Pharmaceutical Research

, Volume 6, Issue 11, pp 903–918 | Cite as

Stability of Protein Pharmaceuticals

  • Mark C. Manning
  • Kamlesh Patel
  • Ronald T. Borchardt


Recombinant DNA technology has now made it possible to produce proteins for pharmaceutical applications. Consequently, proteins produced via biotechnology now comprise a significant portion of the drugs currently under development. Isolation, purification, formulation, and delivery of proteins represent significant challenges to pharmaceutical scientists, as proteins possess unique chemical and physical properties. These properties pose difficult stability problems. A summary of both chemical and physical decomposition pathways for proteins is given. Chemical instability can include proteolysis, deamidation, oxidation, racemization, and β-elimination. Physical instability refers to processes such as aggregation, precipitation, denaturation, and adsorption to surfaces. Current methodology to stabilize proteins is presented, including additives, excipients, chemical modification, and the use of site-directed mutagenesis to produce a more stable protein species.

protein stability biotechnology mutagenesis denaturation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    D. Blohm, C. Bollschweiler, and H. Hillen. Angew. Chem. Int. Ed. Engl. 27:207–225 (1988).Google Scholar
  2. 2.
    L. P. Gage. Am. J. Pharm. Ed. 50:368–370 (1986).Google Scholar
  3. 3.
    H. H. Tallan and W. H. Stein. J. Biol. Chem. 200:507–514 (1953).Google Scholar
  4. 4.
    U. J. Lewis and E. V. Cheever. J. Biol. Chem. 240:247–252 (1965).Google Scholar
  5. 5.
    U. J. Lewis, E. V. Cheever, and W. C. Hopkins. Biochim. Biophys. Acta 214:498–508 (1970).Google Scholar
  6. 6.
    G. W. Becker, P. M. Tackitt, W. W. Bromer, D. S. Lefeber, and R. M. Riggin. Biotech. Appl. Biochem. 10:326–337 (1988).Google Scholar
  7. 7.
    S. A. Berson and R. S. Yalow. Diabetes 15:875–879 (1966).Google Scholar
  8. 8.
    B. V. Fisher and P. B. Porter. J. Pharm. Pharmacol. 33:203–206 (1981).Google Scholar
  9. 9.
    F. S. M. Van Kleef, W. W. de Jong, and H. J. Hoenders. Nature 258:264–266 (1975).Google Scholar
  10. 10.
    T. Flatmark and K. Sletten. J. Biol. Chem. 243:1623–1629 (1968).Google Scholar
  11. 11.
    J. O. Minta and R. H. Painter. Immunochemistry 9:821–832 (1972).Google Scholar
  12. 12.
    R. P. Diaugustine, B. W. Gibson, W. Aberth, M. Kelly, C. M. Ferrua, Y. Tomooka, C. F. Brown, and M. Walker. Anal. Biochem. 165:420–429 (1987).Google Scholar
  13. 13.
    M. F. Perutz and J. H. Fogg. J. Mol. Biol. 138:669–670 (1980).Google Scholar
  14. 14.
    K. U. Yuksel and R. W. Gracy. Arch. Biochem. Biophys. 248:452–459 (1986).Google Scholar
  15. 15.
    P. M. Yuan, J. M. Talent, and R. W. Gray. Mech. Age. Dev. 17:151–162 (1981).Google Scholar
  16. 16.
    H. Maeda and K. Kuromizu. J. Biochem. (Tokyo) 81:25–35 (1977).Google Scholar
  17. 17.
    L. Graf, G. Cseh, I. Nagy, and M. Kurcz. Acta Biochim. Biophys. Acad. Sci. Hung. 5:299–303 (1970).Google Scholar
  18. 18.
    T. J. McDonald, H. Jornvall, K. Tatemoto, and V. Mutt. FEBS Lett. 156:349–356 (1983).Google Scholar
  19. 19.
    L. Graf, S. Bajusz, A. Patthy, E. Barat, and G. Cseh. Acta Biochim. Biophys. Acad. Sci. Hung. 6:415–418 (1971).Google Scholar
  20. 20.
    N. P. Bhatt, K. Patel, and R. T. Borchardt. Pharm. Res. 5:S72 (1988).Google Scholar
  21. 21.
    A. B. Robinson and C. J. Rudd. In B. L. Horecker and E. R. Stadtman (eds.), Current Topics in Cellular Regulations, Vol. 8, Academic Press, New York, 1974, pp. 247–295.Google Scholar
  22. 22.
    E. Sondheimer and R. W. Holley. J. Am. Chem. Soc. 76:2467–2470 (1954).Google Scholar
  23. 23.
    E. E. Haley, B. J. Coreoran, F. E. Dorer, and D. L. Buchanan. Biochemistry 5:3229–3235 (1966).Google Scholar
  24. 24.
    A. R. Battersby and J. C. Robinson. J. Chem. Soc. 259–269 (1955).Google Scholar
  25. 25.
    P. Bornstein and G. Balian. Methods. Enzymol. 47:132–145 (1977).Google Scholar
  26. 26.
    T. Geiger and S. Clarke. J. Biol. Chem. 262:785–794 (1987).Google Scholar
  27. 27.
    Y. C. Meinwald, E. R. Stimson, and H. A. Scheraga. Int. J. Peptide Protein Res. 28:79–84 (1986).Google Scholar
  28. 28.
    D. W. Aswad. J. Biol. Chem. 259:10714–10721 (1984).Google Scholar
  29. 29.
    B. A. Johnson and D. W. Aswad. Biochemistry 24:2581–2586 (1985).Google Scholar
  30. 30.
    P. Bornstein. Biochemistry 9:2408–2421 (1970).Google Scholar
  31. 31.
    A. Di Donato, P. Galletti, and G. D'Alessio. Biochemistry 25:8361–8368 (1986).Google Scholar
  32. 32.
    P. Galletti, A. Ciardiello, D. Ingrosso, A. Di Donato, and G. D'Alessio. Biochemistry 27:1752–1757 (1988).Google Scholar
  33. 33.
    S. Lou, C. Liao, J. F. McClelland, and D. J. Graves. Int. J. Peptide Protein Res. 29:728–733 (1987).Google Scholar
  34. 34.
    K. Patel and R. T. Borchardt. Pharm. Res. 5:S72 (1988).Google Scholar
  35. 35.
    K. Patel, C. Oliyai, R. T. Borchardt, and M. C. Manning. J. Cell. Biochem. 13A:88 (1989).Google Scholar
  36. 36.
    S. A. Bernhard, A. Berger, H. J. Carter, E. Katchalski, M. Sela, and Y. Shalitin. J. Am. Chem. Soc. 84:2421–2434 (1962).Google Scholar
  37. 37.
    Y. Shalitin and S. A. Bernhard. J. Am. Chem. Soc. 88:4711–4721 (1966).Google Scholar
  38. 38.
    M. A. Ondetti, A. Deer, J. T. Sheeham, J. Pluscec, and O. Kocy. Biochemistry 7:4069–4075 (1968).Google Scholar
  39. 39.
