Cation-π interactions in chemistry and biology: A new view of benzene, Phe, Tyr, and Trp

Science

Volumn 271, Issue 5246, 1996, Pages 163-168

  Dougherty, Dennis A ^a  

^a California Institute of Technology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AROMATIC COMPOUND; BENZENE; CATION; PHENYLALANINE; TRYPTOPHAN; TYROSINE;

ARTICLE; CHEMICAL BINDING; HYDROPHOBICITY; MOLECULAR MODEL; PRIORITY JOURNAL; PROTEIN BINDING;

EID: 0030043489     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.271.5246.163     Document Type: Article

References (113)

1. The introduction of several heteroatoms (as, for example, in histidine or the nng systems of the nucleic acids) leads to new types of interactions and complicates the analysis. Certainly, however, electrostatic interactions of the type described here will remain important.
2. J. Sunner, K. Nishizawa, P. Kebarle, J. Phys. Chem. 85, 1814 (1981).
3. R. W Taft et al., Pure Appl. Chem 62, 17 (1990); B. C. Quo, J W Pumell, A. W Castleman Jr., Chem. Phys Lett 168, 155 (1990).
4. R. W Taft et al., Pure Appl. Chem 62, 17 (1990); B. C. Quo, J W Pumell, A. W Castleman Jr., Chem. Phys Lett 168, 155 (1990).
5. R A Kumpf and D A. Dougherty, Science 261, 1708 (1993)
6. + complexes of arenes or oletins (6), is qualitatively different and is not considered here Note also that the cation-π interaction should apply to simpler π systems, such as those in olefins and alkynes
7. For lead references, see J Gross, G Harder, F. Vogtle, H Stephan, K. Gloe, Angew Chem Int. Ed. Engl. 34, 481 (1995)
8. C A. Deakyne and M. Meot-Ner (Mautner), J Am Chem. Soc. 107, 474 (1985); M Meot-Ner (Mautner) and C. A. Deakyne. ibid., p 469
9. C A. Deakyne and M. Meot-Ner (Mautner), J Am Chem. Soc. 107, 474 (1985); M Meot-Ner (Mautner) and C. A. Deakyne. ibid., p 469
10. A quadrupole moment can be thought of as two dipole moments aligned in such a way that there is no net dipole. This can be achieved by the "tail-totail" arrangement of Fig. 2, or by placing two dipoles side by side, with one facing "north" and the other "south."
11. G. R. Dennis and G. L D. Ritchie, J. Phys. Chem. 95, 656 (1991).
12. See, however, J. H. Williams, Acc Chem. Res. 26, 593 (1993).
13. A forceful argument for the importance of the quadrupole moment of benzene has been made by M. Luhmer, K. Bartik, A. Dejaegere, P. Bovy, J. Reisse, Bull. Soc Chim. Fr 131, 603 (1994), see also S. L. Price and A. J Stone, J. Chem. Phys 86, 2859 (1987).
14. A forceful argument for the importance of the quadrupole moment of benzene has been made by M. Luhmer, K. Bartik, A. Dejaegere, P. Bovy, J. Reisse, Bull. Soc Chim. Fr 131, 603 (1994), see also S. L. Price and A. J Stone, J. Chem. Phys 86, 2859 (1987).
15. The multipole expansion senes (pole, dipole, quadrupole, octupole ) is not a perturbation series. That is, there is no reason to expect, a priori, that an ion-quadrupole interaction will always be weaker than an ion-dipole interaction, especially at the short interaction distances considered here.
16. These findings naturally do not imply that ionic structures should be more soluble in benzene than in water. The gas-phase data consider only the first solvation shell of the ion. In bulk water, a great deal of the solvation energy comes from longer range, continuum (Bom) solvation, provided by water's large dielectric constant. Such forces are negligible in benzene.
