Monday, April 26, 2010

J. Am. Chem. Soc., 2010, 132 (16), pp 5556–5557
Fibrillar vs Crystalline Full-Length β-2-Microglobulin Studied by High-Resolution Solid-State NMR Spectroscopy
Emeline Barbet-Massin, Stefano Ricagno, Józef R. Lewandowski, Sofia Giorgetti, Vittorio Bellotti, Martino Bolognes, Lyndon Emsley and Guido Pintacuda

Elucidating the fine structure of amyloid fibrils as well as understanding their processes of nucleation and growth remains a difficult yet essential challenge, directly linked to our current poor insight into protein misfolding and aggregation diseases. Here we consider β-2-microglobulin (β2m), the MHC-1 light chain component responsible for dialysis-related amyloidosis, which can give rise to amyloid fibrils in vitro under various experimental conditions, including low and neutral pH. We have used solid-state NMR to probe the structural features of fibrils formed by full-length β2m (99 residues) at pH 2.5 and pH 7.4. A close comparison of 2D 13C−13C and 15N−13C correlation experiments performed on β2m, in both the crystalline and fibrillar states, suggests that, in spite of structural changes affecting the protein loops linking the protein β-strands, the protein chain retains a substantial share of its native secondary structure in the fibril assembly. Moreover, variations in the chemical shifts of the key Pro32 residue suggest the involvement of a cis−trans isomerization in the process of β2m fibril formation. Lastly, the analogy of the spectra recorded on β2m fibrils grown at different pH values hints at a conserved architecture of the amyloid species thus obtained.

J. Am. Chem. Soc., 2010, 132 (16), pp 5672–5676
NMR-Based Structural Modeling of Graphite Oxide Using Multidimensional 13C Solid-State NMR and ab Initio Chemical Shift Calculations
Leah B. Casabianca†, Medhat A. Shaibat†, Weiwei W. Cai‡, Sungjin Park‡, Richard Piner‡, Rodney S. Ruoff‡ and Yoshitaka Ishii†

Chemically modified graphenes and other graphite-based materials have attracted growing interest for their unique potential as lightweight electronic and structural nanomaterials. It is an important challenge to construct structural models of noncrystalline graphite-based materials on the basis of NMR or other spectroscopic data. To address this challenge, a solid-state NMR (SSNMR)-based structural modeling approach is presented on graphite oxide (GO), which is a prominent precursor and interesting benchmark system of modified graphene. An experimental 2D 13C double-quantum/single-quantum correlation SSNMR spectrum of 13C-labeled GO was compared with spectra simulated for different structural models using ab initio geometry optimization and chemical shift calculations. The results show that the spectral features of the GO sample are best reproduced by a geometry-optimized structural model that is based on the Lerf−Klinowski model (Lerf, A. et al. Phys. Chem. B 1998, 102, 4477); this model is composed of interconnected sp2, 1,2-epoxide, and COH carbons. This study also convincingly excludes the possibility of other previously proposed models, including the highly oxidized structures involving 1,3-epoxide carbons (Szabo, I. et al. Chem. Mater. 2006, 18, 2740). 13C chemical shift anisotropy (CSA) patterns measured by a 2D 13C CSA/isotropic shift correlation SSNMR were well reproduced by the chemical shift tensor obtained by the ab initio calculation for the former model. The approach presented here is likely to be applicable to other chemically modified graphenes and graphite-based systems.

J. Am. Chem. Soc., 2010, 132 (16), pp 5558–5559
Ultrafast MAS Solid-State NMR Permits Extensive 13C and 1H Detection in Paramagnetic Metalloproteins
Ivano Bertini*†‡, Lyndon Emsley§, Moreno Lelli†, Claudio Luchinat†‡, Jiafei Mao† and Guido Pintacuda§

We show here that by combining tailored approaches based on ultrafast (60 kHz) MAS on the CoII-replaced catalytic domain of matrix metalloproteinase 12 (CoMMP-12) we can observe and assign, in a highly paramagnetic protein in the solid state, 13C and even 1H resonances from the residues coordinating the metal center. In addition, by exploiting the enhanced relaxation caused by the paramagnetic center, and the low power irradiation enabled by the fast MAS, this can be achieved in remarkably short times and at very high field (21.2 T), with only less than 1 mg of sample. Furthermore, using the known crystal structure of the compound, we are able to distinguish and measure pseudocontact (PCS) contributions to the shifts up to the coordinating ligands and to unveil structural information.

