Comparative Perturbation Effects Exerted by the Influenza A M2 WT Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2′-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations

Athina Konstantinidi, Nikolaos Naziris, Maria Chountoulesi, Sophia Kiriakidi, Barbara Sartori, Dimitris Kolokouris, Heinz Amentisch, Gregor Mali, Dimitrios Ntountaniotis, Costas Demetzos, Thomas Mavromoustakos, Antonios Kolocouris

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Aminoadamantane drugs are lipophilic amines that block the membrane-embedded influenza A M2 WT (wild type) ion channel protein. The comparative effects of amantadine (Amt) and its synthetic spiro[pyrrolidine-2,2′-adamantane] (AK13) analogue in dimyristoylphosphatidylcholine (DMPC) bilayers were studied using a combination of experimental biophysical methods, differential scanning calorimetry (DSC), X-ray diffraction, solid-state NMR (ssNMR) spectroscopy, and molecular dynamics (MD) simulations. All three experimental methods pointed out that the two analogues perturbed drastically the DMPC bilayers with AK13 to be more effective at high concentrations. AK13 was tolerated in lipid bilayers at very high concentrations, while Amt was crystallized. This is an important consideration in the formulations of drugs as it designates a limitation of Amt incorporation. MD simulations verify provided details about the strong interactions of the drugs in the interface region between phosphoglycerol backbone and lipophilic segments. The two drugs form hydrogen bonding with both water and sn-2 carbonyls in their amine form or water and phosphate oxygens in their ammonium form. Such localization of the drugs explains the DMPC bilayers reorientation and their strong perturbing effect evidenced by all biophysical methodologies applied.

Original languageEnglish
Pages (from-to)9877-9895
Number of pages19
JournalJournal of Physical Chemistry B
Volume122
Issue number43
DOIs
Publication statusPublished - 1 Nov 2018

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Adamantane
influenza
Amantadine
inhibitors
Molecular dynamics
Amines
Dimyristoylphosphatidylcholine
drugs
molecular dynamics
membranes
proteins
Proteins
Membranes
perturbation
Lipid bilayers
Computer simulation
Pharmaceutical Preparations
Nuclear magnetic resonance spectroscopy
Water
Differential scanning calorimetry

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Comparative Perturbation Effects Exerted by the Influenza A M2 WT Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2′-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations. / Konstantinidi, Athina; Naziris, Nikolaos; Chountoulesi, Maria; Kiriakidi, Sophia; Sartori, Barbara; Kolokouris, Dimitris; Amentisch, Heinz; Mali, Gregor; Ntountaniotis, Dimitrios; Demetzos, Costas; Mavromoustakos, Thomas; Kolocouris, Antonios.

In: Journal of Physical Chemistry B, Vol. 122, No. 43, 01.11.2018, p. 9877-9895.

Research output: Contribution to journalArticleResearchpeer-review

Konstantinidi, Athina ; Naziris, Nikolaos ; Chountoulesi, Maria ; Kiriakidi, Sophia ; Sartori, Barbara ; Kolokouris, Dimitris ; Amentisch, Heinz ; Mali, Gregor ; Ntountaniotis, Dimitrios ; Demetzos, Costas ; Mavromoustakos, Thomas ; Kolocouris, Antonios. / Comparative Perturbation Effects Exerted by the Influenza A M2 WT Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2′-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations. In: Journal of Physical Chemistry B. 2018 ; Vol. 122, No. 43. pp. 9877-9895.
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