Water is essential for protein structure and function but still underexplored in ligand discovery. To better understand the key roles of water networks in ligand binding and design we take a threefold experimental perturbation approach. First, we perturb water networks by mutating the protein. This highlights dominant contributions of individual waters to ligand binding. Second, we perturb water networks from a ligand point of view. Combining these insights allows us to propose a simple model that estimates relative changes in ligand affinity using water alone. Third, we perturb water networks by changing crystallographic data collection temperature from typical cryogenic to room temperature. Repopulating the protein conformational landscape with temperature reveals how water networks can drive changes at the protein-ligand interface, informing new avenues for ligand discovery. Finally, combining these experimental approaches with computational methods supports the notion that water networks are essential mediators of binding that can enable the discovery of new chemical matter.

Exploring water network perturbations for ligand discovery

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