J. Am. Chem. Soc., 2010, 132 (16), pp 5607–5609
Toward Flexibility−Activity Relationships by NMR Spectroscopy: Dynamics of Pin1 Ligands
Andrew T. Namanja†, Xiaodong J. Wang‡, Bailing Xu‡, Ana Y. Mercedes-Camacho‡, Brian D. Wilson†, Kimberly A. Wilson†, Felicia A. Etzkorn‡ and Jeffrey W. Peng*†

Drug design involves iterative ligand modifications. For flexible ligands, these modifications often entail restricting conformational flexibility. However, defining optimal restriction strategies can be challenging if the relationship between ligand flexibility and biological activity is unclear. Here, we describe an approach for ligand flexibility−activity studies using Nuclear Magnetic Resonance (NMR) spin relaxation. Specifically, we use 13C relaxation dispersion measurements to compare site-specific changes in ligand flexibility for a series of related ligands that bind a common macromolecular receptor. The flexibility changes reflect conformational reorganization resulting from formation of the receptor−ligand complex. We demonstrate this approach on three structurally similar but flexibly differentiated ligands of human Pin1, a peptidyl-prolyl isomerase. The approach is able to map the ligand dynamics relevant for activity and expose changes in those dynamics caused by conformational locking. Thus, NMR flexibility−activity studies can provide information to guide strategic ligand rigidification. As such, they help establish an experimental basis for developing flexibility−activity relationships (FAR) to complement traditional structure−activity relationships (SAR) in molecular design.

J. Phys. Chem. A, 2010, 114 (16), pp 5365–5371
NMR and Quantum Chemistry Study of Mesoscopic Effects in Ionic Liquids
Vytautas Balevicius*†, Zofia Gdaniec‡, Kestutis Aidas§ and Jelena Tamuliene

1H, 13C, and 81Br NMR spectra of the neat room-temperature ionic liquid (RTIL), namely, 1-decyl-3-methyl-imidazolium bromide ([C10mim][Br]) as well as its solutions in acetonitrile, dichloromethane, methanol, and water have been investigated. The most important observation of the present work is the significant broadening of 81Br NMR signal in the solutions of [C10mim][Br] in organic solvents, which molecules tend to associate into hydrogen bond networks and the appearance of the complex contour of 81Br NMR signal in the neat RTIL as well as in the liquid crystalline (LC) ionogel formed in RTIL/water solution. The complex structure of 81Br signal changes upon heating and dilution in water. It disappears at ca. 353 K and in the aqueous solution below ca. 0.1 mol fraction of RTIL. Several new 1H NMR signals appear at the [C10mim][Br]/water compositions just before the solidification of the sample (0.3 mol fraction of [C10mim][Br]). These additional peaks can be attributed to the H2O protons placed in inhomogeneous regions of the sample or due to the appearance of nonequivalent water sites in LC ionogel, the exchange between which is highly restricted or even frozen. The complex shape of 81Br NMR signal can originate from the presence of supra-molecular structures (mesoscopic domains) that live over the period of the NMR time-scale due to a very high viscosity of [C10mim][Br]. These domains exhibit some features of partially disordered solids (liquid- or plastic crystals). To evaluate the static and dynamic contributions into the relaxation rate of 81Br nuclei, the quantum chemistry calculations of the electronic structure, magnetic shielding, and electric field gradient (EFG) tensors of [C10mim][Br] and related model systems (Br−·6H2O cluster, with addition of the dipoles (hydrogen fluoride) and charged particles − cations: H+ or C1mim+) were performed.

J. Phys. Chem. A, 2010, 114 (16), pp 5279–5286
DFT Calculations of Indirect 29Si−1H Spin−Spin Coupling Constants in Organoalkoxysilanes
Jyothirmai Ambati and Stephen E. Rankin

The performance of four basis sets (6-311+G(2d,p), IGLO-III, cc-PVTZ, and 6-31G) is evaluated in order to find a quantum mechanical technique that can be used to accurately estimate 29Si−1H spin−spin coupling constants in organoalkoxysilanes. The 6-31G basis set with the B3LYP functional is found to be an accurate, efficient, and cost-effective density functional theory method for predicting spin−spin coupling constants of organoalkoxysilanes. Knowledge of these scalar coupling constants and their dependence on structural variations is important to be able to fine-tune NMR experiments that rely on polarization transfer among nuclei, such as 29Si distortionless enhancement by polarization transfer (DEPT). The effects of size and the number of unhydrolyzable alkyl groups attached to silicon and the effects of substitution of alkoxy groups with hydroxyl groups on 29Si−1H spin−spin coupling constants are investigated using this DFT method. The results show that the predicted scalar coupling between silicon and organic groups depends weakly on the degree of hydrolysis of the alkoxysilanes. The effectiveness of this method is also illustrated for the determination of spin−spin coupling constants in a species containing a siloxane bond.

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