Abstract
Absorption of bioactive peptides in the intestinal epithelium take place in the apical or the basolateral tight junctions of the cells. Depending on the peptide size and hydrophobicity, translocation mechanisms involve processes of passive diffusion, active transport by peptide-cotransporters such as members of the PepT family, and transcytosis by internalization vesicles. In this work, we investigated passive diffusion of bioactive peptides of 6, 17, and 30 amino acids into lipid bilayers of (POPC) phospholipid molecules. We initially selected these three peptides because such fragments are produced by partial hydrolysis of β-casein (BCN), and because of their physiological functions: BCN6 is an agonist of opioid receptors; BCN17 is an inhibitor of thrombin and angiotensin-converting enzymes, and BCN30 promotes secretion of the protective mucin barrier in the intestine. Our computational set up consisted of unbiased equilibrium molecular dynamics simulations, at the μs-time scale, using an all-atom force field. Each peptide was allowed to freely fold and unfold, as well as enter and exit the lipid bilayer, which allows determination of peptide affinity for the bilayer interface and hydrophobic core. Passive internalization of BCN6 (YPVEPF), BCN17 (YQEPVLGPVR GPFPIIV), and BCN30 (GVSKVKEAMA PKHKEMPFPK YPVEPFTESQ) displayed different dynamics at the bilayer interface: the BCN6 peptide attached and detached throughout the simulation trajectory; BCN17 and BCN30 attached irreversibly to the bilayer interface, respectively, with N- and C-terminus fragments in close contact with lipid molecules. Quenching of tyrosine fluorescence data suggest interfacial interactions of BCN6, BCN17 and BCN30 in POPC lipid bilayers, consistent with the proposed modeling set up. This approach gave valuable information of peptide insertion and folding at a lipid bilayer, allowing to explore the initial stages of the peptide adsorption at the interface, and providing a model for evaluation of amphipathic properties of potential biofunctional peptides.
Similar content being viewed by others
References
D.P. Mohanty, S. Mohapatra, S. Misra, P.S. Sahu, Saudi J Biol Sci 23(5), 577–583 (2016)
B.N.P. Sah, T. Vasiljevic, S. McKechnie, O.N. Donkor, Compr Rev Food Sci F 14(2), 123–138 (2015)
H.S. Gill, F. Doull, K.J. Rutherfurd, M.L. Cross, Br. J. Nutr. 84(S1), 111–117 (2000)
M.R.u. Haq, R. Kapila, U.K. Shandilya, S. Kapila, Int. J. Food Prop. 17(8), 1726–1741 (2014)
M. Shimizu, Biosci. Biotechnol. Biochem. 74(2), 232-241 (2010)
F. Guettou, E.M. Quistgaard, M. Raba, P. Moberg, C. Löw, P. Nordlund, Nat. Struct. Mol. Biol. 21(8), 728–731 (2014)
M. Satake, M. Enjoh, Y. Nakamura, et al., Biosci. Biotechnol. Biochem. 66(2), 378–384 (2002)
M. Heyman, J.F. Desjeux, J. Pediatr. Gastroenterol. Nutr. 15(1), 48–57 (1992)
L. Barthe, J. Woodley, G. Houin, Fundam Clin Pharmacol 13(2), 154–168 (1999)
H. Teschemacher, Curr. Pharm. Des. 9(16), 1331–1344 (2003)
W. Zhang, J. Miao, S. Wang, Y. Zhang, PLoS One 8(5), e63472 (2013)
C.N.S. McLachlan, Med. Hypotheses 56(2), 262–272 (2001)
Y. Jinsmaa, M. Yoshikawa, Peptides 1999, 957–962 (1999)
R. Rojas-Ronquillo, A. Cruz-Guerrero, A. Flores-Nájera, G. Rodríguez-Serrano, L. Gómez-Ruiz, J.P. Reyes-Grajeda, J. Jiménez-Guzmán, M. García-Garibay, Int. Dairy J. 26(2), 147–154 (2012)
D. Regazzo, D. Mollé, G. Gabai, D. Tomé, D. Dupont, J. Leonil, R. Boutrou, Mol. Nutr. Food Res. 54(10), 1428–1435 (2010)
E.E. Sterchi, J.R. Green, M.J. Lentze, Biochem. Soc. Trans. 9(1), 130–131 (1981)
G. Picariello, P. Ferranti, F. Addeo, Food Res. Int. 88, 327–335 (2016)
P. Plaisancié, R. Boutrou, M. Estienne, G. Henry, J. Jardin, A. Paquet, J. Léonil, J. Dairy Res. 82(1), 36–46 (2015)
P. Plaisancié, J. Claustre, M. Estienne, G. Henry, R. Boutrou, A. Paquet, J. Léonil, J. Nutr. Biochem. 24(1), 213–221 (2013)
J.P. Ulmschneider, J.C. Smith, S.H. White, M.B. Ulmschneider, J. Am, Chem. Soc. 133(39), 15487–15495 (2011)
M.B. Ulmschneider, J.C. Smith, J.P. Ulmschneider, Biophys. J. 98, L60–L62 (2010)
E.T. Kaiser, F.J. Kézdy, Proc.Natl.Acad.Sci.USA 80(4), 1137–1143 (1983)
W.C. Wimley, S.H. White, Nat. Struct. Mol. Biol. 3, 842–848 (1996)
