Each of the four ligands was simulated in complex with the Grb2 SH2 domain, and free in solution (i.e., without protein). The starting coordinates were prepared from the crystal structures of the complexes identified above, using Maestro ; crystallographic waters within 5 Å of the ligand were retained and missing hydrogens were added. For the free ligand simulations, the coordinates of the ligand alone were extracted from the crystal structure and used as a starting point.