Journal of Biomolecular NMR

, Volume 35, Issue 1, pp 39–51 | Cite as

Chemically accurate protein structures: Validation of protein NMR structures by comparison of measured and predicted pKa values

Article

Abstract

A new method is presented for evaluating the quality of protein structures obtained by NMR. This method exploits the dependence between measurable chemical properties of a protein, namely pKa values of acidic residues, and protein structure. The accurate and fast empirical computational method employed by the PROPKA program (http://www.propka.chem.uiowa.edu) allows the user to test the ability of a given structure to reproduce known pKa values, which in turn can be used as a criterion for the selection of more accurate structures. We demonstrate the feasibility of this novel idea for a series of proteins for which both␣NMR and X-ray structures, as well as pKa values of all ionizable residues, have been determined. For the 17 NMR ensembles used in this study, this criterion is shown effective in the elimination of a large number of NMR structure ensemble members.

Key words

pKa structure validation ubiquitin 

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Notes

Acknowledgements

This work was supported by a grant from the National Science Foundation (MCB 209941). We thank Prof. Lawrence McIntosh for helpful suggestions on the manuscript.

References

  1. Assadi-Porter F.M., Fillingame R.H. (1995). Biochemistry 34(49):16186–16193CrossRefGoogle Scholar
  2. Bartik K., Redfield C., Dobson C.M. (1994). Biophys. J. 66(4):1180–1184CrossRefGoogle Scholar
  3. Bode W., Wei A.Z., Huber R., Meyer E., Travis J., Neumann S. (1986). EMBO J. 5(10):2453–2458Google Scholar
  4. Boissy G., de La Fortelle E., Kahn R., Huet J.C., Bricogne G., Pernollet J.C., Brunie S. (1996). Structure 4(12):1429–1439CrossRefGoogle Scholar
  5. Boyer P.D. (1997). Ann. Rev. Biochem. 66:717–749CrossRefGoogle Scholar
  6. Brunger A.T., Adams P.D. (2002). Acc. Chem. Res. 35(6):404–412CrossRefGoogle Scholar
  7. Brunger A.T., Adams P.D., Rice L.M. (1997). Structure 5(3), 325–336CrossRefGoogle Scholar
  8. Bycroft M., Ludvigsen S., Fersht A.R., and Poulsen F.M. (1991). Biochemistry 30(35), 8697–8701CrossRefGoogle Scholar
  9. Chiang C.M., Chang S.L., Lin H.J., Wu W.G. (1996). Biochemistry 35(28):9177–9186CrossRefGoogle Scholar
  10. Chivers P.T., Prehoda K.E., Volkman B.F., Kim B.M., Markley J.L., Raines R.T. (1997). Biochemistry 36(48):14985–14991CrossRefGoogle Scholar
  11. Clore G.M., Gronenborn A.M. (1998a). Trend. Biotechnol. 16(1):22–34CrossRefGoogle Scholar
  12. Clore G.M., Gronenborn A.M. (1998b). PNAS 95(11):5891–5898CrossRefADSGoogle Scholar
  13. Cornilescu G., Marquardt J.L., Ottiger M., Bax A. (1998). J. Am. Chem. Soc. (Communication) v120(27):6836–6837CrossRefGoogle Scholar
  14. Davis I.W., Murray L.W., Richardson J.S., Richardson D.C. (2004). Nucleic Acids Res. 32(Web Server issue): W615–W619CrossRefGoogle Scholar
  15. DePristo M.A., de Bakker P.I., Blundell T.L. (2004). Structure (Camb.) 12(5):831–838CrossRefGoogle Scholar
