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Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity

[Image: see text] Structural mechanisms and underlying thermodynamic determinants of efficient internalization of charged cationic peptides (cell-penetrating peptides, CPPs) such as TAT, polyarginine, and their variants, into cells, cellular constructs, and model membrane/lipid bilayers (large and g...

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Autores principales: Hu, Yuan, Liu, Xiaorong, Sinha, Sudipta Kumar, Patel, Sandeep
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983342/
https://www.ncbi.nlm.nih.gov/pubmed/24506488
http://dx.doi.org/10.1021/jp412600e
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author Hu, Yuan
Liu, Xiaorong
Sinha, Sudipta Kumar
Patel, Sandeep
author_facet Hu, Yuan
Liu, Xiaorong
Sinha, Sudipta Kumar
Patel, Sandeep
author_sort Hu, Yuan
collection PubMed
description [Image: see text] Structural mechanisms and underlying thermodynamic determinants of efficient internalization of charged cationic peptides (cell-penetrating peptides, CPPs) such as TAT, polyarginine, and their variants, into cells, cellular constructs, and model membrane/lipid bilayers (large and giant unilamellar or multilamelar vesicles) continue to garner significant attention. Two widely held views on the translocation mechanism center on endocytotic and nonendocytotic (diffusive) processes. Espousing the view of a purely diffusive internalization process (supported by recent experimental evidence, [Säälik, P.; et al. J. Controlled Release2011, 153, 117–125]), we consider the underlying free energetics of the translocation of a nonaarginine peptide (Arg(9)) into a model DPPC bilayer. In the case of the Arg(9) cationic peptide, recent experiments indicate a higher internalization efficiency of the cyclic structure (cyclic Arg(9)) relative to the linear conformer. Furthermore, recent all-atom resolution molecular dynamics simulations of cyclic Arg(9) [Huang, K.; et al. Biophys. J., 2013, 104, 412–420] suggested a critical stabilizing role of water- and lipid-constituted pores that form within the bilayer as the charged Arg(9) translocates deep into the bilayer center. Herein, we use umbrella sampling molecular dynamics simulations with coarse-grained Martini lipids, polarizable coarse-grained water, and peptide to explore the dependence of translocation free energetics on peptide structure and conformation via calculation of potentials of mean force along preselected reaction paths allowing and preventing membrane deformations that lead to pore formation. Within the context of the coarse-grained force fields we employ, we observe significant barriers for Arg(9) translocation from bulk aqueous solution to bilayer center. Moreover, we do not find free-energy minima in the headgroup–water interfacial region, as observed in simulations using all-atom force fields. The pore-forming paths systematically predict lower free-energy barriers (ca. 90 kJ/mol lower) than the non pore-forming paths, again consistent with all-atom force field simulations. The current force field suggests no preference for the more compact or covalently cyclic structures upon entering the bilayer. Decomposition of the PMF into the system’s components indicates that the dominant stabilizing contribution along the pore-forming path originates from the membrane as both layers of it deformed due to the formation of pore. Furthermore, our analysis revealed that although there is significant entropic stabilization arising from the enhanced configurational entropy exposing more states as the peptide moves through the bilayer, the enthalpic loss (as predicted by the interactions of this coarse-grained model) far outweighs any former stabilization, thus leading to significant barrier to translocation. Finally, we observe reduction in the translocation free-energy barrier for a second Arg(9) entering the bilayer in the presence of an initial peptide restrained at the center, again, in qualitative agreement with all-atom force fields.
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spelling pubmed-39833422015-02-07 Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity Hu, Yuan Liu, Xiaorong Sinha, Sudipta Kumar Patel, Sandeep J Phys Chem B [Image: see text] Structural mechanisms and underlying thermodynamic determinants of efficient internalization of charged cationic peptides (cell-penetrating peptides, CPPs) such as TAT, polyarginine, and their variants, into cells, cellular constructs, and model membrane/lipid bilayers (large and giant unilamellar or multilamelar vesicles) continue to garner significant attention. Two widely held views on the translocation mechanism center on endocytotic and nonendocytotic (diffusive) processes. Espousing the view of a purely diffusive internalization process (supported by recent experimental evidence, [Säälik, P.; et al. J. Controlled Release2011, 153, 117–125]), we consider the underlying free energetics of the translocation of a nonaarginine peptide (Arg(9)) into a model DPPC bilayer. In the case of the Arg(9) cationic peptide, recent experiments indicate a higher internalization efficiency of the cyclic structure (cyclic Arg(9)) relative to the linear conformer. Furthermore, recent all-atom resolution molecular dynamics simulations of cyclic Arg(9) [Huang, K.; et al. Biophys. J., 2013, 104, 412–420] suggested a critical stabilizing role of water- and lipid-constituted pores that form within the bilayer as the charged Arg(9) translocates deep into the bilayer center. Herein, we use umbrella sampling molecular dynamics simulations with coarse-grained Martini lipids, polarizable coarse-grained water, and peptide to explore the dependence of translocation free energetics on peptide structure and conformation via calculation of potentials of mean force along preselected reaction paths allowing and preventing membrane deformations that lead to pore formation. Within the context of the coarse-grained force fields we employ, we observe significant barriers for Arg(9) translocation from bulk aqueous solution to bilayer center. Moreover, we do not find free-energy minima in the headgroup–water interfacial region, as observed in simulations using all-atom force fields. The pore-forming paths systematically predict lower free-energy barriers (ca. 90 kJ/mol lower) than the non pore-forming paths, again consistent with all-atom force field simulations. The current force field suggests no preference for the more compact or covalently cyclic structures upon entering the bilayer. Decomposition of the PMF into the system’s components indicates that the dominant stabilizing contribution along the pore-forming path originates from the membrane as both layers of it deformed due to the formation of pore. Furthermore, our analysis revealed that although there is significant entropic stabilization arising from the enhanced configurational entropy exposing more states as the peptide moves through the bilayer, the enthalpic loss (as predicted by the interactions of this coarse-grained model) far outweighs any former stabilization, thus leading to significant barrier to translocation. Finally, we observe reduction in the translocation free-energy barrier for a second Arg(9) entering the bilayer in the presence of an initial peptide restrained at the center, again, in qualitative agreement with all-atom force fields. American Chemical Society 2014-02-07 2014-03-13 /pmc/articles/PMC3983342/ /pubmed/24506488 http://dx.doi.org/10.1021/jp412600e Text en Copyright © 2014 American Chemical Society
spellingShingle Hu, Yuan
Liu, Xiaorong
Sinha, Sudipta Kumar
Patel, Sandeep
Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
title Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
title_full Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
title_fullStr Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
title_full_unstemmed Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
title_short Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
title_sort translocation thermodynamics of linear and cyclic nonaarginine into model dppc bilayer via coarse-grained molecular dynamics simulation: implications of pore formation and nonadditivity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983342/
https://www.ncbi.nlm.nih.gov/pubmed/24506488
http://dx.doi.org/10.1021/jp412600e
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