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      Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study

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          Abstract

          Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The present structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.

          Abstract

          Abstract

          The structure of the amphotericin B ion channel was elucidated to be a seven-molecule assembly with a single molecular length.

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          GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers

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            Comparison of simple potential functions for simulating liquid water

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              Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems

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                Author and article information

                Contributors
                Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - original draft
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: ResourcesRole: SoftwareRole: ValidationRole: Visualization
                Role: Formal analysisRole: ResourcesRole: Software
                Role: ConceptualizationRole: InvestigationRole: ResourcesRole: ValidationRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Resources
                Role: Formal analysisRole: Investigation
                Role: InvestigationRole: Resources
                Role: MethodologyRole: Project administrationRole: ValidationRole: Writing - review & editing
                Role: InvestigationRole: Validation
                Role: InvestigationRole: MethodologyRole: Resources
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                June 2022
                17 June 2022
                : 8
                : 24
                : eabo2658
                Affiliations
                [1 ]Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.
                [2 ]Project Research Center for Fundamental Sciences, Osaka University, Toyonaka, Osaka 560-0043, Japan.
                [3 ]Department of Materials Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan.
                [4 ]Japan Science and Technology Agency, ERATO, Lipid Active Structure Project, Osaka University, Toyonaka, Osaka 560-0043, Japan.
                [5 ]Department of Chemistry, Graduate School of Science, Kyushu University, Fukuoka 819-0395, Japan.
                [6 ]Research Institute for Interdisciplinary Science, Okayama University, Okayama 700-8530, Japan.
                [7 ]Department of Chemistry, Faculty of Science, Okayama University, Okayama 700-8530, Japan.
                Author notes
                [* ]Corresponding author. Email: murata@ 123456chem.sci.osaka-u.ac.jp (M.M.); shinoda@ 123456okayama-u.ac.jp (W.S.)
                [†]

                These authors contributed equally to this work.

                [‡]

                Present address: Riken, Saitama 351-0198, Japan.

                [§]

                Present address: Oita University, Oita 879-5593, Japan.

                Author information
                https://orcid.org/0000-0002-1057-8119
                https://orcid.org/0000-0002-3284-5388
                https://orcid.org/0000-0003-2956-6756
                https://orcid.org/0000-0002-3555-6223
                https://orcid.org/0000-0002-4422-5389
                https://orcid.org/0000-0003-0554-2303
                https://orcid.org/0000-0003-3102-7890
                https://orcid.org/0000-0002-3057-9354
                https://orcid.org/0000-0003-0495-2044
                https://orcid.org/0000-0002-3388-9227
                https://orcid.org/0000-0002-1600-145X
                Article
                abo2658
                10.1126/sciadv.abo2658
                9205587
                35714188
                eac8db50-5dfd-41b8-be4f-27316baec7da
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 24 January 2022
                : 04 May 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 16H06315
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 17H06406
                Funded by: FundRef http://dx.doi.org/10.13039/501100002241, Japan Science and Technology Agency;
                Award ID: JPMJER1005
                Categories
                Research Article
                Biomedicine and Life Sciences
                SciAdv r-articles
                Life Sciences
                Custom metadata
                Vivian Hernandez

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