Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Phys Chem B ; 128(10): 2398-2411, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38445598

RESUMO

The activation of the muscular nicotinic acetylcholine receptor (nAChR) produces the opening of the channel, with the consequent increase in the permeability of cations, triggering an excitatory signal. Free fatty acids (FFA) are known to modulate the activity of the receptor as noncompetitive antagonists, acting at the membrane-AChR interface. We present molecular dynamics simulations of a model of nAChR in a desensitized closed state embedded in a lipid bilayer in which distinct membrane phospholipids were replaced by two different monounsaturated FFA that differ in the position of a double bond. This allowed us to detect and describe that the cis-18:1ω-9 FFA were located at the interface between the transmembrane segments of α2 and γ subunits diffused into the channel lumen with the consequent potential ability to block the channel to the passage of ions.


Assuntos
Receptores Nicotínicos , Animais , Receptores Nicotínicos/química , Simulação de Dinâmica Molecular , Ácido Oleico , Sítios de Ligação , Membrana Celular/metabolismo , Torpedo/metabolismo
2.
Angew Chem Int Ed Engl ; 63(21): e202317552, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38497459

RESUMO

Celiac disease (CeD) is an autoimmune disorder triggered by gluten proteins, affecting approximately 1 % of the global population. The 33-mer deamidated gliadin peptide (DGP) is a metabolically modified wheat-gluten superantigen for CeD. Here, we demonstrate that the 33-mer DGP spontaneously assembles into oligomers with a diameter of approximately 24 nm. The 33-mer DGP oligomers present two main secondary structural motifs-a major polyproline II helix and a minor ß-sheet structure. Importantly, in the presence of 33-mer DGP oligomers, there is a statistically significant increase in the permeability in the gut epithelial cell model Caco-2, accompanied by the redistribution of zonula occludens-1, a master tight junction protein. These findings provide novel molecular and supramolecular insights into the impact of 33-mer DGP in CeD and highlight the relevance of gliadin peptide oligomerization.


Assuntos
Doença Celíaca , Enterócitos , Gliadina , Humanos , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Células CACO-2 , Gliadina/química , Gliadina/metabolismo , Enterócitos/metabolismo , Superantígenos/química , Superantígenos/metabolismo , Permeabilidade
3.
J Phys Chem B ; 127(11): 2407-2417, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36884001

RESUMO

The 33-mer gliadin peptide and its deamidated metabolite, 33-mer DGP, are the immunodominant peptides responsible for the adaptive immune response in celiac disease (CD). CD is a complex autoimmune chronic disorder triggered by gluten ingestion that affects the small intestine and affects ∼1% of the global population. The 33-mers are polyproline II-rich (PPII) and intrinsically disordered peptides (IDPs), whose structures remain elusive. We sampled the conformational ensembles of both 33-mer peptides via molecular dynamics simulations employing two force fields (FFs) (Amber ff03ws and Amber ff99SB-disp) specifically validated for other IDPs. Our results show that both FFs allow the extensive exploration of the conformational landscape, which was not possible with the standard FF GROMOS53A6 reported before. Clustering analysis of the trajectories showed that the five largest clusters (78-88% of the total structures) present elongated, semielongated, and curved conformations in both FFs. Large average radius of gyration and solvent-exposed surfaces characterized these structures. While the structures sampled are similar, the Amber ff99SB-disp trajectories explored folded conformations with a higher probability. In addition, PPII secondary structure was preserved throughout the trajectories (58-73%) together with a non-negligible content of ß structures (11-23%), in agreement with previous experimental results. This work represents the initial step in studying further the interaction of these peptides with other biologically relevant molecules, which could lead to finally disclose the molecular events that lead to CD.


Assuntos
Âmbar , Gliadina , Gliadina/química , Peptídeos/química , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína
4.
Molecules ; 27(1)2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-35011320

RESUMO

The aggregation of proteins into amyloid fibers is linked to more than forty still incurable cellular and neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease and type 2 diabetes, among others. The process of amyloid formation is a main feature of cell degeneration and disease pathogenesis. Despite being methodologically challenging, a complete understanding of the molecular mechanism of aggregation, especially in the early stages, is essential to find new biological targets for innovative therapies. Here, we reviewed selected examples on α-syn showing how complementary approaches, which employ different biophysical techniques and models, can better deal with a comprehensive study of amyloid aggregation. In addition to the monomer aggregation and conformational transition hypothesis, we reported new emerging theories regarding the self-aggregation of α-syn, such as the alpha-helix rich tetramer hypothesis, whose destabilization induce monomer aggregation; and the liquid-liquid phase separation hypothesis, which considers a phase separation of α-syn into liquid droplets as a primary event towards the evolution to aggregates. The final aim of this review is to show how multimodal methodologies provide a complete portrait of α-syn oligomerization and can be successfully extended to other protein aggregation diseases.


Assuntos
Agregados Proteicos , Agregação Patológica de Proteínas/etiologia , Agregação Patológica de Proteínas/metabolismo , Multimerização Proteica , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Amiloidose , Animais , Suscetibilidade a Doenças , Humanos , Interações Hidrofóbicas e Hidrofílicas , Extração Líquido-Líquido , Modelos Moleculares , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Conformação Proteica , Relação Estrutura-Atividade , alfa-Sinucleína/isolamento & purificação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...