(341b) Nonclassical Mechanisms to Irreversibly Suppress ?-Hematin Crystal Growth

Intricate crystal architectures in nature evolve shepherded by minority solution components; industrial crystals are guided to preferred morphologies by specific modifiers. The modifiers’ activities are commonly ascribed to their adsorption to specific crystal surface sites and the reversibility of adsorption inevitably predicts that growth fully recovers after the inhibitor is removed. Multiple instances of permanently poisoned crystals and terminal crystal sizes stand out of the realm of the classical inhibition mechanisms and remain elusive. Here we demonstrate irreversible inhibition of hematin crystallization, an essential element of heme detoxification of malaria parasites, due to cooperative behaviors that activate at high crystallization driving forces. The evolutions of the crystal shapes after limited-time exposure to both artemisinin- and quinoline-class antimalarials report that crystal growth remains suppressed after the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour drug pulses kill with efficacy comparable to that of drug exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that operate at elevated hematin concentrations and prevent β-hematin growth recovery. The hematin-liganded artemisinins incite copious nucleation of nanocrystals, which invade larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both trapped crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. The two mechanisms of irreversible suppression of crystal growth rely on cooperativity of molecules, in crystal nucleation, or between mesoscopic objects, the steps, driven by high deviations from equilibrium. These and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for the numerous fields that rely on crystalline materials.