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Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes.

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Schiebel J, Gaspari R, Wulsdorf T, Ngo K, Sohn C, Schrader TE, Cavalli A, Ostermann A, Heine A, Klebe G
OpenAccess logo Nat Commun 9 3559 (2018)
Related entries: 5mne, 5mnf, 5mng, 5mnh, 5mnn, 5mno, 5mnq, 5mo0, 5mo2, 5mop, 5moq, 5mos

Cited: 53 times
EuropePMC logo PMID: 30177695

Abstract

Hydrogen bonds are key interactions determining protein-ligand binding affinity and therefore fundamental to any biological process. Unfortunately, explicit structural information about hydrogen positions and thus H-bonds in protein-ligand complexes is extremely rare and similarly the important role of water during binding remains poorly understood. Here, we report on neutron structures of trypsin determined at very high resolutions ≤1.5 Å in uncomplexed and inhibited state complemented by X-ray and thermodynamic data and computer simulations. Our structures show the precise geometry of H-bonds between protein and the inhibitors N-amidinopiperidine and benzamidine along with the dynamics of the residual solvation pattern. Prior to binding, the ligand-free binding pocket is occupied by water molecules characterized by a paucity of H-bonds and high mobility resulting in an imperfect hydration of the critical residue Asp189. This phenomenon likely constitutes a key factor fueling ligand binding via water displacement and helps improving our current view on water influencing protein-ligand recognition.

Articles - 5mnz mentioned but not cited (1)

  1. Neutron crystallographic refinement with REFMAC5 from the CCP4 suite. Catapano L, Long F, Yamashita K, Nicholls RA, Steiner RA, Murshudov GN. Acta Crystallogr D Struct Biol 79 1056-1070 (2023)


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  2. Molecular Boronic Acid-Based Saccharide Sensors. Williams GT, Kedge JL, Fossey JS. ACS Sens 6 1508-1528 (2021)
  3. Applications of water molecules for analysis of macromolecule properties. Mitusińska K, Raczyńska A, Bzówka M, Bagrowska W, Góra A. Comput Struct Biotechnol J 18 355-365 (2020)
  4. Insight into the Structural Features of TSPO: Implications for Drug Development. Lacapere JJ, Duma L, Finet S, Kassiou M, Papadopoulos V. Trends Pharmacol Sci 41 110-122 (2020)
  5. Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective. Ahmad K, Rizzi A, Capelli R, Mandelli D, Lyu W, Carloni P. Front Mol Biosci 9 899805 (2022)
  6. On the Case of the Misplaced Hydrogens. Kumar P, Agarwal PK, Cuneo MJ. Chembiochem 22 288-297 (2021)
  7. Spatially Resolved Hydration Thermodynamics in Biomolecular Systems. Mukherjee S, Schäfer LV. J Phys Chem B 126 3619-3631 (2022)
  8. Molecular docking in organic, inorganic, and hybrid systems: a tutorial review. Mohanty M, Mohanty PS. Monatsh Chem 1-25 (2023)
  9. 17O NMR Spectroscopy: A Novel Probe for Characterizing Protein Structure and Folding. Muniyappan S, Lin Y, Lee YH, Kim JH. Biology (Basel) 10 453 (2021)
  10. Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization. Minetti CA, Remeta DP. Life (Basel) 12 1438 (2022)
  11. Modern Alchemical Free Energy Methods for Drug Discovery Explained. York DM. ACS Phys Chem Au 3 478-491 (2023)

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  2. Multisecond ligand dissociation dynamics from atomistic simulations. Wolf S, Lickert B, Bray S, Stock G. Nat Commun 11 2918 (2020)
  3. Repurposing drugs for treatment of SARS-CoV-2 infection: computational design insights into mechanisms of action. Kandwal S, Fayne D. J Biomol Struct Dyn 40 1316-1330 (2022)
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  5. Are crystallographic B-factors suitable for calculating protein conformational entropy? Caldararu O, Kumar R, Oksanen E, Logan DT, Ryde U. Phys Chem Chem Phys 21 18149-18160 (2019)
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