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Continuum electrostatic calculations of the pKa of ionizable residues in an ion channel: Dynamic vs. static input structure

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Abstract

We have computed the pKa’s of the ionizable residues of a protein ion channel, the Staphylococcus aureus toxin \( \alpha\) -hemolysin, by using two types of input structures, namely the crystal structure of the heptameric \( \alpha\) -hemolysin and a set of over four hundred snapshots from a 4.38ns Molecular Dynamics simulation of the protein inserted in a phospholipid planar bilayer. The comparison of the dynamic picture provided by the Molecular Simulation with the static one based on the X-ray crystal structure of the protein embedded in a lipid membrane allows analyzing the influence of the fluctuations in the protein structure on its ionization properties. We find that the use of the dynamic structure provides interesting information about the sensitivity of the computed pKa of a given residue to small changes in the local structure. The calculated pKa are consistent with previous indirect estimations obtained from single-channel conductance and selectivity measurements.

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References

  1. C.N. Schutz, A. Warshel, Proteins 44, 400 (2001)

    Article  Google Scholar 

  2. C. Tanford, J.G. Kirkwood, J. Am. Chem. Soc. 79, 5333 (1957)

    Article  Google Scholar 

  3. D. Bashford, Frontiers Biosci. 9, 1082 (2004)

    Article  Google Scholar 

  4. C.A. Castañeda, C.A. Fitch, A. Majumdar, V. Khangulov, J.M. Schlessman, B.E. García-Moreno, Proteins 77, 570 (2009)

    Article  Google Scholar 

  5. T. Simonson, Photosynth. Res. 97, 21 (2008)

    Article  Google Scholar 

  6. A. Warshel, S.T. Russell, Q. Rev. Biophys. 17, 283 (1984)

    Article  Google Scholar 

  7. E.G. Alexov, M.R. Gunner, Biophys. J. 72, 2075 (1997)

    Article  ADS  Google Scholar 

  8. E. Alexov, Proteins 50, 94 (2003)

    Article  Google Scholar 

  9. Y. Song, J. Mao, M.R. Gunner, J. Comput. Chem. 30, 2231 (2009)

    Google Scholar 

  10. J. Warwicker, Protein Sci. 13, 2793 (2004)

    Article  Google Scholar 

  11. T.J. You, D. Bashford, Biophys. J. 69, 1721 (1995)

    Article  ADS  Google Scholar 

  12. V.Z. Spassov, L. Yan, Protein Sci. 17, 1955 (2008)

    Article  Google Scholar 

  13. B. Kuhn, P.A. Kollman, M. Stahl, J. Comput. Chem. 25, 1865 (2004)

    Article  Google Scholar 

  14. A. Koumanov, A. Karshikoff, E.P. Friis, T.V. Borchert, J. Phys. Chem. B 105, 9339 (2001)

    Article  Google Scholar 

  15. H.W. van Vlijmen, M. Schaefer, M. Karplus, Proteins 33, 145 (1998)

    Article  Google Scholar 

  16. A.A. Gorfe, P. Ferrara, A. Caflisch, D.N. Marti, H.R. Bosshard, I. Jelesarov, Proteins: Struct. Funct. Genet. 46, 41 (2001)

    Article  Google Scholar 

  17. G. Kieseritzky, E.-W. Knapp, Proteins 71, 1335 (2008)

    Article  Google Scholar 

  18. J. Makowska, K. Bagiñska, M. Makowski, A. Jagielska, A. Liwo, F. Kasprzykowski, L. Chmurzyñski, H.A. Scheraga, J. Phys. Chem. B 110, 4451 (2006)

