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NMR studies at high pressure for characterization of protein intermediate states involved in the folding pathway

Grant number: 12/20381-6
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 01, 2013
Effective date (End): February 28, 2014
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal researcher:Ligia Ely Morganti Ferreira Dias
Grantee:Rosa Maria Chura Chambi
Supervisor abroad: Hans Robert Kalbitzer
Home Institution: Instituto de Pesquisas Energéticas e Nucleares (IPEN). Secretaria de Desenvolvimento Econômico (São Paulo - Estado). São Paulo , SP, Brazil
Research place: University of Regensburg, Germany  

Abstract

Elucidating the mechanism by which a polypeptide folds from a wide range of unstructured states is an important step in protein engineering. To understand this mechanism it is important to structurally characterize all species (native, denatured state and intermediate states) produced along the folding pathway. High pressure promotes the stabilization of intermediary states of the folding under conditions that affect only the volume of the system. This characteristic contrasts with those of perturbations such as high temperature that produces simultaneous changes in the total energy and volume, whereas the effects of denaturant depend on its binding properties, complicating the interpretation of data. Thus, useful information about the conformation of the transition states of proteins, which could not be obtained by other methods, can be usually obtained at high pressure. The application of pressure allows us to structurally characterize the intermediate species of protein folding. These transition states are obtained in the pathway of the correct folding that leads to native protein, and in the pathway of the improper folding, which may lead to the formation of aggregates. Therefore, the study of protein folding can provide insight into these mechanisms, allowing us to improve the folding process. In this project, we will use the technique of multidimensional Nuclear Magnetic Resonance (NMR) for high-resolution detection and characterization of protein intermediate conformational states. This technique is extremely sensitive for this purpose, providing detailed information at residue-specific level. The combination of NMR technique with the application of high pressure can provide an effective mean to study the formation of the intermediates involved in protein folding and their kinetic. Thus, this project will contribute significantly to the development of new strategies for refolding of proteins under high pressure. (AU)

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