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Water Networks Can Determine the Affinity of Ligand Binding to Proteins.
J Am Chem Soc 2019; 141(40):15818-15826JA

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 unfavorable 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 constraint on protein sequence that contributes to ligand affinity and selectivity.

Authors+Show Affiliations

No affiliation info availableDemuris Ltd., The Biosphere , Draymans Way, Newcastle Helix , Newcastle upon Tyne NE4 5BX , United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableVernalis (R&D) Ltd. , Granta Park , Abington, Cambridge CB21 6GB , United Kingdom.Department of Chemical Biology & Therapeutics, and Department of Structural Biology , St. Jude Children's Research Hospital , Memphis , Tennessee 38105 , United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31518131

Citation

Darby, John F., et al. "Water Networks Can Determine the Affinity of Ligand Binding to Proteins." Journal of the American Chemical Society, vol. 141, no. 40, 2019, pp. 15818-15826.
Darby JF, Hopkins AP, Shimizu S, et al. Water Networks Can Determine the Affinity of Ligand Binding to Proteins. J Am Chem Soc. 2019;141(40):15818-15826.
Darby, J. F., Hopkins, A. P., Shimizu, S., Roberts, S. M., Brannigan, J. A., Turkenburg, J. P., ... Fischer, M. (2019). Water Networks Can Determine the Affinity of Ligand Binding to Proteins. Journal of the American Chemical Society, 141(40), pp. 15818-15826. doi:10.1021/jacs.9b06275.
Darby JF, et al. Water Networks Can Determine the Affinity of Ligand Binding to Proteins. J Am Chem Soc. 2019 Oct 9;141(40):15818-15826. PubMed PMID: 31518131.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Water Networks Can Determine the Affinity of Ligand Binding to Proteins. AU - Darby,John F, AU - Hopkins,Adam P, AU - Shimizu,Seishi, AU - Roberts,Shirley M, AU - Brannigan,James A, AU - Turkenburg,Johan P, AU - Thomas,Gavin H, AU - Hubbard,Roderick E, AU - Fischer,Marcus, Y1 - 2019/09/26/ PY - 2019/9/14/pubmed PY - 2019/9/14/medline PY - 2019/9/14/entrez SP - 15818 EP - 15826 JF - Journal of the American Chemical Society JO - J. Am. Chem. Soc. VL - 141 IS - 40 N2 - 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 unfavorable 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 constraint on protein sequence that contributes to ligand affinity and selectivity. SN - 1520-5126 UR - https://www.unboundmedicine.com/medline/citation/31518131/Water_networks_can_determine_the_affinity_of_ligand_binding_to_proteins L2 - https://dx.doi.org/10.1021/jacs.9b06275 DB - PRIME DP - Unbound Medicine ER -