Fig. 7.

The double nucleation mechanism for HbS polymerization (Eaton and Hofrichter, 1990; Ferrone et al., 1985b; Ferrone et al., 1980; Ferrone et al., 2002; Weng et al., 2008). The first fiber in any given volume forms by the classical Osawa nucleation growth model,(Osawa and Sakura, 1975) called homogeneous because it occurs in the solution bulk without any contact to other fibers or surfaces. As indicated by the arrows, the initial aggregation steps are thermodynamically unfavorable because the overall reaction is uphill in free energy until a critical nucleus (*) is formed. The vast majority of fibers are formed by heterogeneous nucleation on the surface of preexisting fibers, which provides additional stability to the nucleus from contacts with the fiber surface. As more fibers form there is more surface for this secondary nucleation process, providing an autocatalytic mechanism that produces the delay period.