The first hydration steps of LA, ProA, and diol is more favorable compared to PA. In addition, the binding free energies are very similar for the addition of the first four water molecules. However, the addition of the fifth water molecule is significantly more favorable for the diol compared to LA and ProA. This can be rationalized from the structures in Figure , where the diol is interacting with all five water molecules in the extended H-bond network, while LA and ProA primarily interact with four water molecules and have the fifth water molecule only interacting with other water molecules and not the acids.