Estudo do enovelamento da enzima SOD1 por simulações de dinâmica molecular
Carregando...
Data
2019-03-07
Autores
Mouro, Paulo Ricardo
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
A ausência de metais ligados (proteína Apo) e mutações na enzima superóxido dismutase humana (SOD1) tem sido associado com a doença Esclerose Lateral Amiotrófica (ELA). A ELA é uma doença neurodegenerativa, que causa a morte de neurônios motores, tanto do córtex cerebral quanto da medula espinhal, levando o portador a um estado avançado de atrofia muscular. Acredita-se que, no mundo, a prevalência de ELA seja de 3-8 portadores para cada 100 mil habitantes. Utilizando o modelo baseado em estrutura, e modificando a energia de interação entre resíduos de aminoácidos do sítio de ligação ao metal, e entre a ligação dissulfeto C57-C146, detectamos diferenças entre o enovelamento do monômero apo e holo, nas formas oxidada e reduzida, da SOD1. A presença de íons metálicos claramente diminui a barreira de energia livre e também sugere que o caminho de enovelamento sofra mudanças para atingir o estado nativo. A cinética de enovelamento das formas apo também se correlaciona com a quantidade de barreira de energia livre no processo de enovelamento. Além disso, a estabilidade do estado nativo é significativamente afetada pela ausência de íons metálicos. Quanto à ligação dissulfeto, os resultados mostram que a sua ausência diminui a estabilidade da estrutura nativa e afeta menos o estado de transição, sugerindo que esta seja feita tardiamente no processo de enovelamento. Além disso, investigamos o efeito da concentração no enovelamento do dímero, e, incluindo simulações com o método ABF, buscamos elucidar algumas questões sobre o processo de dimerização da SOD1 na presença e ausência de metais.
The absence of bound metals (Apo protein) and mutations in the Cu-Zn Human Superoxide Dismutase (SOD1) have been associated with Amyotrophic Lateral Sclerosis (ALS) disease. ALS is a neurodegenerative disease, which causes the death of motor neurons in both the cerebral cortex and the spinal cord, leading to an advanced muscle atrophy state. It is believed that in the world, the ALS prevalence is 3-8 per 100,000 inhabitants. Using a structure based-model and modifying the energy of interaction between amino acids residues in the metal-binding site and between the disulfide bond C57-C146, we detected differences between the folding of the apo and holo, oxidized and reduced monomeric SOD1. The presence of metal ions clearly decreases the free energy barrier and also suggests that the folding pathway may change to reach the native state. The kinetics of folding of the apo forms also correlates with the amount of free energy barrier in the folding process. In addition, the stability of the native state is significantly affected by the absence of the metal ions. As regarding to the disulfide bond, the results show that its absence decreases the stability of the native structure and affects less the transition state, suggesting that it is possible made late in the folding process. Futhermore, we investigated the effect of the concentration on the dimer folding process, and including all-atoms simulations and ABF method, we search to elucidate some questions about SOD1 dimerization process.
The absence of bound metals (Apo protein) and mutations in the Cu-Zn Human Superoxide Dismutase (SOD1) have been associated with Amyotrophic Lateral Sclerosis (ALS) disease. ALS is a neurodegenerative disease, which causes the death of motor neurons in both the cerebral cortex and the spinal cord, leading to an advanced muscle atrophy state. It is believed that in the world, the ALS prevalence is 3-8 per 100,000 inhabitants. Using a structure based-model and modifying the energy of interaction between amino acids residues in the metal-binding site and between the disulfide bond C57-C146, we detected differences between the folding of the apo and holo, oxidized and reduced monomeric SOD1. The presence of metal ions clearly decreases the free energy barrier and also suggests that the folding pathway may change to reach the native state. The kinetics of folding of the apo forms also correlates with the amount of free energy barrier in the folding process. In addition, the stability of the native state is significantly affected by the absence of the metal ions. As regarding to the disulfide bond, the results show that its absence decreases the stability of the native structure and affects less the transition state, suggesting that it is possible made late in the folding process. Futhermore, we investigated the effect of the concentration on the dimer folding process, and including all-atoms simulations and ABF method, we search to elucidate some questions about SOD1 dimerization process.
Descrição
Palavras-chave
modelo baseado em estrutura, SOD1, ELA, Método de força adaptativa, Structure-based model, Adaptive Biasing Force