Theoretical Study of Catalytic Efficiency of a Diels–Alderase Catalytic Antibody: An Indirect Effect Produced During the Maturation Process
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Scholar |
Otros documentos de la autoría: Martí Forés, Sergio; Andres, Juan; Moliner, Vicent; Silla, Estanislao
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Mostrar el registro completo del ítemcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
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http://dx.doi.org/10.1002/chem.200700290 |
Metadatos
Título
Theoretical Study of Catalytic Efficiency of a Diels–Alderase Catalytic Antibody: An Indirect Effect Produced During the Maturation ProcessFecha de publicación
2008-01Editor
WileyISSN
0947-6539Cita bibliográfica
Chemistry - A European Journal, 14, 2, p. 596-602Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
http://onlinelibrary.wiley.com/doi/10.1002/chem.200700290/fullVersión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
The Diels–Alder reaction is one of the most important and versatile transformations available to organic chemists for the construction of complex natural products, therapeutics agents, and synthetic materials. Given ... [+]
The Diels–Alder reaction is one of the most important and versatile transformations available to organic chemists for the construction of complex natural products, therapeutics agents, and synthetic materials. Given the lack of efficient enzymes capable of catalyzing this kind of reaction, it is of interest to ask whether a biological catalyst could be designed from an antibody-combining site. In the present work, a theoretical study of the different behavior of a germline catalytic antibody (CA) and its matured form, 39 A-11, that catalyze a Diels–Alder reaction has been carried out. A free-energy perturbation technique based on a hybrid quantum-mechanics/molecular-mechanics scheme, together with internal energy minimizations, has allowed free-energy profiles to be obtained for both CAs. The profiles show a smaller barrier for the matured form, which is in agreement with the experimental observation. Free-energy profiles were obtained with this methodology, thereby avoiding the much more demanding two-dimensional calculations of the energy surfaces that are normally required to study this kind of reaction. Structural analysis and energy evaluations of substrate–protein interactions have been performed from averaged structures, which allows understanding of how the single mutations carried out during the maturation process can be responsible for the observed fourfold enhancement of the catalytic rate constant. The conclusion is that the mutation effect in this studied germline CA produces a complex indirect effect through coupled movements of the backbone of the protein and the substrate. [-]
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Copyright 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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