17. The other major factor in the cation-π interaction is most likely an induced dipole that arises in the aromatic in response to the nearby charge. If this were the dominating factor, polarizability should be of major importance. However, benzene is not an especially polanzable molecule, and in fact the in-piane polanzability is greater than the out-of-plane polarizability (15). Cyclohexane is more polarizable than benzene (16), but it is a decidedly weaker cation binder (17). As such, induced dipole arguments do not lead to straightforward rationalizations of the observations. On the other hand, the quadrupole moment of cyclohexane (16) is much smaller than that of benzene (9), consistent with observations
18. I. R. Gentle and G L. D. Ritchie, J. Phys. Chem. 93, 7740 (1989)
19. I. E Craven et al., ibid., p. 627.
20. + to cyclohexane is only ∼8 kcal/mol (S. Mecozzi and D. A. Dougherty, unpublished results).
21. J. W Calwell and P A. Kollman, J. Am. Chem. Soc. 117, 4177 (1995) This work suggests that ∼60% of the cation-π interaction is electrostatic. See also J Y. Lee et al , Chem. Phys. Lett. 232, 67 (1995); K. S. Kim, J Y. Lee, S. J. Lee, T.-K. Ha. D. H. Kim. J. Am. Chem. Soc. 116, 7399 (1994).
22. J. W Calwell and P A. Kollman, J. Am. Chem. Soc. 117, 4177 (1995) This work suggests that ∼60% of the cation-π interaction is electrostatic. See also J Y. Lee et al , Chem. Phys. Lett. 232, 67 (1995); K. S. Kim, J Y. Lee, S. J. Lee, T.-K. Ha. D. H. Kim. J. Am. Chem. Soc. 116, 7399 (1994).
23. J. W Calwell and P A. Kollman, J. Am. Chem. Soc. 117, 4177 (1995) This work suggests that ∼60% of the cation-π interaction is electrostatic. See also J Y. Lee et al , Chem. Phys. Lett. 232, 67 (1995); K. S. Kim, J Y. Lee, S. J. Lee, T.-K. Ha. D. H. Kim. J. Am. Chem. Soc. 116, 7399 (1994).
24. 3 dependence assumes, essentially, a point (dimensioniess) quadrupole
25. R. A Kumpf and D A. Dougherty, unpublished results.
26. B. Honig and A. Nicholls, Science 268, 1144 (1995); G Náray-Szabó and G. G Ferenczy, Chem. Rev. 95, 829 (1995)
27. B. Honig and A. Nicholls, Science 268, 1144 (1995); G Náray-Szabó and G. G Ferenczy, Chem. Rev. 95, 829 (1995)
28. See, for example, D. R. Ripoll, C. H Fairman, P. H. Axelsen, I. Silman, J. L Sussman, Proc. Natl. Acad. Sci. U.S.A. 90, 5128 (1993); Y. Shamoo, A M. Friedman, M. R. Parsons, W. H Konigsberg, T. A. Steitz, Nature 376, 362 (1995)
29. See, for example, D. R. Ripoll, C. H Fairman, P. H. Axelsen, I. Silman, J. L Sussman, Proc. Natl. Acad. Sci. U.S.A. 90, 5128 (1993); Y. Shamoo, A M. Friedman, M. R. Parsons, W. H Konigsberg, T. A. Steitz, Nature 376, 362 (1995)
30. S. Suzuki et al., Science 257, 942 (1992); D. A. Rodham et al., Nature 362, 735 (1993).
31. S. Suzuki et al., Science 257, 942 (1992); D. A. Rodham et al., Nature 362, 735 (1993).
32. K. C. Janda et al , J Chem. Phys. 63, 1419 (1975); W. L. Jorgensenand D. L. Severance, J. Am Chem. Soc 112, 4768 (1990); F. Cozzi, M. Cinquini, R Annunziata, T. Dwyer, J. S. Siegel, ibid. 114, 5729 (1992).
