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High-resolution protein structure determination starting with a global fold calculated from exact solutions to the RDC equations

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Abstract

We present a novel structure determination approach that exploits the global orientational restraints from RDCs to resolve ambiguous NOE assignments. Unlike traditional approaches that bootstrap the initial fold from ambiguous NOE assignments, we start by using RDCs to compute accurate secondary structure element (SSE) backbones at the beginning of structure calculation. Our structure determination package, called rdc-Panda (RDC-based SSE PAcking with NOEs for Structure Determination and NOE Assignment), consists of three modules: (1) rdc-exact; (2) Packer; and (3) hana (HAusdorff-based NOE Assignment). rdc-exact computes the global optimal solution of backbone dihedral angles for each secondary structure element by exactly solving a system of quartic RDC equations derived by Wang and Donald (Proceedings of the IEEE computational systems bioinformatics conference (CSB), Stanford, CA, 2004a; J Biomol NMR 29(3):223–242, 2004b), and systematically searching over the roots, each of which is a backbone dihedral ϕ- or ψ-angle consistent with the RDC data. Using a small number of unambiguous inter-SSE NOEs extracted using only chemical shift information, Packer performs a systematic search for the core structure, including all SSE backbone conformations. hana uses a Hausdorff-based scoring function to measure the similarity between the experimental spectra and the back-computed NOE pattern for each side-chain from a statistically-diverse rotamer library, and drives the selection of optimal position-specific rotamers for filtering ambiguous NOE assignments. Finally, a local minimization approach is used to compute the loops and refine side-chain conformations by fixing the core structure as a rigid body while allowing movement of loops and side-chains. rdc-Panda was applied to NMR data for the FF Domain 2 of human transcription elongation factor CA150 (RNA polymerase II C-terminal domain interacting protein), human ubiquitin, the ubiquitin-binding zinc finger domain of the human Y-family DNA polymerase Eta (pol η UBZ), and the human Set2-Rpb1 interacting domain (hSRI). These results demonstrated the efficiency and accuracy of our algorithm, and show that rdc-Panda can be successfully applied for high-resolution protein structure determination using only a limited set of NMR data by first computing RDC-defined backbones.

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Abbreviations

NMR:

Nuclear magnetic resonance

ppm:

Parts per million

RMSD:

Root mean square deviation

HSQC:

Heteronuclear single quantum coherence spectroscopy

NOE:

Nuclear Overhauser effect

NOESY:

Nuclear Overhauser and exchange spectroscopy

RDC:

Residual dipolar coupling

PDB:

Protein Data Bank

pol η UBZ:

Ubiquitin-binding zinc finger domain of the human Y-family DNA polymerase Eta

CH:

Cα-Hα

hSRI:

Human Set2-Rpb1 interacting domain

FF2:

FF Domain 2 of human transcription elongation factor CA150 (RNA polymerase II C-terminal domain interacting protein)

POF:

Principal order frame

SA:

Simulated annealing

MD:

Molecular dynamics

SSE:

Secondary structure element

C′:

Carbonyl carbon

WPS:

Well-packed satisfying

vdW:

van der Waals

SM:

Supplementary Material

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Acknowledgements

We thank Dr. A. Yershova, Mr. J. Martin, Prof. J. Richardson, Prof. D. Richardson, Dr. S. Apaydin and all members of the Donald and Zhou Labs for helpful discussions and comments. We are grateful to Ms. M. Bomar for helping us with pol η UBZ NMR data. We thank Mr. D. Keedy, Prof. J. Richardson, Prof. D. Richardson and other members in the Richardson lab for helpful comments on our computed FF2 structures. This work is supported by the following Grants from National Institutes of Health: R01 GM-65982 to B. R. Donald and R01 GM-079376 to P. Zhou.

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Author notes

  1. Lincong Wang

    Present address: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 06877, USA

Authors and Affiliations

  1. Department of Computer Science, Duke University, Durham, NC, 27708, USA

    Jianyang Zeng, Chittaranjan Tripathy, Lincong Wang, Anthony Yan & Bruce Randall Donald

  2. Department of Biochemistry, Duke University Medical Center, Durham, NC, 27708, USA

    Jeffrey Boyles, Pei Zhou & Bruce Randall Donald

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  1. Jianyang Zeng
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Correspondence to Pei Zhou or Bruce Randall Donald.

Additional information

The methodology developed in this paper has been applied to compute the ensemble of structures for FF2. The atomic coordinates have been deposited into the Protein Data Bank (PDB ID: 2KIQ).

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Zeng, J., Boyles, J., Tripathy, C. et al. High-resolution protein structure determination starting with a global fold calculated from exact solutions to the RDC equations. J Biomol NMR 45, 265–281 (2009). https://doi.org/10.1007/s10858-009-9366-3

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