Molecular dynamics simulation studies on the specific regulation of PTPN18 to the HER2 phospho-peptides

The specific regulation of PTPN18 protein to three HER2 phospho-peptides has been studied by molecular dynamics simulations and free energy calculations. The results revealed that the three HER2 phospho-peptides binding to the PTPN18 catalytic domain is energetically favorable due to substrate specificity of PTPN18, and moreover, the PTPN18 protein have significantly higher affinity to pY1248 peptide (-45.22 kcal/mol) than that of pY1112 (-25.3 kcal/mol) and pY1196 (-31.86 kcal/mol) peptides. Further, the binding of HER2 phospho-peptides to PTPN18 have also caused the closure of WPD-loop with the decrease of the centroid distances between the P-loop and the WPD loop. The WPD-loop closure of PTPN18 relates directly to the new hydrogen bond and hydrophobic interaction formations between the residues Tyr62, Asp64, Val65, Ala231, Arg235, and Ala273 in PTPN18 and Tyr(PO3) in the HER2 phospho-peptides, which suggests that these key residues would contribute to the specific regulation of PTPN18 to the substrates. The correlation analysis revealed the allosteric communication networks from the pY binding loop to the WPD loop through the structural change and the residue interactions in PTPN18. These results will be helpful to understand the specific regulation through the allosteric communication network in the PTPN18 catalytic domain.