    M. Bodanszky and J. Z. Kwei. Int. J. Peptide Protein Res. 12:69–74 (1978).Google Scholar
  40. 40.
    S. A. Bernhard. Ann. N.Y. Acad. Sci. 421:28–40 (1983).Google Scholar
  41. 41.
    J. K. Blodgett, G. M. Loudon, and K. D. Collins. J. Am. Chem. Soc. 107:4305–4313 (1985).Google Scholar
  42. 42.
    S. Capasso, C. A. Mattia, L. Mazzarella, and A. Zagari. Int. J. Peptide Protein Res. 23:248–255 (1984).Google Scholar
  43. 43.
    A. J. Alder, G. D. Fasman, and E. R. Blout. J. Am. Chem. Soc. 85:90–97 (1963).Google Scholar
  44. 44.
    G. Perseo, R. Furino, M. Galantino, B. Gioia, V. Malatesta, and R. D. Castiglione. Int. J. Peptide Protein Res. 27:51–60 (1986).Google Scholar
  45. 45.
    M. Bodanszky and S. Natarajan. J. Org. Chem. 40:2495–2499 (1975).Google Scholar
  46. 46.
    A. B. Robinson, J. W. Scotchler, and J. H. McKerow. J. Am. Chem. Soc. 95:8156–8159 (1973).Google Scholar
  47. 47.
    J. W. Scotchler and A. B. Robinson. Anal. Biochem. 59:319–322 (1974).Google Scholar
  48. 48.
    A. B. Robinson, J. H. McKerrow, and P. Cary. Proc. Natl. Acad. Sci. USA 66:753–757 (1970).Google Scholar
  49. 49.
    A. B. Robinson, J. H. McKerrow, and M. Legaz. Int. J. Peptide Protein Res. 6:31–35 (1974).Google Scholar
  50. 50.
    T. Flatmark. Acta Chem. Scand. 20:1487–1496 (1966).Google Scholar
  51. 51.
    S. Clarke. Int. J. Peptide Protein Res. 30:808–821 (1987).Google Scholar
  52. 52.
    P. Bornstein and G. Balian. J. Biol. Chem. 245:4854–4856 (1970).Google Scholar
  53. 53.
    A. A. Kossiakoff. Science 240:191–194 (1988).Google Scholar
  54. 54.
    R. Lura and V. Schirch. Biochemistry 27:7671–7677 (1988).Google Scholar
  55. 55.
    M. Bodanszky, J. C. Tolle, S. S. Deshmane, and A. Bodanszky. Int. J. Peptide Protein Res. 12:57–68 (1978).Google Scholar
  56. 56.
    B. N. Manjula, A. S. Achary, and P. J. Vithayathil. Int. J. Peptide Protein Res. 8:275–282 (1976).Google Scholar
  57. 57.
    S. Charache, J. Fox, P. McCurdy, H. Kazazian, Jr., and R. Winslow. J. Clin. Invest. 59:652–658 (1977).Google Scholar
  58. 58.
    U. J. Lewis, R. N. P. Singh, L. F. Bonewald, and B. K. Seavey. J. Biol. Chem. 256:11645–11650 (1981).Google Scholar
  59. 59.
    T. J. Ahern and A. M. Klibanov. Science 228:1280–1284 (1985).Google Scholar
  60. 60.
    S. E. Zale and A. M. Klibanov. Biochemistry 25:5432–5444 (1986).Google Scholar
  61. 61.
    C. F. Midelfort and A. H. Mehler. Proc. Natl. Acad. Sci. USA 69:1816–1819 (1972).Google Scholar
  62. 62.
    L. Graf, G. Hajos, A. Patthy, and G. Cseh. Horm. Metab. Res. 5:142–143 (1973).Google Scholar
  63. 63.
    Y. P. Venkatesh and P. J. Vithayathil. Int. J. Peptide Protein Res. 25:27–32 (1985).Google Scholar
  64. 64.
    Y. P. Venkatesh and P. J. Vithayathil. Int. J. Peptide Protein Res. 23:494–505 (1984).Google Scholar
  65. 65.
    G. R. Marshall and R. B. Merrifield. Biochemistry 4:2394–2401 (1965).Google Scholar
  66. 66.
    C. C. Yang and R. B. Merrifield. J. Org. Chem. 41:1032–1041 (1976).Google Scholar
  67. 67.
    E. D. Murray, Jr., and S. Clarke. J. Biol. Chem. 259:10722–10732 (1984).Google Scholar
  68. 68.
    K. Bedii Oray, U. Yuksel, and R. W. Gracy. J. Chromatogr. 265:126–130 (1983).Google Scholar
  69. 69.
    T. Baba, H. Sugiyama, and S. Seto. Chem. Pharm. Bull. 21:207–209 (1973).Google Scholar
  70. 70.
    P. A. Khairallah, F. M. Bumpus, J. H. Page, and R. R. Smeby. Science 140:672–674 (1963).Google Scholar
  71. 71.
    C. Secchi, P. A. Biondi, A. Negri, R. Borroni, and S. Ronchi. Int. J. Peptide Protein Res. 28:298–306 (1986).Google Scholar
  72. 72.
    S. Clarke. In R. T. Borchardt, C. R. Creveling, and P. M. Ueland (eds.), Biological Methylation and Drug Design, Humana Press, Clifton, N.J., 1985, pp. 3–14.Google Scholar
  73. 73.
    B. A. Johnson, J. M. Shirokawa, and D. W. Aswad. Arch. Biochem. Biophys. 268:276–286 (1989).Google Scholar
  74. 74.
    H. B. F. Dixon, S. Moore, M. P. Stack-Dunne, and F. G. Young. Nature 168:1044–1045 (1951).Google Scholar
  75. 75.
    F. A. Kuehl, Jr., M. A. P. Meisinger, N. G. Brink, and K. Folkers. J. Am. Chem. Soc. 75:1955–1959 (1953).Google Scholar
  76. 76.
    H. Rasmussen and L. C. Craig. Recent Prog. Horm. Res. 18:269–295 (1962).Google Scholar
  77. 77.
    W. Vale, J. Spiess, C. Rivier, and J. Rivier. Science 213:1394–1397 (1981).Google Scholar
  78. 78.
    K. Norris, J. Halstrom, and K. Brunfeldt. Acta Chem. Scand. 25:945–954 (1971).Google Scholar
  79. 79.
    M. Coltrera, M. Rosenblatt, and J. T. Potts, Jr. Biochemistry 19:4380–4385 (1980).Google Scholar
  80. 80.
    G. E. Means and R. E. Feeney. In Chemical Modifications of Proteins, Holden-Day, New York, 1971, pp. 162–165.Google Scholar
  81. 81.
    N. Brot and H. Weissbach. Trends Biochem. Sci. 7:137–139 (1982).Google Scholar
  82. 82.
    Y. Shechter, Y. Burstein, and A. Patchornik. Biochemistry 14:4497–4503 (1975).Google Scholar
  83. 83.
    Y. Shechter. J. Biol. Chem. 261:66–70 (1986).Google Scholar
  84. 84.
