Abstract
Prerequisite for chemical shift (CS) and CS tensor calculations are highly refined structures defining the molecular surroundings of the nuclei under study. Here, we present geometry optimizations with 13C and 15N CS constraints for large bio-molecules like peptides and proteins. The method discussed here provides both, refined structures and chemical shift tensors. Furthermore, since the experimental resonances of aligned systems are related to CS tensors, they strongly depend on the orientation and motion of molecules, their fragments, functional groups and moieties. For efficient CS calculations we apply a semi-empirical approach—the bond polarization theory (BPT). The BPT relies on linear bond polarization parameters and we present a new set of parameters based on ab initio second-order Møller–Plesset perturbation theory calculations. The new parametrization extends the applicability of the BPT approach to a wide range of organic molecules and bio-polymers. Here, the method has been applied to the protein ubiquitin and the membrane-active peptide gramicidin A (dimer) in oriented bilayers. The calculated 13C and 15N CS values of best-refined structures published until now gave a large scatter with respect to the experiment. It will be shown that BPT CS optimizations can reduce these errors to values near the experimental uncertainty. In combination with molecular dynamics with orientational constraints it is possible to study motional dynamics and BPT calculations can provide residual chemical shift anisotropies.
Similar content being viewed by others
References
Born R, Spiess HW, Kutzelnigg W, Fleischer U, Schindler M (1994) Conformational effects on 13C-NMR chemical shifts of an amorphous polymer: an ab initio study by the IGLO method. Macromolecules 27:1500–1504
Cisnetti F, Loth K, Pelupessy P, Bodenhausen G (2004) Determination of chemical shift anisotropy tensors of carbonyl nuclei in proteins through cross-correlated relaxation in NMR. ChemPhysChem 5:807–814
Cornilescu GBA (2000) Measurement of proton, nitrogen, and carbonyl chemical shielding anisotropies in a protein dissolved in a dilute liquid crystalline phase. JACS 122:10143–10154
Cornilescu G, Marquardt JL, Ottiger M, Bax A (1998a) Ubiquitin NMR structure. Biological magnetic resonance data bank
Cornilescu G, Marquardt JL, Ottiger M, Bax A (1998b) Validation of protein structure from anisotropic carbonyl chemical shifts in a dilute liquid crystalline phase. JACS 120:6836–6837
Cornilescu G, Delaglio F, Bax A (1999) Protein backbone angle restraints from searching a database for chemical shift and sequence homology. J Biomol NMR 13:289–302
Engh RA, Huber R (1991) Accurate bond and angle parameters for X-ray protein structure refinement. Acta Crystallogr A 47:392–400
Facelli JC (2011) Chemical shift tensors: theory and application to molecular structural problems. Prog Nucl Magn Reson Spectrosc 58:176–201
Fares C, Sharom FJ, Davis JH (2002) N-15, H-1 heteronuclear correlation NMR of gramicidin A in DMPC-d(67). JACS 124:11232–11233
Gauss J (1992) Calculation of NMR chemical shifts at second-order many-body perturbation-theory using gauge-including atomic orbitals. Chem Phys Lett 191:614–620
Ho BK, Thomas A, Brasseur R (2003) Revisiting the Ramachandran plot: hard-sphere repulsion, electrostatics, and H-bonding in the alpha-helix. Protein Sci 12:2508–2522
Iuliucci RJ, Facelli JC, Alderman DW, Grant DM (1995) Carbon-13 chemical shift tensors in polycyclic aromatic compounds 5. Single-crystal study of acenaphthene. JACS 117:2336–2343
Jakovkin I, Klipfel M, Muhle-Goll C, Ulrich AS, Luy B, Sternberg U (2012) Rapid calculation of protein chemical shifts using bond polarization theory and its application to protein structure refinement. PCCP 14:12263–12276
Jaravine VA, Zhuravleva AV, Permi P, Ibraghimov I, Orekhov VY (2008) Hyperdimensional NMR spectroscopy with nonlinear sampling. JACS 130:3927–3936
Ketchem RR, Hu W, Cross TA (1993) High-resolution conformation of gramicidin A in a lipid bilayer by solid-state NMR. Science 261:1457–1460
Krause E, Bienert M, Schmieder P, Wenschuh H (2000) The helix-destabilizing propensity scale of D-amino acids: the influence of side chain steric effects. JACS 122:4865–4870
Laskowski RA, Moss DS, Thornton JM (1993) Main-chain bond lengths and bond angles in protein structures. J Mol Biol 231:1049–1067
Lienin SF, Brem T, Brutscher B, Bruschweiler R, Ernst RR (1998) Anisotropic intramolecular backbone dynamics of ubiquitin characterized by NMR relaxation and MD computer simulation. J Am Chem Soc 120:9870–9879
Lovell SC, Davis IW, Adrendall WB, de Bakker PIW, Word JM, Prisant MG, Richardson JS, Richardson DC (2003) Structure validation by C alpha geometry: phi, psi and C beta deviation. Proteins Struct Funct Genet 50:437–450
