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Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System

[Image: see text] Owing to their potential applicability against multidrug-resistant bacteria, antimicrobial peptides (AMPs) or host defense peptides (HDPs) gain increased attention. Besides diverse immunomodulatory roles, their classical mechanism of action mostly involves membrane disruption of mi...

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Autores principales: Kohut, Gergely, Juhász, Tünde, Quemé-Peña, Mayra, Bősze, Szilvia Erika, Beke-Somfai, Tamás
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223213/
https://www.ncbi.nlm.nih.gov/pubmed/34179620
http://dx.doi.org/10.1021/acsomega.1c01114
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author Kohut, Gergely
Juhász, Tünde
Quemé-Peña, Mayra
Bősze, Szilvia Erika
Beke-Somfai, Tamás
author_facet Kohut, Gergely
Juhász, Tünde
Quemé-Peña, Mayra
Bősze, Szilvia Erika
Beke-Somfai, Tamás
author_sort Kohut, Gergely
collection PubMed
description [Image: see text] Owing to their potential applicability against multidrug-resistant bacteria, antimicrobial peptides (AMPs) or host defense peptides (HDPs) gain increased attention. Besides diverse immunomodulatory roles, their classical mechanism of action mostly involves membrane disruption of microbes. Notably, their unbalanced overexpression has also been associated with host cell cytotoxicity in various diseases. Relatedly, AMPs can be subject to aggregate formation, either via self-assembly or together with other compounds, which has demonstrated a modulation effect on their biological functions, thus highly relevant both for drug targeting projects and understanding their in vivo actions. However, the molecular aspects of the related assembly formation are not understood. Here, we focused in detail on an experimentally studied AMP–drug system, i.e., CM15–suramin, and performed all-atom and coarse-grain (CG) simulations. Results obtained for all systems were in close line with experimental observations and indicate that the CM15–suramin aggregation is an energetically favorable and dynamic process. In the presence of bilayers, the peptide–drug assembly formation was highly dependent on lipid composition, and peptide aggregates themselves were also capable of binding to the membranes. Interestingly, longer CG simulations with zwitterionic membranes indicated an intermediate state in the presence of both AMP–drug assemblies and monomeric peptides located on the membrane surface. In sharp contrast, larger AMP–drug aggregates could not be detected with a negatively charged membrane, rather the AMPs penetrated its surface in a monomeric form, in line with previous in vitro observations. Considering experimental and theoretical results, it is promoted that in biological systems, cationic AMPs may often form associates with anionic compounds in a reversible manner, resulting in lower bioactivity. This is only mildly affected by zwitterionic membranes; however, membranes with a negative charge strongly alter the energetic preference of AMP assemblies, resulting in the dissolution of the complexes into the membrane. The phenomenon observed here at a molecular level can be followed in several experimental systems studied recently, where peptides interact with food colors, drug molecules, or endogenous compounds, which strongly indicates that reversible associate formation is a general phenomenon for these complexes. These results are hoped to be exploited in novel therapeutic strategies aiming to use peptides as drug targets and control AMP bioactivity by directed assembly formation.
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spelling pubmed-82232132021-06-25 Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System Kohut, Gergely Juhász, Tünde Quemé-Peña, Mayra Bősze, Szilvia Erika Beke-Somfai, Tamás ACS Omega [Image: see text] Owing to their potential applicability against multidrug-resistant bacteria, antimicrobial peptides (AMPs) or host defense peptides (HDPs) gain increased attention. Besides diverse immunomodulatory roles, their classical mechanism of action mostly involves membrane disruption of microbes. Notably, their unbalanced overexpression has also been associated with host cell cytotoxicity in various diseases. Relatedly, AMPs can be subject to aggregate formation, either via self-assembly or together with other compounds, which has demonstrated a modulation effect on their biological functions, thus highly relevant both for drug targeting projects and understanding their in vivo actions. However, the molecular aspects of the related assembly formation are not understood. Here, we focused in detail on an experimentally studied AMP–drug system, i.e., CM15–suramin, and performed all-atom and coarse-grain (CG) simulations. Results obtained for all systems were in close line with experimental observations and indicate that the CM15–suramin aggregation is an energetically favorable and dynamic process. In the presence of bilayers, the peptide–drug assembly formation was highly dependent on lipid composition, and peptide aggregates themselves were also capable of binding to the membranes. Interestingly, longer CG simulations with zwitterionic membranes indicated an intermediate state in the presence of both AMP–drug assemblies and monomeric peptides located on the membrane surface. In sharp contrast, larger AMP–drug aggregates could not be detected with a negatively charged membrane, rather the AMPs penetrated its surface in a monomeric form, in line with previous in vitro observations. Considering experimental and theoretical results, it is promoted that in biological systems, cationic AMPs may often form associates with anionic compounds in a reversible manner, resulting in lower bioactivity. This is only mildly affected by zwitterionic membranes; however, membranes with a negative charge strongly alter the energetic preference of AMP assemblies, resulting in the dissolution of the complexes into the membrane. The phenomenon observed here at a molecular level can be followed in several experimental systems studied recently, where peptides interact with food colors, drug molecules, or endogenous compounds, which strongly indicates that reversible associate formation is a general phenomenon for these complexes. These results are hoped to be exploited in novel therapeutic strategies aiming to use peptides as drug targets and control AMP bioactivity by directed assembly formation. American Chemical Society 2021-06-11 /pmc/articles/PMC8223213/ /pubmed/34179620 http://dx.doi.org/10.1021/acsomega.1c01114 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Kohut, Gergely
Juhász, Tünde
Quemé-Peña, Mayra
Bősze, Szilvia Erika
Beke-Somfai, Tamás
Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System
title Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System
title_full Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System
title_fullStr Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System
title_full_unstemmed Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System
title_short Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System
title_sort controlling peptide function by directed assembly formation: mechanistic insights using multiscale modeling on an antimicrobial peptide–drug–membrane system
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223213/
https://www.ncbi.nlm.nih.gov/pubmed/34179620
http://dx.doi.org/10.1021/acsomega.1c01114
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