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Self-assembly, stability and conductance of amphotericin B channels: bridging the gap between structure and function.
Zielinska, Joanna; Wieczór, Milosz; Chodnicki, Pawel; Grela, Ewa; Luchowski, Rafal; Nierzwicki, Lukasz; Baczek, Tomasz; Gruszecki, Wieslaw I; Czub, Jacek.
Afiliación
  • Zielinska J; Department of Pharmaceutical Chemistry, Medical University of Gdansk, Gdansk, Poland.
  • Wieczór M; Department of Physical Chemistry, Gdansk University of Technology, Gdansk, Poland. jacek.czub@pg.edu.pl and Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • Chodnicki P; Department of Physical Chemistry, Gdansk University of Technology, Gdansk, Poland. jacek.czub@pg.edu.pl.
  • Grela E; Department of Biophysics, Institute of Physics, Maria Curie-Sklodowska University, Lublin, Poland.
  • Luchowski R; Department of Biophysics, Institute of Physics, Maria Curie-Sklodowska University, Lublin, Poland.
  • Nierzwicki L; Department of Physical Chemistry, Gdansk University of Technology, Gdansk, Poland. jacek.czub@pg.edu.pl.
  • Baczek T; Department of Pharmaceutical Chemistry, Medical University of Gdansk, Gdansk, Poland.
  • Gruszecki WI; Department of Biophysics, Institute of Physics, Maria Curie-Sklodowska University, Lublin, Poland.
  • Czub J; Department of Physical Chemistry, Gdansk University of Technology, Gdansk, Poland. jacek.czub@pg.edu.pl.
Nanoscale ; 13(6): 3686-3697, 2021 Feb 18.
Article en En | MEDLINE | ID: mdl-33543744
Amphotericin B (AmB), one of the most powerful but also toxic drugs used to treat systemic mycoses, is believed to selectively permeabilize fungal cell membranes to ions in a sterol-dependent manner. Unfortunately, the structure of the biologically active AmB channels has long eluded researchers, obstructing the design of safer alternatives. Here, we investigate the structural and thermodynamic aspects of channel formation, stability, and selective ion conduction. We combine fluorescence lifetime imaging and molecular simulations to trace the process of channel assembly until the formation of stable, roughly octameric double-length channels (DLCs). This stoichiometry is confirmed by matching the predicted channel conductances with the past results of patch-clamp measurements. We then use free energy calculations to explain the effect of sterols on DLC stability and discuss the observed cation selectivity in structural terms, addressing several long-standing controversies in the context of their physiological relevance. Simulations of ion permeation indicate that only solvated ions pass through DLCs, revealing surprising solvation patterns in the channel lumen. We conclude our investigation by inspecting the role of the tail hydroxyl in the assembly of functional channels, pointing at possible origins of the cholesterol-ergosterol selectivity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anfotericina B / Membrana Dobles de Lípidos Idioma: En Revista: Nanoscale Año: 2021 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Reino Unido
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anfotericina B / Membrana Dobles de Lípidos Idioma: En Revista: Nanoscale Año: 2021 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Reino Unido