tetano
Editor, Senior Moderator
Biochim Biophys Acta Biomembr. 2019 Dec 14:183156. doi: 10.1016/j.bbamem.2019.183156. [Epub ahead of print] [h=1]The boundary lipid around DMPC-spanning influenza A M2 transmembrane domain channels: Its structure and potential for drug accommodation.[/h]
Konstantinidi A[SUP]1[/SUP], Chountoulesi M[SUP]2[/SUP], Naziris N[SUP]2[/SUP], Sartori B[SUP]3[/SUP], Amenitsch H[SUP]3[/SUP], Mali G[SUP]4[/SUP], Čendak T[SUP]4[/SUP], Plakantonaki M[SUP]5[/SUP], Triantafyllakou I[SUP]5[/SUP], Tselios T[SUP]5[/SUP], Demetzos C[SUP]2[/SUP], Busath DD[SUP]6[/SUP], Mavromoustakos T[SUP]7[/SUP], Kolocouris A[SUP]8[/SUP].
[h=3]Author information[/h] 1 Section of Pharmaceutical Chemistry. 2 Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences. 3 Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9/IV, A-8010 Graz, Austria. 4 Department of Inorganic Chemistry and Technology, National Institute of Chemistry, Ljubljana SI-1001, Slovenia. 5 Department of Chemistry, School of Natural Sciences, University of Patras, Rion, Patras 26500, Greece. 6 Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. 7 Section of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens 15771, Greece. Electronic address: tmavrom@chem.uoa.gr. 8 Section of Pharmaceutical Chemistry. Electronic address: ankol@pharm.uoa.gr.
[h=3]Abstract[/h] 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.
Copyright ? 2019. Published by Elsevier B.V.
[h=4]KEYWORDS:[/h] Aminoadamantane derivatives; Boundary lipids; DMPC bilayers; DSC; M2TM; Molecular dynamics; Solid state NMR; X-ray scattering
PMID: 31846647 DOI: 10.1016/j.bbamem.2019.183156
Konstantinidi A[SUP]1[/SUP], Chountoulesi M[SUP]2[/SUP], Naziris N[SUP]2[/SUP], Sartori B[SUP]3[/SUP], Amenitsch H[SUP]3[/SUP], Mali G[SUP]4[/SUP], Čendak T[SUP]4[/SUP], Plakantonaki M[SUP]5[/SUP], Triantafyllakou I[SUP]5[/SUP], Tselios T[SUP]5[/SUP], Demetzos C[SUP]2[/SUP], Busath DD[SUP]6[/SUP], Mavromoustakos T[SUP]7[/SUP], Kolocouris A[SUP]8[/SUP].
[h=3]Author information[/h] 1 Section of Pharmaceutical Chemistry. 2 Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences. 3 Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9/IV, A-8010 Graz, Austria. 4 Department of Inorganic Chemistry and Technology, National Institute of Chemistry, Ljubljana SI-1001, Slovenia. 5 Department of Chemistry, School of Natural Sciences, University of Patras, Rion, Patras 26500, Greece. 6 Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. 7 Section of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens 15771, Greece. Electronic address: tmavrom@chem.uoa.gr. 8 Section of Pharmaceutical Chemistry. Electronic address: ankol@pharm.uoa.gr.
[h=3]Abstract[/h] 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.
Copyright ? 2019. Published by Elsevier B.V.
[h=4]KEYWORDS:[/h] Aminoadamantane derivatives; Boundary lipids; DMPC bilayers; DSC; M2TM; Molecular dynamics; Solid state NMR; X-ray scattering
PMID: 31846647 DOI: 10.1016/j.bbamem.2019.183156