Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations

The globally expanding threat of antibiotic resistance calls for the development of new strategies for abating Gram-negative bacterial infections. The use of extracorporeal blood cleansing devices with affinity sorbents to selectively capture bacterial lipopolysaccharide (LPS), which is the major co...

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Autores: González Fernández, Cristina, Öhlknecht, Christoph, Diem, Matthias, Escalona, Yerko, Bringas Elizalde, Eugenio|||0000-0001-8197-6547, Moncalián Montes, Gabriel|||0000-0002-3007-6490, Oostenbrink, Chris, Ortiz Uribe, Inmaculada|||0000-0002-3257-4821
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/28730
Acceso en línea:https://hdl.handle.net/10902/28730
Access Level:acceso abierto
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spelling Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulationsGonzález Fernández, CristinaÖhlknecht, ChristophDiem, MatthiasEscalona, YerkoBringas Elizalde, Eugenio|||0000-0001-8197-6547Moncalián Montes, Gabriel|||0000-0002-3007-6490Oostenbrink, ChrisOrtiz Uribe, Inmaculada|||0000-0002-3257-4821The globally expanding threat of antibiotic resistance calls for the development of new strategies for abating Gram-negative bacterial infections. The use of extracorporeal blood cleansing devices with affinity sorbents to selectively capture bacterial lipopolysaccharide (LPS), which is the major constituent of Gram-negative bacterial outer membranes and the responsible agent for eliciting an exacerbated innate immune response in the host during infection, has received outstanding interest. For that purpose, molecules that bind tightly to LPS are required to functionalize the affinity sorbents. Particularly, anti-LPS factors (ALFs) are promising LPS-sequestrating molecules. Hence, in this work, molecular dynamics (MD) simulations are used to investigate the interaction mechanism and binding pose of the ALF isoform 3 from Penaeus monodon (ALFPm3), which is referred to as "AL3" for the sake of simplicity, and lipid A (LA, the component of LPS that represents its endotoxic principle). We concluded that hydrophobic interactions are responsible for AL3-LA binding and that LA binds to AL3 within the protein cavity, where it buries its aliphatic tails, whereas the negatively charged phosphate groups are exposed to the medium. AL3 residues that are key for its interaction with LA were identified, and their conservation in other ALFs (specifically Lys39 and Tyr49) was also analyzed. Additionally, based on the MD-derived results, we provide a picture of the possible AL3-LA interaction mechanism. Finally, an in vitro validation of the in silico predictions was performed. Overall, the insights gained from this work can guide the design of novel therapeutics for treating sepsis, since they may be significantly valuable for designing LPS-sequestrating molecules that could functionalize affinity sorbents to be used for extracorporeal blood detoxification.Financial support from the Spanish Ministry of Science, Innovation and Universities under the project RTI2018- 093310-B-I00 is gratefully acknowledged. C.G.F. also thanks the Spanish Ministry of Universities for the Margarita Salas postdoctoral fellowship (grants for the requalification of the Spanish university system for 2021−2023, University of Cantabria), funded by the European Union-NextGenerationEU.American Chemical SocietyUniversidad de Cantabria20232023-04-07journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/28730Journal of Chemical Information and Modeling, 2023, 63(8), 2495-2504reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/287302026-06-02T12:39:31Z
dc.title.none.fl_str_mv Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
title Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
spellingShingle Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
González Fernández, Cristina
title_short Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
title_full Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
title_fullStr Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
title_full_unstemmed Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
title_sort Insights into the binding mode of lipid a to the anti-lipopolysaccharide factor ALFPm3 from penaeus monodon: an in silico study through MD simulations
dc.creator.none.fl_str_mv González Fernández, Cristina
Öhlknecht, Christoph
Diem, Matthias
Escalona, Yerko
Bringas Elizalde, Eugenio|||0000-0001-8197-6547
Moncalián Montes, Gabriel|||0000-0002-3007-6490
Oostenbrink, Chris
Ortiz Uribe, Inmaculada|||0000-0002-3257-4821
author González Fernández, Cristina
author_facet González Fernández, Cristina
Öhlknecht, Christoph
Diem, Matthias
Escalona, Yerko
Bringas Elizalde, Eugenio|||0000-0001-8197-6547
Moncalián Montes, Gabriel|||0000-0002-3007-6490
Oostenbrink, Chris
Ortiz Uribe, Inmaculada|||0000-0002-3257-4821
author_role author
author2 Öhlknecht, Christoph
Diem, Matthias
Escalona, Yerko
Bringas Elizalde, Eugenio|||0000-0001-8197-6547
Moncalián Montes, Gabriel|||0000-0002-3007-6490
Oostenbrink, Chris
Ortiz Uribe, Inmaculada|||0000-0002-3257-4821
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
description The globally expanding threat of antibiotic resistance calls for the development of new strategies for abating Gram-negative bacterial infections. The use of extracorporeal blood cleansing devices with affinity sorbents to selectively capture bacterial lipopolysaccharide (LPS), which is the major constituent of Gram-negative bacterial outer membranes and the responsible agent for eliciting an exacerbated innate immune response in the host during infection, has received outstanding interest. For that purpose, molecules that bind tightly to LPS are required to functionalize the affinity sorbents. Particularly, anti-LPS factors (ALFs) are promising LPS-sequestrating molecules. Hence, in this work, molecular dynamics (MD) simulations are used to investigate the interaction mechanism and binding pose of the ALF isoform 3 from Penaeus monodon (ALFPm3), which is referred to as "AL3" for the sake of simplicity, and lipid A (LA, the component of LPS that represents its endotoxic principle). We concluded that hydrophobic interactions are responsible for AL3-LA binding and that LA binds to AL3 within the protein cavity, where it buries its aliphatic tails, whereas the negatively charged phosphate groups are exposed to the medium. AL3 residues that are key for its interaction with LA were identified, and their conservation in other ALFs (specifically Lys39 and Tyr49) was also analyzed. Additionally, based on the MD-derived results, we provide a picture of the possible AL3-LA interaction mechanism. Finally, an in vitro validation of the in silico predictions was performed. Overall, the insights gained from this work can guide the design of novel therapeutics for treating sepsis, since they may be significantly valuable for designing LPS-sequestrating molecules that could functionalize affinity sorbents to be used for extracorporeal blood detoxification.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-04-07
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/28730
url https://hdl.handle.net/10902/28730
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv Journal of Chemical Information and Modeling, 2023, 63(8), 2495-2504
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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