Figure 5.

(A) In the autoinhibited structure of SHP2, the N-SH2 domain (cyan cartoon) blocks the catalytic site (red) of the PTP domain (pink) with the blocking loop (blue). The N-SH2 domain is connected to PTP in tandem with the homologous C-SH2 domain (orange). (B) Open and active structure obtained by pulling simulation coupled with simulated tempering, using the color code of (A). (C) Free energy profiles of SHP2 opening with the N-SH2 restrained to the α state (green line) or to the β state (blue line). The free energy calculations were performed using CHARMM36m force field. The distance between the blocking loop and the catalytic PTP loop, in terms of distance between the backbone centers-of-mass of residues 60–62 and residues 460–462, was taken as reaction coordinate.