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Protein packing defects “heat up” interfacial water

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Abstract

Ligands must displace water molecules from their corresponding protein surface binding site during association. Thus, protein binding sites are expected to be surrounded by non-tightly-bound, easily removable water molecules. In turn, the existence of packing defects at protein binding sites has been also established. At such structural motifs, named dehydrons, the protein backbone is exposed to the solvent since the intramolecular interactions are incompletely wrapped by non-polar groups. Hence, dehydrons are sticky since they depend on additional intermolecular wrapping in order to properly protect the structure from water attack. Thus, a picture of protein binding is emerging wherein binding sites should be both dehydrons rich and surrounded by easily removable water. In this work we shall indeed confirm such a link between structure and dynamics by showing the existence of a firm correlation between the degree of underwrapping of the protein chain and the mobility of the corresponding hydration water molecules. In other words, we shall show that protein packing defects promote their local dehydration, thus producing a region of “hot” interfacial water which might be easily removed by a ligand upon association.

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References

  1. J. Qvist, M. Davidovic, D. Hamelberg, B. Halle, Proc. Natl. Acad. Sci. U.S.A. 105, 6296 (2008)

    Article  ADS  Google Scholar 

  2. T. Young, R. Abel, B. Kim, B.J. Berne, R.A. Friesner, Proc. Natl. Acad. Sci. U.S.A. 104, 808 (2007)

    Article  ADS  Google Scholar 

  3. C. Wang, B.J. Berne, R.A. Friesner, Proc. Natl. Acad. Sci. U.S.A. 108, 1326 (2011)

    Article  ADS  Google Scholar 

  4. A. Fernández, H.A. Scheraga, Proc. Natl. Acad. Sci. U.S.A. 100, 113 (2003)

    Article  ADS  Google Scholar 

  5. A. Fernández, R. Scott, Biophysical. J. 85, 1914 (2003)

    Article  ADS  Google Scholar 

  6. A. Fernández, in Transformative Concepts for Drug Design: Target Wrapping Vol. 1 (Springer: Heidelberg, 2010) pp. 1-224

  7. A. Fernández, R. Scott, Phys. Rev. Lett. 91, 018102 (2003)

    Article  ADS  Google Scholar 

  8. A. Fernández, J. Chen, A. Crespo, J. Chem. Phys. 126, 245103 (2007)

    Article  ADS  Google Scholar 

  9. N. Pietrosemoli, A. Crespo, A. Fernández, J. Prot. Res. 6, 3519 (2007)

    Article  Google Scholar 

  10. A. Fernández, Nat. Biotech. 22, 1081 (2004)

    Article  Google Scholar 

  11. A. Fernández, M. Lynch, Nature 474, 502 (2011)

    Article  Google Scholar 

  12. E. Schulz, M. Frechero, G. Appignanesi, Ariel Fernández, PLoS ONE 5, e12844 (2010)

    Article  Google Scholar 

  13. S.R. Accordino, J.A. Rodríguez-Fris, G.A. Appignanesi, A. Fernández, Eur. Phys. J. E 35, 59 (2012) and arXiv:1108.2618v1 [cond-mat.soft]

    Article  Google Scholar 

  14. S.R. Accordino, M.A. Morini, M.B. Sierra, J.A. Rodríguez Fris, G.A. Appignanesi, A. Fernández, Proteins: Struct., Funct., Bioinf. 80, 1755 (2012)

    Google Scholar 

  15. R.A. Friesner et al., J. Med. Chem. 49, 6177 (2006)

    Article  Google Scholar 

  16. J.L. Kulp et al., JACS 133, 10740 (2011)

    Article  Google Scholar 

  17. S.R. Accordino, J.A. Rodríguez Fris, G.A. Appignanesi, PLoS ONE 8, e55123 (2013)

    Article  ADS  Google Scholar 

  18. P. Ball, Nature 423, 25 (2003)

    Article  ADS  Google Scholar 

  19. W.L. Jorgensen, J. Chandrasekhar, J.D. Madura, R.W. Impey, M.L. Klein, J. Chem. Phys. 79, 926 (1983)

    Article  ADS  Google Scholar 

  20. M.W. Mahoney, W.L. Jorgensen, J. Chem. Phys. 112, 8910 (2000)

    Article  ADS  Google Scholar 

  21. D.A. Case, T.A. Darden, T.E. Cheatham, III, C.L. Simmerling, J. Wang, R.E. Duke, R. Luo, R.C. Walker, W. Zhang, K.M. Merz, B.P. Roberts, B. Wang, S. Hayik, A. Roitberg, G. Seabra, I. Kolossvry, K.F. Wong, F. Paesani, J. Vanicek, J. Liu, X. Wu, S.R. Brozell, T. Steinbrecher, H. Gohlke, Q. Cai, X. Ye, J. Wang, M.-J. Hsieh, G. Cui, D.R. Roe, D.H. Mathews, M.G. Seetin, C. Sagui, V. Babin, T. Luchko, S. Gusarov, A. Kovalenko, P.A. Kollman, AMBER 11, University of California, San Francisco (2010)

