Advertisement

Journal of Computer-Aided Molecular Design

, Volume 29, Issue 1, pp 23–35 | Cite as

Intermediate states in the binding process of folic acid to folate receptor α: insights by molecular dynamics and metadynamics

  • Stefano Della-LongaEmail author
  • Alessandro Arcovito
Article

Abstract

Folate receptor α (FRα) is a cell surface, glycophosphatidylinositol-anchored protein which has focussed attention as a therapeutic target and as a marker for the diagnosis of cancer. It has a high affinity for the dietary supplemented folic acid (FOL), carrying out endocytic transport across the cell membrane and delivering the folate at the acidic pH of the endosome. Starting from the recently reported X-ray structure at pH 7, 100 ns classical molecular dynamics simulations have been carried out on the FRα-FOL complex; moreover, the ligand dissociation process has been studied by metadynamics, a recently reported method for the analysis of free-energy surfaces (FES), providing clues on the intermediate states and their energy terms. Multiple dissociation runs were considered to enhance the configurational sampling; a final clustering of conformations within the averaged FES provides the representative structures of several intermediate states, within an overall barrier for ligand escape of about 75 kJ/mol. Escaping of FOL to solvent occurs while only minor changes affect the FRα conformation of the binding pocket. During dissociation, the FOL molecule translates and rotates around a turning point located in proximity of the receptor surface. FOL at this transition state assumes an “L” shaped conformation, with the pteridin ring oriented to optimize stacking within W102 and W140 residues, and the negatively charged glutamate tail, outside the receptor, interacting with the positively charged R103 and R106 residues, that contrary to the bound state, are solvent exposed. We show that metadynamics method can provide useful insights at the atomistic level on the effects of point-mutations affecting functionality, thus being a very promising tool for any study related to folate-targeted drug delivery or cancer therapies involving folate uptake.

Keywords

Bioinformatics Folate-targeted cancer therapies Folate metabolism Metadynamics Ligand binding dynamics 

Notes

Acknowledgments

Thanks are due to Prof. P. D’ Angelo and Dr. V. Migliorati for stimulating discussions and their help in comparing results from different quantum chemistry methods used to build-up the FOL partial charges. Financial support by the Italian Ministry of University and Research [Linea D1 Università Cattolica Sacro Cuore] is gratefully acknowledged.

Supplementary material

Supplementary material 1 (MOV 14790 kb)

Supplementary material 2 (AVI 4840 kb)

References

  1. 1.
    Antony AC (1992) Blood 79:2807–2820Google Scholar
  2. 2.
    Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, Roon P, Ganapathy V, Smith SB (2000) J Biol Chem 275:20676–20684CrossRefGoogle Scholar
  3. 3.
    Clifton GT, Sears AK, Clive KS, Holmes JP, Mittendorf EA, Ioannides CG, Ponniah S, Peoples GE (2011) Hum Vaccin 7:183–90Google Scholar
  4. 4.
    Solanky N, Requena Jimenez A, D’Souza SW, Sibley CP, Glazier JD (2010) Placenta 31:134–43Google Scholar
  5. 5.
    Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR Jr, Kamen BA (1992) Cancer Res 52:3396–3401Google Scholar
  6. 6.
    Matherly LH, Goldman DI (2003) Vitam Horm 66:403–456CrossRefGoogle Scholar
  7. 7.
    Dosio F, Milla P, Cattel L (2010) Curr Opin Investig Drugs 11:1424–1433Google Scholar
  8. 8.
    Maeng JH, Lee DH, Jung KH, Bae YH, Park IS, Jeong S, Jeon YS, Shim CK, Kim W, Kim J, Lee J, Lee YM, Kim JH, Kim WH, Hong SS (2010) Biomaterials 31:4995–5006CrossRefGoogle Scholar
  9. 9.
    Monaco HL (1997) EMBO J 16:1475–1483CrossRefGoogle Scholar
  10. 10.
    Della-Longa S, Arcovito A (2013) J Mol Graph Model 44:197–207CrossRefGoogle Scholar
  11. 11.
    Chen C, Ke J, Zhou XE, Yi W, Brunzelle JS, Li J, Yong EL, Xu HE, Melcher K (2013) Nature 500:486–489CrossRefGoogle Scholar
  12. 12.
    Berendsen HJC, van der Spoel D, van Drunen R (1995) Comput Phys Commun 91:43–56CrossRefGoogle Scholar
  13. 13.
    Hess B, Kutzner C, Lindhal E (2008) J Chem Theory Comput 4:435–447CrossRefGoogle Scholar
  14. 14.
    Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C (2006) Proteins 65:712–725CrossRefGoogle Scholar
  15. 15.
    Klamt A, Schuurmann G (1993) J Chem Soc Perkin Trans 2:799–805CrossRefGoogle Scholar
  16. 16.
    Breneman CM, Wiberg KB (1990) J Comput Chem 11:361–373CrossRefGoogle Scholar
  17. 17.
    Neese F University of Bonn, GermanyGoogle Scholar
  18. 18.
    Bussi G, Donadio D, Parrinello M (2007) J Chem Phys 126:014101CrossRefGoogle Scholar
  19. 19.
    Berendsen HJC, Postma JPM, van Gunsteren WF, Di Nola A, Haak JR (1984) J. Chem. Phys. 81:3684–3690CrossRefGoogle Scholar
  20. 20.
    Laio A, Parrinello M (2002) Proc Natl Acad Sci USA 99:12562–12566CrossRefGoogle Scholar
  21. 21.
    Tribello GA, Bonomi M, Branduardi D, Camilloni C, Bussi G (2014) Comput Phys Commun 185:604–613CrossRefGoogle Scholar
  22. 22.
    Laio A, Rodriguez-Fortea A, Gervasio FL, Ceccarelli M, Parrinello M (2005) J Phys Chem B 109:6714–6721CrossRefGoogle Scholar
  23. 23.
    Vargiu AV, Ruggerone P, Magistrato A, Carloni P (2008) Nucleic Acids Res 36:5910–5921CrossRefGoogle Scholar
  24. 24.
    Daura X, Gademann K, Jaun B, Seeback D, van Gusteren WF, Mark AE (1999) Angew Chem Int Ed 38:236–240CrossRefGoogle Scholar
  25. 25.
    Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, Ratnam M, Zhang F, Dann CE III (2013) Proc Natl Acad Sci USA 110:15180–15188CrossRefGoogle Scholar
  26. 26.
    Maziarz KM, Monaco HL, Shen F, Ratnam M (1999) J Biol Chem 274:11086–11091CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Dipartimento di Medicina Clinica, Sanità Pubblica, Scienze della Vita e dell’AmbienteUniversità dell’AquilaCoppitoItaly
  2. 2.Istituto di Biochimica e Biochimica ClinicaUniversità Cattolica del Sacro CuoreRomeItaly

Personalised recommendations