Open AccessHuman IL-2Rɑ subunit binding modulation of IL-2 through a decline in electrostatic interactions: A computational and experimental approach
Author(s) -
Arezoo Beig Parikhani,
Kowsar Bagherzadeh,
Rada Dehghan,
Alireza Biglari,
Mohammad Ali Shokrgozar,
Farhad Riazi-Rad,
Sirous Zeinali,
Yeganeh Talebkhan,
Soheila Ajdary,
Reza Ahangari Cohan,
Mahdi Behdani
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0264353
Subject(s) - mutant , protein subunit , monoclonal antibody , flow cytometry , microbiology and biotechnology , immunotherapy , interleukin 2 , chemistry , receptor , biophysics , biology , biochemistry , immunology , antibody , immune system , gene
Although high-dose IL-2 has clear antitumor effects, severe side effects like severe toxicity and activation of Tregs by binding of IL-2 to high-affinity IL-2R, hypotension, and vascular leak syndrome limit its applications as a therapeutic antitumor agent. Here in this study, a rational computational approach was employed to develop and design novel triple-mutant IL-2 variants with the aim of improving IL-2-based immunotherapy. The affinity of the mutants towards IL-2Rα was further computed with the aid of molecular dynamic simulations and umbrella sampling techniques and the obtained results were compared to those of wild-type IL-2. In vitro experiments by flow cytometry showed that the anti-CD25 mAb was able to bind to PBMC cells even after mutant 2 preincubation, however, the binding strength of the mutant to α-subunit was less than of wtIL-2. Additionally, reduction of IL-2Rα subunit affinity did not significantly disturb IL-2/IL2Rβγc subunits interactions.