The role of nucleation in sickle cell pathophysiology: opportunities for innovative treatments

Sickle cell anemia (SCA) is driven by the polymerization of hemoglobin S (HbS), where the nucleation process plays a central role in initiating sickling episodes. Advances in structural biology and computational modeling have significantly deepened our understanding of this process. High-resolution crystallography has elucidated the structural changes in deoxygenated HbS that promote nucleation, revealing critical interactions between valine-substituted β-globin chains. Cryo-electron microscopy (cryo-EM) has provided detailed visualizations of early-stage polymerization, capturing the formation of small HbS aggregates, which are essential for understanding the dynamics of nucleation in physiological conditions. Additionally, computational modeling has offered valuable insights into the kinetics of HbS nucleation, enabling the prediction of polymer formation under varying oxygen tensions. Molecular dynamics simulations have been instrumental in identifying key factors that modulate nucleation, such as intracellular HbS concentration, pH, and ionic strength. These simulations also suggest that heterogeneous nucleation, facilitated by cellular surfaces or macromolecules, may accelerate the sickling process, highlighting potential therapeutic targets for disrupting this interaction. Together, these techniques have led to new opportunities for innovative treatments. For instance, voxelotor, a drug developed using structural insights, binds to HbS and prevents its deoxygenation, reducing nucleation rates. Other strategies, such as CRISPRbased gene editing and allosteric modulators, are emerging as potential therapeutic avenues for altering nucleation kinetics, offering hope for more effective treatments to mitigate the clinical severity of SCA.