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

0498603 - ÚOCHB 2019 RIV US eng J - Článek v odborném periodiku
Březina, Kryštof - Duboué-Dijon, Elise - Palivec, Vladimír - Jiráček, Jiří - Křížek, T. - Viola, C. M. - Ganderton, T. R. - Brzozowski, A. M. - Jungwirth, Pavel
Can Arginine Inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study.
Journal of Physical Chemistry B. Roč. 122, č. 44 (2018), s. 10069-10076. ISSN 1520-6106. E-ISSN 1520-5207
Grant CEP: GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: molecular dynamics * electrophoresis * crystallography * insulin * arginine
Obor OECD: Physical chemistry
Impakt faktor: 2.923, rok: 2018
https://pubs.acs.org/doi/10.1021/acs.jpcb.8b06557

The oligomeric state of the storage form of human insulin in the pancreas, which may be affected by several endogenous components of beta-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, beta-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.
Trvalý link: http://hdl.handle.net/11104/0290917