IL-2 Flexible Loops Might Play a Role in IL-2 Interaction with the High-Affinity IL-2 Receptor: A Molecular Dynamics (MD) Study

Abstract

The clinical use of high-dose IL-2 in cancer immunotherapy faces several drawbacks such as toxicity and unfavorable pharmacokinetic profile. These drawbacks can be avoided by inhibiting IL-2 interaction with the CD25 subunit, which is a component of the high-affinity IL-2 receptor (IL-2Rαβγ). Several studies showed mutations of potential IL-2 residues such as R38, F42, Y45, and Y72 would produce IL-2 that is CD25-independent. In essence, structural comparison between wild-type (WT) IL-2 and CD25-independent IL-2 can be very insightful to assess the role of IL-2 flexibility and conformation in the IL-2 receptor interactions. Here, we investigated the flexibility loops and conformation of IL-2m (F24A, Y45A, and L72G), which is known to be CD25-independent, and IL-2m2 (F42Y and L72R) mutants along with WT IL-2 using MD simulations. Despite residue mutations, both IL-2m and IL-2m2 showed comparable conformational compactness and better stability than WT IL-2. Interestingly, IL-2m and IL-2m2 mutants showed rigid BC and CD loops in comparison to WT IL-2 . Also, the AB loop conformation of IL-2m was a bent structure compared to the WT IL-2 and IL-2m2. Principal component analysis (PCA) and free-energy landscape results suggested IL-2m and IL-2m2 have stable conformations compared to the WT IL-2. Therefore, these mutation sites of IL-2 produced stable and rigid loops that might prevent IL-2 from binding to the CD25 subunit. Our results can help to assess IL-2 flexibility loops to design new CD25-independent IL-2 mutants without compromising the IL-2 structure.