33. K. C. Janda et al , J Chem. Phys. 63, 1419 (1975); W. L. Jorgensenand D. L. Severance, J. Am Chem. Soc 112, 4768 (1990); F. Cozzi, M. Cinquini, R Annunziata, T. Dwyer, J. S. Siegel, ibid. 114, 5729 (1992).
34. K. C. Janda et al , J Chem. Phys. 63, 1419 (1975); W. L. Jorgensenand D. L. Severance, J. Am Chem. Soc 112, 4768 (1990); F. Cozzi, M. Cinquini, R Annunziata, T. Dwyer, J. S. Siegel, ibid. 114, 5729 (1992).
35. T J. Shepodd, M. A. Petti, D. A Dougherty, J. Am. Chem Soc. 108, 6085 (1986).
36. P. C. Kearney et al., ibid. 115, 9907 (1993) and references therein, D A. Dougherty, in Comprehensive Supramolecular Chemistry, J.-M. Lehn. Ed. (Pergamon, New York, in press), vol. 2.
37. P. C. Kearney et al., ibid. 115, 9907 (1993) and references therein, D A. Dougherty, in Comprehensive Supramolecular Chemistry, J.-M. Lehn. Ed. (Pergamon, New York, in press), vol. 2.
38. See, for example, L Garel, B Lozach, J -P. Dutasta, A Collet, J Am Chem. Soc 115. 11652 (1993). M, Dhaenens, J.-M. Lehn, M.-J. Fernandez, New J Chem. 15, 873 (1991); H.-J. Schneider, Angew. Chem Int Ed Engl. 30, 1417 (1991); K Araki, H. Shimizu, S. Shinkai, Chem Lett, 205 (1993).
39. See, for example, L Garel, B Lozach, J -P. Dutasta, A Collet, J Am Chem. Soc 115. 11652 (1993). M, Dhaenens, J.-M. Lehn, M.-J. Fernandez, New J Chem. 15, 873 (1991); H.-J. Schneider, Angew. Chem Int Ed Engl. 30, 1417 (1991); K Araki, H. Shimizu, S. Shinkai, Chem Lett, 205 (1993).
40. See, for example, L Garel, B Lozach, J -P. Dutasta, A Collet, J Am Chem. Soc 115. 11652 (1993). M, Dhaenens, J.-M. Lehn, M.-J. Fernandez, New J Chem. 15, 873 (1991); H.-J. Schneider, Angew. Chem Int Ed Engl. 30, 1417 (1991); K Araki, H. Shimizu, S. Shinkai, Chem Lett, 205 (1993).
41. See, for example, L Garel, B Lozach, J -P. Dutasta, A Collet, J Am Chem. Soc 115. 11652 (1993). M, Dhaenens, J.-M. Lehn, M.-J. Fernandez, New J Chem. 15, 873 (1991); H.-J. Schneider, Angew. Chem Int Ed Engl. 30, 1417 (1991); K Araki, H. Shimizu, S. Shinkai, Chem Lett, 205 (1993).
42. S Dao-pin, U. Sauer, H Nichoison, B.W Matthews, Biochemistry 30, 7142 (1991); Z S Hendsch and B. Tidor, Protein Sci. 3, 211 (1994); C D Waldburger, J F. Schildbach, R T. Sauer, Siruct. Biol 2, 122 (1995).
43. S Dao-pin, U. Sauer, H Nichoison, B.W Matthews, Biochemistry 30, 7142 (1991); Z S Hendsch and B. Tidor, Protein Sci. 3, 211 (1994); C D Waldburger, J F. Schildbach, R T. Sauer, Siruct. Biol 2, 122 (1995).
44. S Dao-pin, U. Sauer, H Nichoison, B.W Matthews, Biochemistry 30, 7142 (1991); Z S Hendsch and B. Tidor, Protein Sci. 3, 211 (1994); C D Waldburger, J F. Schildbach, R T. Sauer, Siruct. Biol 2, 122 (1995).
