Exploring the allosteric effect of SHP2 Tyr62 phosphorylation on the emergence of acquired resistance to allosteric inhibitor SHP099.

The Src homology-2 (SH2)-containing phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, is a key regulator modulating various signaling pathways. Recent studies have revealed that phosphorylation of Tyr62 (pY62) on the N-SH2 domain of SHP2 causes the emergence of acquired resistance to the allosteric inhibitor of SHP2 (SHP099) that occupies the PTP catalytic domain. However, the allosteric mechanism underlying the insensitivity of the allosteric inhibitor SHP099 to the phosphorylated SHP2 (pSHP2) remains unexplored. In this study, multiple replica molecular dynamics (MD) simulations and the post-trajectory analyses (principal component analysis, dynamics cross-correlation matrix analysis, allosteric community analysis, and binding free energy calculations) were performed for the SHP2, pSHP2, SHP2-SHP099, and pSHP2-SHP099 complexes. MD results showed that SHP099 binding contributed to stabilize SHP2, but pY62 had a detrimental role in the stability of the pSHP2-SHP099 complex. Domain correlation analysis showed that pY62 increased the anti-correlated motions between the C-SH2 and N-SH2/PTP domains. Binding free energy calculations revealed that the protein-ligand interactions in the SHP2 - SHP099 complex were stronger than that of the pSHP2 - SHP099 complex. Further, Thr108, Phe113, and Glu250 might be the critical residues responsible for the loss of the binding affinity in the pSHP2 - SHP099 complex through a per-residue decomposition analysis and H-bond occupancy time analysis. Overall, this study may provide a mechanistic insight into the mechanism how the allosteric effect of pY62 of SHP2 on SHP099 binding.