The Protein Structure Initiative (Structural Genomics) aims to understand the structure and function of proteins and protein families, creating the knowledge that will need to be exploited for a wealth of biomedical applications. The main method to obtain the structures necessary for Structural Genomics is macromolecular X-ray crystallography. For Structural Genomics to succeed, it is important to possess methodology that allows rapid, large scale, automatic structure determination. The present research proposal aims to extend the ARP/wARP software for high-quality automated model building and refinement in macromolecular crystallography. This will lead to a major contribution towards automation and high-throughput which are necessary for the above projects and objectives. Traditionally, a research scientist has to build a molecular model into the experimentally available electron density map (the three-dimensional image of the molecule), a task often tedious, time demanding, subjective and heavily relying on experience. The initial macromolecular model then undergoes a refinement procedure in which the parameters of the model are adjusted to best fit the experimental data and stereochemical expectations. As the model improves, the electron density maps improve as well and a better model may be fitted. Model building and refinement are therefore related and tightly linked to each other, and should be regarded as one unified process. The ARP/wARP software, which we wish to further develop, fully automates the above procedure resulting in a faster, efficient, objective and reliable technique compared to traditional procedures. We plan to develop improved new algorithms for model re-parameterization and pattern recognition in three-dimensional space to improve the automated building of the initial macromolecular model. Genetic algorithms, Monte Carlo techniques and semi-definite programming will be exploited to aid in obtaining a more complete and accurate model. A graphical user interface and database and documentation service through the World Wide Web will help the structural biology community and more specifically the Structural Genomics centers to better exploit the developed software.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM062612-01A1
Application #
6478436
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Edmonds, Charles G
Project Start
2002-05-01
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$179,760
Indirect Cost
Name
European Molecular Biology Laboratory
Department
Type
DUNS #
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