    Article  Google Scholar 

  19. A.C. Lee, G.M. Crippen, J. Chem. Inf. Model. 49, 2013 (2009)

    Article  Google Scholar 

  20. E. Hajjar, A. Dejaegere, N. Reuter, J. Phys. Chem. A 113, 11783 (2009)

    Article  Google Scholar 

  21. J.E. Nielsen, J.A. McCammon, Protein Sci. 12, 313 (2003)

    Article  Google Scholar 

  22. T. Simonson, J. Carlsson, D.A. Case, J. Am. Chem. Soc. 126, 4167 (2004)

    Article  Google Scholar 

  23. P. Beroza, D.R. Fredkin, M.Y. Okamura, G. Feher, Proc. Natl. Acad. Sci. U.S.A. 88, 5804 (1991)

    Article  ADS  Google Scholar 

  24. A.M. Baptista, V.H. Teixeira, C.M. Soares, J. Chem. Phys. 117, 8184 (2002)

    Article  Google Scholar 

  25. M. Machuqueiro, A.M. Baptista, J. Phys. Chem. B 110, 2927 (2006)

    Article  Google Scholar 

  26. M. Machuqueiro, A.M. Baptista, J. Am. Chem. Soc. 131, 12586 (2009)

    Article  Google Scholar 

  27. L. Sandberg, O. Edholm, Proteins: Struct. Funct. Genet. 36, 474 (1999)

    Article  Google Scholar 

  28. J. Li, C.L. Fisher, J.L. Chen, D. Bashford, L. Noodleman, Inorg. Chem. 35, 4694 (1996)

    Article  Google Scholar 

  29. D.M. Chipman, J. Phys. Chem. A 106, 7413 (2002)

    Article  Google Scholar 

  30. S.C.L. Kamerlin, M. Haranczyk, A. Warshel, J. Phys. Chem. 113, 1253 (2009)

    Google Scholar 

  31. Y.E. Zevatskii, D.V. Samoliov, N.S. Panina, Russ. J. Gen. Chem. 79, 944 (2009)

    Article  Google Scholar 

  32. R. Gilson, M.C. Durrant, Dalton Trans. 10223 (2009)

  33. J. Mongan, D.A. Case, Curr. Opin. Struct. Biol. 15, 157 (2005)

    Article  Google Scholar 

  34. M.R. Gunner, J. Mao, Y. Song, J. Kim, Biochim. Biophys. Acta 1757, 942 (2006)

    Article  Google Scholar 

  35. B. García-Moreno, C.A. Fitch, Meth. Enzymol. 380, 20 (2004)

    Article  Google Scholar 

  36. A. Davis, S.A. St-Gallay, G.J. Kleywegt, Drug Discov. Today 13, 831 (2008)

    Article  Google Scholar 

  37. M. Colombini, Trends Biochem. Sci. 34, 382 (2009)

    Article  Google Scholar 

  38. M.N. Davies, C.P. Toseland, D.S. Moss, D.R. Flower, BMC Biochem. 7, 18 (2006)

    Article  Google Scholar 

  39. G. Kieseritzky, E.W. Knapp, J. Comput. Chem. 29, 2575 (2008)

    Article  Google Scholar 

  40. U. Zachariae, A. Koumanov, H. Engelhardt, A. Karshikoff, Protein Sci. 11, 1309 (2002)

    Article  Google Scholar 

  41. A. Karshikoff, V. Spassov, S.W. Cowan, R. Ladenstein, T. Schirmer, J. Mol. Biol. 240, 372 (1994)

    Article  Google Scholar 

  42. A. Alcaraz, E.M. Nestorovich, M. Aguilella-Arzo, V.M. Aguilella, S.M. Bezrukov, Biophys. J. 87, 943 (2004)

    Article  Google Scholar 

  43. S. Varma, E. Jakobsson, Biophys. J. 86, 690 (2004)

    Article  ADS  Google Scholar 

  44. D. Bashford, K. Gerwert, J. Mol. Biol. 224, 473 (1992)

    Article  Google Scholar 

  45. L. Song, M.R. Hobaugh, C. Shustak, S. Cheley, H. Bayley, J.E. Gouaux, Science 274, 1859 (1996)

    Article  ADS  Google Scholar 

  46. M. Misakian, J.J. Kasianowicz, J. Membrane Biol. 195, 137 (2003)

    Article  Google Scholar 

  47. S.Y. Noskov, W. Im, B. Roux, Biophys. J. 87, 2299 (2004)

    Article  ADS  Google Scholar 

  48. I. Cozmuta, J.T. O’Keeffe, D. Bose, V. Stolc, Molec. Simul. 31, 79 (2005)

    Article  Google Scholar 

  49. A. Aksimentiev, K. Schulten, Biophys. J. 88, 3745 (2005)

    Article  Google Scholar 

  50. D.B. Wells, V. Abramkina, A. Aksimentiev, J. Chem. Phys. 127, 125101 (2007)

    Article  ADS  Google Scholar 

  51. S. Varma, S.-W. Chiu, E. Jakobsson, Biophys. J. 90, 112 (2006)

    Article  ADS  Google Scholar 

  52. J.E. Nielsen, J. Mol. Graph. Model. 25, 691 (2007)

    Article  Google Scholar 

  53. D. Bashford, M. Karplus, Biochemistry 29, 10219 (1990)

    Article  Google Scholar 

  54. J. Antosiewicz, J.A. McCammon, M.K. Gilson, J. Mol. Biol. 238, 415 (1994)

    Article  Google Scholar 

  55. F. Fogolari, L. Ragona, S. Licciardi, S. Romagnoli, R. Michelutti, R. Ugolini, H. Molinari, Proteins: Struct. Funct. Genet. 39, 317 (2000)

    Article  Google Scholar 

  56. F. Fogolari, A. Brigo, H. Molinari, J. Mol. Recognit. 15, 377 (2002)

    Article  Google Scholar 

  57. J.D. Madura, J.M. Briggs, R.C. Wade, M.E. Davis, B.A. Luty, A. Ilin, J. Antosiewicz, M.K. Gilson, B. Bagheri, L.R. Scott, J.A. McCammon, Comput. Phys. Commun. 91, 57 (1995)

    Article  ADS  Google Scholar 

  58. The protein data bank, http://www.rcsb.org/pdb explore/explore.do?structureId=7AHL

  59. W. Humphrey, A. Dalke, K. Schulten, Molec. Graphics 14, 33 (1996)

    Article  Google Scholar 

  60. S.M. Bezrukov, J.J. Kasianowicz, Phys. Rev. Lett. 70, 2352 (1993)

    Article  ADS  Google Scholar 

  61. J.J. Kasianowicz, S.M. Bezrukov, Biophys. J. 69, 94 (1995)

    Article  ADS  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Physics, Universitat Jaume I, Av. Sos Baynat s/n, E-12078, Castellón, Spain

    M. Aguilella-Arzo & V. M. Aguilella

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  1. M. Aguilella-Arzo
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  2. V. M. Aguilella
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Correspondence to V. M. Aguilella.

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Aguilella-Arzo, M., Aguilella, V.M. Continuum electrostatic calculations of the pKa of ionizable residues in an ion channel: Dynamic vs. static input structure. Eur. Phys. J. E 31, 429–439 (2010). https://doi.org/10.1140/epje/i2010-10597-y

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