An analysis of the interactions between folic acid and aromatic guest molecules

  • Rajat Gupta
  • Sanat Mohanty
Original Paper


The formation of complexes between folate and therapeutic drug molecules is well known. In this work, we attempted to elucidate the role of the aromatic rings of folate and drug molecules in interactions between both of these molecules. A detailed molecular simulation study was carried out to explore the associative behavior of folic acid with phenylalanine and tyrosine, which show fluorescence emission following the excitation of these molecules at 257 nm and 274 nm, respectively. Therefore, studies of fluorescence emission from phenylalanine and tyrosine were performed in this work. The results of these studies indicated that folic acid associates with phenylalanine and tyrosine with binding constants ranging from 1.46 × 104 to 2.66 × 104 M−1. X-ray diffraction studies suggested that folic acid self-assembly is maintained in the presence of associative interactions of the folic acid with guest molecules. These results demonstrate that the aromatic rings in the structures of the folic acid and the therapeutic drug play an important role in the encapsulation of guest molecules through folate self-assembly.


Aromatic ring Folic acid Interaction Self-assembly Molecular simulations 



Folic acid








X-ray diffraction




Radial distribution function


Molecular dynamics


Binding constant


Fluorescence emission intensity with a particular concentration of FA


Fluorescence emission intensity without FA


Number of binding sites


  1. 1.
    Pandey S, Oza G, Mewada A et al (2013) Folic acid mediated synaphic delivery of doxorubicin using biogenic gold nanoparticles anchored to biological linkers. J Mater Chem B 1:1361–1370Google Scholar
  2. 2.
    Le Gourrierec L, Di Giorgio C, Greiner J, Vierling P (2008) Formulation of PEG-folic acid coated nanometric DNA particles from perfluoroalkylated cationic dimerizable detergents and in vitro folate-targeted intracellular delivery. New J Chem 32:2027–2042Google Scholar
  3. 3.
    Keresztessy Z, Bodnar M, Ber E et al (2009) Self-assembling chitosan/poly-γ-glutamic acid nanoparticles for targeted drug delivery. Colloid Polym Sci 287:759–765Google Scholar
  4. 4.
    Fujimori E (1959) Interaction between pteridines and tryptophan. Proc Natl Acad Sci 45:133–136Google Scholar
  5. 5.
    Singh R, Lillard Jr JW (2009) Nanoparticle-based targeted drug delivery. Exp Mol Pathol 86:215–223Google Scholar
  6. 6.
    Madziva H, Kailasapathy K, Phillips M (2005) Alginate–pectin microcapsules as a potential for folic acid delivery in foods. J Microencapsul 22:343–351Google Scholar
  7. 7.
    Madziva H, Kailasapathy K, Phillips M (2006) Evaluation of alginate–pectin capsules in cheddar cheese as a food carrier for the delivery of folic acid. LWT Food Sci Technol 39:146–151Google Scholar
  8. 8.
    Ding X, Yao P (2013) Soy protein/soy polysaccharide complex nanogels: folic acid loading, protection, and controlled delivery. Langmuir 29:8636–8644Google Scholar
  9. 9.
    Gottschalk S, Cristiano RJ, Smith LC, Woo S (1994) Folate receptor mediated DNA delivery into tumor cells: potosomal disruption results in enhanced gene expression. Gene Ther 1:185–191Google Scholar
  10. 10.
    Sudimack J, Lee RJ (2000) Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 41:147–162Google Scholar
  11. 11.
    Weitman SD, Lark RH, Coney LR et al (1992) Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 52:3396–3401Google Scholar
  12. 12.
    Coppen A, Bolander-Gouaille C (2005) Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol 19:59–65Google Scholar
  13. 13.
    Misra R, Upadhyay M, Perumal V, Mohanty S (2015) In vitro control release, cytotoxicity assessment and cellular uptake of methotrexate loaded liquid-crystalline folate nanocarrier. Biomed Pharmacother 69:102–110Google Scholar
  14. 14.
    Gupta R, Mohanty S (2017) Nanoparticle formulation having ability to control the release of protein for drug delivery application. Mater Sci Eng C 70:327–333Google Scholar
