Study of SHP-2 (PTPN11) allosterism on structural movement using solution perturbed molecular dynamics simulation

Src-homology2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP-2) is a ubiquitously expressed protein-tyrosine phosphatase. SHP-2 is linked to human diseases and plays broad roles in cancer pathogenesis. Activity of the SHP-2 catalytic domain is auto-inhibited by an N-SH2 domain, maintaining SHP-2 in an inactive state. N-SH2 conformation switches to expose the catalytic domain, forming an active state. However, the switch mechanism is not clearly described. Although structural and kinetic studies in silicon have simulated the biological catalytic processes, Molecular Dynamics (MD) simulation has not provided sufficient information to explain the allosteric mechanism of SHP2. To further understand the conformational process, we created a novel method, solvent perturbed MD (SPMD), with high kinetic energy solvent to study SHP2 allosterism. We also illustrated the putative factor at the mouth of the opening pocket of SHP-2. We found, based on SPMD simulations, the distance between ASP61, of N-SH2 blocker, and ARG465 at the bottom of the pocket, reached 1 nm. Moreover, SPMD did not denature SHP2; the torsion angle and position of residue ARG465 in the bottom of the pocket were not significantly perturbed. Our SPMD simulation also demonstrated the periodic opening and closing of the blocker. Thus, our findings on the conformational alteration of SHP-2 in a solution interrupted system furthers our understanding of allosterism.