Amantadine interactions with phase separated lipid membranes

Kinnun, Jacob J.; Carrillo, Jan Y.; Collier, Charles Patrick; Smith, Micholas Dean; Katsaras, John

doi:10.1016/j.chemphyslip.2024.105397

Amantadine interactions with phase separated lipid membranes

Journal Article · Sat May 11 00:00:00 EDT 2024 · Chemistry and Physics of Lipids

DOI:https://doi.org/10.1016/j.chemphyslip.2024.105397· OSTI ID:2371073

Kinnun, Jacob J. ^[1]; ^[2]; ^[2]; Smith, Micholas Dean ^[3]; ^[4]

Univ. of Tennessee, Knoxville, TN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Sciences (CNMS)
Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)

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, here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Compute and Data Environment for Science (CADES)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-00OR22725; AC02-05CH11231

OSTI ID:: 2371073

Journal Information:: Chemistry and Physics of Lipids, Journal Name: Chemistry and Physics of Lipids Vol. 262; ISSN 0009-3084

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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