Representação detalhada do relevo de energia de monômeros de β-amilóide e de proteínas de repetições
Carregando...
Data
2021-12-15
Autores
Sanches, Murilo Nogueira
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
O processo pelo qual uma proteína assume sua configuração funcional é denominado enovelamento e corresponde a um problema que intriga os pesquisadores desde a década de 50. Devido à importância que essa classe de macromoléculas possui e às doenças que sua má atividade acarretam, compreender a formação de sua estrutura tridimensional é uma questão fundamental. Contudo, devido à sua complexidade, o processo ocorre em um espaço de fase multidimensional, de forma que sua análise não é trivial. Esse problema se torna ainda mais complicado devido ao fato de existirem classes especiais de proteínas que apresentam certas particularidades, como é o caso das proteínas intrinsecamente desordenadas e das proteínas de repetições. Enquanto a primeira classe apresenta alta flexibilidade e a ausência de um estado nativo de referência, a segunda classe corresponde à estruturas terciárias compostas pela repetição de um mesmo domínio, e que não enovelam de forma independente mas sim por meio de um mecanismo de cooperação. Neste trabalho foram analisados dois sistemas distintos. O primeiro consiste nas dinâmicas moleculares de monômeros de β-amilóides, visando compreender suas diferentes taxas de agregações. O segundo sistema corresponde às simulações de proteínas da família de repetições de anquirina, buscando a compreensão do mecanismo de formação dessas repetições. As análises foram realizadas por meio do Energy Landscape Visualization Method que, usando uma métrica baseada na distância interna entre os resíduos de cada conformação, é capaz de projetar a superfície de energia em espaços 2D e 3D. Os resultados demonstraram que a propensão de agregação das diferentes espécies de β-amilóide está contida no relevo de energia livre dos monômeros, enquanto que as repetições de anquirina apresentaram diferentes rotas de enovelamento com distintas probabilidades de ocorrência.
The process by which a protein assumes its functional configuration is called folding and corresponds to a problem that has intrigued researchers since the 1950s. Due to the importance of this class of macromolecules and the diseases that their harmful activity entail, understanding the formation of its three-dimensional structure is a fundamental question. However, due to its complexity, the process takes place in a multidimensional phase space, so its analysis is not trivial. This problem becomes even more complicated due to the fact that there are special classes of proteins that have certain particularities, such as intrinsically disordered proteins and repeat proteins. While the first class presents high flexibility and the absence of a native state of reference, the second class corresponds to tertiary structures composed by the repetition of the same domain, and which does not fold independently but through a cooperation mechanism. In this work, two distinct systems were analyzed. The first consists of the molecular dynamics of β-amyloid monomers, aiming to understand their different aggregation rates. The second system corresponds to the simulations of proteins from the ankyrin repeat family, in order to understand the mechanism of formation of these repeats. The analyzes were performed using the Energy Landscape Visualization Method. This method uses a metric based on the internal distance between the residues of each conformation, and it is able to represent the ensemble of molecular conformations in an effective 2D and 3D phase space. The results show that the aggregation propensities of different species of amyloid-β are encoded in the free energy spectrum of its monomers, while the ankyrin repetitions presented different folding routes with distinct occurence probability.
The process by which a protein assumes its functional configuration is called folding and corresponds to a problem that has intrigued researchers since the 1950s. Due to the importance of this class of macromolecules and the diseases that their harmful activity entail, understanding the formation of its three-dimensional structure is a fundamental question. However, due to its complexity, the process takes place in a multidimensional phase space, so its analysis is not trivial. This problem becomes even more complicated due to the fact that there are special classes of proteins that have certain particularities, such as intrinsically disordered proteins and repeat proteins. While the first class presents high flexibility and the absence of a native state of reference, the second class corresponds to tertiary structures composed by the repetition of the same domain, and which does not fold independently but through a cooperation mechanism. In this work, two distinct systems were analyzed. The first consists of the molecular dynamics of β-amyloid monomers, aiming to understand their different aggregation rates. The second system corresponds to the simulations of proteins from the ankyrin repeat family, in order to understand the mechanism of formation of these repeats. The analyzes were performed using the Energy Landscape Visualization Method. This method uses a metric based on the internal distance between the residues of each conformation, and it is able to represent the ensemble of molecular conformations in an effective 2D and 3D phase space. The results show that the aggregation propensities of different species of amyloid-β are encoded in the free energy spectrum of its monomers, while the ankyrin repetitions presented different folding routes with distinct occurence probability.
Descrição
Palavras-chave
Superfície de energia, β-amiloide, Proteínas de repetições, Energy landscape, Amyloid-β, Repeat proteins