How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Tipo de documento: | Tese |
Idioma: | eng |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da USP |
Texto Completo: | https://www.teses.usp.br/teses/disponiveis/46/46131/tde-11122023-182928/ |
Resumo: | Cationic alpha-helical antimicrobial peptides (CHAMP) are potential candidates as novel drugs against resistant bacteria. CHAMPs are short amphipathic, membrane-active peptides in many organisms as part of their innate immune defense system. CHAMPs spark interest in pharmaceutical applications due to their ability to bear less risk of inducing bacterial resistance than conventional antibiotics, selectivity towards bacteria and fungi, and fast antimicrobial action. Their detailed mechanism of action on membranes needs to be clarified. Elucidating CHAMPs\' mode of action can provide relevant information that can be used to better design new CHAMPs with higher efficacy and selectivity. Here, we used Molecular Dynamics (MD) simulations to investigate the detailed mode of action of BP100 (H-KKLFKKILKYL-NH2), a promising CHAMP, on membranes. We characterized the initial interaction between a single BP100 and membranes using atomistic simulations. We described peptide flip, a dynamic phenomenon in which BP100 binds to the membranes, rotates and penetrates the membrane core, and causes local membrane effects, such as thinning, negative curvature, and a decrease in lipid lateral diffusion. We show peptide flip is a common step in the CHAMP/membrane interaction, using other similar CHAMPs: Decoralin, Neurokinin-1, and Temporin-L. Using coarse-grained MD, we studied the CHAMPs peptide concentration effect on vesicles, showing CHAMP-induced membrane budding at highly curved regions of negatively charged vesicles at a high peptide:lipid ratios. Our results suggest that the carpet mode of action fits the description of CHAMPs lysis activity, and we discuss the importance of significant hydrophobic residues in CHAMPs design and activity |
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How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspectiveComo os peptídeos antimicrobianos destroem membranas? Uma perspectiva sob o olhar da Dinâmica MolecularAntibióticosAntibioticsAntimicrobial peptidesCoarse-graining MDCoarse-graining MDDinâmica MolecularDrug designMecanismo de açãoMechanism of actionMolecular DynamicsPeptídeos antimicrobianosCationic alpha-helical antimicrobial peptides (CHAMP) are potential candidates as novel drugs against resistant bacteria. CHAMPs are short amphipathic, membrane-active peptides in many organisms as part of their innate immune defense system. CHAMPs spark interest in pharmaceutical applications due to their ability to bear less risk of inducing bacterial resistance than conventional antibiotics, selectivity towards bacteria and fungi, and fast antimicrobial action. Their detailed mechanism of action on membranes needs to be clarified. Elucidating CHAMPs\' mode of action can provide relevant information that can be used to better design new CHAMPs with higher efficacy and selectivity. Here, we used Molecular Dynamics (MD) simulations to investigate the detailed mode of action of BP100 (H-KKLFKKILKYL-NH2), a promising CHAMP, on membranes. We characterized the initial interaction between a single BP100 and membranes using atomistic simulations. We described peptide flip, a dynamic phenomenon in which BP100 binds to the membranes, rotates and penetrates the membrane core, and causes local membrane effects, such as thinning, negative curvature, and a decrease in lipid lateral diffusion. We show peptide flip is a common step in the CHAMP/membrane interaction, using other similar CHAMPs: Decoralin, Neurokinin-1, and Temporin-L. Using coarse-grained MD, we studied the CHAMPs peptide concentration effect on vesicles, showing CHAMP-induced membrane budding at highly curved regions of negatively charged vesicles at a high peptide:lipid ratios. Our results suggest that the carpet mode of action fits the description of CHAMPs lysis activity, and we discuss the importance of significant hydrophobic residues in CHAMPs design and activityPeptídeos antimicrobianos catiônicos helicoidais (CHAMP) são moléculas promissoras a serem utilizadas como novos antibióticos contra bactérias resistentes. CHAMPs são peptídeos de sequência curta, anfipáticos, possuem atividade em membranas e podem ser encontrados em muitos organismos fazendo parte do sistema imune inato. Os CHAMPs despertam interesse em aplicações farmacêuticas por terem menos risco de induzir resistência bacteriana em comparação a antibióticos convencionais, seletividade contra bactérias e ação rápida. Contudo, o seu mecanismo de ação detalhado ainda é desconhecido. Neste trabalho, utilizamos simulações de Dinâmica Molecular (MD) para investigar o modo de ação detalhado do BP100 (H-KKLFKKILKYL-NH2), um promissor CHAMP, em membranas. Utilizando simulações atomísticas, caracterizamos a interação inicial entre um monômero do BP100 e membranas. Descrevemos o peptide flip, um fenômeno dinâmico onde o peptídeo BP100 se liga às membranas, gira e penetra no interior da membrana e causa efeitos locais, como afinamento da membrana, curvatura negativa e diminuição na difusão lateral lipídica. Demonstramos que o peptide flip é uma etapa em comum na interação entre CHAMP e membranas, utilizando outros CHAMPs: Decoralin, Neurokinin-1 e Temporin-L. Utilizando coarse-grained MD, investigamos o efeito da concentração de peptídeo em vesículas-modelo de fosfolipídios, mostrando que CHAMPs induzem a protrusão de membranas em regiões de alta curvatura de