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Molecular Biology

, Volume 52, Issue 5, pp 723–731 | Cite as

Steered Molecular Dynamics Simulation Study of Quantified Effects of Point Mutation Induced by Breast Cancer on Mechanical Behavior of E-Cadherin

  • Sh. Azadi
  • M. Tafazzoli-ShadpourEmail author
  • R. Omidvar
STRUCTURAL-FUNCTIONAL ANALYSIS OF BIOPOLYMERS AND THEIR COMPLEXES
  • 84 Downloads

Abstract

E-cadherin is a member of the cadherin family that plays a key role in the formation of cell-cell adhesion among epithelial tissues. Point mutations are one of the structural abnormalities of E-cadherin in human carcinomas. Such abnormalities can alter mechanical properties of proteins that play an important role in their biological activities. To determine the impact of point mutations on protein mechanical properties, the second fragment of extracellular domain of E-cadherin was modeled using steered molecular dynamics simulations. The molecular dynamics modeling included application of tensile forces in both constant velocity and constant force modes to examine the effects of Met282 to Ile and Asn315 to Ser mutations on mechanical behavior of protein structure. The stabilities of the wild type and mutant structures were also obtained by the protein design foldX algorithm. Results confirmed the lower stability of the mutant domains compared to the wild type. The mutated proteins displayed softer behavior than the reference protein and their stiffness decreased by up to 34%. Our findings suggest that local changes in molecular structure due to mutations may lead to noticeable alterations in mechanical properties within the entire domain. Since the function of protein is related to its structure, these changes may influence the function of the protein.

Keywords:

steered molecular dynamics point mutation breast cancer stiffness protein stability 

Notes

ACKNOWLEDGMENTS

The authors gratefully thank high performance computing research center (HPCRC) of AmirKabir University of technology for the allocation of the supercomputer time used for carrying out these simulations.

