Mechanistic and Structural Insights on the IL-15 System through Molecular Dynamics Simulations

Interleukin 15 (IL-15), a four-helix bundle cytokine, is involved in a plethora of different cellular functions and, particularly, plays a key role in the development and activation of immune responses. IL-15 forms receptor complexes by binding with IL-2R beta- and common gamma (gamma c)-signaling subunits, which are shared with other members of the cytokines family (IL-2 for IL-2R beta- and all other gamma c- cytokines for gamma c). The specificity of IL-15 is brought by the non-signaling alpha-subunit, IL-15R alpha. Here we present the results of molecular dynamics simulations carried out on four relevant forms of IL-15: its monomer, IL-15 interacting individually with IL-15R alpha (IL-15/IL-15R alpha), with IL-2R beta/gamma c subunits (IL-15/IL-2R beta/gamma c) or with its three receptors simultaneously (IL-15/IL-15R alpha/IL-2R beta/gamma c). Through the analyses of the various trajectories, new insights on the structural features of the interfaces are highlighted, according to the considered form. The comparison of the results with the experimental data, available from X-ray crystallography, allows, in particular, the rationalization of the importance of IL-15 key residues (e.g., Asp8, Lys10, Glu64). Furthermore, the pivotal role of water molecules in the stabilization of the various protein-protein interfaces and their H-bonds networks are underlined for each of the considered complexes.