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

Key Points

• The research aims to uncover how isoform selectivity in PI3K is influenced by dynamic interactions and water-mediated processes.
• Utilized an ensemble-based framework to analyze PI3K isoform selectivity.
• Examined correlations between water residence times and hydration site free energies across supercritical residues.
• Established a computational hypothesis for dynamic features influencing inhibitor design.
• Identified a strong correlation (r=0.91) between water residence times and hydration site free energies.
• Proposed that isoform selectivity is driven by dynamic ensembles and allosteric networks.
• Provided a framework for rational design of isoform-selective PI3K inhibitors.