A review about nothing: are apolar cavities in proteins really empty?

Area of Science:

• Biophysics
• Structural Biology
• Protein Science

Background:

• Apolar cavities in proteins often appear empty in crystallographic analyses.
• The presence of disordered water molecules in these cavities has been hypothesized but not definitively observed.
• Understanding protein cavity hydration is crucial for protein function and drug design.

Purpose of the Study:

• To investigate the energetic favorability of water molecule occupancy in apolar protein cavities.
• To determine the detectability of water molecules in protein cavities using X-ray crystallography.
• To correlate cavity size with water molecule clustering and energetic stability.

Main Methods:

• Review of recent experimental studies on protein cavity hydration.
• Theoretical analysis of solvent mobility and occupancy within apolar cavities.
• X-ray crystallography principles applied to solvent detection in protein structures.

Main Results:

• It is energetically unfavorable for a single water molecule to occupy a small apolar protein cavity.
• Larger apolar cavities can favorably accommodate clusters of mutually hydrogen-bonded water molecules.
• High-occupancy solvent in cavities of typical volume should be detectable by X-ray crystallography.

Conclusions:

• The presence and detectability of water in apolar protein cavities are dependent on cavity size.
• Energetics favor water clustering in sufficiently large apolar cavities.
• Further experimental verification is needed to pinpoint the exact cavity size for stable water cluster formation.