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

Johannes Schiebel, Roberto Gaspari, Tobias Wulsdorf, Khang Ngo, Christian Sohn, Tobias E. Schrader, Andrea Cavalli, Andreas Ostermann, Andreas Heine and Gerhard Klebe ()
Additional contact information
Johannes Schiebel: Philipps-Universität Marburg
Roberto Gaspari: Istituto Italiano di Tecnologia
Tobias Wulsdorf: Philipps-Universität Marburg
Khang Ngo: Philipps-Universität Marburg
Christian Sohn: Philipps-Universität Marburg
Tobias E. Schrader: Jülich Centre for Neutron Science at Heinz Maier-Leibnitz Zentrum, Forschungszentrum Jülich
Andrea Cavalli: Istituto Italiano di Tecnologia
Andreas Ostermann: Technische Universität München
Andreas Heine: Philipps-Universität Marburg
Gerhard Klebe: Philipps-Universität Marburg

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-05769-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05769-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-05769-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().