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105. Glutathione Transferase A1-1 : Catalytic Importance of Arginine 15

Author

Dourado, Daniel F A R, Fernandes, Pedro Alexandrino, Mannervik, Bengt, Ramos, Maria João, Dourado, Daniel F A R, Fernandes, Pedro Alexandrino, Mannervik, Bengt, and Ramos, Maria João

Abstract

Glutathione transferases (GSTs) are fundamental enzymes of the cell detoxification system. They catalyze the nucleophilic attack Of glutathione (GSH) on electrophilic substrates to produce less toxic compounds. The resulting Substrate can then be recognized by ATP-dependent transmembrane PUMPS and consequently expelled from the cell. Despite all the existing studies on GSTs, many aspects of the catalytic events are still poorly understood. Recently, using as a model the GSTAI-1 enzyme, we proposed it GSH activation mechanism. Resorting to the density functional theory (DFT), we demonstrated that a water molecule could assist a proton transfer between (lie GSH thiol and (x-carboxylic groups. after all initial conformational rearrangement of GSH, as evidenced by potential of mean force calculations. In this work to elucidate the catalytic role of Arg 15, a strictly conserved active site residue in class alpha GSTs. we analyzed the activation energy barrier and Structural details associated with the GSTAI-1 Mutants R15A, R15R epsilon, eta-c (an Arg residue with the epsilon-eta-nitrogens Substituted by carbons), and R 15Rneutral (a neutral Arg residue due to the a addition of a hydride in the zeta-carbon. A similar mechanism to the one used in Our GSH activation proposal was implemented.

Published
2010
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107. Glutathione transferase : new model for glutathione activation

Author

Dourado, Daniel F A R, Fernandes, Pedro Alexandrino, Mannervik, Bengt, Ramos, Maria João, Dourado, Daniel F A R, Fernandes, Pedro Alexandrino, Mannervik, Bengt, and Ramos, Maria João

Abstract

Glutathione transferases are enzymes of the cellular detoxification system that metabolize a vast spectrum of xenobiotic and endobiotic toxic compounds. They are homodimers or heterodimers and each monomer has an active center composed of a G-site in which glutathione (GSH) binds and an H-site for the electrophilic substrate. When GSH binds to the G-site, the pKa value of its thiol group drops by 2.5 units; this promotes its deprotonation and, therefore, produces a strong nucleophilic thiolate that is able to react with the electrophilic substrate. The mechanism behind the deprotonation of the thiol group is still unknown. Some studies point to the fact that the GSH glutamyl alpha-carboxylate group is essential for GSH activation, whereas others indicate the importance of the active-center water molecules. On the basis of QM/MM calculations, we propose a mechanism of GSH activation in which a water molecule, acting as a bridge, is able to assist in the transfer of the proton from the GSH thiol group to the GSH glutamyl alpha-carboxylate group, after an initial GSH conformational rearrangement. We calculated the potential of mean force of this GSH structural rearrangement that would be necessary for the approach of both groups and we then performed a QM/MM ONIOM scan of water-assisted proton transfer. The overall free-energy barrier for the process is consistent with experimental studies of the enzyme kinetics.

Published
2008
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112. Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms.

Author

Sousa, Sérgio Filipe, Ribeiro, António J. M., Neves, Rui P. P., Brás, Natércia F., Cerqueira, Nuno M. F. S. A., Fernandes, Pedro A., and Ramos, Maria João

Subjects
QUANTUM mechanics, MOLECULAR dynamics, REACTION mechanisms (Chemistry)
Abstract