  22. H. Zhong, H.A. Carlson, Proteins: Struct. Funct. Bioinf. 58, 222 (2005)

    Article  Google Scholar 

  23. D.C. Malaspina, E.P. Schulz, L.M. Alarcón, M.A. Frechero, G.A. Appignanesi, Eur. Phys. J. E 32, 35 (2010)

    Article  Google Scholar 

  24. S.R. Accordino, D.C. Malaspina, J.A. Rodríguez Fris, G.A. Appignanesi, Phys. Rev. Lett. 106, 029801 (2011)

    Article  ADS  Google Scholar 

  25. S.R. Accordino, D.C. Malaspina, J.A. Rodriguez Fris, L.M. Alarcón, G.A. Appignanesi, Phys. Rev. E 85, 031503 (2012)

    Article  ADS  Google Scholar 

  26. A.R. Bizzarri, S. Cannistraro, J. Phys. Chem. B 106, 6617 (2002)

    Article  Google Scholar 

  27. A.R. Bizzarri, A. Paciaroni, S. Cannistraro, Phys. Rev. E 62, 3991 (2000)

    Article  ADS  Google Scholar 

  28. P. Kumar, Z. Yan, L. Xu, M.G. Mazza, S.V. Buldyrev, S.-H. Chen, S. Sastry, H.E. Stanley, Phys. Rev. Lett. 97, 177802 (2006)

    Article  ADS  Google Scholar 

  29. P.G. Debenedetti, Metastable Liquids (Princeton University Press, Princeton, NJ, 1996)

  30. O. Mishima, H.E. Stanley, Nature 396, 329 (1998)

    Article  ADS  Google Scholar 

  31. C.A. Angell, Chem. Rev. 102, 2627 (2002)

    Article  Google Scholar 

  32. C.A. Angell, Annu. Rev. Phys. Chem. 55, 559 (2004)

    Article  ADS  Google Scholar 

  33. E. Shiratani, M. Sasai, J. Chem. Phys. 104, 7671 (1996)

    Article  ADS  Google Scholar 

  34. E. Shiratani, M. Sasai, J. Chem. Phys. 108, 3264 (1998)

    Article  ADS  Google Scholar 

  35. H.-G. Heide, Ultramicroscopy 14, 271 (1984)

    Article  Google Scholar 

  36. T. Loerting, N. Giovambattista, J. Phys.: Condens. Matter 18, 919 (2006)

    Article  ADS  Google Scholar 

  37. F. Sciortino, H. Geiger, H.E. Stanley, Phys. Rev. Lett. 65, 3452 (1990)

    Article  ADS  Google Scholar 

  38. J.A. Rodriguez Fris, G.A. Appignanesi, E. La Nave, F. Sciortino, Phys. Rev. E 75, 041501 (2007)

    Article  ADS  Google Scholar 

  39. G.A. Appignanesi, J.A. Rodriguez Fris, F. Sciortino, Eur. Phys. J. E 29, 305 (2009)

    Article  Google Scholar 

  40. S.R. Accordino, J.A. Rodriguez Fris, F. Sciortino, G.A. Appignanesi, Eur. Phys. J. E 34, 48 (2011)

    Article  Google Scholar 

  41. J.R. Errington, P.G. Debenedetti, Nature 409, 318 (2001)

    Article  ADS  Google Scholar 

  42. D.C. Malaspina, J.A. Rodríguez Fris, G.A. Appignanesi, F. Sciortino, Europhys. Lett. 88, 16003 (2009)

    Article  ADS  Google Scholar 

  43. G.A. Appignanesi, J.A. Rodríguez-Fris, R.A. Montani, W. Kob, Phys. Rev. Lett. 96, 057801 (2006)

    Article  ADS  Google Scholar 

  44. G.A. Appignanesi, J.A. Rodríguez-Fris, M.A. Frechero, Phys. Rev. Lett. 96, 237803 (2006)

    Article  ADS  Google Scholar 

  45. L.M. Iakoucheva, A.K. Dunker, Structure (London) 11, 1316 (2003)

    Article  Google Scholar 

  46. A.K. Dunker, Z. Obradovic, Z. Nat. Biotechnol. 19, 805 (2001)

    Article  Google Scholar 

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Sierra, M.B., Accordino, S.R., Rodriguez-Fris, J.A. et al. Protein packing defects “heat up” interfacial water. Eur. Phys. J. E 36, 62 (2013). https://doi.org/10.1140/epje/i2013-13062-7

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  • DOI: https://doi.org/10.1140/epje/i2013-13062-7

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