Journal of the Iranian Chemical Society

, Volume 14, Issue 9, pp 2023–2039 | Cite as

Are Pro8/Pro18 really critical for functional dynamic behavior of human endostatin N-terminal peptide? A comparative molecular dynamics study

Original Paper
First Online:
Received:
Accepted:

Abstract

Endostatin which is derived from the non-collagenous domain 1 of collagen XVIII and is a recently identified broad spectrum anti-angiogenesis agent, inhibits 65 different tumor types. The N-terminal fragment of endostatin protein (ES) has the same antitumor, antimigration and antipermeability effects as the entire protein. In the current study, we modeled two mutant variants of ES with two mutation sites (M1-ES (Pro8 → Ala) and M2-ES (Pro18 → Ala)) and tried to understand proline’s effect on the peptide structure/stability by introducing P8A/P18A mutations, and then in order to gain functional insight into mutation caused by amino acid substitution to the peptide structure/function, these effects were predicted using computational tools. From the RMSD analyses, it can be concluded that dynamic behavior of wild-type and mutant structures was not significantly different from each other and all systems reached equilibrium. The RMSF analysis also revealed that the M2-ES has smaller overall flexibility than the WT-ES and M1-ES structures. The radius of gyration analysis then confirmed the structure of M2-ES compared to wild-type and M1 variant becomes more compact during simulation of our systems. Finally, molecular dynamics simulation analysis shows that replacement of Pro residue with Ala is able to induce a distinct β-sheet in both mutant structures. Indeed, the docking analysis shows the WT-ES and M2-ES bind to the same region of αvβ3 integrin, suggesting similar interaction pattern with a relatively equal binding energy into this receptor. Our results speculated that the P8A/P18A replacements confer no improvement (or no tangible weakness) in the peptide biological activity although is able to change structural conformation of N-terminal fragment of human endostatin protein.

