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Updated: Jun 5, 2026
10:58
Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
Ligand binding to protein-binding pockets with wet and dry regions
Lingle Wang1, B J Berne, R A Friesner
1Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA.
Summary
Protein-ligand binding is crucial for biological processes. This study introduces a refined WaterMap method, incorporating receptor dry regions, to accurately predict binding affinities, advancing drug design.
Area of Science:
- Computational chemistry
- Structural biology
- Biophysics
Background:
- Protein-ligand binding energetics are vital for drug design but challenging to compute.
- The WaterMap method previously identified water displacement as a key binding driver.
- Receptor active sites can contain dry regions unfavorable to water.
Purpose of the Study:
- To investigate the impact of receptor dry regions on ligand binding affinity.
- To enhance the WaterMap method by including a term for dry region occupation.
- To validate the improved method's predictive power for binding affinities.
Main Methods:
- Utilized the WaterMap method for calculating energetic contributions.
- Introduced a novel term to account for ligand atom occupation of receptor dry regions.
- Applied the combined method to predict relative binding affinities for congeneric ligand series.
Main Results:
- Demonstrated that dry regions in receptors significantly affect ligand binding affinity.
- Achieved excellent agreement between predicted and experimental relative binding affinities.
- Showed the enhanced WaterMap method outperforms a specific MM-GBSA implementation.
Conclusions:
- Dry regions in protein active sites represent a significant molecular recognition motif.
- The refined WaterMap method, including dry region contributions, accurately predicts binding affinities.
- This approach offers improved predictive capabilities for structure-based drug design.
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