45. D. A Stauffer, R. E Barrens Jr., D. A. Dougherty, Angew Chem. Int Ed Engl 29, 915 (1990), A McCurdy, L Jimenez, D A Stauffer, D A. Dougherty, J. Am Chem Soc. 114, 10314 (1992).
46. D. A Stauffer, R. E Barrens Jr., D. A. Dougherty, Angew Chem. Int Ed Engl 29, 915 (1990), A McCurdy, L Jimenez, D A Stauffer, D A. Dougherty, J. Am Chem Soc. 114, 10314 (1992).
47. M. F. Perutz, G Fermi, D. J Abraham, C Poyart, E. Bursaux, J. Am. Chem. Soc 108, 1064 (1986), M. F. Perutz, Philos. Trans R. Soc. London Ser A 345, 105 (1993).
48. M. F. Perutz, G Fermi, D. J Abraham, C Poyart, E. Bursaux, J. Am. Chem. Soc 108, 1064 (1986), M. F. Perutz, Philos. Trans R. Soc. London Ser A 345, 105 (1993).
49. S. K. Burley and G. A Petsko, FEBS Lett 203, 139 (1986); Weakly Polar Interactions in Proteins, vol 39 of Advances in Protein Chemistry (Academic Press, New York, 1988)
50. S. K. Burley and G. A Petsko, FEBS Lett 203, 139 (1986); Weakly Polar Interactions in Proteins, vol 39 of Advances in Protein Chemistry (Academic Press, New York, 1988)
51. J. B.O Mitchell et al., Nature 366, 413 (1993). J. B O Mitchell, C. L Nandi, I K McDonald, J. M. Thomton, S L Price, J. Mol. Biol 239, 315 (1994).
52. J. B.O Mitchell et al., Nature 366, 413 (1993). J. B O Mitchell, C. L Nandi, I K McDonald, J. M. Thomton, S L Price, J. Mol. Biol 239, 315 (1994).
53. C. L. Nandi, J Singh, J M. Thornton, Protein Eng. 6, 247 (1993); E M Duffy, P J Kowalczyk, W L. Jorgensen. J Am Chem. Soc 115, 9271 (1993). M M. Flocco and S. L Mowbray, J. Mol. Biol 235, 709 (1994)
54. C. L. Nandi, J Singh, J M. Thornton, Protein Eng. 6, 247 (1993); E M Duffy, P J Kowalczyk, W L. Jorgensen. J Am Chem. Soc 115, 9271 (1993). M M. Flocco and S. L Mowbray, J. Mol. Biol 235, 709 (1994)
55. C. L. Nandi, J Singh, J M. Thornton, Protein Eng. 6, 247 (1993); E M Duffy, P J Kowalczyk, W L. Jorgensen. J Am Chem. Soc 115, 9271 (1993). M M. Flocco and S. L Mowbray, J. Mol. Biol 235, 709 (1994)
56. D. A. Dougherty and D. A Stauffer, Science 250, 1558 (1990).
57. Y. Satow, G. H. Cohen, E. A Padlan, D. R. Davies, J. mol. Biol 190, 593 (1986); J. Novotny, R. E Bruccolen, F. A Saul, Biochemistry 28, 4735 (1989).
58. Y. Satow, G. H. Cohen, E. A Padlan, D. R. Davies, J. mol. Biol 190, 593 (1986); J. Novotny, R. E Bruccolen, F. A Saul, Biochemistry 28, 4735 (1989).
59. J. L Sussman et al., Science 253, 872 (1991). For a review, see J L. Sussman and I. Silman, Curr Opin. Struct. Biol. 2, 721 (1992).
60. J. L Sussman et al., Science 253, 872 (1991). For a review, see J L. Sussman and I. Silman, Curr Opin. Struct. Biol. 2, 721 (1992).