    M. L. Dedman, T. H. Farmer, and C. J. O. R. Morris. Biochem. J. 78:348–352 (1961).Google Scholar
  85. 85.
    H. B. F. Dixon. Biochim. Biophys. Acta 19:392–394 (1956).Google Scholar
  86. 86.
    A. H. Tashjian, D. A. Ontjes, and P. L. Munson. Biochemistry 3:1175–1182 (1964).Google Scholar
  87. 87.
    J. S. Morley, H. J. Tracey, and R. A. Gregory. Nature 207:1356–1359 (1965).Google Scholar
  88. 88.
    V. B. Riniker, R. Neher, R. Maier, F. W. Kahnt, P. G. H. Byfield, T. V. Gudmundsson, L. Galante, and I. MacIntyre. Helv. Chem. Acta 51:1738–1742 (1968).Google Scholar
  89. 89.
    P. Caldwell, D. C. Luk, H. Weissbach, and N. Brot. Proc. Natl. Acad. Sci. USA 75:5349–5352 (1978).Google Scholar
  90. 90.
    H. Carp and A. Janoff. Am. Rev. Resp. Dis. 118:617–621 (1978).Google Scholar
  91. 91.
    W. R. Abrams, A. Eliraz, P. Kimbel, and G. Weinbaum. Exp. Lung Res. 1:211–223 (1980).Google Scholar
  92. 92.
    C. E. Stauffer and D. Etson. J. Biol. Chem. 244:5333–5338 (1969).Google Scholar
  93. 93.
    W. J. Ray, Jr., and D. E. Koshland, Jr. J. Biol. Chem. 237:2493–2505 (1962).Google Scholar
  94. 94.
    H. Schachter and G. H. Dixon. J. Biol. Chem. 239:813–829 (1964).Google Scholar
  95. 95.
    V. Holeysovsky and M. Lazdunski. Biochim. Biophys. Acta 154:457–467 (1968).Google Scholar
  96. 96.
    U. W. Kenkare and F. M. Richards. J. Biol. Chem. 241:3197–3206 (1966).Google Scholar
  97. 97.
    G. Jori, G. Galiazzo, A. Marzotto, and E. Scoffone. Biochim. Biophys. Acta 154:1–9 (1968).Google Scholar
  98. 98.
    G. Jori, G. Galiazzo, A. Marzotto, and E. Scoffone. J. Biol. Chem. 243:4272–4278 (1968).Google Scholar
  99. 99.
    N. P. Neumann, S. Moore, and W. H. Stein. Biochemistry 1:68–75 (1962).Google Scholar
  100. 100.
    H. Schachter, K. A. Halliday, and G. H. Dixon. J. Biol. Chem. 238:PC3134–PC3136 (1963).Google Scholar
  101. 101.
    B. Kassell. Biochemistry 3:152–155 (1964).Google Scholar
  102. 102.
    W. F. Heath and R. B. Merrifield. Proc. Natl. Acad. Sci. USA 83:6367–6371 (1986).Google Scholar
  103. 103.
    C. George-Nascimento, A. Gyenes, S. M. Halloran, J. Merryweather, P. Valenzuela, K. S. Steimer, F. R. Masiarz, and A. Randolph. Biochemistry 27:797–802 (1988).Google Scholar
  104. 104.
    S. A. Coolican, B. N. Jones, R. D. England, K. C. Flanders, J. D. Condit, and R. S. Gurd. Biochemistry 21:4974–4981 (1982).Google Scholar
  105. 105.
    L. C. Teh, L. J. Murphy, N. L. Huq, A. S. Surus, H. G. Friesen, L. Lazarus, and G. E. Chapman. J. Biol. Chem. 262:6472–6477 (1987).Google Scholar
  106. 106.
    H. G. Gundlach, S. Moore, and W. H. Stein. J. Biol. Chem. 234:1761–1764 (1959).Google Scholar
  107. 107.
    E. Gross and B. Witkop. J. Am. Chem. Soc. 83:1510–1511 (1961).Google Scholar
  108. 108.
    H. B. F. Dixon and M. P. Stack-Dunne. Biochem. J. 61:483–495 (1955).Google Scholar
  109. 109.
    T. B. Lo, J. S. Dixon, and C. H. Li. Biochim. Biophys. Acta 53:584–586 (1961).Google Scholar
  110. 110.
    H. P. J. Bennett, A. M. Hudson, C. McMartin, and G. E. Purdon. Biochem. J. 168:9–13 (1977).Google Scholar
  111. 111.
    D. C. Shaw and C. E. West. J. Chromatogr. 200:185–188 (1980).Google Scholar
  112. 112.
    P. I. Storring and R. J. Tiplady. Anal. Biochem. 141:43–54 (1984).Google Scholar
  113. 113.
    P. C. Jocelyn. Biochemistry of the SH Groups: The Occurrence, Chemical Properties, Metabolism, and Biological Function of Thiols and Disulfides, Academic Press, New York, 1972.Google Scholar
  114. 114.
    C. Little and P. J. O'Brien. Arch. Biochem. Biophys. 122:406–410 (1967).Google Scholar
  115. 115.
    H. Lamfrom and S. O. Nielson. J. Am. Chem. Soc. 79:1966–1970 (1957).Google Scholar
  116. 116.
    D. Cavallini, C. DeMarco, and S. Dupre. Arch. Biochem. Biophys. 124:18–26 (1968).Google Scholar
  117. 117.
    E. S. G. Barron, Z. B. Miller, and G. Kalnitsky. Biochem. J. 41:62–68 (1947).Google Scholar
  118. 118.
    C. G. Overberger and J. J. Ferraro. J. Org. Chem. 27:3539–3545 (1962).Google Scholar
  119. 119.
    L. Philipson. Biochim. Biophys. Acta 56:375–377 (1962).Google Scholar
  120. 120.
    S. J. Tomazic and A. M. Klibanov. J. Biol. Chem. 263:3086–3091 (1988).Google Scholar
  121. 121.
    Y. M. Torchinskii. In Sulfhydryl and Disulfide Groups of Proteins, Consultants Bureau, New York, 1974, pp. 99–124.Google Scholar
  122. 122.
    L. A. Æ. Sluyterman. Biochim. Biophys. Acta 60:557–561 (1962).Google Scholar
  123. 123.
    B. R. DasGupta and D. A. Boroff. Biochim. Biophys. Acta 97:157–159 (1965).Google Scholar
  124. 124.
    L. Weil. Arch. Biochem. Biophys. 110:57–68 (1965).Google Scholar
  125. 125.
    J. D. Spikes and R. Straight. Annu. Rev. Phys. Chem. 18:49–436 (1967).Google Scholar
  126. 126.
    C. S. Foote. Science 162:963 (1968).Google Scholar
  127. 127.
    W. J. Ray. Methods Enzymol. 11:490–497 (1967).Google Scholar
  128. 128.
    P. Hoffee, C. Y. Lai, E. L. Pugh, and B. L. Horecker. Proc. Natl. Acad. Sci. USA 57:107–113 (1967).Google Scholar
  129. 129.
