Role of Molecular Recognition in l -Cystine Crystal Growth Inhibition

Laura N. Poloni, Zina Zhu, Nelson Garcia-Vázquez, Anthony C. Yu, David M. Connors, Longqin Hu, Amrik Sahota, Michael Ward, Alexander G. Shtukenberg

Research output: Contribution to journalArticle

Abstract

l-Cystine kidney stones - aggregates of single crystals of the hexagonal form of l-cystine - afflict more than 20 000 individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth of l-cystine crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of l-cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospective inhibitors drawn from a 31-member library. The most effective molecular imposters for crystal growth inhibition were l-cystine mimics (aka molecular imposters), particularly l-cystine diesters and diamides, for which a kinetic analysis revealed a common inhibition mechanism consistent with Cabrera-Vermilyea step pinning. The amount of inhibitor incorporated by l-cystine crystals, estimated from kinetic data, suggests that imposter binding to the {0001} face is less probable than binding of l-cystine solute molecules, whereas imposter binding to {1010} faces is comparable to that of l-cystine molecules. These estimates were corroborated by computational binding energies. Collectively, these findings identify the key structural factors responsible for molecular recognition between molecular imposters and l-cystine crystal kink sites, and the inhibition of crystal growth. The observations are consistent with the reduction of l-cystine stone burden in mouse models by the more effective inhibitors, thereby articulating a strategy for stone prevention based on molecular design.

Original languageEnglish (US)
Pages (from-to)2767-2781
Number of pages15
JournalCrystal Growth and Design
Volume17
Issue number5
DOIs
StatePublished - May 3 2017

Fingerprint

Cystines
Molecular recognition
Cystine
Crystallization
Crystal growth
crystal growth
inhibitors
rocks
crystals
kidney stones
pathogenesis
kinetics
Crystals
mice
molecules
therapy
solutes
binding energy
atomic force microscopy
anisotropy

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics

Cite this

Poloni, L. N., Zhu, Z., Garcia-Vázquez, N., Yu, A. C., Connors, D. M., Hu, L., ... Shtukenberg, A. G. (2017). Role of Molecular Recognition in l -Cystine Crystal Growth Inhibition. Crystal Growth and Design, 17(5), 2767-2781. https://doi.org/10.1021/acs.cgd.7b00236

Role of Molecular Recognition in l -Cystine Crystal Growth Inhibition. / Poloni, Laura N.; Zhu, Zina; Garcia-Vázquez, Nelson; Yu, Anthony C.; Connors, David M.; Hu, Longqin; Sahota, Amrik; Ward, Michael; Shtukenberg, Alexander G.

In: Crystal Growth and Design, Vol. 17, No. 5, 03.05.2017, p. 2767-2781.

Research output: Contribution to journalArticle

Poloni, LN, Zhu, Z, Garcia-Vázquez, N, Yu, AC, Connors, DM, Hu, L, Sahota, A, Ward, M & Shtukenberg, AG 2017, 'Role of Molecular Recognition in l -Cystine Crystal Growth Inhibition', Crystal Growth and Design, vol. 17, no. 5, pp. 2767-2781. https://doi.org/10.1021/acs.cgd.7b00236
Poloni LN, Zhu Z, Garcia-Vázquez N, Yu AC, Connors DM, Hu L et al. Role of Molecular Recognition in l -Cystine Crystal Growth Inhibition. Crystal Growth and Design. 2017 May 3;17(5):2767-2781. https://doi.org/10.1021/acs.cgd.7b00236
Poloni, Laura N. ; Zhu, Zina ; Garcia-Vázquez, Nelson ; Yu, Anthony C. ; Connors, David M. ; Hu, Longqin ; Sahota, Amrik ; Ward, Michael ; Shtukenberg, Alexander G. / Role of Molecular Recognition in l -Cystine Crystal Growth Inhibition. In: Crystal Growth and Design. 2017 ; Vol. 17, No. 5. pp. 2767-2781.
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