Structural compatibility is not enough: Current challenges in protein-protein interaction prediction.

Structural compatibility alone is insufficient for accurate protein-protein interaction prediction, especially in cases involving dynamics, weak co-evolutionary signals, or cellular context.

• Why it matters: Understanding these limitations is crucial because current methods perform variably across interaction classes, hindering reliable prediction of biologically relevant interactions in complex cellular environments.
• What they did: The authors categorize interaction prediction challenges into four regions: tractable interactions, ambiguous structural compatibility, weak co-evolutionary signals, and context-dependent interactions, highlighting the need for diverse approaches.
• The result: Addressing these challenges will require developing methods that reduce reliance on multiple sequence alignments, improve discrimination of interaction strength and specificity, and incorporate cellular context and dynamics into models.