Understanding the function of biological macromolecules and their complexes at the physicochemical level requires knowledge of both their structure and dynamics. Conventional biophysical techniques, such as crystallography and NMR, have yielded incredibly detailed structural information at the atomic level on highly populated static states.1 In the context of the energy landscape representation of macromolecules, highly populated states are located within the global free energy minimum region of a relatively rough free energy hypersurface.2-5 Much less is known, however, about lowly populated, higher free energy states which cannot be * E-mail: G.M.C., mariusc@mail.nih.gov; J.I., j.iwahara@utmb.edu. † National Institutes of Health. ‡ University of Texas Medical Branch. Chem. Rev. 2009, 109, 4108–4139 4108

Theory, Practice, and Applications of Paramagnetic Relaxation Enhancement for the Characterization of Transient Low-Population States of Biological Macromolecules and Their Complexes

Paramagnetic metal ions offer outstanding opportunities for protein studies by nuclear magnetic resonance (NMR) spectroscopy. The paramagnetic effects manifested in the NMR spectra provide powerful restraints for the determination of the three-dimensional structure of proteins, open new possibilities for the analysis of protein-protein and protein-ligand interactions, and offer widely applicable tools for sensitivity enhancement of NMR experiments, resonance assignments, and studies of conformational heterogeneity and exchange. With the advent of new reagents for site-specific labeling of proteins with paramagnetic metal ions, a range of established and new strategies that used to be reserved for metalloproteins is becoming available for NMR spectroscopy of nonmetalloproteins.

Protein NMR Using Paramagnetic Ions

https://spin.niddk.nih.gov/clore/Pub/pdf/394.pdf

Practical aspects of 1 H transverse paramagnetic relaxation enhancement measurements on macromolecules

http://www.meilerlab.org/index.php/publications/showPublication/pub_id/100

Expanding the utility of NMR restraints with paramagnetic compounds: background and practical aspects.

https://openresearch-repository.anu.edu.au/bitstream/1885/148505/1/ProgNMRSpectr2017_98-99_20.pdf

Pseudocontact shifts in biomolecular NMR using paramagnetic metal tags.

Modulation of the distance dependence of paramagnetic relaxation enhancements by CSA × DSA cross-correlation

Residual dipolar couplings measured for weakly aligned proteins provide important restraints for molecular structure determinations by NMR1 spectroscopy which cannot be obtained otherwise. 2 Residual dipolar couplings are usually measured by comparing multiplet splittings measured in anisotropic phase with those measured in isotropic phase. 2,3 In the absence of scalar couplings, a residual dipolar coupling between two spins in the weak-coupling limit is directly manifested in a doublet splitting, but the sign of the coupling is more difficult to determine. 4,5 Here we show that the sign and magnitude of residual dipolar couplings between the protons of a methyl group are readily measured in a single experiment. These resulting splittings are larger than those due to intra-methyl residual dipolar couplings between 13C and 1H spins, and they depend on the molecular alignment tensor in a way completely analogous to residual dipolar couplings in twospin systems. 6 They are thus straightforward to use as structural parameters. Dipolar couplings lead to line splittings even for isolated methyl groups. 7 The dipolar contribution to the 1H NMR spectrum of an isolated methyl group is determined by the secular part of the dipolar Hamiltonian which can be decomposed into products of spatial and spin terms: 8

Residual dipolar (1)H-(1)H couplings of methyl groups in weakly aligned proteins.

A novel pulse sequence is presented for the correlation of 5′ and 5′′ protons in DNA with phosphorus. Double-quantum coherence between the methylene protons is used to generate 1H5′-31P and 1H5′′-31P cross peaks in an HMQC-type experiment. The resolution for these cross peaks is significantly improved over that of conventional HSQC experiments, as cross peaks between 1H4′ and 31P are largely suppressed and a 3D version of the experiment can be performed with little penalty in sensitivity. In addition, sensitivity is favoured by slower relaxation of the double-quantum coherence and a more favourable multiplet fine structure in the acquisition dimension.

Sensitive 1H-31P correlations with 5' methylene protons of DNA via homonuclear double-quantum coherence.

NMR structure of the LCCL domain

The LCCL domain is a recently discovered, conserved protein module named after its presence in Limulus factor C, cochlear protein Coch-5b2 and late gestation lung protein Lgl1. The LCCL domain plays a key role in the autosomal dominant human deafness disorder DFNA9. Here we report the nuclear magnetic resonance (NMR) structure of the LCCL domain from human Coch-5b2, where dominant mutations leading to DFNA9 deafness disorder have been identified. The fold is novel. Four of the five known DFNA9 mutations are shown to involve at least partially solvent-exposed residues. Except for the Trp91Arg mutant, expression of these four LCCL mutants resulted in misfolded proteins. These results suggest that Trp91 participates in the interaction with a binding partner. The unexpected sensitivity of the fold with respect to mutations of solvent-accessible residues might be attributed to interference with the folding pathway of this disulfide-containing domain.

/pdf/nmr-structure-of-the-lccl-domain-and-implications-for-dfna9-4p9cibbbg3.pdf

NMR structure of the LCCL domain and implications for DFNA9 deafness disorder.

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