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Passive Internalization of Bioactive β-Casein Peptides into Phospholipid (POPC) Bilayers. Free Energy Landscapes from Unbiased Equilibrium MD Simulations at μs-Time Scale

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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.

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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.

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Authors and Affiliations

  1. Departamento de Recursos de la Tierra, Universidad Autónoma Metropolitana, Unidad Lerma, Av. de las Garzas No 10. Col. El Panteón., Estado de México, C. P. 52005, Lerma, Mexico

    Eduardo Jardón-Valadez

  2. Department of Chemistry, King’s College London, London, SE1 1DB,, UK

    Charles H. Chen & Martin B. Ulmschneider

  3. Synthetic Biology Group, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Charles H. Chen

  4. Departamento de Ciencias de la Alimentación, Universidad Autónoma Metropolitana, Unidad Lerma, Av. de las Garzas 10. Col. El Panteón., C. P. 52005, Lerma, Estado de México, Mexico

    Mariano García-Garibay & Judith Jiménez-Guzmán

  5. Departamento de Biotecnología, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Av. San Rafael Atlixco 146, Col. Vicentina, C. P. 09340, Ciudad de México, Mexico

    Mariano García-Garibay

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  1. Eduardo Jardón-Valadez
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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

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