A comprehensive survey of small-molecule binding pockets in proteins

Area of Science:

• Structural biology
• Biochemistry
• Computational chemistry

Background:

• Biological activity often arises from interactions between small molecules (ligands) and protein targets.
• Understanding these interactions is crucial for advancing drug design and comprehending protein functions.

Purpose of the Study:

• To conduct a large-scale structural and physico-chemical characterization of known ligand-binding sites (pockets) in proteins.
• To investigate the diversity and completeness of the structural space of protein pockets.
• To analyze the phenomenon of promiscuity in both protein pockets and ligands.

Main Methods:

• Analysis of a non-redundant dataset comprising approximately 20,000 known protein ligand-binding sites.
• Physico-chemical and structural characterization of these binding sites.
• Examination of trends in the deposition of novel protein pockets in the Protein Data Bank.

Main Results:

• The structural space of protein pockets appears crowded and potentially complete, representable by around 1,000 distinct pocket shapes.
• A declining trend in the discovery rate of novel protein pockets has been observed.
• Significant instances of both pocket and ligand promiscuity were identified, where single pockets bind diverse ligands and single ligands bind diverse pockets.

Conclusions:

• The findings suggest a finite and well-sampled repertoire of protein pocket structures.
• Understanding pocket and ligand promiscuity provides key insights into molecular recognition mechanisms.
• The study offers implications for improving the prediction of protein-ligand interactions through pocket comparison methods.