Keywords

Proline Endostatin MD simulation Molecular docking 

References

  1. 1.
    H. Rasouli, S. Parvaneh, A. Mahnam, M. Rastegari-Pouyani, Z. Hoseinkhani, K. Mansouri, Int. J. Biol. Macromol. 96, 118–128 (2017)CrossRefGoogle Scholar
  2. 2.
    H. Rasouli, L. Mahamed-Khosroushahi, K. Mansouri, J. Rep. Pharm. Sci. 3, 17–18 (2014)Google Scholar
  3. 3.
    K. Mansouri, A. Mostafie, D. Rezazadeh, M. Shahlaei, M.H. Modarressi, Hum. Mol. Genet. 25, 233–244 (2016)CrossRefGoogle Scholar
  4. 4.
    S. Pieraccini, M. Sironi, P. Francescato, G. Speranza, L.M. Vicentini, P. Manitto, Phys. Chem. Chem. Phys. 8, 3066 (2006)CrossRefGoogle Scholar
  5. 5.
    D. Hanahan, J. Folkman, Cell 86, 353 (1996)CrossRefGoogle Scholar
  6. 6.
    X. Qi, Y. Liu, W. Wei, X. Huang, Y. Zuo, Biomed. Rep. 1, 761 (2013)Google Scholar
  7. 7.
    P.H.M. Torres, G.L.S.C. Sousa, P.G. Pascutti, Proteins 79, 2684 (2011)CrossRefGoogle Scholar
  8. 8.
    M. Shichiri, Y. Hirata, FASEB J. 15, 1044 (2001)CrossRefGoogle Scholar
  9. 9.
    S. Tjin Tham, Robert M. Satchi-Fainaro, A.E.B. Ronit, V.M.S. Ramanujam, J. Folkman, K. Javaherian, Cancer Res. 65, 3656 (2005)CrossRefGoogle Scholar
  10. 10.
    M.G. Cattaneo, S. Pola, P. Francescato, F. Chillemi, L.M. Vicentini, Exp. Cell Res. 283, 230 (2003)CrossRefGoogle Scholar
  11. 11.
    M.P. Williamson, Biochem. J. 297, 249 (1994)CrossRefGoogle Scholar
  12. 12.
    A.A. Morgan, E. Rubenstein, PLoS ONE 8, e53785 (2013)CrossRefGoogle Scholar
  13. 13.
    H. Yamaguchi, J.N. Muth, M. Varadi, A. Schwartz, G. Varadi, Proc. Natl. Acad. Sci. USA 96, 1357 (1999)CrossRefGoogle Scholar
  14. 14.
    M.W. MacArthur, J.M. Thornton, J. Mol. Biol. 218, 397 (1991)CrossRefGoogle Scholar
  15. 15.
    M. Levitt, J. Mol. Biol. 145, 251 (1981)CrossRefGoogle Scholar
  16. 16.
    C. M Deber, B. Brodsky, A. Rath, eLS, 1 (2010)Google Scholar
  17. 17.
    D.J.A. Roderer, M.A. Schärer, M. Rubini, R. Glockshuber, Nature 5, 11840 (2015)Google Scholar
  18. 18.
    X. Robert, P. Gouet, Nucleic Acids Res. 42, W320 (2014)CrossRefGoogle Scholar
  19. 19.
    M. Mehrabi, R. Khodarahmi, M. Shahlaei, J. Biomol. Struct. Dyn. 21, 1–60 (2016). [Epub ahead of print] Google Scholar
  20. 20.
    R. De Paris, C.V. Quevedo, D.D. Ruiz, O.N. de Souza, R.C. Barros, Comput. Intell. Neurosci. 15, 1 (2015)CrossRefGoogle Scholar
  21. 21.
    Y.-H. Ding, K. Javaherian, K.-M. Lo, R. Chopra, T. Boehm, J. Lanciotti, B.A. Harris, Y. Li, R. Shapiro, E. Hohenester, R. Timpl, J. Folkman, D.C. Wiley, Proc. Natl. Acad. Sci. USA 95, 10443 (1998)CrossRefGoogle Scholar
  22. 22.
    A. Fiser, R.K. Do, A. Sali, Protein Sci. 9, 1753 (2000)CrossRefGoogle Scholar
  23. 23.
    G. Ratnavali, N. Devi, K. Sri, J. Raju, B. Sirisha, R. Kavitha, Ann. Biol. Res. 2, 114 (2011)Google Scholar
  24. 24.