vesículas negativas em altas concentrações de peptídeo. Nossos resultados sugerem que o modo de ação de carpete melhor descreve atividade de lise dos CHAMPs e discutimos a importância de aminoácidos hidrofóbicos volumosos no design e atividade de CHAMPs.Biblioteca Digitais de Teses e Dissertações da USPCuccovia, Iolanda MideaLima, Filipe da SilvaPark, Peter2023-05-05info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://www.teses.usp.br/teses/disponiveis/46/46131/tde-11122023-182928/reponame:Biblioteca Digital de Teses e Dissertações da USPinstname:Universidade de São Paulo (USP)instacron:USPLiberar o conteúdo para acesso público.info:eu-repo/semantics/openAccesseng2023-12-21T19:32:03Zoai:teses.usp.br:tde-11122023-182928Biblioteca Digital de Teses e Dissertaçõeshttp://www.teses.usp.br/PUBhttp://www.teses.usp.br/cgi-bin/mtd2br.plvirginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.bropendoar:27212023-12-21T19:32:03Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP)false |
dc.title.none.fl_str_mv |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective Como os peptídeos antimicrobianos destroem membranas? Uma perspectiva sob o olhar da Dinâmica Molecular |
title |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective |
spellingShingle |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective Park, Peter Antibióticos Antibiotics Antimicrobial peptides Coarse-graining MD Coarse-graining MD Dinâmica Molecular Drug design Mecanismo de ação Mechanism of action Molecular Dynamics Peptídeos antimicrobianos |
title_short |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective |
title_full |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective |
title_fullStr |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective |
title_full_unstemmed |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective |
title_sort |
How do antimicrobial peptides destroy membranes? A Molecular Dynamics perspective |
author |
Park, Peter |
author_facet |
Park, Peter |
author_role |
author |
dc.contributor.none.fl_str_mv |
Cuccovia, Iolanda Midea Lima, Filipe da Silva |
dc.contributor.author.fl_str_mv |
Park, Peter |
dc.subject.por.fl_str_mv |
Antibióticos Antibiotics Antimicrobial peptides Coarse-graining MD Coarse-graining MD Dinâmica Molecular Drug design Mecanismo de ação Mechanism of action Molecular Dynamics Peptídeos antimicrobianos |
topic |
Antibióticos Antibiotics Antimicrobial peptides Coarse-graining MD Coarse-graining MD Dinâmica Molecular Drug design Mecanismo de ação Mechanism of action Molecular Dynamics Peptídeos antimicrobianos |
description |
Cationic alpha-helical antimicrobial peptides (CHAMP) are potential candidates as novel drugs against resistant bacteria. CHAMPs are short amphipathic, membrane-active peptides in many organisms as part of their innate immune defense system. CHAMPs spark interest in pharmaceutical applications due to their ability to bear less risk of inducing bacterial resistance than conventional antibiotics, selectivity towards bacteria and fungi, and fast antimicrobial action. Their detailed mechanism of action on membranes needs to be clarified. Elucidating CHAMPs\' mode of action can provide relevant information that can be used to better design new CHAMPs with higher efficacy and selectivity. Here, we used Molecular Dynamics (MD) simulations to investigate the detailed mode of action of BP100 (H-KKLFKKILKYL-NH2), a promising CHAMP, on membranes. We characterized the initial interaction between a single BP100 and membranes using atomistic simulations. We described peptide flip, a dynamic phenomenon in which BP100 binds to the membranes, rotates and penetrates the membrane core, and causes local membrane effects, such as thinning, negative curvature, and a decrease in lipid lateral diffusion. We show peptide flip is a common step in the CHAMP/membrane interaction, using other similar CHAMPs: Decoralin, Neurokinin-1, and Temporin-L. Using coarse-grained MD, we studied the CHAMPs peptide concentration effect on vesicles, showing CHAMP-induced membrane budding at highly curved regions of negatively charged vesicles at a high peptide:lipid ratios. Our results suggest that the carpet mode of action fits the description of CHAMPs lysis activity, and we discuss the importance of significant hydrophobic residues in CHAMPs design and activity |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-05-05 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://www.teses.usp.br/teses/disponiveis/46/46131/tde-11122023-182928/ |
url |
https://www.teses.usp.br/teses/disponiveis/46/46131/tde-11122023-182928/ |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
|
dc.rights.driver.fl_str_mv |
Liberar o conteúdo para acesso público. info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Liberar o conteúdo para acesso público. |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.coverage.none.fl_str_mv |
|
dc.publisher.none.fl_str_mv |
Biblioteca Digitais de Teses e Dissertações da USP |
publisher.none.fl_str_mv |
Biblioteca Digitais de Teses e Dissertações da USP |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da USP instname:Universidade de São Paulo (USP) instacron:USP |
instname_str |
Universidade de São Paulo (USP) |
instacron_str |
USP |
institution |
USP |
reponame_str |
Biblioteca Digital de Teses e Dissertações da USP |
collection |
Biblioteca Digital de Teses e Dissertações da USP |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP) |
repository.mail.fl_str_mv |
virginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.br |
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1809090635860279296 |