The boundary lipid around DMPC-spanning influenza A M2 transmembrane domain channels: Its structure and potential for drug accommodation

Athina Konstantinidi, Maria Chountoulesi, Nikolaos Naziris, Barbara Sartori, Heinz Amenitsch, Gregor Mali, Tomaž Čendak, Maria Plakantonaki, Iro Triantafyllakou, Theodore Tselios, Costas Demetzos, David D. Busath, Thomas Mavromoustakos, Antonios Kolocouris

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

We have investigated the perturbation of influenza A M2TM in DMPC bilayers. We have shown that (a) DSC and SAXS detect changes in membrane organization caused by small changes (micromolar) in M2TM or aminoadamantane concentration and aminoadamantane structure, by comparison of amantadine and spiro[pyrrolidine-2,2′-adamantane] (AK13), (b) that WAXS and MD can suggest details of ligand topology. DSC and SAXS show that at a low M2TM micromolar concentration in DPMC bilayers, two lipid domains are observed, which likely correspond to M2TM boundary lipids and bulk-like lipids. At higher M2TM concentrations, one domain only is identified, which constitutes essentially all of the lipid molecules behaving as boundary lipids. According to SAXS, WAXS, and DSC in the absence of M2TM, both aminoadamantane drugs exert a similar perturbing effect on the bilayer at low concentrations. At the same concentrations of the drug when M2TM is present, amantadine and, to a lesser extent, AK13 cause, according to WAXS, a significant disordering of chain-stacking, which also leads to the formation of two lipid domains. This effect is likely due, according to MD simulations, to the preference of the more lipophilic AK13 to locate closer to the lateral surfaces of M2TM when compared to amantadine, which forms stronger ionic interactions with phosphate groups. The preference of AK13 to concentrate inside the lipid bilayer close to the exterior of the hydrophobic M2TM helices may contribute to its higher binding affinity compared to amantadine.

Originalspracheenglisch
Aufsatznummer183156
FachzeitschriftBiochimica et Biophysica Acta - Biomembranes
Jahrgang1862
Ausgabenummer3
DOIs
PublikationsstatusVeröffentlicht - 1 Mär 2020

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Dimyristoylphosphatidylcholine
Amantadine
Human Influenza
Lipids
Pharmaceutical Preparations
Lipid Bilayers
Adamantane
Lipid bilayers
Phosphates
Ligands
Topology
Membranes
Molecules

Schlagwörter

    ASJC Scopus subject areas

    • !!Biophysics
    • !!Biochemistry
    • Zellbiologie

    Fields of Expertise

    • Human- & Biotechnology

    Dies zitieren

    The boundary lipid around DMPC-spanning influenza A M2 transmembrane domain channels : Its structure and potential for drug accommodation. / Konstantinidi, Athina; Chountoulesi, Maria; Naziris, Nikolaos; Sartori, Barbara; Amenitsch, Heinz; Mali, Gregor; Čendak, Tomaž; Plakantonaki, Maria; Triantafyllakou, Iro; Tselios, Theodore; Demetzos, Costas; Busath, David D.; Mavromoustakos, Thomas; Kolocouris, Antonios.

    in: Biochimica et Biophysica Acta - Biomembranes, Jahrgang 1862, Nr. 3, 183156, 01.03.2020.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Konstantinidi, A, Chountoulesi, M, Naziris, N, Sartori, B, Amenitsch, H, Mali, G, Čendak, T, Plakantonaki, M, Triantafyllakou, I, Tselios, T, Demetzos, C, Busath, DD, Mavromoustakos, T & Kolocouris, A 2020, 'The boundary lipid around DMPC-spanning influenza A M2 transmembrane domain channels: Its structure and potential for drug accommodation' Biochimica et Biophysica Acta - Biomembranes, Jg. 1862, Nr. 3, 183156. https://doi.org/10.1016/j.bbamem.2019.183156
    Konstantinidi, Athina ; Chountoulesi, Maria ; Naziris, Nikolaos ; Sartori, Barbara ; Amenitsch, Heinz ; Mali, Gregor ; Čendak, Tomaž ; Plakantonaki, Maria ; Triantafyllakou, Iro ; Tselios, Theodore ; Demetzos, Costas ; Busath, David D. ; Mavromoustakos, Thomas ; Kolocouris, Antonios. / The boundary lipid around DMPC-spanning influenza A M2 transmembrane domain channels : Its structure and potential for drug accommodation. in: Biochimica et Biophysica Acta - Biomembranes. 2020 ; Jahrgang 1862, Nr. 3.
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    abstract = "We have investigated the perturbation of influenza A M2TM in DMPC bilayers. We have shown that (a) DSC and SAXS detect changes in membrane organization caused by small changes (micromolar) in M2TM or aminoadamantane concentration and aminoadamantane structure, by comparison of amantadine and spiro[pyrrolidine-2,2′-adamantane] (AK13), (b) that WAXS and MD can suggest details of ligand topology. DSC and SAXS show that at a low M2TM micromolar concentration in DPMC bilayers, two lipid domains are observed, which likely correspond to M2TM boundary lipids and bulk-like lipids. At higher M2TM concentrations, one domain only is identified, which constitutes essentially all of the lipid molecules behaving as boundary lipids. According to SAXS, WAXS, and DSC in the absence of M2TM, both aminoadamantane drugs exert a similar perturbing effect on the bilayer at low concentrations. At the same concentrations of the drug when M2TM is present, amantadine and, to a lesser extent, AK13 cause, according to WAXS, a significant disordering of chain-stacking, which also leads to the formation of two lipid domains. This effect is likely due, according to MD simulations, to the preference of the more lipophilic AK13 to locate closer to the lateral surfaces of M2TM when compared to amantadine, which forms stronger ionic interactions with phosphate groups. The preference of AK13 to concentrate inside the lipid bilayer close to the exterior of the hydrophobic M2TM helices may contribute to its higher binding affinity compared to amantadine.",
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    AU - Chountoulesi, Maria

    AU - Naziris, Nikolaos

    AU - Sartori, Barbara

    AU - Amenitsch, Heinz

    AU - Mali, Gregor

    AU - Čendak, Tomaž

    AU - Plakantonaki, Maria

    AU - Triantafyllakou, Iro

    AU - Tselios, Theodore

    AU - Demetzos, Costas

    AU - Busath, David D.

    AU - Mavromoustakos, Thomas

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    KW - Molecular dynamics

    KW - Solid state NMR

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