    M. Martinez-Carrion, R. Kuczenski, D. C. Tiemeier, and D. L. Peterson. J. Biol. Chem. 245:799–805 (1970).Google Scholar
  130. 130.
    M. Martinez-Carrion, C. Turano, F. Riva, and P. Fasella. J. Biol. Chem. 242:1426–1430 (1967).Google Scholar
  131. 131.
    M. Nakatani. J. Biochem. (Tokyo) 48:633–639 (1960).Google Scholar
  132. 132.
    R. D. Hill and R. R. Laing. Biochim. Biophys. Acta 99:352–359 (1965).Google Scholar
  133. 133.
    J. Schulz. Methods Enzymol. 11:255–263 (1967).Google Scholar
  134. 134.
    A. Light. Methods Enzymol. 11:417–420 (1967).Google Scholar
  135. 135.
    A. S. Inglis. Methods Enzymol. 91:324–332 (1983).Google Scholar
  136. 136.
    D. Piszkiewicz, M. Landon, and E. L. Smith. Biochem. Biophys. Res. Commun. 40:1173–1178 (1970).Google Scholar
  137. 137.
    K. Poulsen, K. J. Kevin, and E. Haber. Proc. Natl. Acad. Sci. USA 69:2495–2499 (1972).Google Scholar
  138. 138.
    F. Marcus. Int. J. Peptide Protein Res. 25:542–546 (1985).Google Scholar
  139. 139.
    D. L. Swallow and E. P. Abraham. Biochem. J. 70:364–373 (1958).Google Scholar
  140. 140.
    M. A. Naughton, F. Sanger, B. S. Hartley, and D. C. Shaw. Biochem. J. 77:149–163 (1960).Google Scholar
  141. 141.
    M. Bodanszky, G. F. Sigler, and A. Bodanszky. J. Am. Chem. Soc. 95:2352–2357 (1973).Google Scholar
  142. 142.
    M. Bodanszky, M. A. Ondetti, S. D. Levine, and N. J. Williams. J. Am. Chem. Soc. 89:6753–6757 (1967).Google Scholar
  143. 143.
    K. K. Han, C. Richard, and G. Biserte. Int. J. Biochem. 15:875–884 (1983).Google Scholar
  144. 144.
    P. Desnuelle and A. Casal. Biochim. Biophys. Acta 2:64–75 (1948).Google Scholar
  145. 145.
    U. K. Laemmli. Nature 227:680–685 (1970).PubMedGoogle Scholar
  146. 146.
    J. B. Fleischman. Immunochemistry 10:401–407 (1973).Google Scholar
  147. 147.
    V. Braun and W. A. Schroeder. Arch. Biochem. Biophys. 118:241–252 (1967).Google Scholar
  148. 148.
    W. R. Gray. Methods Enzymol. 25:121–138 (1972).Google Scholar
  149. 149.
    J. L. Meuth. Biochemistry 21:3750–3757 (1982).Google Scholar
  150. 150.
    P. Edman and G. Begg. Eur. J. Biochem. 1:80–91 (1967).Google Scholar
  151. 151.
    K. A. Walsh, L. H. Ericsson, D. C. Parmelee, and K. Titani. Annu. Rev. Biochem. 50:261–284 (1981).Google Scholar
  152. 152.
    D. Kahne and W. C. Still. J. Am. Chem. Soc. 110:7529–7534 (1988).Google Scholar
  153. 153.
    R. Cecil and J. R. McPhee. Adv. Protein Chem. 14:255–389 (1959).Google Scholar
  154. 154.
    V. L. Lumper and H. Zahn. Adv. Enzymol. Relat. Areas Mol. Biol. 27:199–238 (1965).Google Scholar
  155. 155.
    D. B. Volkin and A. M. Klibanov. J. Biol. Chem. 262:2945–2950 (1987).Google Scholar
  156. 156.
    R. E. Benesch and R. Benesch. J. Am. Chem. Soc. 80:1666–1669 (1958).Google Scholar
  157. 157.
    A. P. Ryle and F. Sanger. Biochem. J. 60:535–540 (1955).Google Scholar
  158. 158.
    Y. M. Torchinsky. In Sulfur in Proteins, Pergamon Press, New York, 1981, pp. 82–86.Google Scholar
  159. 159.
    E. Haber and C. B. Anfinsen. J. Biol. Chem. 237:1839–1844 (1962).Google Scholar
  160. 160.
    A. Galat, T. E. Creighton, R. C. Lord, and E. R. Blout. Biochemistry 20:594–601 (1981).Google Scholar
  161. 161.
    A. Neuberger. Adv. Protein Chem. 4:297–383 (1948).Google Scholar
  162. 162.
    G. G. Smith and B. S. Desol. Science 207:765–767 (1980).Google Scholar
  163. 163.
    M. Friedman and P. M. Masters. J. Food Sci. 47:760 (1982).Google Scholar
  164. 164.
    P. J. M. van den Oestelaar and H. J. Hoenders. Adv. Exp. Med. Biol. 231:261–267 (1988).Google Scholar
  165. 165.
    T. M. Florence. Biochem. J. 189:507–520 (1980).Google Scholar
  166. 166.
    J. R. Whitaker and R. E. Feeney. CRC Crit. Rev. Food Sci. Nutr. 19:173–212 (1983).Google Scholar
  167. 167.
    L. C. Sen, E. Gonzalez-Flores, R. E. Feeney, and J. R. Whitaker. J. Agr. Food Chem. 25:632–638 (1977).Google Scholar
  168. 168.
    H. S. Lee, D. T. Osuga, A. S. Nashef, A. I. Ahmed, J. R. Whitaker, and R. E. Feeney. J. Agr. Food Chem. 25:1153–1158 (1977).Google Scholar
  169. 169.
    A. S. Nashef, D. T. Osuga, H. S. Lee, A. I. Ahmed, J. R. Whitaker, and R. E. Feeney. J. Agr. Food Chem. 25:245–251 (1977).Google Scholar
  170. 170.
    T. E. Creighton. Proteins, W. H. Freeman, New York, 1983.Google Scholar
  171. 171.
    C. Ghelis and J. Yon. Protein Folding, Academic Press, New York, 1982.Google Scholar
  172. 172.
    W. Kauzmann. Adv. Protein Chem. 14:1–63 (1959).Google Scholar
  173. 173.
    P. L. Privalov. Adv. Protein Chem. 33:167 (1979).Google Scholar
  174. 174.
    K. Dill. Biochemistry 24:1501–1509 (1985).Google Scholar
  175. 175.
    Y. R. Hsu and T. Arakawa. Biochemistry 24:7959–7963 (1985).Google Scholar
  176. 176.
    T. Arakawa and W. C. Kenney. Int. J. Peptide Protein Res. 31:468–473 (1988).Google Scholar
  177. 177.
    T. Arakawa, T. Boone, J. M. Davis, and W. C. Kenney. Biochemistry 25:8274–8277 (1986).Google Scholar
  178. 178.