  16. Dillet V., Dyson H.J., Bashford D. (1998). Biochemistry 37(28):10298–10306CrossRefGoogle Scholar
  17. Dmitriev O.Y., Jones P.C., Fillingame R.H. (1999). Proc. Natl. Acad. Sci. USA 96(14):7785–7790CrossRefADSGoogle Scholar
  18. Doreleijers J.F., Vriend G., Raves M.L., Kaptein R. (1999). Proteins 37(3):404–416CrossRefGoogle Scholar
  19. Durbin S.D., Feher G. (1996). Ann. Rev. Phys. Chem. 47:171–204CrossRefADSGoogle Scholar
  20. Dyson H.J., Jeng M.-F., Tennant L.L., Slaby I., Lindell M., Cui D.-S., Kuprin S., Holmgren A. (1997). Biochemistry 36(9):2622 - 2636CrossRefGoogle Scholar
  21. Ebina S., Wuthrich K. (1984). J. Mol. Biol. 179(2):283–288CrossRefGoogle Scholar
  22. Elcock A.H. (2001). J. Mol. Biol. 312(4):885–896CrossRefGoogle Scholar
  23. Fedorov A.A., Joseph-McCarthy D., Fedorov E., Sirakova D., Graf I., Almo S.C. (1996). Biochemistry 35(50):15962–15979CrossRefGoogle Scholar
  24. Fefeu S., Bouaziz S., Huet J.C., Pernollet J.C., Guittet E. (1997). Protein Sci. 6(11):2279–2284CrossRefGoogle Scholar
  25. Forsyth W.R., Antosiewicz J.M., Robertson A.D. (2002). Proteins 48(2):388–403CrossRefGoogle Scholar
  26. Fujiwara M., Kato T., Yamazaki T., Yamasaki K., Nagayam K. (2000). Biol. Pharm. Bull. 23(10):1147–1152Google Scholar
  27. Garavito R.M., Ferguson-Miller S. (2001). J. Biol. Chem. 276(35):32403–32406CrossRefGoogle Scholar
  28. Georgescu R.E., Alexov E.G., Gunner M.R. (2002). Biophys. J. 83(4):1731–1748CrossRefADSGoogle Scholar
  29. Girvin M.E., Rastogi V.K., Abildgaard F., Markley J.L., Fillingame R.H. (1998). Biochemistry 37(25):8817–8824CrossRefGoogle Scholar
  30. Gleason F.K. (1992). Protein Sci. 1(5):609–616CrossRefGoogle Scholar
  31. Gooley P.R., Keniry M.A., Dimitrov R.A., Marsh D.E., Keizer D.W., Gayler K.R., Grant B.R. (1998). J. Biomol. NMR12(4):523–534CrossRefGoogle Scholar
  32. Guex N., Peitsch M.C. (1997). Electrophoresis 18(15):2714–2723CrossRefGoogle Scholar
  33. Hall R.J., Hindle S.A., Burton N.A., Hillier I.H. (2000). J. Comput. Chem. 21(16):1433–1441CrossRefGoogle Scholar
  34. Harata K. (1994). Acta Crystallogr. D Biol. Crystallogr. v50:250–257CrossRefGoogle Scholar
  35. Harris T.K.T., G.J. (2002). IUBMB LIFE 53:85–98CrossRefGoogle Scholar
  36. Hooft R.W., V.G., Sander C., Abola E.E. (1996). Nature 381:272CrossRefADSGoogle Scholar
  37. Jorgensen A.M., Kristensen S.M., Led J.J., Balschmidt P. (1992). J. Mol. Biol. 227(4):1146–1163CrossRefGoogle Scholar
  38. Kalyan S. Chakrabarti B.S.S.S.V. (2004). Chemistry & Biodiversity 1(5):802–818CrossRefGoogle Scholar
  39. Katayanagi K., Miyagawa M., Matsushima M., Ishikawa M., Kanaya S., Nakamura H., Ikehara M., Matsuzaki T., Morikawa K. (1992). J. Mol. Biol. 223(4):1029–1052CrossRefGoogle Scholar
  40. Kesvatera T., Jonsson B., Thulin E., Linse S. (1996). J. Mol. Biol. 259(4):828–839CrossRefGoogle Scholar
  41. Kim J., Raines R.T. (1993). Protein Sci. 2(3):348–356CrossRefGoogle Scholar
  42. Kohda D., Sawada T., Inagaki F. (1991). Biochemistry 30(20):4896–4900CrossRefGoogle Scholar
