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

Abstract

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.

Interaction of Asn297-Linked Glycan Ligands with the Fc Fragment of the Immunoglobulin Class G1: A Molecular Dynamics Simulation Study

“…The root-mean-square fluctuation (RMSF) values of residues are a measure of fluctuations and flexibility of backbone Cα of protein over the trajectory broken down by residues in comparison to the average structures. , RMSF of the Cα atoms of each residues was calculated as follows: where T is the number of snapshots considered in the time trajectory, r i (t) represents the position of the Cα atom of reisdue i at time t , and <r i > denotes the time-averaged position of the Cα atom of residues i . RMSF i = 1 T ∑ t = 1 T false( r i false( t false) − ⟨ r i ⟩ false) 2 …”

“…Molecular dynamic processes of the three models (Fc-wt, H10-03-6/L1/L2, and STAB19/L3/L4) were simulated by the GPU-accelerated pmemd.cuda program in the Amber18 package. Details for the MD protocol are found in the Supporting Information and our previous studies. , In addition to our previous studies, three replica simulations for each simulation system starting from the heat stage were carried out, i.e., from T = 0 to T = 300 K by the weak-coupling method. The equilibration stage was 200 ps at a constant temperature and pressure (without restraints).…”