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Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations

[Image: see text] We performed molecular dynamics (MD) simulations to obtain insights into the structure and molecular interactions of colloidal structures present in fasted state intestinal fluid. Drug partitioning and interaction were studied with a mixed system of the bile salt taurocholate (TCH)...

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Autores principales: Holmboe, Michael, Larsson, Per, Anwar, Jamshed, Bergström, Christel A. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271571/
https://www.ncbi.nlm.nih.gov/pubmed/27934534
http://dx.doi.org/10.1021/acs.langmuir.6b03008
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author Holmboe, Michael
Larsson, Per
Anwar, Jamshed
Bergström, Christel A. S.
author_facet Holmboe, Michael
Larsson, Per
Anwar, Jamshed
Bergström, Christel A. S.
author_sort Holmboe, Michael
collection PubMed
description [Image: see text] We performed molecular dynamics (MD) simulations to obtain insights into the structure and molecular interactions of colloidal structures present in fasted state intestinal fluid. Drug partitioning and interaction were studied with a mixed system of the bile salt taurocholate (TCH) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC). Spontaneous aggregation of TCH and DLiPC from unconstrained MD simulations at the united-atom level using the Berger/Gromos54A7 force fields demonstrated that intermolecular hydrogen bonding between TCH molecules was an important factor in determining the overall TCH and DLiPC configuration. In bilayered systems, these intermolecular hydrogen bonds resulted in embedded transmembrane TCH clusters. Free energy simulations using the umbrella sampling technique revealed that the stability of these transmembrane TCH clusters was superior when they consisted of 3 or 4 TCH per bilayer leaflet. All-atom simulations using the Slipids/GAFF force fields showed that the TCH embedded in the bilayer decreased the energy barrier to penetrate the bilayer (ΔG(pen)) for water, ethanol, and carbamazepine, but not for the more lipophilic felodipine and danazol. This suggests that diffusion of hydrophilic to moderately lipophilic molecules through the bilayer is facilitated by the embedded TCH molecules. However, the effect of embedded TCH on the overall lipid/water partitioning was significant for danazol, indicating that the incorporation of TCH plays a crucial role for the partitioning of lipophilic solutes into e.g. lipidic vesicles existing in fasted state intestinal fluids. To conclude, the MD simulations revealed important intermolecular interactions in lipidic bilayers, both between the bile components themselves and with the drug molecules.
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spelling pubmed-52715712017-01-30 Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations Holmboe, Michael Larsson, Per Anwar, Jamshed Bergström, Christel A. S. Langmuir [Image: see text] We performed molecular dynamics (MD) simulations to obtain insights into the structure and molecular interactions of colloidal structures present in fasted state intestinal fluid. Drug partitioning and interaction were studied with a mixed system of the bile salt taurocholate (TCH) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC). Spontaneous aggregation of TCH and DLiPC from unconstrained MD simulations at the united-atom level using the Berger/Gromos54A7 force fields demonstrated that intermolecular hydrogen bonding between TCH molecules was an important factor in determining the overall TCH and DLiPC configuration. In bilayered systems, these intermolecular hydrogen bonds resulted in embedded transmembrane TCH clusters. Free energy simulations using the umbrella sampling technique revealed that the stability of these transmembrane TCH clusters was superior when they consisted of 3 or 4 TCH per bilayer leaflet. All-atom simulations using the Slipids/GAFF force fields showed that the TCH embedded in the bilayer decreased the energy barrier to penetrate the bilayer (ΔG(pen)) for water, ethanol, and carbamazepine, but not for the more lipophilic felodipine and danazol. This suggests that diffusion of hydrophilic to moderately lipophilic molecules through the bilayer is facilitated by the embedded TCH molecules. However, the effect of embedded TCH on the overall lipid/water partitioning was significant for danazol, indicating that the incorporation of TCH plays a crucial role for the partitioning of lipophilic solutes into e.g. lipidic vesicles existing in fasted state intestinal fluids. To conclude, the MD simulations revealed important intermolecular interactions in lipidic bilayers, both between the bile components themselves and with the drug molecules. American Chemical Society 2016-11-14 2016-12-06 /pmc/articles/PMC5271571/ /pubmed/27934534 http://dx.doi.org/10.1021/acs.langmuir.6b03008 Text en Copyright © 2016 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Holmboe, Michael
Larsson, Per
Anwar, Jamshed
Bergström, Christel A. S.
Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations
title Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations
title_full Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations
title_fullStr Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations
title_full_unstemmed Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations
title_short Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations
title_sort partitioning into colloidal structures of fasted state intestinal fluid studied by molecular dynamics simulations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271571/
https://www.ncbi.nlm.nih.gov/pubmed/27934534
http://dx.doi.org/10.1021/acs.langmuir.6b03008
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