Atomistic Insight into Inhibition Mechanisms of Suppressors of Cytokine Signaling on Janus Kinase
Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK-STAT) signaling pathway by inhibiting the activity of JAK kinase. The kinase inhibitory region (KIR) of SOCS1 targets the substrate binding groove of JAK with high specificity as demonstrated by significantly higher IC50 following mutation any of residue. To gain a greater understanding of mechanisms of inhibition of SOCS1 for JAK1, binding mode, binding free energy decomposition, and desorption mechanism of JAK-SOCS1 complexes as well as a number of mutant systems were identified by use of extensive molecular dynamics (MD) simulations and the constant pulling velocity (PCV) method. Electrostatic interactions were identified for their contribution to protein-protein binding, which drove interactions between JAK1 and SOCS1. The polar residues Arg56, Arg59, Asp105 of SOCS1 and Asp1042, Asp1040 of JAK1 were keys in binding and electrostatic interaction of side chains was prominent. Binding free energies of the six mutant proteins were lesser when compared to control proteins and side chain interaction was weaken. The residue Asp1040 played a crucial role in KIR closing to binding groove of JAK1. Meanwhile, salt bridges contributed significantly to JAK1 and SOCS1 binding and cleavage processes. The work presented herein provides a comprehensive understanding of thermodynamic and dynamic processes of SOCS1 and JAK1 binding that will contribute meaningfully to the design of future studies related to peptide inhibitors based on SOCS1.