61. + with water is comparable to its interaction with benzene (7), which establishes that an OH can bind a cation through electrostatic interactions
62. For lead references on the nAChR, see (39) as well as A. Kariin, Curr Opin Neurobiol 3, 299 (1993), S. N. Abramson, W. Fenical, P Taytor, Drug Dev. Res. 24, 297 (1991), J. B. Cohen, S D Sharp, W. S. Liu, J. Biol. Chem. 266, 23354 (1991), T. L Lentz, Biochemistry 34, 1316 (1995); Y Fraenkel, J M. Gershoni, G. Navon, FEBS Lett. 291, 225 (1991), M. W. Nowak et al., Science 268, 439 (1995)
63. For lead references on the nAChR, see (39) as well as A. Kariin, Curr Opin Neurobiol 3, 299 (1993), S. N. Abramson, W. Fenical, P Taytor, Drug Dev. Res. 24, 297 (1991), J. B. Cohen, S D Sharp, W. S. Liu, J. Biol. Chem. 266, 23354 (1991), T. L Lentz, Biochemistry 34, 1316 (1995); Y Fraenkel, J M. Gershoni, G. Navon, FEBS Lett. 291, 225 (1991), M. W. Nowak et al., Science 268, 439 (1995)
64. For lead references on the nAChR, see (39) as well as A. Kariin, Curr Opin Neurobiol 3, 299 (1993), S. N. Abramson, W. Fenical, P Taytor, Drug Dev. Res. 24, 297 (1991), J. B. Cohen, S D Sharp, W. S. Liu, J. Biol. Chem. 266, 23354 (1991), T. L Lentz, Biochemistry 34, 1316 (1995); Y Fraenkel, J M. Gershoni, G. Navon, FEBS Lett. 291, 225 (1991), M. W. Nowak et al., Science 268, 439 (1995)
65. For lead references on the nAChR, see (39) as well as A. Kariin, Curr Opin Neurobiol 3, 299 (1993), S. N. Abramson, W. Fenical, P Taytor, Drug Dev. Res. 24, 297 (1991), J. B. Cohen, S D Sharp, W. S. Liu, J. Biol. Chem. 266, 23354 (1991), T. L Lentz, Biochemistry 34, 1316 (1995); Y Fraenkel, J M. Gershoni, G. Navon, FEBS Lett. 291, 225 (1991), M. W. Nowak et al., Science 268, 439 (1995)
66. For lead references on the nAChR, see (39) as well as A. Kariin, Curr Opin Neurobiol 3, 299 (1993), S. N. Abramson, W. Fenical, P Taytor, Drug Dev. Res. 24, 297 (1991), J. B. Cohen, S D Sharp, W. S. Liu, J. Biol. Chem. 266, 23354 (1991), T. L Lentz, Biochemistry 34, 1316 (1995); Y Fraenkel, J M. Gershoni, G. Navon, FEBS Lett. 291, 225 (1991), M. W. Nowak et al., Science 268, 439 (1995)
67. For lead references on the nAChR, see (39) as well as A. Kariin, Curr Opin Neurobiol 3, 299 (1993), S. N. Abramson, W. Fenical, P Taytor, Drug Dev. Res. 24, 297 (1991), J. B. Cohen, S D Sharp, W. S. Liu, J. Biol. Chem. 266, 23354 (1991), T. L Lentz, Biochemistry 34, 1316 (1995); Y Fraenkel, J M. Gershoni, G. Navon, FEBS Lett. 291, 225 (1991), M. W. Nowak et al., Science 268, 439 (1995)
68. J -L Galzi, F Revah, A Bessis, J -P Changeux, Annu. Rev. Pharmacol 31, 37 (1991 ); J.-L Galzi and J.-P Changeux, Curr Opin Struct. Biol 4, 554 (1994).
69. J -L Galzi, F Revah, A Bessis, J -P Changeux, Annu. Rev. Pharmacol 31, 37 (1991 ); J.-L Galzi and J.-P Changeux, Curr Opin Struct. Biol 4, 554 (1994).
70. N. Unwin, J. Mol. Biol 229, 1101 (1993).
71. Evidence also exists for more classical (ion-pair) electrostatic interactions contributing to the binding in the nAChR [C. Cazjkowski, C Kaufmann, A Karlin, Proc. Natl. Acad Sci. U.S.A 90, 6285 (1993)]
72. D. Donnelly and J. B. C. Findlay, Curr. Opin. Struct. Biol 4, 582 (1994).
73. S. Trumpp-Kallmeyer, J. Hoflack, A. Bruinvels, M. Hibert, J Med. Chem. 35, 3448 (1992).
74. M. F. Hibert, S. Trumpp-Kallmeyer, A Bruinvels, J. Hoflack, Mol Pharmacol. 40, 8 (1991).
75. J. Wess, R. Maggio, J R. Palmer, Z. Vogel, J Biol Chem. 267, 19313 (1992); G Nordvall and U. Hacksell, J Med Chem. 36, 967 (1993).
76. J. Wess, R. Maggio, J R. Palmer, Z. Vogel, J Biol Chem. 267, 19313 (1992); G Nordvall and U. Hacksell, J Med Chem. 36, 967 (1993).
77. H. Moereels and J. F. Leysen, Receptors Channels 1, 89 (1993)
78. For reviews, see C Miller, Science 252, 1092 (1991), B A. Wible and A. M Brown, Drug Dev. Res. 33, 225 (1994).
79. For reviews, see C Miller, Science 252, 1092 (1991), B A. Wible and A. M Brown, Drug Dev. Res. 33, 225 (1994).
80. + -selective channels, Gly-Tyr-Gly is replaced by Gly-Phe-Gly.
81. L Heginbotham and R. MacKinnon, Neuron 8, 483 (1992)
82. Some support for this proposal comes from computational models of the channel [S. R. Durell and H. R. Guy, Biophys J. 62, 238 (1992); S. Bogusz, A. Boxer, D D Busath, Protein Eng 5, 285 (1992)].
83. Some support for this proposal comes from computational models of the channel [S. R. Durell and H. R. Guy, Biophys J. 62, 238 (1992); S. Bogusz, A. Boxer, D D Busath, Protein Eng 5, 285 (1992)].
84. + channels.
85. R MacKinnon and G Yellen, Science 250, 276 (1990), G. Yellen, M. E Jurman, T Abramson, R. MacKinnon, ibid 251, 939 (1991); M. P. Kavanaugh et al , Neuron 8, 493 (1992).
86. R MacKinnon and G Yellen, Science 250, 276 (1990), G. Yellen, M. E Jurman, T Abramson, R. MacKinnon, ibid 251, 939 (1991); M. P. Kavanaugh et al , Neuron 8, 493 (1992).
87. R MacKinnon and G Yellen, Science 250, 276 (1990), G. Yellen, M. E Jurman, T Abramson, R. MacKinnon, ibid 251, 939 (1991); M. P. Kavanaugh et al , Neuron 8, 493 (1992).
88. J Satin et al., Science 256, 1202 (1992); P. H. Backx, D. T Yue, J H Lawrence, E Marban, G. F. Tomaselli, ibid. 257, 248 (1992), L.-Q. Chen, M Chahine, R. G Kallen, R. L. Barchi, R Horn. FEBS Lett. 309, 253 (1992).
89. J Satin et al., Science 256, 1202 (1992); P. H. Backx, D. T Yue, J H Lawrence, E Marban, G. F. Tomaselli, ibid. 257, 248 (1992), L.-Q. Chen, M Chahine, R. G Kallen, R. L. Barchi, R Horn. FEBS Lett. 309, 253 (1992).
90. J Satin et al., Science 256, 1202 (1992); P. H. Backx, D. T Yue, J H Lawrence, E Marban, G. F. Tomaselli, ibid. 257, 248 (1992), L.-Q. Chen, M Chahine, R. G Kallen, R. L. Barchi, R Horn. FEBS Lett. 309, 253 (1992).
