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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References
Page, M.I. & Jencks, W.P. Proc. Natl. Acad. Sci. USA 68, 1678–1683 (1971).
Tidor, B. & Karplus, M. J. Mol. Biol. 238, 405–414 (1994).
Janin, J. & Chothia, C. Biochemistry 17, 2943–2948 (1978).
Williams, D.H. et al. J. Am. Chem. Soc. 113, 7020– 7030 (1991).
Tanford, C. The hydrophobic effect: formation of micelles and biological membranes. (John Wiley & Sons, New York; 1980).
Muller, N. Acc. Chem. Res. 23, 23–28 (1990).
Blokzijl, W. & Engberts, J.B.F.N. Angew. Chem. Int. Edn Engl. 32, 1545–1579 ( 1993).
Karplus, P.A. Protein Sci. 6, 1302–1307 (1997).
Silverstein, K.A.T., Haymet, A.D.J. & Dill, K.A. J. Am. Chem. Soc. 120, 3166 –3175 (1998).
Novotny, M., Harvey, S., Jemiolo, B. & Alberts, J. Proc. Natl. Acad. Sci. USA 82, 2059–2061 ( 1986).
Jemiolo, B., Harvey, S. & Novotny, M. Proc. Natl. Acad. Sci. USA 83, 4576–4579 (1986).
Robertson, D.H.L., Beynon, R.J. & Evershed, R.P. J. Chem. Ecol. 19, 1405– 1416 (1992).
Hurst, J.L., Robertson, D.H.L. & Beynon R.J. Anim. Behav. 55, 1289– 1297 (1998).
Böcskei, Z. et al. Nature 360, 186– 188 (1992).
Flower, D.R. Biochem J. 318, 1–14 ( 1996).
Zídek, L. et al. Biochemistry, 38, 9850– 9861(1999).
Akke, M., Brüschweiler, R. & Palmer, A.G. J. Am. Chem. Soc. 115, 9832 –9833 (1993).
Lipari, G. & Szabo, A. J. Am. Chem. Soc. 104, 4546–4559 (1982).
Yang, D. & Kay, L.E. J. Mol. Biol. 263 369–382 (1996).
Fersht, A. Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding. (W.H. Freeman, New York; 1998).
Cheng, J.-W., Lepre, C.A. & Moore, J.M. Biochemistry 33, 4093– 4100 (1994).
Rischel, C., Madsen, J.C., Anderson, K.V. & Poulsen F.M. Biochemistry 33, 13997–14002 (1994).
Fushman, D., Weisemann, R., Thuring, H. & Ruterjans, H. J. Biomol. NMR 4, 61–78 (1994).
Hodson, M.E. & Cistola, D.P. Biochemistry 36, 2278–2290 (1997).
Akke, M., Skelton, N.J., Kördel, J., Palmer, A.G. & Chazin, W.J. Biochemistry 32, 9832–9844 (1993).
Hodson, M.E. & Cistola, D.P. Biochemistry 36, 1450–1460 (1997).
Yu, L., Zhu, C.-X., Tse-Dinh, Y.-C. & Fesik, S.W. Biochemistry 35, 9661–9666 (1996).
Farrow, N.A. et al. Biochemistry 33, 5984– 6003 (1994).
Stivers, J.T., Abeygunawardana, C. & Mildvan, A.S. Biochemistry 35, 16036– 16047 (1996).
Doig, A.J. & Sternberg, J.E. Protein Sci. 4, 2247–2251 (1995).
Eisenberg, D. & McLachlan, A.D. Nature 319, 199–203 (1986).
Chothia, C. & Janin, J. Nature 256, 705–708 (1975).
Froloff, N., Windemuth, A., & Honig, B. Protein Sci. 6, 1293– 1301 (1997).
Philippopoulos, M., Mandel, A.M., Palmer, A.G. & Lim, C. Proteins Struct. Funct. Genet. 28, 481–493 (1997).
Novotny, M.V. et al. Experientia 51, 738– 743 (1995).
Wüthrich, K. NMR of proteins and nucleic acids. (John Wiley & Sons, New York; 1986).
Mandel, A.M., Akke, M. & Palmer, A.G. J. Mol. Biol. 246 144– 163 (1995).
Barbato, G., Ikura, M., Kay, L.E., Pastor, R.W., & Bax, A. Biochemistry 31, 5269– 5278 (1992).
Clore, G.M. et al. J. Am. Chem. Soc. 112, 4989– 4991 (1990).
Palmer, A.G., Williams, J. & McDermott, A. J. Phys. Chem. 100, 13293– 13310 (1996).
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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