Human β-cardiac myosin plays a critical role in generating the mechanical forces necessary for cardiac muscle contraction. This process relies on a delicate dynamic equilibrium between the disordered relaxed state (DRX) and the super-relaxed state (SRX) of myosin. Disruptions in this equilibrium due to mutations can lead to heart diseases. However, the structural characteristics of SRX and the molecular mechanisms underlying pathogenic mutations have remained elusive. To bridge this gap, we conducted molecular dynamics simulations and free energy calculations to explore the conformational changes in myosin. Our findings indicate that the size of the phosphate-binding pocket can serve as a valuable metric for characterizing the transition from the DRX to SRX state. Importantly, we established a global dynamic coupling network within the myosin motor head at the residue level, elucidating how the pathogenic mutation E483K impacts the equilibrium between SRX and DRX through allosteric effects. Our work illuminates molecular details of SRX and offers valuable insights into disease treatment through the regulation of SRX.