• The method performs well for complexes involving hydrogen-bonding, aromatic, and hydrophobic interactions.
• The approach shows limitations for halogen-bonds and interactions involving fullerene π-surfaces.

Conclusions:

• AIPs and the SSIMPLE algorithm offer a robust framework for quantifying non-covalent interactions and predicting binding affinities.
• The developed computational tools facilitate the identification of critical binding determinants.
• Further refinement is needed to improve accuracy for specific interaction types like halogen-bonds.