Investigação do modo de ação independente de receptores do endocanabinóide anandamida por dinâmica molecular
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2019-03-15
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Universidade Estadual Paulista (Unesp)
Resumo
A anandamida é uma molécula anfipática que tem papel fundamental nas funções neurofisiológicas, sendo o agonista endógeno dos receptores canabinóides conhecidos como CB1 e CB2, os mesmos receptores dos compostos psicoativos da Cannabis sativa. Estudos mostram que a anandamida é capaz de realizar suas funções neurofisiológicas mesmo com seus receptores inativos, sugerindo uma atuação independente de receptores. Essa hipótese aliada com a teoria dos lipídios sugere que a anandamida interaja com os fosfolipídios alterando suas propriedades elásticas que levam a uma abertura ou fechamento das proteínas de membrana que são responsáveis por seu efeito biológico. As propriedades elásticas de uma bicamada lipídica podem ser associadas com seu perfil de pressão lateral, dessa forma, para obtermos informações a respeito do modo de ação independente de receptor investigamos como a anandamida particiona em uma bicamada de DOPC e quais propriedades estruturais e elásticas são alteradas por ela. Os resultados mostraram que a preferência do AEA é particionar na bicamada com seus grupos hidrofílicos voltados para a fase aquosa, na posição próxima ao grupo fosfato e éster e mantendo uma estrutura preferencial estendida, onde sua cauda acílica fica protegida das moléculas de água no núcleo hidrofóbico da bicamada. A crescente concentração de AEA não é capaz de alterar significantemente propriedades da membrana como, espessura, área por lipídio e parâmetro de ordem, porém altera significantemente o perfil de pressão lateral e seus parâmetros elásticos, representados pelos momentos da pressão lateral. Para compreender se a crescente concentração de AEA é suficiente para fazer uma proteína transitar do seu estado ativo para o inativo, e vice versa, dois modelos foram utilizados, a inclinação cooperativa e Hélice dobrada. Os resultados em ambos modelos mostram que a AEA tem capacidade de ativação das proteínas de membrana, sendo que na concentração aproximada de 1,7 mol% de AEA é capaz de ativar todas as proteínas.
Anandamide is an amphipathic molecule that plays a fundamental role in neurophysiological functions, being the endogenous agonist of the cannabinoid receptors known as CB1 and CB2, the same receptors of the psychoactive compounds of Cannabis sativa. Studies show that anandamide is able to perform its neurophysiological functions even with its inactive receptors, suggesting an independent performance of receptors. This hypothesis allied with the lipid theory suggests that anandamide interacts with the phospholipids by altering its elastic properties that lead to an opening or closing of the membrane proteins that are responsible for its biological effect. The elastic properties of a lipid bilayer can be associated with its lateral pressure profile, so, to obtain information about the receptor-independent mode of action, we investigated how anandamide partitions in a DOPC bilayer and which structural and elastic properties are altered for her. The results showed that the AEA preference is to partition the bilayer with its hydrophilic groups facing the aqueous phase, in the position close to the phosphate and ester group and maintaining an extended preferred structure, where its acrylic tail is protected from the water molecules in the hydrophobic core of the bilayer. The increasing concentration of AEA is not capable of significantly changing membrane properties such as thickness, area by lipid and order parameter, but it significantly alters the lateral pressure profile and its elastic parameters, represented by lateral pressure moments. To understand if the increasing concentration of AEA is sufficient to make a protein transit from its active to inactive state, and vice versa, two models were used, the cooperative slope and folded propeller. The results in both models show that the AEA has the ability to activate the membrane proteins, and in the approximate concentration of 1.7 mol% of AEA is able to activate all proteins.
Anandamide is an amphipathic molecule that plays a fundamental role in neurophysiological functions, being the endogenous agonist of the cannabinoid receptors known as CB1 and CB2, the same receptors of the psychoactive compounds of Cannabis sativa. Studies show that anandamide is able to perform its neurophysiological functions even with its inactive receptors, suggesting an independent performance of receptors. This hypothesis allied with the lipid theory suggests that anandamide interacts with the phospholipids by altering its elastic properties that lead to an opening or closing of the membrane proteins that are responsible for its biological effect. The elastic properties of a lipid bilayer can be associated with its lateral pressure profile, so, to obtain information about the receptor-independent mode of action, we investigated how anandamide partitions in a DOPC bilayer and which structural and elastic properties are altered for her. The results showed that the AEA preference is to partition the bilayer with its hydrophilic groups facing the aqueous phase, in the position close to the phosphate and ester group and maintaining an extended preferred structure, where its acrylic tail is protected from the water molecules in the hydrophobic core of the bilayer. The increasing concentration of AEA is not capable of significantly changing membrane properties such as thickness, area by lipid and order parameter, but it significantly alters the lateral pressure profile and its elastic parameters, represented by lateral pressure moments. To understand if the increasing concentration of AEA is sufficient to make a protein transit from its active to inactive state, and vice versa, two models were used, the cooperative slope and folded propeller. The results in both models show that the AEA has the ability to activate the membrane proteins, and in the approximate concentration of 1.7 mol% of AEA is able to activate all proteins.
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Biofísica molecular, Anandamida, Pressão lateral, Dinâmica molecular, Umbrella sampling, Molecular biophysics, Anandamide, AEA, Lateral pressure, Molecular dynamics