Molecular Insights into the Membrane Phase Separation Influenced by Membrane/Lipid Structural Changes

Abstract

Cell membranes exhibit complex phase behaviors governed by intricate lipid-lipid interactions, which play pivotal roles in cellular processes, such as signaling and membrane trafficking. However, the molecular mechanisms underlying these phenomena, particularly their associations of lipid structural modifications (e.g., peroxidation) and membrane architecture (monolayer vs. bilayer), remain poorly understood. Here, we employ coarse-grained molecular dynamics simulations to systematically investigate the influence of membrane and lipid structure on phase separation. Our simulations found that monolayers exhibit stronger phase separation and higher lipid ordering than bilayers, underscoring the regulatory role of trans-bilayer coupling. Furthermore, we also found that even minor lipid structural modifications induced by peroxidation is able to enhance phase separation through three distinct mechanisms: increased lipid area, reduced diffusion coefficients, and altered cholesterol orientation. These findings provide molecular-level insights into the interplay between membrane architecture, lipid structure, and phase behavior, with potential implications for biomedical applications.

Keywords

Molecular dynamics simulation / Lipid / Cell membrane / Phase separation

References

[1] Mouritsen O G. Life—As Matter Fat, 2005, Switzerland, Springer International Publishing

[2] Hitaishi P, Mandal P, Ghosh S K. ACS Omega, 2021, 6: 34546

[3] van Meer G, Voelker D R, Feigenson G W. Nat. Rev. Mol. Cell Biol., 2008, 9: 112

[4] Edidin M. Annu. Rev. Biophys. Biomol. Struct., 2003, 32: 257

[5] Simons K, Ikonen E. Nature, 1997, 387: 569

[6] Sigismund S, Confalonieri S, Ciliberto A, Polo S, Scita G, Di Fiore P P. Physiol. Rev., 2012, 92: 273

[7] Wei Y, Xu F, Xu R, Li X, Yan Y, Long R, Li N, Yuan B. Chem. Res. Chinese Universities, 2025, 42: 643

[8] Jacobson K, Mouritsen O G, Anderson R G. Nat. Cell Biol., 2007, 9: 7

[9] Samsonov A V, Mihalyov I, Cohen F S. Biophys. J., 2001, 81: 1486

[10] Lingwood D, Simons K. Science, 2010, 327: 46

[11] Balakrishnan M, Kenworthy A K. J. Am. Chem. Soc., 2024, 146: 1374

[12] Borst J W, Visser N V, Kouptsova O, Visser A J. Biochim. Biophys. Acta, 2000, 1487: 61

[13] Agmon E, Solon J, Bassereau P, Stockwell B R. Sci. Rep., 2018, 8: 5155

[14] Gęgotek A, Skrzydlewska E. Chem. Phys. Lipids, 2019, 221: 46

[15] Kinnunen P K, Kaarniranta K, Mahalka A K. Biochim. Biophys. Acta, 2012, 1818: 2446

[16] Ye L F, Chaudhary K R, Zandkarimi F, Harken A D, Kinslow C J, Upadhyayula P S, Dovas A, Higgins D M, Tan H, Zhang Y, Buonanno M, Wang T J C, Hei T K, Bruce J N, Canoll P D, Cheng S K, Stockwell B R. ACS Chem. Biol., 2020, 15: 469

[17] Barayeu U, Schilling D, Eid M, Xavier da Silva T N, Schlicker L, Mitreska N, Zapp C, Gräter F, Miller A K, Kappl R, Schulze A, Friedmann Angeli J P, Dick T P. Nat. Chem. Biol., 2023, 19: 28

[18] von Krusenstiern A N, Robson R N, Qian N, Qiu B, Hu F, Reznik E, Smith N, Zandkarimi F, Estes V M, Dupont M, Hirschhorn T, Shchepinov M S, Min W, Woerpel K A, Stockwell B R. Nat. Chem. Biol., 2023, 19: 719

[19] Singer S J, Nicolson G L. Science, 1972, 175: 720

[20] May S. Soft Matter, 2009, 5: 3148

[21] Wagner A J, Loew S, May S. Biophys. J., 2007, 93: 4268

[22] Allender D W, Schick M. Biophys. J., 2006, 91: 2928

[23] Zadoorian A, Du X, Yang H. Nat. Rev. Endocrinol., 2023, 19: 443

[24] Krahmer N, Farese R V Jr, Walther T C. EMBO Mol. Med., 2013, 5: 973

[25] Olzmann J A, Carvalho P. Nat. Rev. Mol. Cell Biol., 2019, 20: 137

[26] Song J, Mizrak A, Lee C-W, Cicconet M, Lai Z W, Tang W-C, Lu C-H, Mohr S E, Farese R V, Walther T C. Nat. Cell Biol., 2022, 24: 1364