    T. Arakawa, Y.-R. Hsu, and D. A. Yphantis. Biochemistry 26:5428–5432 (1987).Google Scholar
  179. 179.
    W. W. Fish, A. Danielsson, K. Nordling, S. H. Miller, C. F. Lam, and I. Björk. Biochemistry 24:1510–1517 (1985).Google Scholar
  180. 180.
    D. N. Brems, S. M. Plaisted, E. W. Kauffman, and H. A. Havel. Biochemistry 25:6539–6543 (1986).Google Scholar
  181. 181.
    T. F. Holzman, D. N. Brems, and J. J. Dougherty, Jr. Biochemistry 25:6907–6917 (1986).Google Scholar
  182. 182.
    D. N. Brems, S. M. Plaisted, H. A. Havel, and C.-S. C. Tomich. Proc. Natl. Acad. Sci. USA 85:3367–3371 (1988).Google Scholar
  183. 183.
    D. N. Brems. Biochemistry 27:4541–4546 (1988).Google Scholar
  184. 184.
    Y. Goto and A. L. Fink. Biochemistry 28:945–952 (1989).Google Scholar
  185. 185.
    J. Baum, C. M. Dobson, P. A. Evans, and C. Hanley. Biochemistry 28:7–13 (1989).Google Scholar
  186. 186.
    D. N. Brems, S. M. Plaisted, J. J. Dougerty, Jr., and T. F. Holzman. J. Biol. Chem. 262:2590–2594 (1987).Google Scholar
  187. 187.
    D. N. Brems, S. M. Plaisted, H. A. Havel, E. W. Kauffman, J. D. Stodola, L. C. Eaton, and R. C. White. Biochemistry 24:7662–7668 (1985).Google Scholar
  188. 188.
    H. A. Havel, E. W. Kauffman, S. M. Plaisted, and D. N. Brems. Biochemistry 25:6533–6538 (1986).Google Scholar
  189. 189.
    W. Pfeil. Mol. Cell. Biochem. 40:2–38 (1981).Google Scholar
  190. 190.
    M. P. Tombs. J. Appl. Biochem. 7:3–24 (1985).Google Scholar
  191. 191.
    W. J. Becktel and J. A. Schellman. Biopolymers 26:1859–1877 (1987).Google Scholar
  192. 192.
    C. Tanford. Adv. Protein Chem. 23:121–282 (1968).Google Scholar
  193. 193.
    J. A. Schellman. Annu. Rev. Biophys. Biophys. Chem. 16:115–137 (1987).Google Scholar
  194. 194.
    C. N. Pace. CRC Crit. Rev. Biochem. 3:1–43 (1975).Google Scholar
  195. 195.
    H. Neurath, J. P. Greenstein, F. W. Putnam, and J. O. Erickson. Chem. Rev. 34:157–265 (1944).Google Scholar
  196. 196.
    J. M. Thornton. J. Mol. Biol. 151:261–287 (1981).Google Scholar
  197. 197.
    T. J. Ahern and A. M. Klibanov. Meth. Biochem. Anal. 33:91–127 (1985).Google Scholar
  198. 198.
    C. B. Anfinsen and H. A. Scheraga. Adv. Protein Chem. 29:205–300 (1975).Google Scholar
  199. 199.
    T. E. Creighton. Prog. Biophys. Mol. Biol. 33:231–297 (1978).Google Scholar
  200. 200.
    P. L. Privalov. Adv. Protein Chem. 35:1 (1982).Google Scholar
  201. 201.
    J. F. Brandts. In S. N. Timasheff and G. D. Fasman (eds.), Biological Macromolecules Series, Vol. 2, Structure and Stability of Biological Macromolecules, Marcel Dekker, New York, 1967, p. 213.Google Scholar
  202. 202.
    R. Wetzel, L. J. Perry, W. A. Baase, and W. J. Becktel. Proc. Natl. Acad. Sci. USA 85:401–405 (1988).Google Scholar
  203. 203.
    W. J. Becktel and W. A. Baase. Biopolymers 26:619–623 (1987).Google Scholar
  204. 204.
    J. Novotny, A. A. Rashin, and R. E. Bruccoleri. Proteins: Structure, Function, Genetics 4:19–30 (1988).Google Scholar
  205. 205.
    M. H. Zehfus and G. D. Rose. Biochemistry 25:5759–5765 (1986).Google Scholar
  206. 206.
    S. H. Bryant and L. M. Anzel. Int. J. Peptide Protein Res. 29:46–52 (1986).Google Scholar
  207. 207.
    A. M. Klibanov. Adv. Appl. Microbiol. 29:1–28 (1983).Google Scholar
  208. 208.
    R. Lumry and H. Eyring. J. Phys. Chem. 58:110–120 (1954).Google Scholar
  209. 209.
    T. Arakawa, N. K. Alton, and Y.-R. Hsu. J. Biol. Chem. 260:14435–14439 (1985).Google Scholar
  210. 210.
    D. A. Yphantis and T. Arakawa. Biochemistry 26:5422–5427 (1987).Google Scholar
  211. 211.
    T. Hoshino, Y. Mikura, H. Shimidzu, J. Kawai, and H. Toguchi. Biochim. Biophys. Acta 916:245–250 (1987).Google Scholar
  212. 212.
    T. A. Horbett. ACS Adv. Chem. Ser. 199:233–244 (1982).Google Scholar
  213. 213.
    T. A. Horbett. ACS Symp. Ser. 343:239–260 (1987).Google Scholar
  214. 214.
    J. R. Brennan, S. S. P. Gebhart, and W. G. Blackard. Diabetes 34:353–359 (1985).Google Scholar
  215. 215.
    D. E. James, A. B. Jenkins, E. W. Kraegen, and D. J. Chisholm. Diabetologia 21:554–557 (1981).Google Scholar
  216. 216.
    W. D. Lougheed, H. Woulfe-Flanagan, J. R. Clement, and A. M. Albisser. Diabetologia 19:1–9 (1980).Google Scholar
  217. 217.
    L. Peterson, J. Caldwell, and J. Hoffman. Diabetes 25:72–74 (1976).Google Scholar
  218. 218.
    M. V. Sefton. ACS Adv. Chem. Ser. 199:511–522 (1982).Google Scholar
  219. 219.
    A. S. Chawla, I. Hinberg, P. Blais, and D. Johnson. Diabetes 34:420–424 (1985).Google Scholar
  220. 220.
    G. K. Iwamoto, R. A. Van Wagenen, and J. D. Andrade. J. Colloid Interface Sci. 86:581–585 (1982).Google Scholar
  221. 221.
    E. H. Massey and T. A. Sheliga. Pharm. Res. 5:S34 (1988).Google Scholar
  222. 222.
    W. D. Lougheed, A. M. Albisser, H. M. Martindale, J. C. Chow, and J. R. Clement. Diabetes 32:424–432 (1983).Google Scholar
  223. 223.
    S. Sato, C. D. Ebert, and S. W. Kim. J. Pharm. Sci. 72:228–232 (1983).Google Scholar
  224. 224.
