Abstract
NMR and molecular dynamics simulations revealed distinct conformational dynamics and allosteric networks in computationally re-designed IL-2 superkines compared to wild-type IL-2, despite their similar crystal structures.The superkines S1 and S15 exhibit altered sampling of excited state conformations at an intermediate timescale, with slower conformational exchange rates compared to wild-type IL-2.A rationally designed mutation (L56A) in the S1 superkine's core allosteric network partially reverted its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2.Our study demonstrates that IL-2 core dynamics play a critical role in receptor binding and signaling function, providing a foundation for engineering more selective IL-2-based immunotherapies.
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