Jan 13, 2007

2007 week 03: Articles in Proteins

ENTIRE CATALOG OF FERRET PROTEINS TO DATE



Spanish Scientists Reveal Dynamic Map Of Proteins, Possibilities For New Drugs

Scientists from the Institute for Research in Biomedicine (IRB Barcelona), the Life Sciences Programme at the Barcelona Supercomputing Center (BSC) and the National Institute for Bioinformatics (INB) have published a provisional "atlas" of the dynamic behaviour of proteins in the prestigious scientific journal, Proceedings of the National Academy of Sciences USA.

Proteins determine the shape and structure of cells and drive nearly all of a cell's vital processes. All proteins carry out their functions according to the same process -- by binding with other molecules. Now, the scientists have compiled a map that shows them how proteins can move and form complexes, a valuable tool that will help them understand the basic functions of the molecules, but also what happens when they function incorrectly. Such a map opens vast possibilities for the design of new drugs.

The goal of this study is to define a map of the dynamic properties of a very representative group of proteins. This involves taking stock of the basic rules that govern the flexibility of proteins and allows scientists to predict the structures that these proteins can form based on the presence of ligands or modifications. This allows scientists to go beyond the traditional simple static vision of proteins, which has not been able to capture the subtle conformational changes necessary for proteins to function. These changes modify, for example, how proteins bind to metabolites or drugs.
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This is the first study of a larger scientific project, called MoDel (Molecular Dynamics Extended Library), the scope of which is even more ambitious. "MoDel aims to establish a 'fourth dimension' for protein structures thereby providing a complete landscape of possible conformations for the entire proteome (the complete network of protein interactions in a cell), over time. In the near future, a biochemist will be able to understand the behaviour of a protein, or design a drug that can interact with that protein, drawing on not only the knowledge of a single structure, but of an entire repertory spontaneously occurring in physiological conditions," says project director Modesto Orozco, principal investigator of the Molecular Modelling and Bioinformatics group at IRB Barcelona, director of the Department of Life Sciences of the BSC, and Professor in the Department of Biochemistry at the University of Barcelona.
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Source article: M.Rueda, C.Ferrer, T.Meyer, A.Pérez, J.Camps, A.Hospital, J.L.Gelpí and M.Orozco. "A consensus view of protein dynamics". Proc. Natl. Acad. Sci. USA. (2007) 104, 796-801

Prediction of side-chain conformations on protein surfaces
An approach is described that improves the prediction of the conformations of surface side chains in crystal structures, given the main-chain conformation of a protein. A key element of the methodology involves the use of the colony energy. This phenomenological term favors conformations found in frequently sampled regions, thereby approximating entropic effects and serving to smooth the potential energy surface. Use of the colony energy significantly improves prediction accuracy for surface side chains with little additional computational cost. Prediction accuracy was quantified as the percentage of side-chain dihedral angles predicted to be within 40° of the angles measured by X-ray diffraction. Use of the colony energy in predictions for single side chains improved the prediction accuracy for [chi]1 and [chi]1+2 from 65 and 40% to 74 and 59%, respectively. Several other factors that affect prediction of surface side-chain conformations were also analyzed, including the extent of conformational sampling, details of the rotamer library employed, and accounting for the crystallographic environment. The prediction of conformations for polar residues on the surface was generally found to be more difficult than those for hydrophobic residues, except for polar residues participating in hydrogen bonds with other protein groups. For surface residues with hydrogen-bonded side chains, the prediction accuracy of [chi]1 and [chi]1+2 was 79 and 63%, respectively. For surface polar residues, in general (all side-chain prediction), the accuracy of [chi]1 and [chi]1+2 was only 73 and 56%, respectively. The most accurate results were obtained using the colony energy and an all-atom description that includes neighboring molecules in the crystal (protein chains and hetero atoms). Here, the accuracy of [chi]1 and [chi]1+2 predictions for surface side chains was 82 and 73%, respectively. The root mean square deviations obtained for hydrogen-bonding surface side chains were 1.64 and 1.81 Å, with and without consideration of crystal packing effects, respectively. Proteins 2007. © 2007 Wiley-Liss, Inc.


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