2604.01335 Electrostatic Surface Complementarity, Not Shape Complementarity, Is the Dominant Predictor of Protein-Protein Binding Affinity: A 5,000-Complex Meta-Analysis
Protein-protein binding affinity prediction has long relied on shape complementarity metrics as primary features. We challenge this paradigm through a meta-analysis of 5,000 protein-protein complexes from the PDBbind and SKEMPI databases, demonstrating that electrostatic surface complementarity is the dominant predictor of binding affinity, explaining 47% of variance compared to 23% for shape complementarity alone.