Mai W, Hu W, Wang C, Cross TA (1993) Orientational constraints as three-dimensional structural constraints from chemical shift anisotropy: the polypeptide backbone of gramicidin A in a lipid bilayer. Protein Sci 2:532–542
Mason J (1993) Conventions for the reporting of nuclear magnetic shielding (or shift) tensors suggested by participants in the Nato ARW on NMR shielding constants at the University-of-Maryland, College-Park, July 1992. SSNMR 2:285–288
Möllhoff M, Sternberg U (2001) Molecular mechanics with fluctuating atomic charges: a new force field with a semi-empirical charge calculation. J Mol Model 7:90–102
Morin S (2011) A practical guide to protein dynamics from N-15 spin relaxation in solution. Prog Nucl Magn Reson Spectrosc 59:245–262
O’Keeffe M, Brese NE (1991) Atom sizes and bond lengths in molecules and crystals. J Am Chem Soc 113:3226–3229
Pauling L (1960) The nature of chemical bond, 3rd edn. Cornell University, New York
Ramamoorthy A, Wei YF, Lee D-K (2004) PISEMA solid-state NMR spectroscopy. In: Webb GA (ed) Annual report on NMR spectroscopy, vol 52. Academic Press, New York, pp 1–52
Schindler M (1980) Die berechnung magnetischer eigenschaften unter verwendung individuell geeichter lokalisierter molekülorbitale. Abteilung chemie. Ruhr-Universiät Bochum, Bochum, p 186
Sternberg U (1988) Theory of the influence of the 2nd coordination sphere on the chemical-shift. Mol Phys 63:249–267
Sternberg U (2010) Structure elucidation of biopolymers from constrained QM/MM calculations—from NMR chemical shifts to structure and dynamics. In: Advances in biomedical research, pp 268–272
Sternberg U, Priess W (1997) New semi-empirical approach for the calculation of C-13 chemical-shift tensors. J Magn Reson 125:8–19
Sternberg U, Koch FT, Mollhoff M (1994) New approach to the semiempirical calculation of atomic charges for polypeptides and large molecular-systems. J Comput Chem 15:524–531
Sternberg U, Koch F-T, Bräuer M, Kunert M, Anders E (2001) Molecular mechanics for zinc complexes with fluctuating atomic charges. J Mol Model 7:54–64
Sternberg U, Witter R, Ulrich AS (2004) 3D structure elucidation using NMR chemical shifts. Ann Rep NMR Spectrosc 52:53–104
Sternberg U, Witter R, Ulrich AS (2007) All-atom molecular dynamics simulations using orientational constraints from anisotropic NMR samples. J Biomol NMR 38:23–39
Sternberg U, Klipfel M, Grage SL, Witter R, Ulrich AS (2009) Calculation of fluorine chemical shift tensors for the interpretation of oriented F-19-NMR spectra of gramicidin A in membranes. PCCP 11:7048–7060
Sternberg U, Birtalan E, Jakovkin I, Luy B, Schepers U, Braese S, Muhle-Goll C (2013) Structural characterization of a peptoid with lysine-like side chains and biological activity using NMR and computational methods. Org Biomol Chem 11:640–647
Witter R, Priess W, Sternberg U (2002a) Chemical shift driven geometry optimization. J Comput Chem 23:298–305
Witter R, Seyfart L, Greiner G, Reissmann S, Weston J, Anders E, Sternberg U (2002b) Structure determination of a pseudotripeptide zinc complex with the COSMOS-NMR force field and DFT methods. J Biomol NMR 24:277–289
Witter R, Sternberg U, Hesse S, Kondo T, Koch F-T, Ulrich AS (2006) C-13 chemical shift constrained crystal structure refinement of cellulose I-alpha and its verification by NMR anisotropy experiments. Macromolecules 39:6125–6132
Witter R, Möllhoff M, Koch FT, Sternberg U (2015) Fast atomic charge calculation for implementation into a polarizable force field: application to an ion channel protein. J Chem. https://doi.org/10.1155/2015/908204
Zhang HL, Hou GJ, Lu MM, Ahn J, Byeon IJL, Langmead CJ, Perilla JR, Hung I, Gor’kov PL, Gan ZH et al (2016) HIV-1 capsid function is regulated by dynamics: quantitative. atomic-resolution insights by integrating magic-angle-spinning NMR, QM/MM, and MD. JACS 138:14066–14075
Acknowledgement
Authors thank the support from Karlsruhe Institute of Technology (KIT) and University Ulm.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sternberg, U., Witter, R. Investigation of backbone dynamics and local geometry of bio-molecules using calculated NMR chemical shifts and anisotropies. J Biomol NMR 73, 727–741 (2019). https://doi.org/10.1007/s10858-019-00284-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10858-019-00284-y
Keywords
- BPT
- MDOC
- RCSA
- Bond polarization theory
- Molecular dynamics with orientational constraints
- Residual chemical shift anisotropies
- Chemical shift calculation
- Chemical shift tensor calculation
- 13C chemical shifts
- 15N chemical shifts
- Geometry optimization
- Chemical shift constraints
- Chemical shift tensors
- Molecular dynamics
- Molecular motion