Interplay of hydrophobic and hydrophilic interactions in sequence-dependent cell penetration of spontaneous membrane-translocating peptides revealed by bias-exchange metadynamics simulations

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Cao, Zanxia
Liu, Lei
Hu, Guodong
Bian, Yunqiang
Li, Haiyan
Wang, Jihua
Zhou, Yaoqi
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2020
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Abstract

Spontaneous Membrane Translocating Peptides (SMTPs) can translocate silently across the bilayer and, thus, have the best potential to improve the delivery of therapeutic molecules to cells without toxicity. However, how their translocation mechanisms are affected by a specific peptide sequence remains poorly understood. Here, bias-exchange metadynamics simulations were employed to investigate the translocation mechanisms of five SMTPs with the same composition of amino acids (LLRLR, LRLLR, LLLRR, RLLLR, and LRLRL). Simulation results yield sequence-dependent free energy barrier using the FESs along the z-directional distance. An in-depth analysis of sequence-dependent interactions in different regions of the bilayers indicates that the free-energy barrier height of a specific sequence is resulted from the accessibility balance of isolated or clustered hydrophobic residues (L) and hydrophilic residues (R) that leads to different levels of resistance for moving of a peptide into the hydrophobic center of the membrane. At the maximal of the free-energy barrier, all peptides have a conformation parallel to the membrane surface with the barrier height determined by their affinity to the hydrophobic region. The appropriate bilayer perturbation and GDM+ pairing are beneficial for peptide translocation. These results provide an improved microscopic understanding of how peptide sequence influences the translocation efficiency and mechanism.

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Biochimica et Biophysica Acta (BBA) - Biomembranes

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1862

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10

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© 2020 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.

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Biochemistry and cell biology

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Chemical engineering

Science & Technology

Life Sciences & Biomedicine

Biochemistry & Molecular Biology

Biophysics

Spontaneous Membrane Translocating Peptides

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Cao, Z; Liu, L; Hu, G; Bian, Y; Li, H; Wang, J; Zhou, Y, Interplay of hydrophobic and hydrophilic interactions in sequence-dependent cell penetration of spontaneous membrane-translocating peptides revealed by bias-exchange metadynamics simulations, Biochimica et Biophysica Acta (BBA) - Biomembranes, 2020, 1862 (10), pp. 183402

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