Decoding PI3K isoform selectivity through an ensemble-based framework integrating correlated motions, allosteric networks, and hydration thermodynamics

= 0.91) between water residence times and hydration site free energies across all 20 supercritical residues. Together, these findings suggest that isoform selectivity may be primarily governed by dynamic ensembles, allosteric pathways, and water-mediated interactions, establishing a computational hypothesis framework to guide the future rational design of isoform-selective PI3K inhibitors that target dynamic rather than purely static features.