Antagonistic cooperativity between crystal growth modifiers

Ubiquitous processes in nature and the industry exploit crystallization from multicomponent environments1–5; however, laboratory efforts have focused on the crystallization of pure solutes6,7 and the effects of single growth modifiers8,9. Here we examine the molecular mechanisms employed by pairs of inhibitors in blocking the crystallization of haematin, which is a model organic compound with relevance to the physiology of malaria parasites10,11. We use a combination of scanning probe microscopy and molecular modelling to demonstrate that inhibitor pairs, whose constituents adopt distinct mechanisms of haematin growth inhibition, kink blocking and step pinning12,13, exhibit both synergistic and antagonistic cooperativity depending on the inhibitor combination and applied concentrations. Synergism between two crystal growth modifiers is expected, but the antagonistic cooperativity of haematin inhibitors is not reflected in current crystal growth models. We demonstrate that kink blockers reduce the line tension of step edges, which facilitates both the nucleation of crystal layers and step propagation through the gates created by step pinners. The molecular viewpoint on cooperativity between crystallization modifiers provides guidance on the pairing of modifiers in the synthesis of crystalline materials. The proposed mechanisms indicate strategies to understand and control crystallization in both natural and engineered systems, which occurs in complex multicomponent media1–3,8,9. In a broader context, our results highlight the complexity of crystal–modifier interactions mediated by the structure and dynamics of the crystal interface.