Exploring the reason for increased activity of SHP2 caused by D61Y mutation through molecular dynamics. (February 2019) - Wang, Rui-Rui
Graphical abstract: In order to find the cause of activity enhancement, this study explore the difference between SHP2-WT and SHP2-D61Y by molecular dynamics method. Post-dynamic analyses reveal that the N-SH2 domain moving away from PTP domain which caused the catalytical active site in the PTP domain to be exposed to the substrate and further resulted in the increased activity of SHP2 protein. The findings may provide valuable information to understand the conformational change in functional mechanism of the proteins. Highlights: Due to the D61Y-mutation, the flexibility of residues at the catalytically active site was enhanced, and the protein structure became incompact. There were differences in the secondary structure of residues at the catalytically active site between SHP2-WT and SHP2-D61Y The detailed reasons for the increased activity of SHP2-D61Y protein were found by residues interaction network and the calculation of binding free energy and hydrogen bond occupancy. Abstract: Juvenile myelomonocytic leukaemia, an aggressive myeloproliferative neoplasm, is characterized by thrombocytopenia, splenomegaly, fever and excess myelomonocytic cells. Approximately 35% of patients with JMML occur D61Y mutation in PTPN11, and it increases the activity of the protein. However, the effect of the D61Y mutation on SHP2 conformations in molecular basis is poorly understood. Therefore, the molecular dynamics simulations on SHP2-D61Y and SHP2-WT were performed to explore the effect of D61Y mutation on SHP2 and explain the reason for high activity of SHP2-D61Y mutant. The study on the RMSF, per-residue RMSD, PCA, DCCM and secondary structure found that the flexibilities of regions (residues His458-Ser460 and Gln506-Ala509) in SHP2-D61Y were higher than the corresponding regions in SHP2-WT, and the conformations of these regions almost transformed from α-helix and β-strand to Turn, respectively. Thus, the catalytical sites in the PTP domain (residues Asn217-Thr524) were exposed to the substrate easily, which contributed to the enhancement of SHP2-D61Y activity. Moreover, the residue interaction network, H bond occupancy and binding free energy were calculated, revealing that conformational difference were caused by distinctions in residue-residue interactions between Asp/Tyr61-Gln506, Gln506-Gln510, Gln506-Phe251, Gln506-Gly60, Gln506-Tyr63, Asp/Tyr61-Cys459, Cys459-Ile463 and Cys459-Arg465. The study here may offer the valuable information to explore the reason for the increased activity of SHP2 after D61Y-mutation.