  15. 15.
    Misra R, Katyal H, Mohanty S (2014) Controlled release of folic acid through liquid-crystalline folate nanoparticles. Mater Sci Eng C 44:352–361Google Scholar
  16. 16.
    Misra R, Lonare M, Gupta R, Mohanty S (2014) Engineering chromonic nanoparticles from liquid-crystalline folate solutions. Sci Adv Mater 6:835–843Google Scholar
  17. 17.
    Gupta R, Mohanty S (2017) Controlled release of insulin from folic acid-insulin complex nanoparticles. Colloids Surf B Biointerfaces 154:48–54Google Scholar
  18. 18.
    Misra R, Mohanty S (2014) Sustained release of methotrexate through liquid-crystalline folate nanoparticles. J Mater Sci Mater Med 25:2095–2109Google Scholar
  19. 19.
    Bourassa P, Hasni I, Tajmir-Riahi HA (2011) Folic acid complexes with human and bovine serum albumins. Food Chem 129:1148–1155Google Scholar
  20. 20.
    Kanie K, Nishii M, Yasuda T et al (2001) Self-assembly of thermotropic liquid-crystalline folic acid derivatives: hydrogen-bonded complexes forming layers and columns. Basis of a presentation given at materials discussion no. 4, 11–14 September 2001, Grasmere, UK. J Mater Chem 11:2875–2886Google Scholar
  21. 21.
    Agrawal AK, Harde H, Thanki K, Jain S (2014) Improved stability and antidiabetic potential of insulin containing folic acid functionalized polymer stabilized multilayered liposomes following oral administration. Biomacromolecules 15:350–360Google Scholar
  22. 22.
    Liang L, Subirade M (2010) Beta-lactoglobulin/folic acid complexes: formation, characterization, and biological implication. J Phys Chem B 114:6707–6712Google Scholar
  23. 23.
    Zhang J, Liu Y, Liu X et al (2014) The folic acid/β-casein complex: characteristics and physicochemical implications. Food Res Int 57:162–167Google Scholar
  24. 24.
    Ciuchi F, Di Nicola G, Franz H et al (1994) Self-recognition and self-assembly of folic acid salts: columnar liquid crystalline polymorphism and the column growth process. J Am Chem Soc 116:7064–7071Google Scholar
  25. 25.
    Motkar G, Lonare M, Patil O, Mohanty S (2013) Self-assembly of folic acid in aqueous media. AICHE J 59:1360–1368Google Scholar
  26. 26.
    Kamikawa Y, Nishii M, Kato T (2004) Self-assembly of folic acid derivatives: induction of supramolecular chirality by hierarchical chiral structures. Chem Eur J 10:5942–5951Google Scholar
  27. 27.
    Parmar R, Misra R, Mohanty S (2015) In vitro controlled release of rifampicin through liquid-crystalline folate nanoparticles. Colloids Surf B Biointerfaces 129:198–205Google Scholar
  28. 28.
    Gupta R, Kalita P, Patil O, Mohanty S (2015) An investigation of folic acid–protein association sites and the effect of this association on folic acid self-assembly. J Mol Model 21:308Google Scholar
  29. 29.
    Brun F, Toulmé JJ, Hélène C (1975) Interactions of aromatic residues of proteins with nucleic acids. Fluorescence studies of the binding of oligopeptides containing tryptophan and tyrosine residues to polynucleotides. Biochemistry 14:558–563Google Scholar
  30. 30.
    Simonian MH, Smith JA (2006) Spectrophotometric and colorimetric determination of protein concentration. Curr Protoc Mol Biol 76:10.1.1–10.1A.9Google Scholar
  31. 31.
    Schmid FX (2001) Biological macromolecules: UV-visible spectrophotometry. In: Encyclopedia of life sciences (eLS). Macmillan, LondonGoogle Scholar
  32. 32.
    Patil O, Mohanty S (2014) Why folates self-assemble: a simulation-based study. Mol Simul 40:1147–1156Google Scholar
  33. 33.
    Teale FW, Weber G (1957) Ultraviolet fluorescence of the aromatic amino acids. Biochem J 65:476–482Google Scholar
  34. 34.
    Fraiji LK, Hayes DM, Werner TC (1992) Static and dynamic fluorescence quenching experiments for the physical chemistry laboratory. J Chem Educ 69:424Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemical EngineeringIndian Institute of Technology DelhiNew DelhiIndia

Personalised recommendations