A hydrogen bond of the carboxlate group of the deprotonated fragment and the side chain hydroxl group of Thr 183 breaks and reforms but is stable for extended trajectory segments, with bond stable for durations of more than 100 ns at around 200 ns of simulation, but breaks at around 800 ns of simulation time. However, the deprotonated benzoic acid fragment gains a new hydrogen bond with the side chain of Lys 72 as it reorientates in the PKA ligand binding site. Importantly, the carboxlate group apparently drives the rearrangement and starts to interact with water molecules rather than the PKA (Fig. ). The deprotonated fraggment also perturbs PKA structure as tracked RMSD and leads to larger RMSF valuees indicating local flexibility beyond what is seen for the protonated fragment (SI Fig 1). Since molecular dynamics simulations afford us the opportunity to straightforwardly extend our investigation to additional compounds and as a control for our simulations, we also simulated the complex of PKA with bezamide. The benzamide fragment has been shown by X-ray crystallography to form similar interactions, in particular hydrogen bonds to PKA. Consequently, we expect this fragment to behave similar to the protonated benzoic acid fragment [6]. Two hydrogen bonds between the protein and the fragment are typically maintained throughout the 1 µs trajectory.