Experimentally Guided Modeling of Protein Complexes: Application to disease-related proteins
||Experimentally Guided Modeling of Protein Complexes: Application to disease-related proteins|
||Björn Wallner <email@example.com>|
||2014-04-29 – 2015-05-01|
||10601 10203 10610|
Proteins are key players in virtually all biological events that take place within and between cells. They often accomplish their function as part of larger protein complexes. Unfortunately, compared to structure determination of individual proteins, structural characterization of large macromolecular assemblies is much more difficult and no single experimental method can accomplish this task alone. In this proposal we suggest an integrative approach to combine all available experimental information about a given assembly using computational modeling. To this end we will develop an INTEGRATIVE MODELING FRAMEWORK capable of handling the different resolution ranges for the different types of experimental data, ranging from putative interaction data all the way to atomic X-ray structures. Even though this is ultimate goal, we will initially study interacting proteins in complex purely by computational means. The reasoning is that incorporating experimental data at the end can only make the result better and by focusing on the more difficult problem without experimental information it is clear that any improvements can be attributed the computational algorithm. As part of this we will also develop IMPROVED SCORING and SAMPLING TECHNIQUES for DOCKING. Finally, we will apply the developed methodology combined with existing tools to several disease-related proteins for which we have first hand access to experimental data, including TTR, TRIM21 and Myc.
This work involves serious computational power; we will continue develop our own software, which will be a crucial part of the modeling framework. It will also involve large benchmarks to compare performance to existing tools. Just to give a ballpark figure, a benchmark I am about to submit will involve 300,000 core hours for just one particular setting