  43. Kordel J., Skelton N.J., Akke M., Chazin W.J. (1993). J. Mol. Biol. 231(3):711–734CrossRefGoogle Scholar
  44. Kortemme T., Darby N.J., Creighton T.E. (1996). Biochemistry 35(46):14503–14511CrossRefGoogle Scholar
  45. Kragh-Hansen U., le Maire M., Moller J.V. (1998). Biophys. J. 75(6):2932–2946CrossRefGoogle Scholar
  46. Krezel A.M., Darba P., Robertson A.D., Fejzo J., Macura S., Markley J.L. (1994). J. Mol. Biol. 242(3):203CrossRefGoogle Scholar
  47. Kuriyan J., Brunger A.T., Karplus M., Hendrickson W.A. (1989). Acta Crystallogr. A 45(Pt 6):396–409CrossRefGoogle Scholar
  48. Laskowski R.A., MacArthur M.W., Thornton J.M. (1998). Curr. Opin. Struct. Biol. 8(5):631–639CrossRefGoogle Scholar
  49. Laskowski R.A., Rullmann J.A.C., MacArthur M.W., Kaptein R., Thornton J.M. (1996). J. Biomol. NMR (Historical Archive) 8(4):477CrossRefGoogle Scholar
  50. Li H., Robertson A.D., Jensen J.H. (2004). Proteins 55(3):689–704CrossRefGoogle Scholar
  51. Li, H., Robertson, A.D. and Jensen, J.H. (2005). Struct. Funct. Bioinform. 61(4), 704-21Google Scholar
  52. Linge, J. P., Williams, M. A., Spronk, C. A. E. M., Bonvin, A.␣M. J. J. and Nilges M. (2003). Proteins Struct. Funct. Genet. 50(3): 496-06.Google Scholar
  53. Mauguen Y., Hartley R.W., Dodson E.J., Dodson G.G., Bricogne G., Chothia C., Jack A. (1982). Nature 297(5862):162–164CrossRefADSGoogle Scholar
  54. Montelione G.T., Wuthrich K., Burgess A.W., Nice E.C., Wagner G., Gibson K.D., Scheraga H.A. (1992). Biochemistry 31(1):236–249CrossRefGoogle Scholar
  55. Montelione G.T., Zheng D., Huang Y.J., Gunsalus K.C., Szyperski T. (2000). Nat. Struct. Mol. Biol. Nov:982CrossRefGoogle Scholar
  56. Nabuurs S.B., Spronk C.A., Krieger E., Maassen H., Vriend G., Vuister G.W. (2003). J. Am. Chem. Soc. 125(39):12026–12034CrossRefGoogle Scholar
  57. Nagendra H.G., Sukumar, N. and Vijayan, M. (1998). Proteins Struct. Funct. Genet. 32(2):229–240CrossRefGoogle Scholar
  58. Nielsen J.E., McCammon J.A. (2003a). Protein Sci. 12(9):1894–1901CrossRefGoogle Scholar
  59. Nielsen J.E., McCammon J.A. (2003b). Protein Sci 12(2):313–326CrossRefGoogle Scholar
  60. Nielsen J.E., Vriend G. (2001). Proteins 43(4):403–412CrossRefGoogle Scholar
  61. Oda Y., Yamazaki T., Nagayama K., Kanaya S., Kuroda Y., Nakamura H. (1994). Biochemistry 33(17):5275–5284CrossRefGoogle Scholar
  62. Oliveberg M., Arcus V.L., Fersht A.R. (1995). Biochemistry 34(29):9424–9433CrossRefGoogle Scholar
  63. Ondrechen M.J., Clifton J.G., Ringe D. (2001). Proc. Natl. Acad. Sci. USA 98(22):12473–12488CrossRefADSGoogle Scholar
  64. Ottensmeyer F.P., Beniac D.R., Luo R.Z., Yip C.C. (2000). Biochemistry 39(40):12103–12112CrossRefGoogle Scholar
  65. Perez-Canadillas J.M., Campos-Olivas R., Lacadena J., del Pozo A.M., Gavilanes J.G., Santoro J., Rico M., Bruix M. (1998). Biochemistry 37(45):15865–15876CrossRefGoogle Scholar
  66. Perez-Canadillas J.M., Santoro J., Campos-Olivas R., Lacadena J., Martinez del Pozo A., Gavilanes J.G., Rico M., Bruix M. (2000). J. Mol. Biol. 299(4):1061–1073CrossRefGoogle Scholar
