Binding Selectivity Analysis from Alchemical Receptor Hopping and Swapping Free Energy Calculations

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Accurate prediction of ligand-receptor binding is crucial for drug development.
• Estimating binding selectivity between multiple targets is computationally challenging.

Purpose of the Study:

• To introduce novel Alchemical Transfer Method (ATM) based protocols: receptor hopping and receptor swapping.
• To enable efficient and accurate modeling of ligand binding selectivity for arbitrary receptors.

Main Methods:

• Developed receptor hopping protocol for direct binding selectivity free energy (BSFE) calculation.
• Developed receptor swapping protocol for relative binding selectivity differences, combined with DiffNet algorithm.
• Validated methods on host-guest systems and applied to trypsin and thrombin protease selectivity analysis.

Main Results:

• Receptor hopping and swapping protocols yield results consistent with experimental data.
• Methods align with conventional binding free energy calculations.
• Demonstrated potential for structure-based drug discovery and ligand optimization.

Conclusions:

• Receptor hopping and swapping offer streamlined and computationally efficient approaches for ligand selectivity studies.
• These methods facilitate optimization of ligand binding across protein mutants and homologs.
• The presented protocols represent a significant advancement in computational drug design.