G. Mandalari, A.M. Mackie, N.M. Rigby, M.J.S. Wickham, E.N.C. Mills, Mol. Nutr. Food Res. 53, S131–S139 (2009)
F.J. Moreno, A.R. Mackie, E.N.C. Mills, J. Agric, Food Chem. 53(25), 9810–9816 (2005)
Schrödinger, LLC. The PyMOL Molecular Graphics System, Version 2.0 https://www.schrodinger.com/pymol Accessed 9th Aug 2020
S. Li, M. Hong, J. Am, Chem. Soc. 133(5), 1534–1544 (2011)
W. Humphrey, W. Dalke, K. Schulten, J. Mol. Graphics 14(1), 33–38 (1996)
M.J. Abraham, T. Murtola, R. Schulz, et al., Softwarex 1, 19–25 (2015)
G. Bussi, D. Donadio, M. Parrinello, J. Chem. Phys. 126(014101), 014101–014107 (2007)
H.J.C. Berendsen, J.P.M. Postma, W.F. van Gunsteren, A. DiNola, J.R. Haak, J. Chem. Phys. 81(8), 3684–3690 (1984)
B. Hess, H. Bekker, H.J.C. Berendsen, J.G.E.M. Fraaije, J. Comput. Biol. 18, 1463–1472 (1997)
M. Parrinello, A. Rahman, J. Appl. Phys. 52(12), 7182–7190 (1981)
M.B. Ulmschneider, J.P.F. Doux, J.A. Killian, J.C. Smith, J.P. Ulmschneider, J. Am. Chem. Soc. 132(10), 3452–3460 (2010)
S.H. White, W.C. Wimley, Annu.Rev.Biophys.Biomol.Struc. 28(1), 319–365 (1999)
C.H. Chen, G. Wiedman, A. Khan, M.B. Ulmschneider, BBA-Biomembranes 1838, 2243–2249 (2014)
R.B. Best, X. Zhu, J. Shim, P.E.M. Lopes, J. Mittal, M. Feig, A.D. MacKerell Jr., J. Chem. Theory Comput. 8(9), 3257–3273 (2012)
A.D. MacKerell Jr., D. Bashford, M. Bellott, et al., J.Phys.Chem.B 102(18), 3586–3616 (1998)
A.D. MacKerell Jr., M. Feig, C.L. Brooks II, J.Comput.Chem. 25, 1400–1415 (2004)
A.D. MacKerell, M. Feig, C.L. Brooks, J. Am, Chem. Soc. 126(3), 698–699 (2004)
J.P. Ulmschneider, M.B. Ulmschneider, J. Chem. Theory Comput. 5, 1803–1813 (2009)
W.L. Jorgensen, J. Chandrasekhar, J.D. Madura, R.W. Impey, M.L. Klein, J. Chem. Phys. 79(2), 926–935 (1983)
A. Altis, M. Otten, P.H. Nguyen, R. Hegger, G. Stock, J. Chem. Phys 128(24), 06B620 (2008)
E. Lindahl, M. J. Abraham, B. Hess and D. van der Spoel. GROMACS 2020 Manual. https://zenodo.org/record/3562512 Accessed 14th August 2020
B. Hess, Phys. Rev. E 65, 031910–031910 (2001)
T. Mendes Ferreira, F. Coreta-Gomes, O.H.S. Ollila, M.J. Moreno, W.L.C. Vaz, T. Topgaard, Phys. Chem. Chem. Phys. 15, 1976–1989 (2013)
M. Andersson, J.P. Ulmschneider, M.B. Ulmschneider, S.H. White, Biophys. J. 104(6), L12–L14 (2013)
Y. Wang, C.H. Chen, D. Hu, M.B. Ulmschneider, J.P. Ulmschneider, Nat. Commun. 7, 13535 (2016)
X. Zhao, F. Pan, H. Xu, M. Yaseen, H. Shan, C.A. Hauser, S. Zhang, J.R. Lu, Chem. Soc. Rev. 39(9), 3480–3498 (2010)
A.Q. Zhou, C.S. O'Hern, L. Regan, Proteins 82(10), 2574–2584 (2014)
A. Altis, P.H. Nguyen, R. Hegger, G. Stock, J. Chem. Phys. 126(24), 244111 (2007)
W. Kabsch, C. Sander, Biopolymers 22(12), 2577–2637 (1983)
N.G. Zhdanova, E.A. Shirshin, E.G. Maksimov, I.M. Panchishin, A.M. Saletsky, V.V. Fadeev, Photochem Photobiol Sci 14(5), 897–908 (2015)
N.G. Zhdanova, E.A. Shirshin, E.G. Maksimov, I.M. Panchishin, A.M. Saletsky, V.V. Fadeev, Photochem. Photobiol. Sci. 14(5), 897–908 (2015)
J.C. Gumbart, M.B. Ulmschneider, A. Hazel, S.H. White, J.P. Ulmschneider, J. Membrane Biol. 251, 345–356 (2018)
J.M. Dyer, A. Grosvenor, in , ed. by M. Boland, M. Golding, H. Singh. Food Structures, Digestion and Health (Academic Press, San Diego, 2014), pp. 303–317
Acknowledgements
C.H.C. was supported by KCL PhD scholarships. Authors thank to Universidad Autónoma Metropolitana for providing computer time in supercomputing facilities: cluster Yoltla, and cluster Axolotl.
Availability of Data and Material
All relevant data is provided in the manuscript and the Online Resource.
Code Availability
‘Not applicable’.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest/Competing Interests
The authors have no financial or proprietary interests in any material discussed in this article.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(PDF 1.13 kb)
Rights and permissions
About this article
Cite this article
Jardón-Valadez, E., Chen, C.H., García-Garibay, M. et al. Passive Internalization of Bioactive β-Casein Peptides into Phospholipid (POPC) Bilayers. Free Energy Landscapes from Unbiased Equilibrium MD Simulations at μs-Time Scale. Food Biophysics 16, 70–83 (2021). https://doi.org/10.1007/s11483-020-09651-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11483-020-09651-x