(324h) Molecular Mechanisms Employed By Antimalarial Drugs to Control Hematin Crystallization

Survival of malaria parasites in human erythrocytes is enabled by the crystallization of toxic hematin. Malarial drugs are known to act by controlling the crystallization of the hematin. Here we employed experiments and molecular dynamics (MD) simulations to elucidate the hematin crystallization mechanism in presence of three drugs, chloroquine (CQ), mefloquine (MQ), pyronaridine (PY), and a heme adduct of another drug artemisinin (H-ART). We demonstrate that hematin crystal nucleate nonclassically, inside mesoscopic amorphous hematin-rich clusters. The drugs selectively invoke distinct behaviors: H-ART accelerates the nucleation rate, PY suppresses the nucleation rate, whereas CQ and MQ has no effect on nucleation rate. We found that these drugs exhibit a qualitatively similar behavior on the population of mesoscopic hematin-rich clusters which host and assist nucleation of hematin crystals. MD simulations revealed that the charges on drugs and heme are stabilized by water nanodroplets which results in substantial electrostatic attraction or repulsion between heme and drugs and enforce the distinct nucleation impacts. H-ART acts as a crowder due to a charge similar to that of hematin (both are negatively charged) and hence accelerate the nucleation by accelerating precursor formation. CQ and MQ are positively charged and passivated by hematin dimers. Interestingly PY, also positively charged, distinctly promotes larger aggregates and sequesters significant amount of the hematin available for precursors which lowers the aggregation driving force and suppresses the nucleation rate. The found molecular mechanisms to enhance or suppress crystal nucleation by additives by controlling the precursor populations illuminate intricacies involved during crystallization and provide powerful tools to control nucleation and hence crystallization for application in both industries and laboratories.