[27] Prévost C, Sharp M E, Kory N, Lin Q, Voth G A, Farese R V, Walther T C. Dev. Cell, 2018, 44: 73

[28] Dhiman R, Caesar S, Thiam A R, Schrul B. Semin. Cell Dev. Biol., 2020, 108: 4

[29] Tu W, Dong X, Ou L, Zhang X, Yuan B, Yang K. Chem. Res. Chinese Universities, 2023, 39: 829

[30] Xu C, Ma W, Wang K, He K, Chen Z, Liu J, Yang K, Yuan B. J. Phys. Chem. Lett., 2020, 11: 4834

[31] Deng Z, You X, Lin Z, Dong X, Yuan B, Yang K. J. Phys. Chem. Lett., 2023, 14: 6422

[32] Ma W, Jiang X, Dou Y, Zhang Z, Li J, Yuan B, Yang K. J. Phys. Chem. Lett., 2021, 12: 11629

[33] Ou L, Chen H, Yuan B, Yang K. ACS Nano, 2022, 16: 18090

[34] Zhao J, Wu J, Heberle F A, Mills T T, Klawitter P, Huang G, Costanza G, Feigenson G W. Biochim. Biophys. Acta, 2007, 1768: 2764

[35] Baoukina S, Mendez-Villuendas E, Tieleman D P. J. Am. Chem. Soc., 2012, 134: 17543

[36] Risselada H J, Marrink S J. Proc. Natl. Acad. Sci. USA, 2008, 105: 17367

[37] Weiner M D, Feigenson G W. J. Phys. Chem. B, 2018, 122: 8193

[38] Jo S, Kim T, Iyer V G, Im W. J. Comput. Chem., 2008, 29: 1859

[39] Qi Y, Ingólfsson H I, Cheng X, Lee J, Marrink S J, Im W. J. Chem. Theory Comput., 2015, 11: 4486

[40] de Jong D H, Singh G, Bennett W F D, Arnarez C, Wassenaar T A, Schäfer L V, Periole X, Tieleman D P, Marrink S J. J. Chem. Theory Comput., 2013, 9: 687

[41] Luo Z, Bai X, Yue T, Hu G. Nano Today, 2022, 45: 101525

[42] Guo Y, Baulin V A, Thalmann F. Soft Matter, 2016, 12: 263

[43] Marrink S J, de Vries A H, Mark A E. J. Phys. Chem. B, 2004, 108: 750

[44] Weber G, Charitat T, Baptista M S, Uchoa A F, Pavani C, Junqueira H C, Guo Y, Baulin V A, Itri R, Marques C M, Schroder A P. Soft Matter, 2014, 10: 4241

[45] Aoki P H, Schroder A P, Constantino C J, Marques C M. Soft Matter, 2015, 11: 5995

[46] Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A E, Berendsen H J. J. Comput. Chem., 2005, 26: 1701

[47] Abraham M J, Murtola T, Schulz R, Páll S, Smith J C, Hess B, Lindahl E. Software X, 2015, 1/2: 19

[48] Humphrey W, Dalke A, Schulten K. J. Mol. Graph., 1996, 14: 33

[49] McGibbon R T, Beauchamp K A, Harrigan M P, Klein C, Swails J M, Hernández C X, Schwantes C R, Wang L-P, Lane T J, Pande V S. Biophys. J., 2015, 109: 1528

[50] Konstantinovsky D, Yan E C Y, Hammes-Schiffer S. J. Phys. Chem. Lett., 2023, 14: 5260

[51] Simons K, Ikonen E. Science, 2000, 290: 1721

[52] Pöhnl M, Trollmann M F W, Böckmann R A. Nat. Commun., 2023, 14: 8038

[53] Hung W C, Lee M T, Chen F Y, Huang H W. Biophys. J., 2007, 92: 3960

[54] Drew B W F, Joan-Emma S, Peter T D. Biophys. J., 2018, 114: 2595

RIGHTS & PERMISSIONS

Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH