On the determinants of residence times and dissociation mechanisms of complexes of interleukin-13 with its low and high affinity receptors

<jats:p>Interleukin-13 (IL-13) is an immunomodulatory cell signaling cytokine that has been implicated in neurodegenerative disease and chronic inflammation. IL-13 binds to its low and high affinity receptors, IL-13 receptor α1 (IL-13Rα1) and IL-13 receptor α2 (IL-13Rα2), respectively, with residence times that vary accordingly. As the binding kinetics of the cytokine-receptor complexes influence cellular responses, we employed the molecular dynamics (MD) simulation-based τ-random acceleration molecular dynamics method (τRAMD) to compute relative residence times for wild-type (WT) IL-13 and 19 IL-13 mutants to the two receptors. Comparison with experimental kinetic data shows that the τRAMD computations capture the trends in residence times. Analysis of simulated dissociation trajectories of the cytokine-receptor complexes reveals two distinct dissociation pathways of IL-13 from each of the receptors. This study thus pinpoints key determinants of the interaction of IL-13 with its receptors which could be targeted for therapeutic design.</jats:p>