Modeling the Formation of the Hemozoin Crystal in the Presence of Antimalarials: A Theoretical Study

Abstract

ABSTRACT: This thesis centers around the modeling of the malaria crystal hemozoin (HZ), formed in the interior of the parasites digestive vacuole. In particular, the interaction of the antimalarials artesunate and chloroquine with the synthetic analog of HZ, β-hematin (BH).

To answer this question, we worked with experimental data provided to us by our collaborators in the Solid State, Residue Analysis and Malaria Research Groups, from the Faculty of Exact and Natural Sciences of the University of Antioquia and fitted the kinetics of BH formation in an aqueous and aqueous-octanol solutions that mimic the interior environment of the parasites digestive vacuole DV (where the crystal forms) in the presence and absence of the aforementioned antimalarial under a 10 and 30 mg concentration of each, to 10 kinetics models of crystallization, but only working with the two most relevant ones for the reminder of this work. One proposed by Pasternack et al. 1 ., and a second order model proposed by the collaboration 2 . Both models use the classical nucleation theory (CNT) description of the nucleation and growth process to represent the experimental data, but only our model proposes a term associated with the formation of the basic crystallization unit needed to form the crystal (a β-hematin dimer). We proceeded to use the experimental IR data, also provided by the mentioned groups, to the BH crystal when zero and 30 mg of the antimalarial chloroquine is present in the solution that formed the studied crystals, and proceeded to simulate the IR spectra of the β-hematin dimer with ASE 3 and GPAW 4 codes, and compared the simulated and experimental peaks, analyzing the vibrations/trajectories generated by the simulations to known peaks to confirm the validity of the obtained results and proceeded to extrapolate to the variations observed on the experimental peaks between the no drug and the 30 mg case, suggesting that the differences observed correspond to the absence of methyl and vinyl group bonds attributed to theantimalarial. This work finishes with a simple implementation of a nucleation and growth model under the CNT assumptions using a cellular automaton based on Conway’s game of life automaton with modified neighbor rules to represent the seed formation process in the solution as we change the concentration of available solute and seeing how these changes affect the morphology of the generated seeds.

We hope that this theoretical work, can shed some light into possible yet simple avenues to explore the crystallization process that underlies the survival of the malaria parasite, aiding our understanding of its behavior and helping us develop new antimalarials, as the crystal is a target of current ones, shielding vulnerable populations from the deadly and ever-evolving parasite.