Dewetting transitions in protein cavities.

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Solvation of protein active sites is crucial for molecular recognition.
• A previous study observed a drying transition in the cyclooxygenase-2 (Cox-2) active site.
• Hydrophobic binding cavities may undergo a transition where water is expelled.

Purpose of the Study:

• To investigate if the drying transition observed in Cox-2 is a unique phenomenon.
• To identify other proteins exhibiting active site drying transitions.
• To explore the implications of active site drying on ligand binding affinity.

Main Methods:

• Utilized a metric to identify potential drying cavities.
• Conducted an extensive search of the Protein Data Bank (PDB).
• Performed molecular dynamics simulations to confirm drying transitions in identified protein active sites.

Main Results:

• Identified five additional proteins exhibiting active site drying transitions.
• The identified proteins showed similar drying behaviors to Cox-2.
• Drying cavities do not require desolvation before binding hydrophobic ligands.

Conclusions:

• Active site drying is not unique to Cox-2.
• The phenomenon of protein active site drying is more widespread than previously thought.
• Drying active sites are associated with potentially very large binding affinities for hydrophobic ligands.