Physical determinants of reliable RNA-ligand binding prediction revealed by P-RISE.

P-RISE identifies three coupled physical requirements for reliable RNA-ligand binding prediction—ion-sensitive pocket integrity, electrostatic error cancellation via elevated internal dielectric, and linked entropy–solvent modeling—enabling stable affinity ranking.

• Why it matters: RNA-targeted small-molecule discovery is limited by few experimentally characterized RNA-ligand complexes and by poor transferability of existing computational methods across chemically diverse systems.
• What they did: The framework systematically tests force fields, ionic environments, dielectric treatments, and entropy corrections, then integrates the best-performing physics components into an evaluation layer for affinity ranking and pose discrimination.
• The result: P-RISE yields stable affinity ranking, defines a physics-grounded applicability domain, localizes metal ion sites accurately, and improves binding pose discrimination versus established RNA docking/scoring, including benefits for AlphaFold3 co-folding models.

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