    N. Eswar, D. Eramian, B. Webb, MY. Shen, A. Sali, Methods Mol Biol. 426, 145 (2008)CrossRefGoogle Scholar
  25. 25.
    R.A. Laskowski, M.W. MacArthur, D.S. Moss, J.M. Thornton, J. Appl. Crystallogr. 26, 283 (1993)CrossRefGoogle Scholar
  26. 26.
    C. Colovos, T.O. Yeates, Protein Sci. 2, 1511 (1993)CrossRefGoogle Scholar
  27. 27.
    B. Hess, J. Chem. Theory Comput. 4, 116 (2008)CrossRefGoogle Scholar
  28. 28.
    G. Bussi, D. Donadio, M. Parrinello, J. Chem. Phys. 126, 1 (2007)CrossRefGoogle Scholar
  29. 29.
    M. Parrinello, A. Rahman, J. Appl. Phys. 52, 7182 (1981)CrossRefGoogle Scholar
  30. 30.
    T. Darden, D. York, L. Pedersen, J. Chem. Phys. 98, 10089 (1993)CrossRefGoogle Scholar
  31. 31.
    D.E. Tanner, K.-Y. Chan. J. C. Phillips, K. Schulten. J. Chem. Theory Comput. 7, 3635 (2011)CrossRefGoogle Scholar
  32. 32.
    M.Ø. Jensen, T.R. Jensen, K. Kjaer, T. Bjørnholm, O.G. Mouritsen, G.H. Peters, Biophys. J. 83, 98 (2002)CrossRefGoogle Scholar
  33. 33.
    M. Shahlaei, B. Rahimi, M.R. Ashrafi-Koosh, K. Sadrjavadi, R. Khodarahmi, J. Lumin. 158, 91 (2015)CrossRefGoogle Scholar
  34. 34.
    W. Kabsch, C. Sander, Biopolymers 22, 2577 (1983)CrossRefGoogle Scholar
  35. 35.
    T.J. Dolinsky, P. Czodrowski, H. Li, J.E. Nielsen, G. Klebe, N.A. Baker, Nucleic Acids Res. 35, W522 (2007)CrossRefGoogle Scholar
  36. 36.
    N.A. Baker, D. Sept, S. Joseph, M.J. Holst, J.A. McCammon, Proc. Natl. Acad. Sci. USA 98, 10037 (2001)CrossRefGoogle Scholar
  37. 37.
    K. Lee, Int. J. Mol. Sci. 9, 65 (2008)CrossRefGoogle Scholar
  38. 38.
    H. Rasouli, S. Hosseini-Ghazvini, H.R. Adibi, Khodarahmi, Food Funct. 1 (2017)Google Scholar
  39. 39.
    J.B. Ghasemi, E. Nazarshodeh, H. Abedi, J. Iran Chem. Soc. 12, 1789 (2015)CrossRefGoogle Scholar
  40. 40.
    S.R. Comeau, D.W. Gatchell, S. Vajda, C.J. Camacho, Bioinformatics 20, 45 (2004)CrossRefGoogle Scholar
  41. 41.
    A. Rakhmetov, S.P. Lee, D. Grebinyk, L. Ostapchenko, H.Z. Chae, J. Appl. Pharm. Sci. 5, 8011 (2015)Google Scholar
  42. 42.
    J.-P. Xiong, B. Mahalingham, J.L. Alonso, L.A. Borrelli, X. Rui, S. Anand, B.T. Hyman, T. Rysiok, D. Müller-Pompalla, S.L. Goodman, M.A. Arnaout, J. Cell Biol. 186, 589 (2009)CrossRefGoogle Scholar
  43. 43.
    R.A. Laskowski, Nucleic Acids Res. 29, 221 (2001)CrossRefGoogle Scholar
  44. 44.
    A. Elengoe, M. Abu Naser, S. Hamdan, Int. J. Mol. Sci. 15, 6797 (2014)CrossRefGoogle Scholar
  45. 45.
    U.B. Sonavane, S.K. Ramadugu, R.R. Joshi, J. Biomol. Struct. Dyn. 26, 203 (2008)CrossRefGoogle Scholar
  46. 46.
    M. Sekijima, C. Motono, S. Yamasaki, K. Kaneko, Y. Akiyama, Biophys. J. 85, 1176 (2003)CrossRefGoogle Scholar
  47. 47.
    D. van der Spoel, H.J. Vogel, H.J.C. Berendsen, Proteins Struct. Funct. Genet. 24, 450 (1996)CrossRefGoogle Scholar
  48. 48.
