Amantadine interactions with phase separated lipid membranes

Jacob J. Kinnun; Jan Michael Y. Carrillo; C. Patrick Collier; Micholas Dean Smith; John Katsaras

doi:10.1016/j.chemphyslip.2024.105397

Amantadine interactions with phase separated lipid membranes

Jacob J. Kinnun
, Jan Michael Y. Carrillo
, C. Patrick Collier
, Micholas Dean Smith
, John Katsaras

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson's disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine's interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

Original language	English
Article number	105397
Journal	Chemistry and Physics of Lipids
Volume	262
DOIs	https://doi.org/10.1016/j.chemphyslip.2024.105397
State	Published - Aug 2024

Funding

J. J. K. and J. K. are supported through the Scientific User Facilities Division of the Department of Energy (DOE) Office of Science, sponsored by the Basic Energy Science (BES) Program, DOE Office of Science, under Contract No. DEAC05–00OR22725. M. D. S. was supported by the Genomic Science Program, Office of Biological and Environmental Research, U. S. Department of Energy (DOE), under Contract FWP ERKP752. C. P. C. and J. M. Y. C performed data collection, analysis and manuscript preparation at the Center for Nanophase Materials Sciences, which is a U.S. DOE Office of Science User Facility. This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05–00OR22725. Additional computational resources were provided by the National Energy Research Scientific Computing Center(NERSC), a U.S. Department of Energy Office of Science User Facility located at Lawrence Berkeley National Laboratory, operated under Contract No. DE-AC02–05CH11231 using NERSC award ALCC-ERCAP-M4196; and by the Compute and Data Environment for Science (CADES) at Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05–00OR22725. J.K. and J.J.K. conceived the experiments. J.J.K. performed the Langmuir monolayer and DSC measurements, and C.P.C. performed the DIB measurements. M.D.S carried out the MD simulations and J.M.Y.C. provided technical assistance. All authors contributed to the writing of the manuscript. This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725. Additional computa- tional resources were provided by the National Energy Research Scientific Computing Center (NERSC), a U.S. Department of Energy Office of Science User Facility located at Lawrence Berkeley National Laboratory, operated under Contract No. DE-AC02-05CH11231 using NERSC award ALCC-ERCAP-M4196; and by the Compute and Data Environment for Sci- ence (CADES) at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725. J. J. K. and J. K. are supported through the Scientific User Facilities Division of the De- partment of Energy (DOE) Office of Science, sponsored by the Basic Energy Science (BES) Program, DOE Office of Science, under Contract No. DEAC05-00OR22725. M. D. S. was supported by the Genomic Science Program, Office of Biological and Envi- ronmental Research, U. S. Department of Energy (DOE), under Contract FWP ERKP752.

Keywords

Amantadine
Droplet interface bilayers
Langmuir films
Lipids
Molecular Dynamics

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10.1016/j.chemphyslip.2024.105397

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title = "Amantadine interactions with phase separated lipid membranes",

abstract = "Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson's disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine's interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.",

keywords = "Amantadine, Droplet interface bilayers, Langmuir films, Lipids, Molecular Dynamics",

author = "Kinnun, \{Jacob J.\} and Carrillo, \{Jan Michael Y.\} and Collier, \{C. Patrick\} and Smith, \{Micholas Dean\} and John Katsaras",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier B.V.",

year = "2024",

month = aug,

doi = "10.1016/j.chemphyslip.2024.105397",

language = "English",

volume = "262",

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T1 - Amantadine interactions with phase separated lipid membranes

AU - Kinnun, Jacob J.

AU - Carrillo, Jan Michael Y.

AU - Collier, C. Patrick

AU - Smith, Micholas Dean

AU - Katsaras, John

PY - 2024/8

Y1 - 2024/8

N2 - Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson's disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine's interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

AB - Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson's disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine's interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

KW - Amantadine

KW - Droplet interface bilayers

KW - Langmuir films

KW - Lipids

KW - Molecular Dynamics

UR - https://www.scopus.com/pages/publications/85193430865

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DO - 10.1016/j.chemphyslip.2024.105397

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VL - 262

JO - Chemistry and Physics of Lipids

JF - Chemistry and Physics of Lipids

M1 - 105397

ER -

Amantadine interactions with phase separated lipid membranes

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