Xplor‐NIH for molecular structure determination from NMR and other data sources

Schwieters, Charles D.; Bermejo, Guillermo A.; Clore, G. Marius

doi:10.1002/pro.3248

Cited by 189 publications

(208 citation statements)

References 68 publications

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“…10,11 In general, missing NMR signals result in a lack of structural information such as distance restraints derived from the nuclear Overhauser effect (NOE). To overcome this limitation, several NMR approaches that can provide structural restraints have been reported; for instance, paramagnetic relaxation enhancement (PRE), 12,13 which provides relatively longer distance restraints (e.g., 25 Å) than the NOE (e.g., 6 Å), and residual dipolar coupling, 14,15 which provides orientation restraints rather than distance restraints. However, to obtain the information, NMR signals must be observed in the NMR spectra.…”

Section: Introductionmentioning

confidence: 99%

Paramagnetic relaxation enhancement‐assisted structural characterization of a partially disordered conformation of ubiquitin

et al. 2019

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Nuclear magnetic resonance (NMR) is a powerful tool to study three‐dimensional structures as well as protein conformational fluctuations in solution, but it is compromised by increases in peak widths and missing signals. We previously reported that ubiquitin has two folded conformations, N1 and N2 and plus another folded conformation, I, in which some amide group signals of residues 33–41 almost disappeared above 3 kbar at pH 4.5 and 273 K. Thus, well‐converged structural models could not be obtained for this region owing to the absence of distance restraints. Here, we reexamine the problem using the ubiquitin Q41N variant as a model for this locally disordered conformation, I. We demonstrate that the variant shows pressure‐induced loss of backbone amide group signals at residues 28, 33, 36, and 39–41 like the wild‐type, with a similar but smaller effect on CαH and CβH signals. In order to characterize this I structure, we measured paramagnetic relaxation enhancement (PRE) under high pressure to obtain distance restraints, and calculated the structure assisted by Bayesian inference. We conclude that the more disordered I conformation observed at pH 4.0, 278 K, and 2.5 kbar largely retained the N2 conformation, although the amide groups at residues 33–41 have more heterogeneous conformations and more contact with water, which differ from the N1 and N2 states. The PRE‐assisted strategy has the potential to improve structural characterization of proteins that lack NMR signals, especially for relatively more open and hydrated protein conformations.

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Section: Introductionmentioning

confidence: 99%

Paramagnetic relaxation enhancement‐assisted structural characterization of a partially disordered conformation of ubiquitin

et al. 2019

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“…These distances allowed us to use Xplor-NIH 17 to generate an approximate model of the dimer by docking the structure of the htt NT Q 7 helical monomer (Figure 2B) employing the ansatz that helix–helix interactions are secondary to peptide–micelle interactions (see SI). The dimer model shown in Figure 4B (bottom) displays good agreement between experimental and calculated P ( r ) distributions (Figure 4B, top).…”

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confidence: 99%

Interaction of Huntingtin Exon-1 Peptides with Lipid-Based Micellar Nanoparticles Probed by Solution NMR and Q-Band Pulsed EPR

et al. 2018

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Lipid-based micellar nanoparticles promote aggregation of huntingtin exon-1 peptides. Here we characterize the interaction of two such peptides, httNTQ7 and httNTQ10 comprising the N-terminal amphiphilic domain of huntingtin followed by 7 and 10 glutamine repeats, respectively, with 8 nm lipid micelles using NMR chemical exchange saturation transfer (CEST), circular dichroism and pulsed Q-band EPR. Exchange between free and micelle-bound httNTQn peptides occurs on the millisecond time scale with a KD ~ 0.5–1 mM. Upon binding micelles, residues 1–15 adopt a helical conformation. Oxidation of Met7 to a sulfoxide reduces the binding affinity for micelles ~3–4-fold and increases the length of the helix by a further two residues. A structure of the bound monomer unit is calculated from the backbone chemical shifts of the micelle-bound state obtained from CEST. Pulsed Q-band EPR shows that a monomer–dimer equilibrium exists on the surface of the micelles and that the two helices of the dimer adopt a parallel orientation, thereby bringing two disordered polyQ tails into close proximity which may promote aggregation upon dissociation from the micelle surface.

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“…Each of 1000 structures was calculated using simulated annealing (initial temperature=1000 K, final temperature=100 K). The energy of each conformer was calculated using a default force field implemented in Xplor‐NIH . Additional ϕ and ψ dihedral angles restraints defining the α‐helix conformation indicated by CD with the deviation of ±40° were applied for peptide chains with the exception of β‐alanine, N‐terminal, and C‐terminal residues.…”

Section: Methodsmentioning

confidence: 99%

“…The energy of each conformer was calculated using ad efault force field implemented in Xplor-NIH. [60] Additional f and y dihedral angles restraints defining the a-helix conformation indicated by CD with the deviation of AE 408 were applied for peptide chains with the exception of b-alanine, N-terminal, and C-terminal residues. Only inter-chain hydrophobic interactions of the Leu residues were described in the restraints section of input data, as deduced from the CD spectra of ordered TASP molecules.…”

Section: Molecular Modelingmentioning

confidence: 99%

Self‐Synthesizing Models of Helical Proteins Based on Aromatic Disulfide Chemistry

Wołczański

Cal

Waliczek

et al. 2018

Chemistry A European J

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A new method of synthesis of peptide conjugates with aromatic moieties substituted with two sulfhydryl groups at 1,3-positions is proposed. Amphiphilic peptides derivatized in such a way under oxidative conditions spontaneously form cyclic, covalent trimers and tetramers dominated by α-helical conformations. The tendency to form tri- or tetrahelical bundles depends on sequences of the peptides and on the oxidation conditions, pH, and additives.

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Xplor‐NIH for molecular structure determination from NMR and other data sources

Cited by 189 publications

References 68 publications

Paramagnetic relaxation enhancement‐assisted structural characterization of a partially disordered conformation of ubiquitin

Paramagnetic relaxation enhancement‐assisted structural characterization of a partially disordered conformation of ubiquitin

Interaction of Huntingtin Exon-1 Peptides with Lipid-Based Micellar Nanoparticles Probed by Solution NMR and Q-Band Pulsed EPR

Self‐Synthesizing Models of Helical Proteins Based on Aromatic Disulfide Chemistry

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