    N.S.F. Mazlan, N.B.A. Khairudin, J. Biomol. Struct. Dyn. 34, 1486 (2015)CrossRefGoogle Scholar
  49. 49.
    M.Y. Lobanov, N.S. Bogatyreva, O.V. Galzitskaya, Mol. Biol. 42, 623 (2008)CrossRefGoogle Scholar
  50. 50.
    H.-L. Liu, Y.-C. Wu, J.-H. Zhao, H.-W. Fang, Y. Ho, J. Biomol. Struct. Dyn. 24, 229 (2006)CrossRefGoogle Scholar
  51. 51.
    S. Dalal, A. Mhashal, N. Kadoo, S.M. Gaikwad, J. Biomol. Struct. Dyn. 35, 330 (2016)CrossRefGoogle Scholar
  52. 52.
    R.E. Hubbard, K.H. Muhammad, Encyclopedia of Life Sciences (Wiley, Chichester, 2010)Google Scholar
  53. 53.
    S. Stahl, S. Gaetzner, T.D. Mueller, U. Felbor, Genes Cells 10, 929 (2005)CrossRefGoogle Scholar
  54. 54.
    P.K. Weiner, R. Langridge, J.M. Blaney, R. Schaefer, P.A. Kollman, Proc. Natl. Acad. Sci. USA 79, 3754 (1982)CrossRefGoogle Scholar
  55. 55.
    C. Carvalho, D. Vlachakis, G. Tsiliki, V. Megalooikonomou, S. Kossida, Peer J. 1, e185 (2013)CrossRefGoogle Scholar
  56. 56.
    A.-B. H. Mekky. H. G. Elhaes. M. M. El-Okr, M. A. Ibrahim, J. Nanomater. Mol. Nanotechnol. 2015 (2015)Google Scholar
  57. 57.
    Z. Zhe, W. Shawn, A. Emil, Phys. Biol. 8, 035001 (2011)CrossRefGoogle Scholar
  58. 58.
    X.-Y. Meng, H.-X. Zhang, M. Mezei, M. Cui, Curr. Comput. Aided Drug Des. 7, 146 (2011)CrossRefGoogle Scholar
  59. 59.
    B.J. McConkey, V. Sobolev, M. Edelman, Curr. Sci. 83, 845 (2002)Google Scholar
  60. 60.
    R.C. Turaga, L. Yin, J.J. Yang, H. Lee, I. Ivanov, C. Yan, H. Yang, H.E. Grossniklaus, S. Wang, C. Ma, L. Sun, R. Liu, Nature 7, 11675 (2016)Google Scholar
  61. 61.
    R.O. Hynes, Cell 110, 673 (2002)CrossRefGoogle Scholar
  62. 62.
    R. Chamani, S.M. Asghari, A.M. Alizadeh, K. Mansouri, T. Doroudi, P.H. Kolivand, H. Ghafouri, S. Ehtesham, H. Rabouti, F. Mehrnejad, Biochim. Biophys. Acta (BBA)-Proteins Proteom. 1864, 1765 (2016)CrossRefGoogle Scholar
  63. 63.
    R. Chamani, S.M. Asghari, A.M. Alizadeh, S. Eskandari, K. Mansouri, R. Khodarahmi, M. Taghdir, Z. Heidari, A. Gorji, A. Aliakbar, B. Ranjbar, K. Khajeh, Vasc. Pharmacol. 72, 73 (2016)CrossRefGoogle Scholar
  64. 64.
    C. Faye, C. Moreau, E. Chautard, R. Jetne, N. Fukai, F. Ruggiero, M.J. Humphries, B.R. Olsen, S. Ricard-Blum, J. Biol. Chem. 284, 22029 (2009)CrossRefGoogle Scholar
  65. 65.
    N.M. Pandya, N.S. Dhalla, D.D. Santani, Vasc. Pharmacol. 44, 265 (2006)CrossRefGoogle Scholar
  66. 66.
    N. Yamaguchi, B. Anand-Apte, M. Lee, T. Sasaki, N. Fukai, R. Shapiro, I. Que, C. Lowik, R. Timpl, B. Oslen, EMBO J. 18, 4414 (1999)CrossRefGoogle Scholar
  67. 67.
    S.A. Wickström, K. Alitalo, J. Keski-Oja, Adv. Cancer Res. 94, 197 (2005)CrossRefGoogle Scholar
  68. 68.
    M.S. O’Reilly, T. Boehm, Y. Shing, N. Fukai, G. Vasios, W.S. Lane, E. Flynn, J.R. Birkhead, B.R. Olsen, J. Folkman, Cell 88, 277 (1997)CrossRefGoogle Scholar
  69. 69.