  67. Qin J., Clore G.M., Gronenborn A.M. (1994). Structure 2(6):503–522CrossRefGoogle Scholar
  68. Qin J., Clore G.M., Gronenborn A.M. (1996). Biochemistry 35(1):7–13CrossRefGoogle Scholar
  69. Rico, M., Santoro, J., Gonzalez, C., Bruix, M. and Neira, J. L. (1990). Structure, Mechanism and Function of Ribonucleases Proceedings of the 2nd International Meeting.Google Scholar
  70. Santoro J., Gonzalez C., Bruix M., Neira J.L., Nieto J.L., Herranz J., Rico M. (1993). J. Mol. Biol. 229(3):22–34CrossRefGoogle Scholar
  71. Schaller W., Robertson A.D. (1995). Biochemistry 34(14):4714–4723CrossRefGoogle Scholar
  72. Schwalbe H., Grimshaw S.B., Spencer A., Buck M., Boyd J., Dobson C.M., Redfield C., Smith L.J. (2001). Protein Sci. 10(4):677–688CrossRefGoogle Scholar
  73. Singhal A.K., Chien K.Y., Wu W.G., Rule G.S. (1993). Biochemistry 32(31):8036–8044CrossRefGoogle Scholar
  74. Skelton N.J., Kordel J., Chazin W.J. (1995). J. Mol. Biol. 249(2):441–462CrossRefGoogle Scholar
  75. Snyder D.A., Bhattacharya A., Huang Y.J., Montelione G.T. (2005). Proteins 59(4):655–661CrossRefGoogle Scholar
  76. Sorensen M.D., Led J.J. (1994). Biochemistry 33(46):13727–13733CrossRefGoogle Scholar
  77. Spronk C.A.E.M., Linge J.P., Hilbers C.W., Vuister G.W. (2002). J. Biomol. NMR 22(3):281CrossRefGoogle Scholar
  78. Sun Y.J., Wu W.G., Chiang C.M., Hsin A.Y., Hsiao C.D. (1997). Biochemistry 36(9):2403–2413CrossRefGoogle Scholar
  79. Sundd M., Iverson N., Ibarra-Molero B., Sanchez-Ruiz J.M., Robertson A.D. (2002). Biochemistry 41(24):7586–7596CrossRefGoogle Scholar
  80. Svensson L.A., Thulin E., Forsen S. (1992). J. Mol. Biol. 223(3):601–606CrossRefGoogle Scholar
  81. Szyperski T., Antuch W., Schick M., Betz A., Stone S.R., Wuthrich K. (1994). Biochemistry 33(31):9303–9310CrossRefGoogle Scholar
  82. Szyperski T., Guntert P., Stone S.R., Wuthrich K. (1992). J. Mol. Biol. 228(4):1193–1205CrossRefGoogle Scholar
  83. Tarek M., Tobias D.J. (2002). Phys. Rev. Lett. 88(13):138101CrossRefADSGoogle Scholar
  84. Trautwein K., Holliger P., Stackhouse J., Benner S.A. (1991). FEBS Lett. 281(1-):275–277CrossRefGoogle Scholar
  85. Vijay-Kumar S., Bugg C.E., Cook W.J. (1987). J. Mol. Biol. 194(3):531–544CrossRefGoogle Scholar
  86. Warshel A. (1981). Acc. Chem. Res. 14:284–290CrossRefGoogle Scholar
  87. Weber J., Senior A.E. (2003). FEBS Lett. 545(1):61–70CrossRefGoogle Scholar
  88. Weichsel A., Gasdaska J.R., Powis G., Montfort W.R. (1996). Structure 4(6):735–751CrossRefGoogle Scholar
  89. Wiencek J.M. (1999). Ann. Rev. Biomed. Eng. 1:505-34CrossRefGoogle Scholar
  90. Williamson M.P., Havel T.F., Wuthrich K. (1985). J. Mol. Biol. 182(2):295–315CrossRefGoogle Scholar
  91. Zhang Y., Kua J., McCammon J.A. (2002). J. Am. Chem. Soc. 124(35):10572–10577CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of IowaIowa CityUSA
  2. 2.Department of Physics and AstronomyUniversity of IowaIowa CityUSA

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