Molecular Dynamics Study of Insulin Mutants

  • Olga Zhytniakivska Department of Medical Physics and Biomedical Nanotechnologies, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine https://orcid.org/0000-0002-2068-5823
  • Uliana Tarabara Department of Medical Physics and Biomedical Nanotechnologies, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine https://orcid.org/0000-0002-7677-0779
  • Valeriya Trusova Department of Medical Physics and Biomedical Nanotechnologies, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine https://orcid.org/0000-0002-7087-071X
  • Kateryna Vus Department of Medical Physics and Biomedical Nanotechnologies, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine https://orcid.org/0000-0003-4738-4016
  • Galyna Gorbenko Department of Medical Physics and Biomedical Nanotechnologies, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine https://orcid.org/0000-0002-0954-5053
Keywords: human insulin, mutants, molecular dynamics simulation, amyloid

Abstract

Human insulin, a small protein hormone consisting of A-chain (21 residues) and B-chain (30 residues) linked by three disulfide bonds, is crucial for controlling the hyperglycemia in type I diabetes. In the present work molecular dynamics simulation (MD) with human insulin and its mutants was used to assess the influence of 10 point mutations (HisA8, ValA10, AspB10, GlnB17, AlaB17, GlnB18, AspB25, ThrB26, GluB27, AspB28), 6 double mutations (GluA13+GluB10, SerA13+GluB27, GluB1+GluB27, SerB2+AspB10, AspB9+GluB27, GluB16+GluB27) and one triple mutation (GluA15+AspA18+AspB3) in the protein sequence on the structure and dynamics of human insulin. A series of thermal unfolding MD simulations with wild type (WT) human insulin and its mutants was performed at 400 K with GROMACS software (version 5.1) using the CHARMM36m force field. The MD results have been analyzed in terms of the parameters characterizing both the global and local protein structure, such as the backbone root mean-square deviation, gyration radius, solvent accessible surface area, the root mean-square fluctuations and the secondary structure content. The MD simulation data showed that depending on time evolution of integral characteristics, the examined mutants can be tentatively divided into three groups: 1) the mutants HisA8, ValA10, AlaB17, AspB25, ThrB26, GluB27, GluA13+GluB10, GluB1+GluB27 and GluB16+GluB27, which exert stabilizing effect on the protein structure in comparison with wild type insulin; 2) the mutants GlnB17, AspB10, SerB2+AspB10 and GluA15+AspA18+AspB3 that did not significantly affect the dynamical properties of human insulin with a minimal stabilizing impact; 3) the mutants AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18, destabilizing the protein structure. Analysis of the secondary structure content provided evidence for the influence of AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18 on the insulin unfolding. Our MD results indicate that the replacement of superficial nonpolar residues in the insulin structure by hydrophilic ones gives rise to the increase in protein stability in comparison with the wild type protein.

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Published
2021-04-30
Cited
0 article
How to Cite
Zhytniakivska, O., Tarabara, U., Trusova, V., Vus, K., & Gorbenko, G. (2021). Molecular Dynamics Study of Insulin Mutants. East European Journal of Physics, (2), 168-176. https://doi.org/10.26565/2312-4334-2021-2-15