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

Chem Phys Lipids. 2024 May 11:262:105397. doi: 10.1016/j.chemphyslip.2024.105397. Online ahead of print.

Authors

Jacob J Kinnun¹, Jan Michael Y Carrillo², C Patrick Collier², Micholas Dean Smith³, John Katsaras⁴

Affiliations

¹ Department of Chemistry, University of Tennessee, Knoxville, TN 37996, United States. Electronic address: jkinnun@utk.edu.
² Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States.
³ Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, United States; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, TN 37831, United States.
⁴ Labs and Soft Matter Group, Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States; Shull-Wollan Center, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States; Department of Physics and Astronomy, University of Tennessee, Knoxville, TN 37996, United States. Electronic address: katsarasj@ornl.gov.

PMID: 38740276
DOI: 10.1016/j.chemphyslip.2024.105397

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.