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)
Program Officer
Edmonds, Charles G
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UT-Battelle, LLC-Oak Ridge National Lab
Oak Ridge
United States
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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
Gerlits, Oksana; Das, Amit; Keshwani, Malik M et al. (2014) Metal-free cAMP-dependent protein kinase can catalyze phosphoryl transfer. Biochemistry 53:3179-86
Langan, Paul; Chen, Julian C-H (2013) Seeing the chemistry in biology with neutron crystallography. Phys Chem Chem Phys 15:13705-12
Jogl, Gerwald; Wang, Xiaoping; Mason, Sax A et al. (2011) High-resolution neutron crystallographic studies of the hydration of the coenzyme cob(II)alamin. Acta Crystallogr D Biol Crystallogr 67:584-91
Kovalevsky, Andrey Y; Hanson, B Leif; Seaver, Sean et al. (2011) Preliminary joint X-ray and neutron protein crystallographic studies of endoxylanase II from the fungus Trichoderma longibrachiatum. Acta Crystallogr Sect F Struct Biol Cryst Commun 67:283-6
Fisher, Zoe; Kovalevsky, Andrey Y; Mustyakimov, Marat et al. (2011) Neutron structure of human carbonic anhydrase II: a hydrogen-bonded water network "switch" is observed between pH 7.8 and 10.0. Biochemistry 50:9421-3
Fenn, Timothy D; Schnieders, Michael J; Mustyakimov, Marat et al. (2011) Reintroducing electrostatics into macromolecular crystallographic refinement: application to neutron crystallography and DNA hydration. Structure 19:523-33
Schuman, B; Fisher, S Z; Kovalevsky, A et al. (2011) Preliminary joint neutron time-of-flight and X-ray crystallographic study of human ABO(H) blood group A glycosyltransferase. Acta Crystallogr Sect F Struct Biol Cryst Commun 67:258-62
Grosse-Kunstleve, Ralf W; Wong, Buddy; Mustyakimov, Marat et al. (2011) Exact direct-space asymmetric units for the 230 crystallographic space groups. Acta Crystallogr A 67:269-75
Kovalevsky, Andrey Y; Chatake, Toshiyuki; Shibayama, Naoya et al. (2010) Direct determination of protonation states of histidine residues in a 2 A neutron structure of deoxy-human normal adult hemoglobin and implications for the Bohr effect. J Mol Biol 398:276-91

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