Computational Dehydration of Crystalline Hydrates Using Molecular Dynamics Simulations

Molecular dynamics (MD) simulations have evolved to an increasingly reliable and accessible technique and are today implemented in many areas of biomedical sciences. We present a generally applicable method to study dehydration of hydrates based on MD simulations and apply this approach to the dehydration of ampicillin trihydrate. The crystallographic unit cell of the trihydrate is used to construct the simulation cell containing 216 ampicillin and 648 water molecules. This system is dehydrated by removing water molecules during a 2200 ps simulation, and depending on the computational dehydration rate, different dehydrated structures were observed. Removing all water molecules immediately and removing water relatively fast (10 water molecules/10 ps) resulted in an amorphous system, whereas relatively slow computational dehydration (3 water molecules/10 ps) resulted in a crystalline anhydrate. The structural changes could be followed in real time, and in addition, an intermediate amorphous phase was identified. The computationally identified dehydrated structure (anhydrate) was slightly different from the experimentally known anhydrate structure suggesting that the simulated computational structure could represent a kinetically trapped dehydration intermediate.