ensemble descriptions of disordered proteins and their complexes

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Proteins are like strands of beads, in this case made up of a chain of different types of amino acid residues. While many proteins adopt a relatively static and ordered 3-dimensional shape in order to function, it has become clear recently that a large class of "disordered" proteins do not. They function in a highly flexible state, primarily in binding to other proteins. Upon binding, some disordered proteins do become ordered but others retain much of their flexibility. Disordered proteins are found throughout biology, from viruses to plants and animals, and are associated with controlling critical biological events as well as in disease. In order to better understand the nature of these proteins and the biology they perform, realistic descriptions of disordered proteins and their dynamic complexes are essential. While a static protein needs one structure to describe it, a disordered protein or dynamic complex requires many structures (an ensemble) to represent it, not possible with standard structural approaches. Thus, we have been developing the computer approach ENSEMBLE that calculates collections of structures that together are consistent with a large amount of experimental data and together represent the disordered protein. Many aspects of this approach must be further developed since there is not enough data to define the ensemble and there are issues with the interpretation of the data and the optimization of the algorithm. Thus, we propose the following aims: (1) Develop ENSEMBLE to better characterize isolated disordered proteins. Using a model system, we will obtain experimental data and explore better ways to extract structural information from them, perform different types of computational simulations and determine the best algorithms to utilize within ENSEMBLE. (2) Develop approaches to characterize complexes of disordered proteins. Using a different model system, will explore new methods to reduce problems with poor NMR data due to motion in dynamic complexes and expand ENSEMBLE's capability to describe dynamic complexes. Our efforts will provide a powerful tool that will be widely available to the structural community for studying this important yet challenging class of highly dynamic proteins.