Abstract
For complexes between proteins and very small hydrophobic ligands, hydrophobic effects alone may be insufficient to outweigh the unfavorable entropic terms resulting from bimolecular association. NMR relaxation experiments indicate that the backbone flexibility of mouse major urinary protein increases upon binding the hydrophobic mouse pheromone 2-sec-butyl-4,5-dihydrothiazole. The associated increase in backbone conformational entropy of the protein appears to make a substantial contribution toward stabilization of the protein–pheromone complex. This term is likely comparable in magnitude to other important free energy contributions to binding and may represent a general mechanism to promote binding of very small ligands to macromolecules.
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Acknowledgements
The authors thank J. Ye for many discussions, M. Seewald for automating the data processing protocol, the Indiana University NMR Facility staff for valuable technical help, and T.S. Widlanski for critical reading of the manuscript. We appreciate the generosity of L.E. Kay (University of Toronto), A.G. Palmer (Columbia University) and M. Akke (Lund University), who provided pulse sequence and data analysis programs. This work was supported by grants to M.J.S. and to M.V.N. from the National Institutes of Health, and by a grant to M.J.S. from the National Science Foundation.
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Zídek, L., Novotny, M. & Stone, M. Increased protein backbone conformational entropy upon hydrophobic ligand binding. Nat Struct Mol Biol 6, 1118–1121 (1999). https://doi.org/10.1038/70057
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DOI: https://doi.org/10.1038/70057
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