Ligand binding: evaluating the contribution of the water molecules network using the Fragment Molecular Orbital method

Water molecules play a crucial role in protein–ligand binding, and many tools exist that aim to predict the position and relative energies of these important, but challenging participants of biomolecular recognition. The available tools are, in general, capable of predicting the location of water molecules. However, predicting the effects of their displacement is still very challenging. In this work, a linear-scaling quantum mechanics-based approach was used to assess water network energetics and the changes in network stability upon ligand structural modifications. This approach offers a valuable way to improve understanding of SAR data and help guide compound design. Supplementary Information The online version contains supplementary material available at 10.1007/s10822-021-00416-3.