REFERENCES

  1. 1.
    Patel S.D., Chen C.P., Bahna F., Honig B., Shapiro L. 2003. Cadherin-mediated cell–cell adhesion: Sticking together as a family. Curr. Opin. Struct. Biol. 13, 690‒698.CrossRefPubMedGoogle Scholar
  2. 2.
    Hulpiau P., van Roy F. 2009. Molecular evolution of the cadherin superfamily. Int. J. Biochem. Cell Biol. 41, 349‒369.CrossRefPubMedGoogle Scholar
  3. 3.
    Shapiro L., Weis W.I. 2009. Structure and biochemistry of cadherins and catenins. Cold. Spring. Harb. Perspect. Biol. 1, a003053.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Birchmeier W., Behrens J. 1994. Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta. 1198, 11‒26.PubMedGoogle Scholar
  5. 5.
    Takeichi M. 1990. Cadherins: A molecular family important in selective cell–cell adhesion. Annu. Rev. Biochem. 59, 237‒252.CrossRefPubMedGoogle Scholar
  6. 6.
    Kase S., Sugio K., Yamazaki K., Okamoto T., Yano T., Sugimachi K. 2000. Expression of E-cadherin and β‑catenin in human non-small cell lung cancer and the clinical significance. Clin. Cancer. Res. 6, 4789‒4796.PubMedGoogle Scholar
  7. 7.
    Berx G., Becker K.-F., Höfler H., van Roy F. 1998. Mutations of the human E-cadherin (CDH1) gene. Hum. Mutat. 12 (4), 226‒237.CrossRefPubMedGoogle Scholar
  8. 8.
    Kanai Y., Oda T., Tsuda H., Ochiai A., Hirohashi S. 1994. Point mutation of the E-cadherin gene in invasive lobular carcinoma of the breast. Jpn. J. Cancer. Res. 85, 1035‒1039.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hiraguri S., Godfrey T., Nakamura H., Graff J., Collins C., Shayesteh L., Doggett N., Johnson K., Wheelock M., Herman J., Baylin S., Pinkel D., Gray J. 1998. Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Res. 58, 1972‒1977.PubMedGoogle Scholar
  10. 10.
    Chanock S.J., Burdett L., Yeager M., Llaca V., Langerod A., Presswalla S., Kaaresen R., Strausberg R.L., Gerhard D.S., Kristensen V., Perou C.M., Børresen-Dale A.L. 2007. Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas. Breast Cancer Res. 9, R5.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Weng J., Wang W. 2014. Molecular dynamics simulation of membrane proteins. In: Protein Conformational Dynamics. Springer, pp. 305‒329.Google Scholar
  12. 12.
    Sotomayor M., Schulten K. 2007. Single-molecule experiments in vitro and in silico. Science. 316, 1144‒1148.CrossRefPubMedGoogle Scholar
  13. 13.
    Lindahl E. 2008. Molecular dynamics simulations. In: Molecular Modeling of Proteins, vol. 443. Ed. Kukol A. New York: Humana Press, pp. 3‒23.Google Scholar
  14. 14.
    Bozorgmehr M.R., Monhemi H. 2015. How can a free amino acid stabilize a protein? Insights from molecular dynamics simulation. J. Solution Chem. 44, 45‒53.CrossRefGoogle Scholar
  15. 15.
    Navizet I., Cailliez F., Lavery R. 2004. Probing protein mechanics: Residue-level properties and their use in defining domains. Biophys. J. 87, 1426‒1435.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Isralewitz B., Baudry J., Gullingsrud J., Kosztin D., Schulten K. 2001. Steered molecular dynamics investigations of protein function. J. Mol. Graph. Model. 19, 13‒25.CrossRefPubMedGoogle Scholar
  17. 17.
    Lu H., Schulten K. 1999. Steered molecular dynamics simulations of force-induced protein domain unfolding. Proteins. 35, 453‒463.CrossRefPubMedGoogle Scholar
  18. 18.
    Isralewitz B., Gao M., Schulten K. 2001. Steered molecular dynamics and mechanical functions of proteins. Curr. Opin. Struct. Biol. 11, 224‒230.CrossRefPubMedGoogle Scholar
  19. 19.
    Xu C., Li D., Cheng Y., Liu M., Zhang Y., Ji B. 2015. Pulling out a peptide chain from beta-sheet crystallite: Propagation of instability of H-bonds under shear force. Acta Mech. Sinica. 31 (3), 416‒424.CrossRefGoogle Scholar
  20. 20.
    Guzmán D.L., Randall A., Baldi P., Guan Z. 2010. Computational and single-molecule force studies of a macro domain protein reveal a key molecular determinant for mechanical stability. Proc. Natl. Acad. Sci. U. S. A. 107, 1989‒1994.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yoon Y.J., Cho K.H., Han S.Y. 2014. Viscoelastic behavior of a single collagen molecule. Int. J. Precis. Eng. Man. 15, 783‒786.CrossRefGoogle Scholar
  22. 22.
    Pradhan S., Katti D., Katti K. 2011. Steered molecular dynamics study of mechanical response of full length and short collagen molecules. J. Nanomech. Micromech. 1, 104‒110.CrossRefGoogle Scholar
  23. 23.
    Li D., Zhang Y., Zhao R.N., Fan S., Han J.G. 2014. Investigation on the mechanism for the binding and drug resistance of wild type and mutations of G86 residue in HIV-1 protease complexed with Darunavir by molecular dynamic simulation and free energy calculation. J. Mol. Model. 20, 1‒11.Google Scholar
  24. 24.
    Allen W.J., Wiley M.R., Myles K.M., Adelman Z.N. Bevan D.R. 2014. Steered molecular dynamics identifies critical residues of the Nodamura virus B2 suppressor of RNAi. J. Mol. Model. 20, 1‒10.CrossRefGoogle Scholar
  25. 25.
