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

RNA-targeted small-molecule discovery is challenged by the scarcity of experimentally characterized RNA-ligand complexes and by the limited transferability of current computational approaches across chemically diverse systems. Here we present P-RISE, a physics-grounded framework for RNA-ligand binding prediction, and use it to identify the physical determinants underlying reliable performance. Systematic evaluation of force fields, ionic environments, dielectric treatments, and entropy corrections reveals three coupled requirements: preservation of RNA-binding pocket integrity under ion-sensitive conditions; an effective electrostatic error cancellation regime enabled by an elevated internal dielectric constant; and an empirically observed coupling between entropy correction and solvent modeling. Integrating these features, P-RISE provides stable affinity ranking, physics-grounded delineation of its physicochemical applicability domain, accurate metal ion site localization, and improved binding pose discrimination relative to established RNA docking and scoring approaches. Crucially, benchmarking against AlphaFold3 reveals that co-folding models, optimized for structure generation rather than energetic ranking, benefit from an explicit physics-based evaluation layer. Furthermore, diverse machine-learning comparisons demonstrate that purely data-driven methods lack stability and generalization in this data-poor regime. Ultimately, P-RISE provides a mechanistic understanding of RNA-ligand modeling, serving as a principled physical baseline that defines reliable prediction boundaries, and guides future data-driven integration.