A major current focus of modern structural biology is the determination of the structures of macromolecular assemblies and machines. Such systems are often not amenable to high-resolution x-ray crystallographic techniques. This proposal aims to develop powerful new methods which integrate NMR data, information from homologous structures, cryo electron microscopy data, low resolution x-ray crystallographic data, evolutionary covariance data, and other sources of information to generate models with atomic level accuracy for macromolecular assemblies and machines. With collaborators, the new methodology will be used to solve cutting-edge structural biology problems which cannot be solved by currently available methods. The new methodology will be incorporated into the freely available Rosetta software suite for use throughout the scientific community.

Public Health Relevance

Proteins are the workhorses of living things. The structures of proteins are critical to carrying out their functions. This research will contribute to determining the structures of protein assemblies critical to life and human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wehrle, Janna P
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University of Washington
Schools of Medicine
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Ovchinnikov, Sergey; Park, Hahnbeom; Kim, David E et al. (2018) Protein structure prediction using Rosetta in CASP12. Proteins 86 Suppl 1:113-121
Park, Hahnbeom; Ovchinnikov, Sergey; Kim, David E et al. (2018) Protein homology model refinement by large-scale energy optimization. Proc Natl Acad Sci U S A 115:3054-3059
Alford, Rebecca F; Leaver-Fay, Andrew; Jeliazkov, Jeliazko R et al. (2017) The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design. J Chem Theory Comput 13:3031-3048
Anishchenko, Ivan; Ovchinnikov, Sergey; Kamisetty, Hetunandan et al. (2017) Origins of coevolution between residues distant in protein 3D structures. Proc Natl Acad Sci U S A 114:9122-9127
Ovchinnikov, Sergey; Park, Hahnbeom; Varghese, Neha et al. (2017) Protein structure determination using metagenome sequence data. Science 355:294-298
Park, Hahnbeom; DiMaio, Frank; Baker, David (2016) CASP11 refinement experiments with ROSETTA. Proteins 84 Suppl 1:314-22
Ovchinnikov, Sergey; Kim, David E; Wang, Ray Yu-Ruei et al. (2016) Improved de novo structure prediction in CASP11 by incorporating coevolution information into Rosetta. Proteins 84 Suppl 1:67-75
Safarian, Schara; Rajendran, Chitra; Müller, Hannelore et al. (2016) Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science 352:583-6
Ovchinnikov, Sergey; Park, Hahnbeom; Kim, David E et al. (2016) Structure prediction using sparse simulated NOE restraints with Rosetta in CASP11. Proteins 84 Suppl 1:181-8
Park, Hahnbeom; Bradley, Philip; Greisen Jr, Per et al. (2016) Simultaneous Optimization of Biomolecular Energy Functions on Features from Small Molecules and Macromolecules. J Chem Theory Comput 12:6201-6212

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