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Use of chemical shifts data in the characterization of non native and partially folded states in proteins

Objective

Non-native conformations of proteins have recently attracted considerable attention in molecular and cell biology. Bionformatics studies of complete genomes suggested that a fairly large fraction of the proteins encoded by the DNA of different organisms ma y contain unstructured regions in the cell. Partially folded states of proteins have also been associated with misfolding diseases, such as Alzheimer's, type II diabetes and the transmissible encephalophaties.

In this research plan I propose to develop a strategy that uses experimental chemical shifts as a bias in computer simulations to determine the ensembles of structures corresponding to non-native states of proteins. Chemical shifts represent the diamagnetic screening on the atomic nuclei created by nearby electronic currents. They are relatively easy to measure experimentally by nuclear magnetic resonance (NMR) spectroscopy and they can be translated into structural information.

The proposed method will be applied using recent experimental results about the partially folded states of alpha-lactalbumin and Staphylococcal Nuclease. A combination of experiments and simulations will be carried out in order to characterize the mechanism of folding and the free energy landscape of these proteins. It will also be possible to study of the effect of mutations on the structure of native and partially folded states of proteins. Planned applications will include a study of Bovine pancreatic trypsin inhibitor (BTPTI), the SH3 (drk) domain and Barnase.

Call for proposal

FP6-2002-MOBILITY-5
See other projects for this call

Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Address
The Old Schools, Trinity Lane
Cambridge
United Kingdom