    Z. J. Twardowski, K. D. Nolph, T. J. McGary, and H. L. Moore. Am. J. Hosp. Pharm. 40:583–586 (1983).Google Scholar
  225. 225.
    Z. J. Twardowski, K. D. Nolph, T. J. McGary, H. L. Moore, P. Collin, R. K. Ausman, and W. S. Slimack. Am. J. Hosp. Pharm. 40:575–579 (1983).Google Scholar
  226. 226.
    Z. J. Twardowski, K. D. Nolph, T. J. McGary, and H. L. Moore. Am. J. Hosp. Pharm. 40:579–581 (1983).Google Scholar
  227. 227.
    M. L. Anson. In C. L. A. Schmidt (ed.), The Chemistry of the Amino Acids and Proteins, Charles Thomas, Springfield, Ill., 1938, pp. 407–428.Google Scholar
  228. 228.
    A. E. Mirsky and L. Pauling. Proc. Natl. Acad. Sci. USA 22:439–447 (1936).Google Scholar
  229. 229.
    J. K. Krueger, M. H. Kulke, C. Schutt, and J. Stock. BioPharm. Mar.:41–45 (1989).Google Scholar
  230. 230.
    F. A. O. Marston. Biochem. J. 240:1–12 (1986).Google Scholar
  231. 231.
    J. M. Schoemaker, A. H. Brasnett, and F. A. O. Marston. EMBO J. 4:775–780 (1985).Google Scholar
  232. 232.
    D. L. Hartley and J. F. Kane. Biochem. Soc. Trans. 16:101–102 (1988).Google Scholar
  233. 233.
    D. C. Williams, R. M. Van Frank, W. L. Muth, and J. P. Burnett. Science 215:687 (1982).Google Scholar
  234. 234.
    J. King. Bio/technology 4:297–303 (1986).Google Scholar
  235. 235.
    M. Gribskov and R. R. Burgess. Gene 26:109–118 (1983).Google Scholar
  236. 236.
    F. A. O. Marston, P. A. Lowe, M. T. Doel, J. M. Schoemaker, S. White, and S. Angal. Bio/technology 2:800–804 (1984).Google Scholar
  237. 237.
    S. Cabilly, A. D. Riggs, H. Pande, J. E. Shirely, W. E. Holmes, M. Rey, L. J. Perry, R. Wetzel, and H. L. Heynecker. Proc. Natl. Acad. Sci. USA 81:3273–3277 (1984).Google Scholar
  238. 238.
    M. E. Winkler, M. Blabel, G. L. Bennett, W. Holmes, and G. A. Vehar. Bio/technology 3:990–1000 (1985).Google Scholar
  239. 239.
    H. J. George, J. J. L'Italien, W. P. Pilancinski, D. L. Glassman, and R. A. Krzyzek. DNA 4:273–281 (1985).Google Scholar
  240. 240.
    R. C. Fahey, J. S. Hunt, and G. C. Winham. J. Mol. Evol. 10:155–160 (1977).Google Scholar
  241. 241.
    T. Arakawa and S. N. Timasheff. Biochemistry 23:5912–5923 (1984).Google Scholar
  242. 242.
    T. Arakawa and S. N. Timasheff. Biochemistry 21:6545–6552 (1982).Google Scholar
  243. 243.
    F. Ahmad and C. C. Bigelow. J. Protein Chem. 5:355–367 (1986).Google Scholar
  244. 244.
    R. Bhat and J. C. Ahluwalia. Int. J. Peptide Protein Res. 30:145–152 (1985).Google Scholar
  245. 245.
    F. Ahmad. Can J. Biochem. Cell Biol. 63:1058–1063 (1985).Google Scholar
  246. 246.
    R. Almog. Biophys. Chem. 17:111–118 (1983).Google Scholar
  247. 247.
    E. Stellwagen and J. Babul. Biochemistry 14:5135–5140 (1975).Google Scholar
  248. 248.
    L. O. Narhi, M. K. Zukowski, and T. Arakawa. Biophys. J. 55:23a (1989).Google Scholar
  249. 249.
    M. W. Pantoliano, M. Whitlow, J. F. Wood, M. L. Rollence, B. C. Finzel, G. L. Gilliland, T. L. Poulos, and P. N. Bryant. Biochemistry 27:8311–8317 (1988).Google Scholar
  250. 250.
    A. J. Russell and A. R. Fersht. Nature 328:496–500 (1987).Google Scholar
  251. 251.
    C. N. Pace and G. R. Grimsley. Biochemistry 27:3242–3246 (1988).Google Scholar
  252. 252.
    F. W. Dahlquist, J. W. Long, and W. L. Bigbee. Biochemistry 15:1103–1111 (1976).Google Scholar
  253. 253.
    G. Voordouw, C. Milo, and R. S. Roche. Biochemistry 15:3716–3724 (1976).Google Scholar
  254. 254.
    V. V. Filimonov, W. Pfeil, T. N. Tsalkova, and P. L. Privalov. Biophys. Chem. 8:117–122 (1978).Google Scholar
  255. 255.
    H. Schulz. FEBS Lett. 78:303–308 (1977).Google Scholar
  256. 256.
    J. F. Chlebowski, S. Mabrey, and M. C. Falk. J. Biol. Chem. 254:5745–5753 (1979).Google Scholar
  257. 257.
    J. F. Chlebowski and S. Mabrey. J. Biol. Chem. 252:7042–7050 (1977).Google Scholar
  258. 258.
    S. Linse, P. Brodin, C. Johansson, E. Thulin, T. Grundström, and S. Forsén. Nature 335:651–653 (1988).Google Scholar
  259. 259.
    E. Stellwagen and H. Wilgus. In S. M. Friedman (ed.), Biochemistry of Thermophily, Academic Press, New York, 1978, pp. 228–232.Google Scholar
  260. 260.
    J. A. Roe, A. Butler, D. M. Scholler, J. S. Valentine, L. Marky, and K. J. Breslauer. Biochemistry 27:950–958 (1988).Google Scholar
  261. 261.
    Y. Hiroka, T. Segawa, K. Kawajima, S. Sugai, and N. Murai. Biochem. Biophys. Res. Commun. 95:1098–1104 (1980).Google Scholar
  262. 262.
    M. Mitani, Y. Harushima, K. Kawajima, M. Ikeguchi, and S. Sugai. J. Biol. Chem. 261:8824–8829 (1986).Google Scholar
  263. 263.
    J. Desmet, I. Hanssens, and F. van Cauwelaert. Biochim. Biophys. Acta 912:211–219 (1987).Google Scholar
  264. 264.
    R. Palmieri, R. W.-K. Lee, and M. F. Dunn. Biochemistry 27:3387–3397 (1988).Google Scholar
  265. 265.
    K. Gekko and S. N. Timasheff. Biochemistry 20:4667–4676 (1981).Google Scholar
  266. 266.
    K. Gekko and S. N. Timasheff. Biochemistry 20:4677–4686 (1981).Google Scholar
  267. 267.
