BPS2026 – Genome-informed molecular simulations reveal mechanistic links between oncogenic kinase mutations, structural dynamics, and drug resistance

Recent progress in cancer genomics has uncovered numerous patient-derived mutations in oncogenic kinases, yet the molecular mechanisms by which these alterations reshape protein function and therapeutic response remain unclear. To bridge genomic variation with structural and functional outcomes, we apply a multiscale molecular simulation framework—integrating nanosecond-to-microsecond molecular dynamics (MD), binding free energy calculations, and quantum mechanical methods—to mutations in five clinically relevant kinases (EGFR, HER2, PI3Kα, ALK, and RET). Our simulations reveal mutation-specific mechanisms of dysregulation: kinase-domain mutations in EGFR and PI3Kα stabilize active conformations, whereas extracellular-domain mutations in HER2 and RET promote dimerization. We further identify two mechanistic routes to drug resistance: (1) local rearrangements of the inhibitor-binding pocket captured by short-timescale MD, and (2) distal mutations inducing global conformational shifts detectable only in microsecond-scale simulations. These findings align with reported reductions in inhibitor efficacy. By directly linking patient-derived mutations to altered structural dynamics and drug-binding energetics, this study suggests that genome-guided simulations may help clarify molecular mechanisms of oncogenic activation and drug resistance, providing insights that support precision oncology and the rational design of next-generation therapeutics.