For success in the structural genomics initiatives, it is essential that the methods be as powerful, as reliable,? and as automated as possible. In work on our new program, Phaser, we have been applying likelihood-based? methods to solving the phase problem of X-ray crystallography by both molecular replacement and? experimental phasing. Likelihood-based methods have two advantages in the context of automation. First,? they are more powerful and therefore have a greater convergence radius. Second, likelihood is a natural? scoring function to measure success in satisfying the data, which makes it an excellent criterion for? automated decision-making. We will enhance the automation features that already exist in the molecular? replacement and experimental phasing modules of Phaser so that, as much as possible, only the diffraction? data and sequence information are needed as input. We will work to increase the sophistication and power? of our methods, by taking account of more of the correlations that have been neglected to date in order to? reduce the computational demands. We will also work to make our algorithms easily accessible to other? Projects within PHENIX, by using the Boost.Python library to make them available from the Python scripting? language that underpins PHENIX. This will allow the development of automated pipelines combining? algorithms from all the components of PHENIX.? With the completion of the human genome, there is a new focus on finding ways to exploit the wealth of? information it has revealed. In many cases, knowing the 3D structure of the proteins encoded by the genes? is invaluable in understanding how they work together, and the primary method to determine those structures? is the method of X-ray crystallography. Our work on applying statistical methods to 3D structure? determination is helping to make those methods faster, more automatic and more powerful.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM063210-07
Application #
7477055
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
7
Fiscal Year
2007
Total Cost
$142,323
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Richardson, Jane S; Williams, Christopher J; Hintze, Bradley J et al. (2018) Model validation: local diagnosis, correction and when to quit. Acta Crystallogr D Struct Biol 74:132-142
Herzik Jr, Mark A; Fraser, James S; Lander, Gabriel C (2018) A Multi-model Approach to Assessing Local and Global Cryo-EM Map Quality. Structure :
Kryshtafovych, Andriy; Monastyrskyy, Bohdan; Adams, Paul D et al. (2018) Distribution of evaluation scores for the models submitted to the second cryo-EM model challenge. Data Brief 20:1629-1638
Moriarty, Nigel W; Liebschner, Dorothee; Klei, Herbert E et al. (2018) Interactive comparison and remediation of collections of macromolecular structures. Protein Sci 27:182-194
Kryshtafovych, Andriy; Adams, Paul D; Lawson, Catherine L et al. (2018) Evaluation system and web infrastructure for the second cryo-EM model challenge. J Struct Biol 204:96-108
Terwilliger, Thomas C; Adams, Paul D; Afonine, Pavel V et al. (2018) Map segmentation, automated model-building and their application to the Cryo-EM Model Challenge. J Struct Biol 204:338-343
Williams, Christopher J; Headd, Jeffrey J; Moriarty, Nigel W et al. (2018) MolProbity: More and better reference data for improved all-atom structure validation. Protein Sci 27:293-315
Terwilliger, Thomas C; Adams, Paul D; Afonine, Pavel V et al. (2018) A fully automatic method yielding initial models from high-resolution cryo-electron microscopy maps. Nat Methods 15:905-908
Richardson, Jane S; Williams, Christopher J; Videau, Lizbeth L et al. (2018) Assessment of detailed conformations suggests strategies for improving cryoEM models: Helix at lower resolution, ensembles, pre-refinement fixups, and validation at multi-residue length scale. J Struct Biol 204:301-312
Hintze, Bradley J; Richardson, Jane S; Richardson, David C (2017) Mismodeled purines: implicit alternates and hidden Hoogsteens. Acta Crystallogr D Struct Biol 73:852-859

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