    J. C. Lee and S. N. Timasheff. J. Biol. Chem. 256:7193–7201 (1981).Google Scholar
  268. 268.
    J. C. Lee and S. N. Timasheff. Biochemistry 13:257–265 (1974).Google Scholar
  269. 269.
    J. C. Lee and S. N. Timasheff. Biochemistry 14:5183–5187 (1975).Google Scholar
  270. 270.
    S. N. Timasheff, J. C. Lee, E. P. Pittz, and N. Tweedy. J. Colloid Interface Sci. 55:658–663 (1976).Google Scholar
  271. 271.
    J. C. Lee and S. N. Timasheff. Biochemistry 16:1754–1764 (1977).Google Scholar
  272. 272.
    I. D. Kuntz, Jr., and W. Kauzmann. Adv. Protein Chem. 28:239–345 (1974).Google Scholar
  273. 273.
    V. Prakesh, P. K. Nandi, and B. Jirgensons. Int. J. Peptide Protein Res. 15:305–313 (1980).Google Scholar
  274. 274.
    B. Jirgensons. J. Protein Chem. 1:71 (1982).Google Scholar
  275. 275.
    B. Jirgensons. Macromol. Chem. Rapid Commun. 2:213–217 (1981).Google Scholar
  276. 276.
    F. F. Shih and A. D. Kalmar. J. Agr. Food Chem. 35:672–675 (1987).Google Scholar
  277. 277.
    K. Takeda, K. Sasa, M. Nagao, and P. P. Batra. Biochim. Biophys. Acta 957:340–344 (1988).Google Scholar
  278. 278.
    K. Fukushima, Y. Murata, N. Nishikido, G. Sugihara, and M. Tanaka. Bull. Chem. Soc. Jap. 54:3122–3127 (1981).Google Scholar
  279. 279.
    J. L. Bohnert and T. A. Horbett. J. Colloid Interface Sci. 111:363–377 (1986).Google Scholar
  280. 280.
    J. Piatigorsky, J. Horwitz, and R. T. Simpson. Biochim. Biophys. Acta 490:279–289 (1977).Google Scholar
  281. 281.
    S. Tandon and P. M. Horowitz. J. Biol. Chem. 262:4486–4491 (1987).Google Scholar
  282. 282.
    P. S. Banerjee and W. A. Ritschel. J. Pharm. Sci. 76:S48 (1987).Google Scholar
  283. 283.
    A. L. Daugherty, H. D. Liggitt, J. G. McCabe, J. A. Moore, and J. S. Patton. Int. J. Pharm. 45:197–206 (1988).Google Scholar
  284. 284.
    D. Shortle. J. Biol. Chem. 264:5315–5318 (1989).Google Scholar
  285. 285.
    E. Querol and A. Padilla. Enzyme Microbial Technol. 9:238–244 (1987).Google Scholar
  286. 286.
    M. H. Hecht, J. M. Sturtevant, and R. T. Sauer. Proteins Struct. Funct. Genet. 1:43–46 (1986).Google Scholar
  287. 287.
    P. J. Carter, G. Winter, A. J. Wilkinson, and A. R. Fersht. Cell 38:835–840 (1984).Google Scholar
  288. 288.
    B. W. Matthews, H. Nicholson, and W. J. Becktel. Proc. Natl. Acad. Sci. USA 84:6663–6667 (1987).Google Scholar
  289. 289.
    G. N. Ramachandran and V. Sasisekharan. Adv. Protein Chem. 23:283–437 (1968).Google Scholar
  290. 290.
    S. K. Burley and G. A. Petsko. Science 225:23–28 (1985).Google Scholar
  291. 291.
    S. K. Burley and G. A. Petsko. Adv. Protein Chem. 39:125–189 (1988).Google Scholar
  292. 292.
    J. T. Kellis, Jr., K. Nyberg, D. Sali, and A. R. Fersht. Nature 333:784–786 (1988).Google Scholar
  293. 293.
    M. Matsumura, W. J. Becktel, and B. W. Matthews. Nature 334:406–410 (1988).Google Scholar
  294. 294.
    T. Alber, S. Dao-pin, K. Wilson, J. A. Wozniak, S. P. Cook, and B. W. Matthews. Nature 330:41–46 (1987).Google Scholar
  295. 295.
    J. F. Reidhaar-Olson and R. T. Sauer. Science 241:53–57 (1988).Google Scholar
  296. 296.
    M. L. Elwell and J. A. Schellman. Biochim. Biophys. Acta 494:367–383 (1977).Google Scholar
  297. 297.
    M. H. Hecht, J. M. Sturtevant, and R. T. Sauer. Proc. Natl. Acad. Sci. USA 81:5685–5689 (1984).Google Scholar
  298. 298.
    D. Shortle and A. K. Meeker. Proteins Struct. Funct. Genet. 1:81–89 (1986).Google Scholar
  299. 299.
    D. Shortle and A. K. Meeker. Biochemistry 28:936–944 (1989).Google Scholar
  300. 300.
    H. Nicholson, W. J. Becktel, and B. W. Matthews. Nature 336:651–656 (1988).Google Scholar
  301. 301.
    R. Hawkes, M. G. Grutter, and J. Schellman. J. Mol. Biol. 175:195–212 (1984).Google Scholar
  302. 302.
    M. Grutter, R. Hawkes, and B. Matthews. Nature 277:667–669 (1979).Google Scholar
  303. 303.
    W. J. Becktel, W. A. Baase, B. L. Chen, D. C. Muchmore, C. G. Schellman, and J. A. Schellman. Biophys. J. 49:572a (1986).Google Scholar
  304. 304.
    M. Grutter and B. Matthews. J. Mol. Biol. 154:525–535 (1982).Google Scholar
  305. 305.
    T. Alber, S. Dao-pin, J. A. Nye, D. C. Muchmore, and B. W. Matthews. Biochemistry 26:3754–3758 (1987).Google Scholar
  306. 306.
    B. W. Matthews. Biochemistry 26:6885–6887 (1987).Google Scholar
  307. 307.
    W. G. J. Hol, P. T. van Duijnen, and H. J. C. Berendsen. Nature 273:443–446 (1978).Google Scholar
  308. 308.
    W. G. J. Hol. Prog. Biophys. Mol. Biol. 45:149–195 (1985).Google Scholar
  309. 309.
    W. G. J. Hol. Angew. Chem. Int. Ed. Engl. 25:767–778 (1986).Google Scholar
  310. 310.
    W. G. J. Hol, L. M. Halie, and C. Sander. Nature 294:532–536 (1981).Google Scholar
  311. 311.
    R. P. Sheridan, R. M. Levy, and F. R. Salemme. Proc. Natl. Acad. Sci. USA 80:4545–4549 (1982).Google Scholar
  312. 312.
    K.-C. Chou, G. M. Maggiora, G. Nemethy, and H. A. Scheraga. Proc. Natl. Acad. Sci. USA 85:4295–4299 (1988).Google Scholar
  313. 313.
    J. S. Richardson. Adv. Protein Chem. 34:167–339 (1981).Google Scholar
  314. 314.
