Prediction of the Peptide-TIM3 Binding Site in Inhibiting TIM3-Galectin 9 Binding Pathways.

T-cell immunoglobulin and mucin domain-containing protein-3 (TIM3) is an important receptor protein that modulates the immune system. The binding of TIM3 with Galectin 9 (GAL9) triggers immune system suppression, but the TIM3-GAL9 binding can be inhibited by binding of the peptide P26 to TIM3. A fast and accurate prediction of the P26-TIM3 binding site is crucial and a prerequisite for the investigation of P26-TIM3 interactions and TIM3-GAL9 binding pathways. Here, we present a machine learning approach, which considers protein conformational changes, to quickly identify the ligand-binding site on TIM3. Our results show that the P26 binding site is located near the C″-D loop of TIM3. Further simulations show that the binding pose is stabilized by a variety of electrostatic and hydrophobic interactions. Binding of P26 can alter the conformations of nearby glycan side chains on TIM3, providing possible mechanisms of how P26 inhibits TIM3-GAL9 binding pathways. The insights from this work will facilitate the identification of other peptides or antibodies that may also inhibit the TIM3-GAL9 pathways and eventually lead to improved attempts in the modulation of the TIM3-GAL9 immunosuppression pathways. The strategies and machine learning method can be generalized to study ligand-receptor binding when the conformational changes during the binding are important.