Title: Conformational Plasticity in IL-2 Is Captured Via in Silico Fragment-Based Drug Design Using SILCS Fragmaps
Abstract: The IL-2 protein is an experimentally well-characterized example of conformational plasticity in a protein-protein binding interface. Whereas the original crystal structure of the IL-2 protein lacked a particular binding pocket at the interface, subsequent structures of the protein complexed with small-molecule inhibitors have shown the creation of a hydrophobic pocket in order to accommodate inhibitor binding poses. A new in silico fragment-based drug design methodology (SILCS FragMaps) was applied to the original IL-2 crystal structure and has been found to recapitulate this pocket observed in the complexes. Furthermore, the pocket is seen to have an affinity for hydrophobic fragments, consistent with experimental inhibitor binding poses. As the SILCS FragMaps methodology is based on explicit-water all-atom molecular dynamics simulations, the methodology is able to capture both the conformational plasticity in the IL-2 surface required for pocket formation as well as the selective partitioning of small hydrophobic fragments into the pocket from bulk solution.