Can Arginine Inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

The Journal of Physical Chemistry. B
Kryštof BřezinaPavel Jungwirth

Abstract

The oligomeric state of the storage form of human insulin in the pancreas, which may be affected by several endogenous components of β-cell storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerization is investigated independently by protein crystallography, molecular dynamics simulations, and capillary electrophoresis. The combined results point to a strong effect of ionic strength on insulin assembly. Molecular simulations and electrophoretic measurements at low/mM salt concentrations show no significant effect of arginine on insulin aggregation. In contrast, crystallographic data at high/molar ionic strength indicate inhibition of insulin hexamerization by arginine due to its binding at the site relevant for intermolecular contacts, which was also observed in MD simulations. Our results thus bracket the in vivo situation in pancreatic β-cell storage granules, where the ionic strength is estimated to be in the hundreds of millimolar to submolar range. The present findings add to a molecular understanding of in vivo insulin oligomerization and storage, with additional implications for insulin stability in arginine-rich injections.

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Citations

Nov 16, 2019·International Journal of Biological Macromolecules·Sepideh Haghighi-PoodehAzadeh Ebrahim-Habibi
Feb 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Nicholas B RegoAmish J Patel
Jul 17, 2021·International Journal of Biological Macromolecules·Robert Dec, Wojciech Dzwolak
Jun 2, 2020·Journal of Chemical Information and Modeling·Santanu Santra, Madhurima Jana
Dec 6, 2019·ACS Applied Materials & Interfaces·Delyan R HristovDavid J Brayden

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