Mechanistic Insights into Dioxygen Transport Routes in the PHD2 Oxygenase from Long-Time Scale Simulations

Understanding how dioxygen accesses buried catalytic centers in metalloenzymes is critical for elucidating enzymatic kinetics and guiding strategies to modulate catalytic activity. Here, we report over 20 μs of classical molecular dynamics simulations of the PHD2 oxygenase, a metalloenzyme regulating hypoxia signaling via HIF-1α hydroxylation. Our extended simulations reveal multiple dynamic dioxygen transport routes from solvent-exposed regions through the cupin fold to the metal active site, c