(599d) Irreversible Inhibition of Hematin Crystallization By Cooperative Phase Behaviors Induced By Antimalarials

Crystallization is the central process of materials synthesis in biological, geological, and extraterrestrial systems. Nature achieves remarkable diversity of shapes, patterns, compositions, and functions of the arising crystalline structures by combining simple strategies to control the number of nucleated crystal and the sizes to which they grow. To promote or inhibit crystallization in both natural and engineered environments, soluble foreign substances are deployed that interact with the solute or the crystal-solution interface. For solution grown crystals, two classes of inhibition of step propagation are discussed. In the first mechanism, known as step-pinning, inhibitors bind to flat terraces and arrest step growth over broad areas of the crystal surface. Alternatively, inhibitors may associate and block kinks, the sites where solute molecules incorporate into steps. We examine the growth of beta-hematin crystals, a component of the physiology of malaria parasites, in the presence of artemisinin and quinoline derivatives, drugs that represent the current front line of antimalarial defense. We demonstrate two novel mechanisms of growth inhibition. At moderate hematin concentrations, a heme-artemisinin adduct, H-ART, promotes copious nucleation of hematin nanocrystals in the solution bulk, but impedes their growth above ca. 100 nm. The nanocrystals associate to the surface of larger hematin crystals and completely arrest their growth. The strain due to the imperfect incorporation of the nanocrystals constrains growth even after H-ART is removed, leading to irreversible inhibition. Pyronaridine, PYR, a quinoline of relatively large size, suppresses nucleation of nanocrystals in the solution bulk and exhibits an entirely different mechanism of growth suppression. PYR stabilizes pairs of steps and leads to abundant step bunching. At elevated hematin concentrations, the step bunches engender solute occlusions that resolve as screw dislocations outcropping on the crystal interface. The high density of steps originating at the screw dislocations strongly delays step propagation owing to competition for supply between adjacent steps. Removal of PYR does not restore the initial growth rate value since the high step density is preserved. The two examples of nonclassical irreversible and partially reversible inhibition may provide guidance in the search for suitable inhibitors control crystallization of pathological, biomimetic, and synthetic materials. In a broader context, our results highlight modifier interactions mediated by the dynamics and structures in the solution and on the crystal interface as a primary element of the regulation of the shapes and patterns of crystalline structures in nature and industry.