Solvent Structure and Dynamics near the Surfaces of β-Hematin Crystals

Hematin crystallization, which is an essential component of the physiology of malaria parasites and the most successful target for antimalarial drugs, proceeds in mixed organic-aqueous solvents both in vivo and in vitro. Here we employ molecular dynamics simulations to examine the structuring and dynamics of a water-normal octanol mixture (a solvent that mimics the environment hosting hematin crystallization in vivo) in the vicinity of the typical faces in the habit of a hematin crystal. The simulations reveal that the properties of the solvent in the layer adjacent to the crystal are strongly impacted by the distinct chemical and topological features presented by each crystal face. The solvent organizes into at least three distinct layers. We also show that structuring of the solvent near the different faces of β-hematin strongly impacts the interfacial dynamics. The relaxation time of n-octanol molecules is longest in the contact layers and correlates with the degree of structural ordering at the respective face. We show that the macroscopically homogeneous water-octanol solution holds clusters of water and n-octanol connected by hydrogen bonds that entrap the majority of the water but are mostly smaller than 30 water molecules. Near the crystal surface the clusters anchor on hematin carboxyl groups. These results provide a direct example that solvent structuring is not restricted to aqueous and other hydrogen-bonded solutions. Our findings illuminate two fundamental features of the mechanisms of hematin crystallization: the elongated shapes of natural and synthetic hematin crystals and the stabilization of charged groups of hematin and antimalarials by encasing in water clusters. In addition, these findings suggest that hematin crystallization may be controlled by additives that disrupt or reinforce solvent structuring.