Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

Nuno Martinho,1–3 Liana C Silva,1,4 Helena F Florindo,1 Steve Brocchini,2 Mire Zloh,3 Teresa S Barata2 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; 2Department of Pharmaceutics, UCL School of Pharmacy, London, 3School of...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Martinho N, Silva LC, Florindo HF, Brocchini S, Zloh M, Barata TS
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	Dendrimers Peptide Dendrimers Molecular dynamics fluorescence CHARMM Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/5c2b5972c2a7494c9beb56c04a2afabc
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5c2b5972c2a7494c9beb56c04a2afabc
record_format	dspace
spelling	oai:doaj.org-article:5c2b5972c2a7494c9beb56c04a2afabc2021-12-02T03:55:32ZRational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties1178-2013https://doaj.org/article/5c2b5972c2a7494c9beb56c04a2afabc2017-09-01T00:00:00Zhttps://www.dovepress.com/rational-design-of-novel-fluorescent-tagged-glutamic-acid-dendrimers-w-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Nuno Martinho,1–3 Liana C Silva,1,4 Helena F Florindo,1 Steve Brocchini,2 Mire Zloh,3 Teresa S Barata2 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; 2Department of Pharmaceutics, UCL School of Pharmacy, London, 3School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 4Centro de Química-Física Molecular and IN – Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal Abstract: Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(L-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system. Keywords: dendrimers, peptide dendrimers, molecular dynamics, fluorescence, CHARMM, structure-activity, surface propertiesMartinho NSilva LCFlorindo HFBrocchini SZloh MBarata TSDove Medical PressarticleDendrimersPeptide DendrimersMolecular dynamicsfluorescenceCHARMMMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 7053-7073 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Dendrimers Peptide Dendrimers Molecular dynamics fluorescence CHARMM Medicine (General) R5-920
spellingShingle	Dendrimers Peptide Dendrimers Molecular dynamics fluorescence CHARMM Medicine (General) R5-920 Martinho N Silva LC Florindo HF Brocchini S Zloh M Barata TS Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
description	Nuno Martinho,1–3 Liana C Silva,1,4 Helena F Florindo,1 Steve Brocchini,2 Mire Zloh,3 Teresa S Barata2 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; 2Department of Pharmaceutics, UCL School of Pharmacy, London, 3School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 4Centro de Química-Física Molecular and IN – Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal Abstract: Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(L-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system. Keywords: dendrimers, peptide dendrimers, molecular dynamics, fluorescence, CHARMM, structure-activity, surface properties
format	article
author	Martinho N Silva LC Florindo HF Brocchini S Zloh M Barata TS
author_facet	Martinho N Silva LC Florindo HF Brocchini S Zloh M Barata TS
author_sort	Martinho N
title	Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
title_short	Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
title_full	Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
title_fullStr	Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
title_full_unstemmed	Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
title_sort	rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/5c2b5972c2a7494c9beb56c04a2afabc
work_keys_str_mv	AT martinhon rationaldesignofnovelfluorescenttaggedglutamicaciddendrimerswithdifferentterminalgroupsandinsilicoanalysisoftheirproperties AT silvalc rationaldesignofnovelfluorescenttaggedglutamicaciddendrimerswithdifferentterminalgroupsandinsilicoanalysisoftheirproperties AT florindohf rationaldesignofnovelfluorescenttaggedglutamicaciddendrimerswithdifferentterminalgroupsandinsilicoanalysisoftheirproperties AT brocchinis rationaldesignofnovelfluorescenttaggedglutamicaciddendrimerswithdifferentterminalgroupsandinsilicoanalysisoftheirproperties AT zlohm rationaldesignofnovelfluorescenttaggedglutamicaciddendrimerswithdifferentterminalgroupsandinsilicoanalysisoftheirproperties AT baratats rationaldesignofnovelfluorescenttaggedglutamicaciddendrimerswithdifferentterminalgroupsandinsilicoanalysisoftheirproperties
_version_	1718401551116009472

Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

Ejemplares similares