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J Chem Inf Model. 2016 Jan 25;56(1):148-58. doi: 10.1021/acs.jcim.5b00638. Epub 2016 Jan 8.

Exploration of Interfacial Hydration Networks of Target-Ligand Complexes.

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Department of Genetics, Eötvös Loránd University , Pázmány Péter sétány 1/C, 1117 Budapest, Hungary.
MTA NAP-B Molecular Neuroendocrinology Group, Institute of Physiology, Szentágothai Research Center, Center for Neuroscience, University of Pécs , Szigeti út 12, 7624 Pécs, Hungary.
Department of Biochemistry, Eötvös Loránd University , Pázmány Péter sétány 1/C, 1117 Budapest, Hungary.
Chemistry Doctoral School, University of Szeged , Dugonics tér 13, 6720 Szeged, Hungary.
Uppsala Center for Computational Chemistry, Science for Life Laboratory, Department of Cell and Molecular Biology, University of Uppsala , Box 596, SE-75124 Uppsala, Sweden.
MTA-ELTE Molecular Biophysics Research Group, Hungarian Academy of Sciences , Pázmány sétány 1/C, 1117 Budapest, Hungary.


Interfacial hydration strongly influences interactions between biomolecules. For example, drug-target complexes are often stabilized by hydration networks formed between hydrophilic residues and water molecules at the interface. Exhaustive exploration of hydration networks is challenging for experimental as well as theoretical methods due to high mobility of participating water molecules. In the present study, we introduced a tool for determination of the complete, void-free hydration structures of molecular interfaces. The tool was applied to 31 complexes including histone proteins, a HIV-1 protease, a G-protein-signaling modulator, and peptide ligands of various lengths. The complexes contained 344 experimentally determined water positions used for validation, and excellent agreement with these was obtained. High-level cooperation between interfacial water molecules was detected by a new approach based on the decomposition of hydration networks into static and dynamic network regions (subnets). Besides providing hydration structures at the atomic level, our results uncovered hitherto hidden networking fundaments of integrity and stability of complex biomolecular interfaces filling an important gap in the toolkit of drug design and structural biochemistry. The presence of continuous, static regions of the interfacial hydration network was found necessary also for stable complexes of histone proteins participating in chromatin assembly and epigenetic regulation.

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