Are protein-protein interfaces special regions on a protein's surface?

Area of Science:

• Structural biology
• Biochemistry
• Computational biology

Background:

• Protein-protein interactions (PPIs) are crucial for cellular functions.
• Experimentally determined protein structures reveal protein interfaces (half-interfaces, HIs).
• Canonical HIs are typically hydrophobic and cover about one-third of a protein's surface.

Purpose of the Study:

• To investigate the existence and characteristics of geometric protein interfaces beyond known canonical ones.
• To challenge the classical view of unique and well-defined protein interfaces.
• To explore the implications of geometric interfaces for protein interaction promiscuity.

Main Methods:

• Concept of geometric half-interfaces (HIs) introduced, defined by geometric similarity to known interfaces.
• Geometric HIs were identified by copying HIs from monomers with similar folds in solved quaternary structures.
• Analysis of the surface coverage and residue composition of geometric HIs compared to canonical HIs.

Main Results:

• Geometric HIs cover a significantly larger portion of a protein's surface (three-quarters on average) compared to canonical HIs.
• Geometric HIs can represent potential physical interaction sites, though not always biologically relevant.
• These newly identified HIs are generally more charged than canonical HIs, suggesting a bias in current databases.

Conclusions:

• The classical view of a few unique, well-defined protein interfaces is likely an oversimplification.
• Proteins exhibit interface "fuzziness" and promiscuity, utilizing a broader range of potential interaction surfaces.
• Geometric HIs represent a form of "coarse-graining" employed by nature in protein interactions.