    P. S. Kim and R. L. Baldwin. Nature 307:329–334 (1984).Google Scholar
  315. 315.
    K. R. Shoemaker, P. S. Kim, D. N. Brems, S. Marqusee, E. J. York, I. M. Chaiken, J. M. Stewart, and R. L. Baldwin. Proc. Natl. Acad. Sci. USA 82:2349–2353 (1985).Google Scholar
  316. 316.
    C. Mitchinson and R. L. Baldwin. Proteins Struct. Funct. Genet. 1:23–33 (1986).Google Scholar
  317. 317.
    K. G. Strehlow and R. L. Baldwin. Biochemistry 28:2130–2133 (1989).Google Scholar
  318. 318.
    S. Marqusee and R. L. Baldwin. Proc. Natl. Acad. Sci. USA 84:8898–8902 (1987).Google Scholar
  319. 319.
    H. A. Scheraga. Proc. Natl. Acad. Sci. USA 82:5585–5587 (1985).Google Scholar
  320. 320.
    M. F. Perutz and G. Fermi. Proteins Struct. Funct. Genet. 4:294–295 (1988).Google Scholar
  321. 321.
    P. C. Lyu, L. A. Marky, and N. R. Kallenbach. J. Am. Chem. Soc. 111:2733–2734 (1989).Google Scholar
  322. 322.
    R. J. Abraham, B. D. Hudson, W. A. Thomas, and A. Krohn. J. Mol. Graph. 4:28–32 (1986).Google Scholar
  323. 323.
    D. Sali, M. Bycroft, and A. R. Fersht. Nature 335:740–743 (1988).Google Scholar
  324. 324.
    W. J. Becktel, W. A. Baase, R. Wetzel, and L. J. Perry. Biophys. J. 49:109a (1986).Google Scholar
  325. 325.
    M. H. Hecht, K. M. Hehir, H. C. M. Nelson, J. M. Sturtevant, and R. T. Sauer. J. Cell. Biochem. 29:217–224 (1985).Google Scholar
  326. 326.
    J. E. Villafranca, E. E. Howell, D. H. Voet, M. S. Strobel, R. C. Ogden, J. N. Abelson, and J. Kraut. Science 222:782–788 (1983).Google Scholar
  327. 327.
    J. A. Wells and D. B. Powers. J. Biol. Chem. 261:6564–6570 (1986).Google Scholar
  328. 328.
    M. W. Pantoliano, R. C. Ladner, P. N. Bryan, M. L. Rollence, J. F. Wood, and T. L. Poulos. Biochemistry 26:2077–2082 (1987).Google Scholar
  329. 329.
    R. T. Sauer, K. Hehir, R. S. Stearman, M. A. Weiss, A. Jeitler-Nilsson, E. G. Suchanek, and C. O. Pabo. Biochemistry 25:5992–5998 (1986).Google Scholar
  330. 330.
    M. Matsumura and B. W. Matthews. Science 243:792–794 (1989).Google Scholar
  331. 331.
    L. J. Perry and R. Wetzel. Science 226:555–557 (1984).Google Scholar
  332. 332.
    L. J. Perry and R. Wetzel. Biochemistry 25:733–739 (1986).Google Scholar
  333. 333.
    M. G. Mulkerrin, L. J. Perry, and R. Wetzel. In D. L. Oxender (ed.), Protein Structure, Folding, and Design, Alan Liss, New York, 1986, pp. 297–305.Google Scholar
  334. 334.
    G. McLendon and E. Radany. J. Biol. Chem. 253:6335–6337 (1978).Google Scholar
  335. 335.
    T. J. Ahern, J. I. Casal, G. A. Petsko, and A. M. Klibanov. Proc. Natl. Acad. Sci. USA 84:675–679 (1987).Google Scholar
  336. 336.
    P. T. Wingfield, R. J. Mattaliano, H. R. MacDonald, S. Craig, G. M. Clore, A. M. Gronenborn, and U. Schmeissner. Protein Eng. 1:413–417 (1987).Google Scholar
  337. 337.
    A. Abuchowski. J. Cell. Biochem. 11A:174 (1987).Google Scholar
  338. 338.
    P. Koziej, M. Mutter, H.-U. Gremlich, and G. Hölzemann. Z. Naturforsch. 40B:1570–1574 (1985).Google Scholar
  339. 339.
    M. Mutter, H. Mutter, R. Uhlmann, and E. Bayer. Biopolymers 15:917–927 (1976).Google Scholar
  340. 340.
    P. V. N. Rajasekharan and M. Mutter. Acc. Chem. Res. 14:122–130 (1981).Google Scholar
  341. 341.
    A. A. Ribiero, R. P. Saltman, M. Goodman, and M. Mutter. Biopolymers 21:2225–2239 (1982).Google Scholar
  342. 342.
    M. Hashimoto, K. Takada, Y. Kiso, and S. Muanishi. Pharm. Res. 6:171–176 (1989).Google Scholar
  343. 343.
    D. D. Chow and K. J. Hwang. J. Pharm. Sci. 76:S49 (1987).Google Scholar
  344. 344.
    E. R. Jakoi, P. E. Ross, H. P. Ting-Beall, B. Kaufman, and T. C. Vanaman. J. Biol. Chem. 262:1300–1304 (1987).Google Scholar
  345. 345.
    D. A. Towler, S. R. Eubanks, D. S. Towery, S. P. Adams, and L. Glaser. J. Biol. Chem. 262:1030–1036 (1987).Google Scholar
  346. 346.
    Y. A. Ovchinnikov, N. G. Abdulaev, and A. S. Bogachuk. FEBS Lett. 230:1–5 (1988).Google Scholar
  347. 347.
    F. S. Qaw and J. M. Brewer. Mol. Cell. Biochem. 71:121–127 (1986).Google Scholar
  348. 348.
    A. T. Fojo, P. L. Whitney, and M. W. Awad, Jr. Arch. Biochem. Biophys. 224:636–642 (1983).Google Scholar
  349. 349.
    P. Cujo, W. El-Deiry, P. L. Whitney, and W. M. Awad, Jr. J. Biol. Chem. 255:10828–10833 (1980).Google Scholar
  350. 350.
    R. Wolfenden, L. Anderson, P. M. Cullis, and C. C. B. Southgate. Biochemistry 20:849–855 (1981).Google Scholar
  351. 351.
    R. Desrosiers and R. M. Tanguay. J. Biol. Chem. 263:4686–4692 (1988).Google Scholar
  352. 352.
    R. M. Epand and K. E. Raymer. Int. J. Peptide Protein Res. 30:515–521 (1987).Google Scholar
  353. 353.
    H. Koide, S. Yokoyama, G. Kawai, J.-M. Ha, T. Oka, S. Kawai, T. Miyake, T. Fuwa, and T. Miyazawa. Proc. Natl. Acad. Sci. USA 85:6237–6241 (1988).Google Scholar

Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Mark C. Manning
    • 1
  • Kamlesh Patel
    • 1
  • Ronald T. Borchardt
    • 1
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrence

Personalised recommendations