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Exploration of Interfacial Hydration Networks of Target Ligand Complexes
Eotvos Lorand Univ, Dept Genet, Pazmany Peter Setany 1-C, H-1117 Budapest, Hungary.;Univ Pecs, Ctr Neurosci, Szentagothai Res Ctr, MTA NAP B Mol Neuroendocrinol Grp,Inst Physiol, Szigeti Ut 12, H-7624 Pecs, Hungary..
Eotvos Lorand Univ, Dept Biochem, Pazmany Peter Setany 1-C, H-1117 Budapest, Hungary..
Univ Szeged, Chem Doctoral Sch, Dugon Ter 13, H-6720 Szeged, Hungary..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2016 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 56, no 1, 148-158 p.Article in journal (Refereed) PublishedText
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 56, no 1, 148-158 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-280102DOI: 10.1021/acs.jcim.5b00638ISI: 000368864600014PubMedID: 26704050OAI: oai:DiVA.org:uu-280102DiVA: diva2:910113
Available from: 2016-03-08 Created: 2016-03-08 Last updated: 2016-03-08Bibliographically approved

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van der Spoel, David
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