Molecular Imposters Functioning as Versatile Growth Modifiers of Urate Crystallization

Interactions between molecular modifiers and crystal surfaces govern numerous processes and structural outcomes of natural, biological, and synthetic crystallization. An efficient method of tailoring modifier–crystal interactions involves the design of imposters with structures and chemical functionalities that closely match those of the solute with subtle changes that preserve molecular recognition for modifier binding to crystal surfaces. Modifiers can function as inhibitors, promoters, or combinations of both to alter processes of crystal nucleation and growth. Here, we examine molecular modifiers that perturb the crystallization of ammonium urate (NH4HU), a pathological component of kidney stones, and a model system for assessing modifier–crystal interactions. Bulk crystallization assays were used to identify effective inhibitors and promoters of NH4HU crystallization. Two potent inhibitors, methyluric acid (MA) and poly(ethyleneimine) (PEIM), were identified where PEIM completely suppresses crystal growth at concentrations above 1.0 μg/mL, and MA displays a maximum growth inhibition of 60%. Time-resolved studies using a combination of microfluidics and atomic force microscopy elucidated the mechanisms by which each modifier influences layer generation and spreading on crystal surfaces. We used these techniques for select modifiers to quantify their effects on the anisotropic rates of crystallization and concomitant impact on crystal size and morphology. In situ characterization revealed that subtle changes in modifier functionality determine whether these imposters operate by either step pinning or kink blocking mechanisms. We demonstrated that molecular imposters of NH4HU crystallization operate by multiple, and sometimes opposing, roles of promotion and inhibition depending on the judicious selection of growth conditions. Collectively, our findings uncover trends among molecular imposters that are unique in relation to previously reported cases of crystal growth modification.