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Water networks can determine the affinity of ligand binding to proteins

DOI: 10.1021/jacs.9b06275 DOI Help

Authors: John F. Darby (University of York) , Adam P. Hopkins (Demuris Ltd.) , Seishi Shimizu (University of York) , Shirley M. Roberts (University of York) , James A. Brannigan (University of York) , Johan P. Turkenburg (University of York) , Gavin H. Thomas (University of York) , Roderick E. Hubbard (University of York; Vernalis (R&D) Ltd) , Marcus Fischer (St. Jude Children’s Research Hospital)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 306 , 7864

Abstract: Solvent organization is a key but underexploited contributor to the thermodynamics of protein–ligand recognition, with implications for ligand discovery, drug resistance and protein engineering. Here, we explore the contribution of solvent to ligand binding in the Haemophilus influenzae virulence protein SiaP. By introducing a single mutation without direct ligand contacts, we observed a >1000-fold change in sialic acid binding affinity. Crystallographic and calorimetric data of wild-type and mutant SiaP showed that this change results from an enthalpically unfavourable perturbation of the solvent network. This disruption is reflected by changes in the normalized atomic displacement parameters of crystallographic water molecules. In SiaP’s enclosed cavity, relative differences in water-network dynamics serve as a simple predictor of changes in the free energy of binding upon changing protein, ligand or both. This suggests that solvent structure is an evolutionary con-straint on protein sequence that contributes to ligand affinity and selectivity.

Journal Keywords: Protein-ligand interactions; water network; water-mediated molecular interactions; room-temperature crystallography; thermodynamics

Subject Areas: Chemistry

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: ESRF