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Analytical Chemistry

NMR Structures Get Sharper With Rosetta

Computer program refines nuclear magnetic resonance structures of proteins, making them more similar to X-ray crystal structures

by Erika Gebel Berg
January 30, 2014 | A version of this story appeared in Volume 92, Issue 5

Comparison of NMR structures and X-ray crystal structure of the protein SATB1.
Credit: J. Am. Chem. Soc.
Rosetta refined the NMR structure of the protein SATB1 (light blue) into one (dark blue) that nearly matches the protein’s crystal structure (purple).

For determining protein structure, X-ray crystallography typically beats nuclear magnetic resonance spectroscopy for accuracy. But chemists now report that, in most cases, NMR structures refined by a computer program called Rosetta match more closely with those determined by crystallography than do unrefined ones.

Although X-ray crystallography is the gold standard for solving protein structures, not all proteins crystallize well. Also, floating in solution could be a more realistic condition for proteins than sitting in a crystal lattice, says Gaetano T. Montelione of Rutgers University. For those reasons, chemists would like to improve the accuracy of NMR structures.

Scientists have started using Rosetta in the past several years to do just that. The program takes the relative positions of the protein’s atoms determined by NMR and then moves them around to produce a more stable structure based on basic physical chemistry principles and information about protein folds found in the Protein Data Bank.

Montelione and his colleagues looked at a range of proteins to perform the first analysis of how much Rosetta improved NMR structures. They used 39 pairs of NMR and crystal structures of the same proteins. The team applied the Rosetta refinement to each NMR structure and ensured that the tweaked structure still agreed with the NMR data collected in the lab. Finally, they compared the positions of corresponding carbon atoms in the refined NMR structure and the crystal structure to determine how similar the two were. For 32 of the 39 proteins, the refined NMR structure was more similar to the crystal structure than to the unrefined NMR structure (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja409845w).

Thomas Szyperski of the University at Buffalo, SUNY, thinks others in the field will start using Rosetta more, possibly making it a standard for refining NMR structures. But Charles D. Schwieters of the National Institutes of Health cautions that the ability of Rosetta to improve an NMR structure may depend on how that structure was solved to begin with.



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