Abstract
| - We have performed a comprehensive analysis of water molecules at the protein−ligand interfaces observedin 392 high-resolution crystal structures. There are a total of 1829 ligand-bound water molecules in these392 complexes; 18% are surface water molecules, and 72% are interfacial water molecules. The number ofligand-bound water molecules in each complex structure ranges from 0 to 21 and has an average of 4.6. Ofthese interfacial water molecules, 76% are considered to be bridging water molecules, characterized byhaving polar interactions with both ligand and protein atoms. Among a number of factors that may influencethe number of ligand-bound water molecules, the polar van der Waals (vdw) surface area of ligands has thehighest Pearson linear correlation coefficient of 0.63. Our regression analysis predicted that one more ligand-bound water molecule is expected for every additional 24 Å2 in the polar vdw surface area of the ligand. Incontrast to the observation that the resolution is the primary factor influencing the number of water moleculesin crystallographic models of proteins, we found that there is only a weak relationship between the numberof ligand-bound water molecules and the resolution of the crystal structures. An analysis of the isotropic Bfactors of buried ligand-bound water molecules suggested that, when water molecules have fewer than twopolar interactions with the protein−ligand complex, they are more mobile than protein atoms in the crystalstructures; when they have more than three polar interactions, they are significantly less mobile than proteinatoms.
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