The aim of this project is to continue to invent, refine and apply generalizable computational tools for neutron protein crystallography. Our primary focus will be to provide innovative, but practical solutions, that can be rapidly deployed to the target user community to address the computational bottleneck in neutron protein crystallography and to determine the neutron structures of a series of proteins, many with high biomedical importance, that span a spectrum of size and complexity. We will continue our current work adapting these computational tools for incorporation into PHENIX (Python-based Hierarchical Environment for Integrated Xtallography) for automated crystallography as extensible C++ and Python modules. The software will use and contribute towards the basic programming tools for crystallography in the Computational Crystallographic Toolbox (cctbx). Our vision is to contribute to a computational workbench that structural biologist, with a range of crystallographic experience, can use alternately for neutron, X-ray, or global neutron/X-ray/energy crystallography. The computational tools will integrate all tasks required for handling neutron intensity data scaling, wavelength normalization, attenuation correction and handling, determination and computation of phases, map generation and innovative solutions to multiple map representation, automated map interpretation, model building and refinement into one system. Automatic decision-making concepts will minimize human interventions and decrease time needed to refine structures. Our software developments will also be generalizable to X-ray crystallography. These tools will allow structure determination, model building, and refinement against any combination of neutron, X-ray and energy minimization functions. Structural biologists will use the same system in an interoperable way for structure determination and refinement based on X-ray, neutron and energetic data.

Public Health Relevance

Neutron crystallography is a technique that provides unique types of information on the enzymatic function and drug binding properties of biological macromolecules that are highly relevant to public health.
The aim of this project is to continue to invent, refine and apply generalizable computational tools that can be applied to address the computational bottlenecks in neutron protein crystallography and then to use those tools to study a series of proteins of high biomedical importance that span a spectrum of size and complexity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Edmonds, Charles G
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UT-Battelle, LLC-Oak Ridge National Lab
Oak Ridge
United States
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Dajnowicz, Steven; Seaver, Sean; Hanson, B Leif et al. (2016) Visualizing the Bohr effect in hemoglobin: neutron structure of equine cyanomethemoglobin in the R state and comparison with human deoxyhemoglobin in the T state. Acta Crystallogr D Struct Biol 72:892-903
Das, Amit; Gerlits, Oksana; Parks, Jerry M et al. (2015) Protein Kinase A Catalytic Subunit Primed for Action: Time-Lapse Crystallography of Michaelis Complex Formation. Structure 23:2331-2340
Wan, Qun; Parks, Jerry M; Hanson, B Leif et al. (2015) Direct determination of protonation states and visualization of hydrogen bonding in a glycoside hydrolase with neutron crystallography. Proc Natl Acad Sci U S A 112:12384-9
Michalczyk, Ryszard; Unkefer, Clifford J; Bacik, John-Paul et al. (2015) Joint neutron crystallographic and NMR solution studies of Tyr residue ionization and hydrogen bonding: Implications for enzyme-mediated proton transfer. Proc Natl Acad Sci U S A 112:5673-8
Gerlits, Oksana; Tian, Jianhui; Das, Amit et al. (2015) Phosphoryl Transfer Reaction Snapshots in Crystals: INSIGHTS INTO THE MECHANISM OF PROTEIN KINASE A CATALYTIC SUBUNIT. J Biol Chem 290:15538-48
Gerlits, Oksana; Das, Amit; Keshwani, Malik M et al. (2014) Metal-free cAMP-dependent protein kinase can catalyze phosphoryl transfer. Biochemistry 53:3179-86
Wan, Qun; Zhang, Qiu; Hamilton-Brehm, Scott et al. (2014) X-ray crystallographic studies of family 11 xylanase Michaelis and product complexes: implications for the catalytic mechanism. Acta Crystallogr D Biol Crystallogr 70:11-23
Wan, Qun; Kovalevsky, Andrey Y; Wilson, Mark A et al. (2014) Preliminary joint X-ray and neutron protein crystallographic studies of ecDHFR complexed with folate and NADP+. Acta Crystallogr F Struct Biol Commun 70:814-8
Wan, Qun; Bennett, Brad C; Wilson, Mark A et al. (2014) Toward resolving the catalytic mechanism of dihydrofolate reductase using neutron and ultrahigh-resolution X-ray crystallography. Proc Natl Acad Sci U S A 111:18225-30
Gerlits, Oksana; Waltman, Mary Jo; Taylor, Susan et al. (2013) Insights into the phosphoryl transfer catalyzed by cAMP-dependent protein kinase: an X-ray crystallographic study of complexes with various metals and peptide substrate SP20. Biochemistry 52:3721-7

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