91. G. L Cantoni, Annu. Rev. Biochem. 49, 435 (1975); G. A. Maw, in The Chemistry of the Sulphonium Group, C J. M. Stirling and S. Patai, Eds. (Wiley, New York, 1981), chap. 17; E. Q. Lederer, Rev. Chem. Soc. 23, 453 (1969), C Walsh, Enzyme Reaction Mechanisms (Freeman, New York, 1979), pp 851-863
92. G. L Cantoni, Annu. Rev. Biochem. 49, 435 (1975); G. A. Maw, in The Chemistry of the Sulphonium Group, C J. M. Stirling and S. Patai, Eds. (Wiley, New York, 1981), chap. 17; E. Q. Lederer, Rev. Chem. Soc. 23, 453 (1969), C Walsh, Enzyme Reaction Mechanisms (Freeman, New York, 1979), pp 851-863
93. G. L Cantoni, Annu. Rev. Biochem. 49, 435 (1975); G. A. Maw, in The Chemistry of the Sulphonium Group, C J. M. Stirling and S. Patai, Eds. (Wiley, New York, 1981), chap. 17; E. Q. Lederer, Rev. Chem. Soc. 23, 453 (1969), C Walsh, Enzyme Reaction Mechanisms (Freeman, New York, 1979), pp 851-863
94. G. L Cantoni, Annu. Rev. Biochem. 49, 435 (1975); G. A. Maw, in The Chemistry of the Sulphonium Group, C J. M. Stirling and S. Patai, Eds. (Wiley, New York, 1981), chap. 17; E. Q. Lederer, Rev. Chem. Soc. 23, 453 (1969), C Walsh, Enzyme Reaction Mechanisms (Freeman, New York, 1979), pp 851-863
95. X Cheng, S. Kumar, J. Postai, J. W. Pflugrath, R. J. Roberts, Cell 74, 299 (1993)
96. Electrostatic maps similar to those of Fig. 2 indicate that, in a trialkylsulfonium system, the site of greatest positive electrostatic potential is at the sulfur, consistent with the alignment of Fig. 5 (A McCurdy and D. A. Dougherty, unpublished results).
97. R M Kagan and S. Clarke, Arch. Biochem. Biophys. 310, 417 (1994).
98. W. S. Johnson, S. D. Lindell, J. Steele, J Am Chem. Soc. 109, 5882 (1987).
99. K. Poralla et al , Trends Biochem. Sci. 19, 157 (1994); Z Shi, C. J. Buntel, J. H. Griffin, Proc. Natl. Acad Sci. U.S.A 91, 7370 (1994); C. J. Buntel and J. H. Griffin, in Isopentenoids and Other Natural Products (Amencan Chemical Society, Washington, DC, 1994), pp. 44-54; D. Ochs, C. Kaletta, K. D. Entian, A. Becksickinger, K. Poralla, J Bacteriol. 174, 298 (1992); C. A. Roessner et al., Gene 127, 149 (1993).
100. K. Poralla et al , Trends Biochem. Sci. 19, 157 (1994); Z Shi, C. J. Buntel, J. H. Griffin, Proc. Natl. Acad Sci. U.S.A 91, 7370 (1994); C. J. Buntel and J. H. Griffin, in Isopentenoids and Other Natural Products (Amencan Chemical Society, Washington, DC, 1994), pp. 44-54; D. Ochs, C. Kaletta, K. D. Entian, A. Becksickinger, K. Poralla, J Bacteriol. 174, 298 (1992); C. A. Roessner et al., Gene 127, 149 (1993).
