ChemMedChem

Cover image for Vol. 10 Issue 8

Editor: Katja Paff

Impact Factor: 2.968

ISI Journal Citation Reports © Ranking: 2014: 19/59 (Chemistry Medicinal); 83/254 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

June 29, 2012

VIP: Water Makes the Difference: Rearrangement of Water Solvation Layer Triggers Non-additivity of Functional Group Contributions in Protein–Ligand Binding

VIP: Water Makes the Difference: Rearrangement of Water Solvation Layer Triggers Non-additivity of Functional Group Contributions in Protein–Ligand BindingAdam Biela, Michael Betz, Andreas Heine, Gerhard Klebe*

Water plays an essential role in protein–ligand binding; however, the nature of its impact is still poorly understood given the lack of experimental data available. Using thermolysin as a model enzyme representative of a whole class of zinc-dependent metalloproteases, Gerhard Klebe and colleagues at Philips University Marburg (Germany) described water's role in mediating binding interactions through high-resolution crystallographic data and isothermal titration calorimetry, determined with a series of closely related thermolysin inhibitors.

There are no structural differences in the binding modes of the ligands, but the thermodynamic data indicated significant effects, suggesting non-additivity for functional group replacements. Therefore, the team carefully investigated the local water structures next to the binding pockets. Crystal structures determined at very high resolution allowed Klebe's group to see important details in the structure of the water networks; to their surprise, the water network is ruptured for structural reasons in one of the complexes. This has an important impact on binding affinity and the thermodynamic signature of protein–ligand binding.

Received April 14, 2012; published online June 25, 2012, DOI: 10.1002/cmdc.201200206.

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