Structural Biology in general and the Protein Structure Initiative in particular, aim to understand the structure and function of macromolecules, their complexes and families, creating a knowledge that is further explored for a wealth of biomedical applications. X-ray crystallography has become the most commonly used method to assist the investigation into biological phenomena by providing detailed atomic models of the bio- molecules of interest. To maximize the efficiency of X-ray crystallography, automation of labor intensive, repetitive tasks in protein structure determination is crucial. As such, the step of building an atomic model in the electron density map has to be made fast, reliable and highly automated. The ARP/wARP software has pioneered this automation step and helped to obtain a large number of novel structures of macromolecules. Scientific developments in ARP/wARP, mostly funded by the NIH over the last three years, landmarked considerable advancement of the overall software package. The developed algorithms and scientific concepts allow construction of more complete models and to extend the interpretation of lower resolution electron density maps. The software became easier to use for non-expert researchers via graphical user interfaces and WWW-based execution of remotely submitted tasks. The overall performance of the ARP/wARP software in terms of speed and convergence was improved. In the course of the requested renewal of the grant we will extend the aims of the project towards seamless automation of macromolecular 3-D structure determination, while we will deliver more complete and validated models with lower resolution of the experimental diffraction data. We will achieve our goals by developing further the pattern recognition-based algorithms; improving interlinks between different steps of structure determination with emphasis to large and multimeric structures; delivering truly complete models including poorly ordered surface regions, with special emphasis to building bound ligands; developing an 'expert control system' that would be capable of basic decision making based on the accumulated history; and by continuing to improve the accessibility of the software by the community. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062612-06
Application #
7227818
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (02))
Program Officer
Edmonds, Charles G
Project Start
2002-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
6
Fiscal Year
2007
Total Cost
$199,249
Indirect Cost
Name
European Molecular Biology Laboratory
Department
Type
DUNS #
321691735
City
Heidelberg
State
Country
Germany
Zip Code
69117
Langer, Gerrit G; Evrard, Guillaume X; Carolan, Ciaran G et al. (2012) Fragmentation-tree density representation for crystallographic modelling of bound ligands. J Mol Biol 419:211-22
Joosten, Robbie P; Joosten, Krista; Cohen, Serge X et al. (2011) Automatic rebuilding and optimization of crystallographic structures in the Protein Data Bank. Bioinformatics 27:3392-8
Joosten, Robbie P; te Beek, Tim A H; Krieger, Elmar et al. (2011) A series of PDB related databases for everyday needs. Nucleic Acids Res 39:D411-9
Heuser, Philipp; Langer, Gerrit G; Lamzin, Victor S (2009) Interpretation of very low resolution X-ray electron-density maps using core objects. Acta Crystallogr D Biol Crystallogr 65:690-6
Mooij, Wijnand T M; Cohen, Serge X; Joosten, Krista et al. (2009) ""Conditional Restraints"": Restraining the Free Atoms in ARP/wARP. Structure 17:183-9
Joosten, Krista; Cohen, Serge X; Emsley, Paul et al. (2008) A knowledge-driven approach for crystallographic protein model completion. Acta Crystallogr D Biol Crystallogr 64:416-24
Langer, Gerrit; Cohen, Serge X; Lamzin, Victor S et al. (2008) Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7. Nat Protoc 3:1171-9
Evrard, Guillaume X; Langer, Gerrit G; Perrakis, Anastassis et al. (2007) Assessment of automatic ligand building in ARP/wARP. Acta Crystallogr D Biol Crystallogr 63:108-17
Bahar, M; Ballard, C; Cohen, S X et al. (2006) SPINE workshop on automated X-ray analysis: a progress report. Acta Crystallogr D Biol Crystallogr 62:1170-83
Cohen, Serge X; Morris, Richard J; Fernandez, Francisco J et al. (2004) Towards complete validated models in the next generation of ARP/wARP. Acta Crystallogr D Biol Crystallogr 60:2222-9