Search

Interleukin-2 (IL-2) was originally used therapeutically as an immune stimulatory agent due to its characteristics of immune regulation. Previous work showed that binding of IL2 to its α-subunit receptor induced low blood pressure, vascular leak syndrome and cardiac toxicity. It was reported that there would be no side effects if the mutein of IL-2 could bind directly with the IL-2β/IL-2Rγ complex, and without mediating with IL-2Rα. With the aim to understand the differences in the binding affinity between IL-2 and the mutein to IL-2Rβ/IL-2Rγ complex at an atomic level, we constructed the theoretical binding models of a wild type and a mutated type (D10) of IL-2 utilising homology modelling. We analysed the interactive differences between the two systems after the MD simulations were completed. Our results suggested that (1) the mutation Q74H caused the conformational change of the loop and led to a new binding mode, which consequently caused an increased binding affinity for IL-2Rβ; (2) the residue mutation of I92F provided more favourable interactions; (3) the mutation of R81D provided an increased binding affinity, a contribution by both direct and indirect interactions. The newly designed mutants, D10_D81E, D10_ F92 W and D10_N119E, were predicted to have a better potency, especially at the residue 119, which was firstly found to improve the binding activity of IL-2Rγ. These results are expected to facilitate the discovery and rational design of novel IL-2 stimulatory agents, a potential treatment for cancer patients. [ABSTRACT FROM AUTHOR]