Journal of Biomolecular NMR

, Volume 56, Issue 2, pp 125–137 | Cite as

Solution NMR refinement of a metal ion bound protein using metal ion inclusive restrained molecular dynamics methods

  • Dhruva K. Chakravorty
  • Bing Wang
  • Chul Won Lee
  • Alfredo J. Guerra
  • David P. Giedroc
  • Kenneth M. MerzJr.


Correctly calculating the structure of metal coordination sites in a protein during the process of nuclear magnetic resonance (NMR) structure determination and refinement continues to be a challenging task. In this study, we present an accurate and convenient means by which to include metal ions in the NMR structure determination process using molecular dynamics (MD) simulations constrained by NMR-derived data to obtain a realistic and physically viable description of the metal binding site(s). This method provides the framework to accurately portray the metal ions and its binding residues in a pseudo-bond or dummy-cation like approach, and is validated by quantum mechanical/molecular mechanical (QM/MM) MD calculations constrained by NMR-derived data. To illustrate this approach, we refine the zinc coordination complex structure of the zinc sensing transcriptional repressor protein Staphylococcus aureus CzrA, generating over 130 ns of MD and QM/MM MD NMR-data compliant sampling. In addition to refining the first coordination shell structure of the Zn(II) ion, this protocol benefits from being performed in a periodically replicated solvation environment including long-range electrostatics. We determine that unrestrained (not based on NMR data) MD simulations correlated to the NMR data in a time-averaged ensemble. The accurate solution structure ensemble of the metal-bound protein accurately describes the role of conformational sampling in allosteric regulation of DNA binding by zinc and serves to validate our previous unrestrained MD simulations of CzrA. This methodology has potentially broad applicability in the structure determination of metal ion bound proteins, protein folding and metal template protein-design studies.


Protein allostery QM/MM MD Zinc sensor protein Metalloregulatory protein Transcriptional repressor MRD-NMR refinement MTK+ MCPB Metal ion based NMR refinement CzrA Metal ion force field 



Assisted model building with energy refinement


Density functional theory


Metal center parameter builder


Molecular dynamics


Metal restrained dynamics nuclear magnetic resonance


Nuclear magnetic resonance


Nuclear Overhauser enhancements


Quantum mechanical/molecular mechanical


Quantum mechanical/molecular mechanical molecular dynamics


Residual dipolar couplings


Restrained dynamics nuclear magnetic resonance


Root mean square deviation


X-ray absorption spectroscopy


Protein data bank



We gratefully acknowledge the United States National Institutes of Health for support of this study (GM044974 to K.M.M. and GM042569 to D.P.G.) and high performance computing at the University of Florida (UFHPC) for providing and maintaining the computational resources used to perform this study. We also thank Sarah Gordon for helpful discussions.

Supplementary material

10858_2013_9729_MOESM1_ESM.pdf (13 mb)
Supplementary material 1 (PDF 13332 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Dhruva K. Chakravorty
    • 1
  • Bing Wang
    • 1
  • Chul Won Lee
    • 2
    • 3
  • Alfredo J. Guerra
    • 2
  • David P. Giedroc
    • 2
  • Kenneth M. MerzJr.
    • 1
  1. 1.Department of Chemistry and the Quantum Theory ProjectUniversity of FloridaGainesvilleUSA
  2. 2.Department of ChemistryIndiana UniversityBloomingtonUSA
  3. 3.Department of ChemistryChonnam National UniversityKwangjuKorea

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