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Perini DA, Aguilella-Arzo M, Alcaraz A, et al. Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations. Comput Struct Biotechnol J. 2021;20:230-240doi: 10.1016/j.csbj.2021.12.021.
Perini, D. A., Aguilella-Arzo, M., Alcaraz, A., Perálvarez-Marín, A., & Queralt-Martín, M. (2022). Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations. Computational and structural biotechnology journal, 20230-240. https://doi.org/10.1016/j.csbj.2021.12.021
Perini, D Aurora, et al. "Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations." Computational and structural biotechnology journal vol. 20 (2022): 230-240. doi: https://doi.org/10.1016/j.csbj.2021.12.021
Perini DA, Aguilella-Arzo M, Alcaraz A, Perálvarez-Marín A, Queralt-Martín M. Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations. Comput Struct Biotechnol J. 2021 Dec 16;20:230-240. doi: 10.1016/j.csbj.2021.12.021. eCollection 2022. PMID: 35024095; PMCID: PMC8718563.
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Comput Struct Biotechnol J. 2021 Dec 16;20:230-240. doi: 10.1016/j.csbj.2021.12.021. eCollection 2022.

Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations.

Computational and structural biotechnology journal

D Aurora Perini, Marcel Aguilella-Arzo, Antonio Alcaraz, Alex Perálvarez-Marín, María Queralt-Martín

Affiliations

  1. Laboratory of Molecular Biophysics. Department of Physics. Universitat Jaume I, 12071 Castellón, Spain.
  2. Biophysics Unit, Department of Biochemistry and Molecular Biology, School of Medicine, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
  3. Institute of Neuroscience, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.

PMID: 35024095 PMCID: PMC8718563 DOI: 10.1016/j.csbj.2021.12.021

Abstract

Dynorphins are endogenous neuropeptides that function as ligands for the κ-opioid receptor. In addition to opioid activity, dynorphins can induce several pathological effects such as neurological dysfunctions and cell death. Previous studies have suggested that Dynorphin A (DynA) mediates some pathogenic actions through formation of transient pores in lipid domains of the plasma membrane. Here, we use planar bilayer electrophysiology to show that DynA induces pore formation in negatively charged membranes. We find a large variability in pore conformations showing equilibrium conductance fluctuations, what disregards electroporation as the dominant mechanism of pore formation. Ion selectivity measurements showing cationic selectivity indicate that positive protein charges of DynA are stabilized by phosphatidyl serine negative charges in the formation of combined structures. We complement our study with computational simulations that assess the stability of diverse peptide arrangements in the hydrophobic core of the bilayer. We show that DynA is capable of assembling in charged membranes to form water-filled pores that conduct ions.

© 2021 The Authors.

Keywords: Computational simulations; Dynorphin; Ion channel; Membrane permeabilization; Noise and fluctuations; Protein-lipid interactions; Proteolipidic pores

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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