Water networks can determine the affinity of ligand binding to proteins

TY - JOUR

T1 - Water networks can determine the affinity of ligand binding to proteins

AU - Darby, John Fintan

AU - Hopkins, Adam

AU - Hubbard, Roderick Eliot

AU - Roberts, Shirley M.

AU - Shimizu, Seishi

AU - Brannigan, James A.

AU - Turkenburg, Johan

AU - Thomas, Gavin Hugh

AU - Fischer, Marcus

N1 - This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2019/10/9

Y1 - 2019/10/9

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 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.

AB - 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.

U2 - 10.1021/jacs.9b06275

DO - 10.1021/jacs.9b06275

M3 - Article

SN - 0002-7863

VL - 141

SP - 15818

EP - 15826

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 40

ER -