Interaction between cell penetrating peptide S4(13) and plasma membranes by molecular dynamics simulations

GAO Jin; CUI Wei

doi:10.7523/j.issn.2095-6134.2021.06.006

Journal of University of Chinese Academy of Sciences >

2021 , Vol. 38 >Issue 6: 758 - 771

DOI: https://doi.org/10.7523/j.issn.2095-6134.2021.06.006

Innovation Article

Interaction between cell penetrating peptide S4(13) and plasma membranes by molecular dynamics simulations

GAO Jin ,
CUI Wei

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School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 101408, China

Received date: 2021-03-09

Revised date: 2021-04-30

Online published: 2021-11-16

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Abstract

The derivatives of cell penetrating peptide S4(13) have been used as good drug carriers carrying nucleic acid into cells to play a therapeutic role, which has potential application value in anti-tumor targeted therapy and other fields. However, the mechanism of membrane penetration of S4(13) is still unclear. In this work, we employed molecular dynamics simulation method for study. Firstly, we built systems of single and multiple S4(13) molecules in different membrane models and aqueous solutions, respectively. Thereafter, we performed classical molecular dynamics simulations as well as umbrella sampling molecular dynamics simulations and we analyzed the trajectory to determine the means of single S4(13) and multiple S4(13) molecules with different plasma membranes. The results suggest that S4(13) binds to the bacterial plasma membrane more strongly than interacting with eukaryotic membrane in the form of a single molecule. In addition, multiple S4(13) molecules trend to aggregate to form tetramers in aqueous solution and eukaryotic model membrane. Our work investigates the mechanism of cell penetrating peptide S4(13) to penetrate membrane at the molecular level, and provides a theoretical basis for the application of S4(13) derivatives as drug carriers in the future.

Key words： S4(13); POPC membrane; POPG membrane; molecular dynamics simulations; umbrella sampling

Cite this article

GAO Jin , CUI Wei . Interaction between cell penetrating peptide S4(13) and plasma membranes by molecular dynamics simulations[J]. Journal of University of Chinese Academy of Sciences, 2021 , 38(6) : 758 -771 . DOI: 10.7523/j.issn.2095-6134.2021.06.006