    Arakelov G.G., Osipov O.V., Nazaryan K.B. 2015. Effects of M680I and M694V pyrin mutations on the tertiary structure of domain B30. 2 and its interaction with caspase-1: In silico analysis. Mol. Biol. (Moscow). 49, 736–741.CrossRefGoogle Scholar
  26. 26.
    Miño G., Baez M., Gutierrez G. 2013. Effect of mutation at the interface of Trp-repressor dimeric protein: A steered molecular dynamics simulation. Eur. Biophys. J. 42, 683‒690.CrossRefPubMedGoogle Scholar
  27. 27.
    Chatterjee P., Sengupta N. 2012. Effect of the A30P mutation on the structural dynamics of micelle-bound alphaSynuclein released in water: A molecular dynamics study. Eur. Biophys. J. 41, 483‒489.CrossRefPubMedGoogle Scholar
  28. 28.
    Gautieri A., Vesentini S., Redaelli A., Buehler M.J. 2009. Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains. Protein Sci. 18, 161‒168.PubMedGoogle Scholar
  29. 29.
    Lee W., Strumpfer J., Bennett V., Schulten K., Marszalek P.E. 2012. Mutation of conserved histidines alters tertiary structure and nanomechanics of consensus ankyrin repeats. J. Biol. Chem. 287, 19 115‒19 121.CrossRefGoogle Scholar
  30. 30.
    Chen X., Zhu S., Wang S., Yang D., Zhang J. 2013. Molecular dynamics study on the stability of wild-type and the R220K mutant of human prion protein. Mol. Simulat. 40, 504‒513.CrossRefGoogle Scholar
  31. 31.
    Cailliez F., Lavery R. 2005. Cadherin mechanics and complexation: The importance of calcium binding. Biophys. J. 89, 3895‒3903.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cailliez F., Lavery R. 2006. Dynamics and stability of E-cadherin dimers. Biophys. J. 91, 3964‒3971.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    van Roy F., Berx G. 2008. The cell-cell adhesion molecule E-cadherin. Cell. Mol. Life Sci. 65, 3756‒3788.CrossRefPubMedGoogle Scholar
  34. 34.
    Parisini E., Higgins J.M., Liu J.H., Brenner M.B., Wang J.H. 2007. The crystal structure of human E-cadherin domains 1 and 2, and comparison with other cadherins in the context of adhesion mechanism. J. Mol. Biol. 373, 401‒411.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kiefer F., Arnold K., Kunzli M., Bordoli L., Schwede T. 2009. The SWISS-MODEL Repository and associated resources. Nucleic Acids Res. 37, D387‒D392.CrossRefPubMedGoogle Scholar
  36. 36.
    Biasini M., Bienert S., Waterhouse A., Arnold K., Studer G., Schmidt T., Kiefer F., Cassarino T.G., Bertoni M., Bordoli L., Schwede T. 2014. SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 42, W252‒W258.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schymkowitz J., Borg J., Stricher F., Nys R., Rousseau F., Serrano L. 2005. The FoldX web server: An online force field. Nucleic Acids Res. 33, W382‒W388.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Schymkowitz J.W., Rousseau F., Martins I.C., Ferkinghoff-Borg J., Stricher F., Serrano L. 2005. Prediction of water and metal binding sites and their affinities by using the Fold-X force field. Proc. Natl. Acad. Sci. U. S. A. 102, 10 147‒10 152.CrossRefGoogle Scholar
  39. 39.
    Guerois R., Nielsen J.E., Serrano L. 2002. Predicting changes in the stability of proteins and protein complexes: A study of more than 1000 mutations. J. Mol. Biol. 320, 369‒387.CrossRefPubMedGoogle Scholar
  40. 40.
    Joana S.-C., Joana F., Rui L., François S., Carla O., Luis S., Raquel S. 2012. E-Cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer. PLoS One. 7, e33783.CrossRefGoogle Scholar
  41. 41.
    Kalé L., Skeel R., Bhandarkar M., Brunner R., Gursoy A., Krawetz N., Phillips J., Shinozaki A., Varadarajan K., Schulten, K. 1999. NAMD2: Greater scalability for parallel molecular dynamics. J. Comput. Phys. 151, 283‒312.CrossRefGoogle Scholar
  42. 42.
    MacKerell A.D., Bashford D., Bellott Dunbrack R.L., Evanseck J.D., Field M.J., Fischer S., Gao J., Guo H., Ha S., Joseph-McCarthy D., Kuchnir L., Kuczera K., Lau F.T., Mattos C., Michnick S., et al. 1998. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B. 102, 3586‒3616.CrossRefPubMedGoogle Scholar
  43. 43.
    York D.M., Darden T.A., Pedersen L.G. 1993. The effect of long-range electrostatic interactions in simulations of macromolecular crystals: A comparison of the Ewald and truncated list methods. J. Chem. Phys. 99, 8345‒8348.CrossRefGoogle Scholar
  44. 44.
    Cheatham T.E., III Miller J.L., Fox T., Darden T.A., Kollman P.A. 1995. Molecular dynamics simulations on solvated biomolecular systems: The particle mesh Ewald method leads to stable trajectories of DNA, RNA, and proteins. J. Am. Chem. Soc. 117, 4193‒4194.CrossRefGoogle Scholar
  45. 45.
    Bayas M.V., Schulten K., Leckband D. 2003. Forced detachment of the CD2–CD58 complex. Biophys. J. 84, 2223‒2233.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Humphrey W., Dalke A., Schulten K. 1996. VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33‒38, 27‒38.Google Scholar
  47. 47.
    Boal D.H. 2002. Mechanics of the Cell. Cambridge: Cambridge Univ. Press.Google Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  1. 1.Faculty of Biomedical Engineering, Amirkabir University of TechnologyTehranIran

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