Quantum mechanics/molecular mechanics ( QM/ MM) methods offer a very appealing option for the computational study of enzymatic reaction mechanisms, by separating the problem into two parts that can be treated with different computational methods. Hence, in a QM/ MM formalism, the part of the system in which catalysis actually occurs and that involves the active site, substrates and directly participating amino acid residues is treated at an adequate quantum mechanical level to describe the chemistry taking place. For the remaining of the enzyme, which does not participate directly in the reaction, but that typically involves a much larger number of atoms, molecular mechanics is employed, traditionally through the application of a biomolecular force field. When applied with care, QM/ MM methods can be used with great advantage in comparing, at a structural and energetic level, different mechanistic proposals, discarding mechanistic alternatives and proposing new mechanistic pathways that are consistent with the available experimental data. With time, diverse flavors within the QM/ MM methods have emerged, differing in a variety of technical and conceptual aspects. Hence present alternatives differ between additive and subtractive QM/ MM schemes, the type of boundary schemes, and the way in which the electrostatic interactions between the two regions are accounted for. Also, single-conformation QM/ MM, multi- PES approaches, and QM/ MM Molecular Dynamics coexist today, each type with its own advantages and limitations. This review focuses on the application of QM/ MM methods in the study of enzymatic reaction mechanisms, briefly presenting also the most important technical aspects involved in these calculations. Particular attention is dedicated to the application of the single-conformation QM/ MM, multi- PES QM/ MM studies, and QM/ MM-FEP methods and to the advantages and disadvantages of the different types of QM/ MM. Recent breakthroughs are also introduced. A selection of hand-picked examples is used to illustrate such features. WIREs Comput Mol Sci 2017, 7:e1281. doi: 10.1002/wcms.1281 For further resources related to this article, please visit the . [ABSTRACT FROM AUTHOR]

Published
2017
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113. Are hot-spots occluded from water?

Author

Moreira, Irina Sousa, primary, Ramos, Rui Miguel, additional, Martins, Joao Miguel, additional, Fernandes, Pedro Alexandrino, additional, and Ramos, Maria João, additional

Published
2013
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114. Representação gráfica de quantidades em crianças de 5 anos: Berlindes e livros

Author

Ramos, Maria João and Ramalho, Glória

Abstract

Dissertação de Mestrado em Psicologia Educacional Neste trabalho aborda-se o tema da representação gráfica de quantidades associadas a referentes em crianças de 5 anos que frequentam o Jardim de Infância. Do quadro teórico de referência destacam-se as contribuições da teoria dos campos conceptuais de Vergnaud (1988), os estudos sobre a representação gráfica das quantidades de F.Siegrist e H.Sinclair (1983) e os trabalhos sobre desenvolvimento dos processos de contagem de Gallistel e Gelman (1987) e Fuson (1988). Foram objecto deste estudo: i) a representação gráfica de quantidades inferiores e superiores a 10 associadas a referentes, ii) a comparação dos processos de contagem com e sem suporte gráfico; e finalmente iii) a escrita de números. O instrumento utilizado foi a entrevista individual de tipo piagetiano. Verificou-se que o desenho foi a representação gráfica mais frequente coexistindo com outras representações numéricas igualmente disponíveis. No que se refere à contagem, a existência de um suporte gráfico permitiu que as crianças contassem até números superiores aos atingidos nas contagens sem suporte. A maioria das crianças revelou ter conhecimentos ao nível da escrita de números até ao número 10. Constatou-se que os conhecimentos ao nível da contagem e da escrita de números, nem sempre foram mobilizados para representar graficamente quantidades associadas a referentes. Apresentam-se algumas implicações dos resultados obtidos para as práticas educativas do Jardim de Infância e 1o ano de escolaridade.

Published
1996

117. A representação do volume e da organização espacial dos objectos em desenhos de crianças e jovens dos 7 aos 17 anos

Author

Ramos, Maria João Paulo Lopes Santos and Marchand, Helena d Orey, 1948

Subjects
Psicologia do desenvolvimento, Percepção, Teses de mestrado - 1995, Crianças, Organização espacial, Ciências Sociais::Ciências da Educação [Domínio/Área científica], Desenho
Abstract

Dissertação de Mestrado em Ciências da Educação, área de Análise e Organização do Ensino, 1995 Submitted by Biblioteca FPIE-ULisboa (bibliorul@fpie.ulisboa.pt) on 2018-03-20T14:22:17Z No. of bitstreams: 2 ulfp005036_tm_tese.pdf: 4435914 bytes, checksum: 85ff04b9566076aa25d1f1d99d0f3c28 (MD5) ulfp005037_tm_anexos.pdf: 2629198 bytes, checksum: b88fceb5d7550a0ca8d3978780ecb5bd (MD5) Made available in DSpace on 2018-03-20T14:24:24Z (GMT). No. of bitstreams: 2 ulfp005036_tm_tese.pdf: 4435914 bytes, checksum: 85ff04b9566076aa25d1f1d99d0f3c28 (MD5) ulfp005037_tm_anexos.pdf: 2629198 bytes, checksum: b88fceb5d7550a0ca8d3978780ecb5bd (MD5) Previous issue date: 1995

Published
1995

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