References

[1] Lipinski C A, Lombardo F, Dominy B W, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J]. Advanced Drug Delivery Reviews, 1997, 23(1-3):3-25.
[2] 涂展春, 欧阳钟灿. 生物膜弹性的几何理论[J]. 中国科学院研究生院学报, 2008, 25(6):849-854.
[3] 秦飞, 姚鑫. 环糊精固载量不同的壳聚糖药物载体合成及性能[J]. 中国科学院大学学报, 2015, 32(1):51-56.
[4] Dissanayake S, Denny W A, Gamage S, et al. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides[J]. Journal of Controlled Release, 2017, 250:62-76.
[5] Borrelli A, Tornesello A L, Tornesello M L, et al. Cell penetrating peptides as molecular carriers for anti-cancer agents[J]. Molecules, 2018, 23(2):295.
[6] Taylor R E, Zahid M. Cell penetrating peptides, novel vectors for gene therapy[J]. Pharmaceutics, 2020, 12(3):225.
[7] Wang F H, Wang Y, Zhang X, et al. Recent progress of cellpenetrating peptides as new carriers for intracellular cargo delivery[J]. Journal of Controlled Release, 2014, 174:126-136.
[8] 何小林, 王大成. 中国马氏钳蝎神经毒素BmK M1和M4的晶体结构研究[J]. 中国科学院研究生院学报, 2001, 18(1):97-100.
[9] Singh T, Murthy A S N, Yang H J, et al. Versatility of cell-penetrating peptides for intracellular delivery of siRNA[J]. Drug Delivery, 2018, 25(1):1996-2006.
[10] Cardoso A M S, Trabulo S, Cardoso A L, et al. S4(13)-PV cell-penetrating peptide induces physical and morphological changes in membrane-mimetic lipid systems and cell membranes:Implications for cell internalization[J]. Biochimica et Biophysica Acta(BBA)-Biomembranes, 2012, 1818(3):877-888.
[11] Morais C M, Cardoso A M, Aguiar L, et al. Lauroylated histidine-enriched S4₁₃-PV peptide as an efficient gene silencing mediator in cancer cells[J]. Pharmaceutical Research, 2020, 37(10):188.
[12] Morais C M, Cardoso A M, Cunha P P, et al. Acylation of the S4₁₃-PV cell-penetrating peptide as a means of enhancing its capacity to mediate nucleic acid delivery:relevance of peptide/lipid interactions[J]. Biochimica et Biophysica Acta(BBA)-Biomembranes, 2018, 1860(12):2619-2634.
[13] Hariton-Gazal E, Feder R, Mor A, et al. Targeting of nonkaryophilic cell-permeable peptides into the nuclei of intact cells by covalently attached nuclear localization signals[J]. Biochemistry, 2002, 41(29):9208-9214.
[14] Trabulo S, Mano M, Faneca H, et al. S4₁₃-PV cell penetrating peptide and cationic liposomes act synergistically to mediate intracellular delivery of plasmid DNA[J]. The Journal of Gene Medicine, 2008, 10(11):1210-1222.
[15] Mano M, Teodósio C, Paiva A, et al. On the mechanisms of the internalization of S4₁₃-PV cell-penetrating peptide[J]. The Biochemical Journal, 2005, 390(Pt2):603-612.
[16] Mano M, Henriques A, Paiva A, et al. Cellular uptake of S4₁₃-PV peptide occurs upon conformational changes induced by peptide-membrane interactions[J]. Biochimica et Biophysica Acta(BBA)-Biomembranes, 2006, 1758(3):336-346.
[17] Mano M, Henriques A, Paiva A, et al. Interaction of S4₁₃-PV cell penetrating peptide with model membranes:relevance to peptide translocation across biological membranes[J]. Journal of Peptide Science, 2007, 13(5):301-313.
[18] Padari K, Koppel K, Lorents A, et al. S4₁₃-PV cell-penetrating peptide forms nanoparticle-like structures to gain entry into cells[J]. Bioconjugate Chemistry, 2010, 21(4):774-783.
[19] Xu Y C, Jiang H L. Molecular dynamics simulations studies on the structure-function relationship of protein targets related to Alzheimer's disease[J]. Journal of the Graduate School of the Chinese Academy of Sciences, 2009, 26(2):280-287.
[20] 方磊, 计明娟. PTP1B选择性抑制剂的分子动力学模拟及结合自由能计算[J]. 中国科学院研究生院学报, 2009, 26(1):58-64.
[21] Gautam A, Singh H, Tyagi A, et al. CPPsite:a curated database of cell penetrating peptides[J]. Database:the Journal of Biological Databases and Curation, 2012, 2012:bas015.
[22] Kardani K, Bolhassani A. Cppsite 2.0:an available database of experimentally validated cell-penetrating peptides predicting their secondary and tertiary structures[J]. Journal of Molecular Biology, 2020, 433(11):166703.
[23] Agrawal P, Bhalla S, Usmani S S, et al. CPPsite 2.0:a repository of experimentally validated cell-penetrating peptides[J]. Nucleic Acids Research, 2016, 44(D1):D1098-D1103.
[24] Bagheri M, Keller S, Dathe M. Interaction of W-substituted analogs of cyclo-RRRWFW with bacterial lipopolysaccharides:the role of the aromatic cluster in antimicrobial activity[J]. Antimicrobial Agents and Chemotherapy, 2011, 55(2):788-797.
[25] Kim S, Chen J, Cheng T J, et al. PubChem 2019 update:improved access to chemical data[J]. Nucleic Acids Research, 2019, 47(D1):D1102-D1109.
[26] Frisch M J, Trucks G W, Schlegel H B, et al. Gaussian 09, Revision A.01[CP]. Gaussian, Inc, Wallingford CT, 2009.
[27] Wang J M, Wolf R M, Caldwell J W, et al. Development and testing of a general amber force field[J]. Journal of Computational Chemistry, 2004, 25(9):1157-1174.
[28] Case D A, Ben-Shalom I Y, Brozell S R, et al. AMBER 2018[CP]. University of California, San Francisco, 2018.
[29] Sousa da Silva A W, Vranken W F. ACPYPE-AnteChamber PYthon parser interface[J]. BMC Research Notes, 2012, 5(1):367.
[30] Wang J M, Cieplak P, Kollman P A. How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules?[J]. Journal of Computational Chemistry, 2000, 21(12):1049-1074.
[31] Martínez L, Andrade R, Birgin E G, et al. PACKMOL:a package for building initial configurations for molecular dynamics simulations[J]. Journal of Computational Chemistry, 2009, 30(13):2157-2164.
[32] Maier J A, Martinez C, Kasavajhala K, et al. ff14SB:improving the accuracy of protein side chain and backbone parameters from ff99SB[J]. Journal of Chemical Theory and Computation, 2015, 11(8):3696-3713.
[33] Jorgensen W L, Chandrasekhar J, Madura J D, et al. Comparison of simple potential functions for simulating liquid water[J]. The Journal of Chemical Physics, 1983, 79(2):926-935.
[34] Ryckaert J P, Ciccotti G, Berendsen H J C. Numerical integration of the Cartesian equations of motion of a system with constraints:molecular dynamics of n-alkanes[J]. Journal of Computational Physics, 1977, 23(3):327-341.
[35] Darden T, York D, Pedersen L. Particle mesh Ewald:an N·log(N) method for Ewald sums in large systems[J]. The Journal of Chemical Physics, 1993, 98(12):10089-10092.
[36] Kumar S, Rosenberg J M, Bouzida D, et al. The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method[J]. Journal of Computational Chemistry, 1992, 13(8):1011-1021.
[37] Souaille M, Roux B. Extension to the weighted histogram analysis method:combining umbrella sampling with free energy calculations[J]. Computer Physics Communications, 2001, 135(1):40-57.
[38] Roe D R, Cheatham T E. PTRAJ and CPPTRAJ:software for processing and analysis of molecular dynamics trajectory data[J]. Journal of Chemical Theory and Computation, 2013, 9(7):3084-3095.

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