We studied two pairs of these ligands, where each pair contains the same central residue, either valine (V) or glutamine (Q). The structures of these ligands in complex with the Grb2 SH2 domain were previously solved and are available in the RSCB PDB : fpYNVN (3C7I) and cpYVN (2HUW); fpYQN (3IMD) and cpYQN (3IN7). With the multiple-GPU version of AMBER PMEMD , and long (4 fs) time steps made possible by hydrogen mass repartitioning , we were able to achieve up to 450 ns of simulation per day, and generated about 250 µs cumulative simulation time for each bound system. The present study thus presses the state of the art in protein-ligand simulations accessible with GPU computing. The results are informative not only about the physics of molecular recognition, but also about the convergence of enthalpies by the direct method. 3 Methods