Nature Publishing Group, publisher of Nature, and other science journals and reference works
Nature
my account e-alerts subscribe register
   
Wednesday 20 September 2017
Journal Home
Current Issue
AOP
Archive
Download PDF
References
Export citation
Export references
Send to a friend
More articles like this

Letters to Nature
Nature 334, 270 - 272 (21 July 1988); doi:10.1038/334270a0

Why ion pair reversal by protein engineering is unlikely to succeed

Jenn-Kang Hwang & Arieh Warshel

Department of Chemistry, University of Southern California, Los Angeles, California 90089-0482, USA

Genetic engineering is a powerful tool for exploring correlations between structure and function in proteins, but as yet we are unable to use it for effective protein design. One of the most interesting examples, which would seem to be obvious, is reversing the polarity of an ion pair. Changing a positively charged protein group, that provides a strong binding for negative substrates, to a negative group is expected to provide an effective binding site for a positively charged substrate. But several recent experiments on aspartate aminotransferase1,2, trypsin3 and aspartate transcarbamoylase (Schachman, H. K. personal communication) have indicated that polarity reversal is not so successful. Here we argue that the same factors that make the enzyme an effective system for the (−+) pair will make it a much less effective system for the ( +−)pair. We also point out that the unusually low effective dielectric constant (ε 13) for the (−+) interaction is due to its microenviron-ment and this will destabilize a (+−) arrangement having an entirely different dielectric constant (ε 80). The calculations presented here evaluate the energetics of ion pairs in protein active sites on a semiquantitative level. This is particularly important when dealing with strong, functionally important interactions that are difficult to evaluate with macroscopic models.

------------------

References

1. Cronin, C. N., Malcolm, B. A. & Kirsch, J. F. J. Am. chem. Soc. 109, 2222−2223 (1987). | Article | ChemPort |
2. Cronin, C. N. & Kirsch, J. F. Biochemistry (manuscript submitted).
3. Graf, L. et al. Biochemistry 26, 2616−2638 (1987). | Article | PubMed | ISI | ChemPort |
4. Warshel, A. Biochemistry 20, 3167−3177 (1981). | Article | PubMed | ISI | ChemPort |
5. Warshel, A., Sussman, F. & King, G. Biochemistry 25, 8368−8372 (1986). | Article | PubMed | ChemPort |
6. Warshel, A. & Sussman, F. Proc. natn. Acad. Sci. U.S.A 83, 3806−3810 (1986). | ChemPort |
7. Hwang, J-K & Warshel, A. Biochemistry 26, 2669−2673 (1987). | Article | PubMed | ChemPort |
8. Warshel, A. & Russell, S. T. Q. Rev. Biophys. 17, 283−422 (1984). | PubMed | ISI | ChemPort |
9. Rao, S. N., Singh, U. C., Bash, P. A. & Kollman, P. A. Nature 328, 551−554 (1987). | Article | PubMed | ChemPort |
10. Mezei, M., Mehrotra, P. K. & Beveridge, D. L. J. Am. chem. Soc. 107, 2239−2245 (1985). | Article | ChemPort |
11. Arnone, A. et. al. in Molecular Structure and Biological Activity (eds Griffen, J. F. & Duax, W. L.) 57−74 (Elsevier, New York, 1982). | ChemPort |
12. Kirsch, J. F. et al. J. mol. Biol. 174, 497−525 (1984). | Article | PubMed | ISI | ChemPort |
13. Warshel, A., Russell, S. T. & Churg, A. K. Proc. natn. Acad. Sci. U.S.A. 81, 4785−4789 (1984). | ChemPort |
14. Warshel, A. Proc. natn Acad. Sci. U.S.A. 75, 5250−5254 (1978). | ChemPort |
15. Quiocho, F. A., Sack, J. S. & Vyas, N. K. Nature 329, 561−564 (1987). | Article | PubMed | ChemPort |
16. Wells, J. A., Powers, D. B., Bott, R. R., Craycar, T. P. & Estell, D. A. Proc. natn. Acad. Sci. U.S.A. 84, 1219−1223 (1989).
17. Sternberg, M. J. E., Hayes, F. R. F., Russell, A. J., Thomas, P. G. & Fersht, A. R. Nature 305, 86−88 (1987).
18. Russell, A. J. & Fersht, A. R. Nature 328, 496−500 (1987). | Article | PubMed | ISI | ChemPort |
19. Gilson, M. K. & Honig, B. H. Nature 330, 84−86 (1987). | Article | PubMed | ISI | ChemPort |
20. Warshel, A. Nature 330, 15−16 (1987). | Article | PubMed | ChemPort |



© 1988 Nature Publishing Group
Privacy Policy