101. K. Poralla et al , Trends Biochem. Sci. 19, 157 (1994); Z Shi, C. J. Buntel, J. H. Griffin, Proc. Natl. Acad Sci. U.S.A 91, 7370 (1994); C. J. Buntel and J. H. Griffin, in Isopentenoids and Other Natural Products (Amencan Chemical Society, Washington, DC, 1994), pp. 44-54; D. Ochs, C. Kaletta, K. D. Entian, A. Becksickinger, K. Poralla, J Bacteriol. 174, 298 (1992); C. A. Roessner et al., Gene 127, 149 (1993).
102. K. Poralla et al , Trends Biochem. Sci. 19, 157 (1994); Z Shi, C. J. Buntel, J. H. Griffin, Proc. Natl. Acad Sci. U.S.A 91, 7370 (1994); C. J. Buntel and J. H. Griffin, in Isopentenoids and Other Natural Products (Amencan Chemical Society, Washington, DC, 1994), pp. 44-54; D. Ochs, C. Kaletta, K. D. Entian, A. Becksickinger, K. Poralla, J Bacteriol. 174, 298 (1992); C. A. Roessner et al., Gene 127, 149 (1993).
103. K. Poralla et al , Trends Biochem. Sci. 19, 157 (1994); Z Shi, C. J. Buntel, J. H. Griffin, Proc. Natl. Acad Sci. U.S.A 91, 7370 (1994); C. J. Buntel and J. H. Griffin, in Isopentenoids and Other Natural Products (Amencan Chemical Society, Washington, DC, 1994), pp. 44-54; D. Ochs, C. Kaletta, K. D. Entian, A. Becksickinger, K. Poralla, J Bacteriol. 174, 298 (1992); C. A. Roessner et al., Gene 127, 149 (1993).
104. R. Loewenthal, J. Sancho, A. R Fersht, J. Mol. Biol. 224, 759 (1992).
105. G. Waksman, Cell. Mol Biol. 40, 611 (1994).
106. J. L. Jorgensen, U. Esser, B. Fazekas de St. Groth, P. A. Reay, M. M. Davis, Nature 355, 224 (1992).
107. A. R. Ortiz, T. Pisabarro, J. Gallego, F. Gago, Biochemistry 31, 2887 (1992).
108. L Brocchien and S. Karlin, Proc. Natl. Acad. Sci. U.S.A. 91, 9297 (1994); S. Karlin, M. Zuker, L. Brocchien, J. Mol. Biol. 239, 227 (1994).
109. L Brocchien and S. Karlin, Proc. Natl. Acad. Sci. U.S.A. 91, 9297 (1994); S. Karlin, M. Zuker, L. Brocchien, J. Mol. Biol. 239, 227 (1994).
110. S. W. Cowan and J. P. Rosenbusch. Science 264, 914 (1994).
111. Aromatic residues appear with abnormally high frequencies at many types of biological binding sites, even those not necessarily targeted to cations. These include the binding sites of antibodies [I. S. Mian, A. H. Bradwell, A. J. Oleon, J. Mol. Biol. 217, 133 (1991)] and the transmembrane regions of multidrug resistance proteins [A. B. Pawagi, J. Wang, M. Silverman, R. A. F. Reithmeier, C. M. Deber, ibid. 235, 554 (1994)].
112. Aromatic residues appear with abnormally high frequencies at many types of biological binding sites, even those not necessarily targeted to cations. These include the binding sites of antibodies [I. S. Mian, A. H. Bradwell, A. J. Oleon, J. Mol. Biol. 217, 133 (1991)] and the transmembrane regions of multidrug resistance proteins [A. B. Pawagi, J. Wang, M. Silverman, R. A. F. Reithmeier, C. M. Deber, ibid. 235, 554 (1994)].
113. Contribution No. 9016 from the Arnold and Mabel Beckman Laboratories of Chemical Synthesis. Supported by NIH (GM43936), the Office of Naval Research (N00014-91-J-1344), and Zeneca Pharmaceuticals. D.A.D. thanks many outstanding students and postdoctoral colleagues for their contributions to this work.