Figure 2. A non-crystallographic open conformation of SHP2 is stabilized by Glu/Asp139 electrostatic interactions in molecular dynamics simulations.

(A) Representative sampling of structures from MD simulation trajectories of SHP2^WT/6CRF (left), SHP2^WT/AF2 (middle), and SHP2^E139D/AF2 (right). Yellow, pink, and green represent N-SH2, C-SH2, and PTP domains, respectively. N-SH2 domain positioning in the closed conformation (PDB code 4DGP) is shown in gray as a reference, and all states are aligned over just the PTP domain residues. (B) Distribution of N-SH2 rotation angles from the closed conformation (PDB code 4DGP) to the positions seen in the SHP2^WT/6CRF, SHP2^WT/AF2, and SHP2^E139D/AF2 simulations. (C) Same as (B) but measuring C-SH2 rotation. (D) Minimum distance between Arg4 side-chain N atoms and Glu/Asp139 side-chain O atoms in the SHP2^WT/6CRF, SHP2^WT/AF2, and SHP2^E139D/AF2 simulations. (E) Same as (D), but for Arg5. In panels (B) to (E), the red line indicates the median value of the distribution, and the red dot denotes the measurement in the starting model used for that simulation. (F) Renderings of structures from SHP2^E139D/AF2 simulations, highlighting Arg4 and Arg5 interactions with Asp139. (G) Concurrent Arg4-Asp139 and Arg5-Asp139 distances across SHP2^E139D/AF2 simulations, showing a population of frames where both interactions occur simultaneously (dashed red box). The red dot denotes the measurement in the starting model used for that simulation.