    S.A. Wickström, K. Alitalo, J. Keski-Oja, J. Biol. Chem. 279, 20178 (2004)CrossRefGoogle Scholar
  70. 70.
    M. Rehn, T. Veikkola, E. Kukk-Valdre, H. Nakamura, M. Ilmonen, C.R. Lombardo, T. Pihlajaniemi, K. Alitalo, K. Vuori, Proc. Natl. Acad. Sci. USA 98, 1024 (2001)CrossRefGoogle Scholar
  71. 71.
    A.K. Olsson, I. Johansson, H. Åkerud, B. Einarsson, R. Christofferson, T. Sasaki, R. Timpl, L. Claesson-Welsh, Cancer Res. 64, 9012 (2004)CrossRefGoogle Scholar
  72. 72.
    S.P. Balasubramanian, S.S. Cross, J. Globe, A. Cox, N.J. Brown, M.W. Reed, BMC Cancer 7, 1 (2007)CrossRefGoogle Scholar
  73. 73.
    A. Abdollahi, L. Hlatky, P.E. Huber, Drug Resist. Update 8, 59 (2005)CrossRefGoogle Scholar
  74. 74.
    A. Kolozsi, A. Jancsó, N.V. Nagy, T. Gajda, J. Inorg. Biochem. 103, 940 (2009)CrossRefGoogle Scholar
  75. 75.
    K. Javaherian, T.-Y. Lee, R.M. Tjin Tham Sjin, D.E. Parris, L. Hlatky, Dose Response 9, 369 (2011)CrossRefGoogle Scholar
  76. 76.
    A.M. Thayer, Chem. Eng. News 89, 13 (2011)Google Scholar
  77. 77.
    C. Borghouts, C. Kunz, B. Groner, J. Pept. Sci. 11, 713 (2005)CrossRefGoogle Scholar
  78. 78.
    A. Zambrowicz, M. Timmer, A. Polanowski, G. Lubec, T. Trziszka, Amino Acids 44, 315 (2013)CrossRefGoogle Scholar
  79. 79.
    J. Thundimadathil, J. Amino Acids 2012, 1 (2012)CrossRefGoogle Scholar
  80. 80.
    C.G.P. Doss, B. Rajith, N. Garwasis, P.R. Mathew, A.S. Raju, K. Apoorva, D. William, N. Sadhana, T. Himani, I. Dike, Appl. Transl. Genom. 1, 37 (2012)CrossRefGoogle Scholar
  81. 81.
    M. Hacke, T. Gruber, C. Schulenburg, J. Balbach, U. Arnold, FEBS J. 280, 4454 (2013)CrossRefGoogle Scholar
  82. 82.
    A.K. Jha, A. Colubri, M.H. Zaman, S. Koide, T.R. Sosnick, K.F. Freed, Biochemistry 44, 9691 (2005)CrossRefGoogle Scholar
  83. 83.
    V. Vieille, G.J. Zeikus, Microbiol. Mol. Biol. Rev. 65, 1 (2001)CrossRefGoogle Scholar
  84. 84.
    W.J. Wedemeyer, E. Welker, H.A. Scheraga, Biochemistry 41, 14637 (2002)CrossRefGoogle Scholar
  85. 85.
    T.F. Huang, Cell. Mol. Life Sci. 54, 527 (1998)CrossRefGoogle Scholar
  86. 86.
    L.A. Calderon, J.C. Sobrinho, D.K. Zaqueo, A.A. De Moura, A.N. Grabner, M.V. Mazzi, S. Marcussi, A. Nomizo, C.F.C. Fernandes, J.P. Zuliani, B.M.N. Carvalho, S.L. da Silva, R.G. Stábeli, A.M. Soares, BioMed. Res. Int. 1, 1 (2014)CrossRefGoogle Scholar
  87. 87.
    Z. Liu, F. Wang, X. Chen, Drug Dev. Res. 69, 329 (2008)CrossRefGoogle Scholar

Copyright information

© Iranian Chemical Society 2017

Authors and Affiliations

  1. 1.Medical Biology Research CenterKermanshah University of Medical SciencesKermanshahIran
  2. 2.Department of Biophysics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
  3. 3.Department of Pharmacognosy and Biotechnology, Faculty of PharmacyKermanshah University of Medical SciencesKermanshahIran

Personalised recommendations