C<scp>HEMICAL</scp>S<scp>HIFTS IN</scp>A<scp>MINO</scp>A<scp>CIDS</scp>, P<scp>EPTIDES</scp>,<scp>AND</scp>P<scp>ROTEINS</scp>: From Quantum Chemistry to Drug Design

Oldfield, Eric

doi:10.1146/annurev.physchem.53.082201.124235

Cited by 117 publications

(79 citation statements)

References 80 publications

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“…3b). This is similar to previously found correlations between 13 C and 17 O chemical shielding and bond length (Oldfield 2002;Aidas et al 2007). Our continuum-only calculations for NMA showed that elongation of the NH bond by 0.02 Å results in reduction of 15 N chemical shielding by 2.33 ppm (~1.8%), and the elongation of the CO bond by 0.03 Å reduces this shielding by 3.92 ppm (~3.1%).…”

Section: Resultssupporting

confidence: 92%

Density functional calculations of 15N chemical shifts in solvated dipeptides

2008

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SummaryWe performed density functional calculations to examine the effects of solvation, hydrogen bonding, backbone conformation, and the side chain on 15 N chemical shielding in proteins. We used Nmethylacetamide (NMA) and N-formyl-alanyl-X (with X being one of the 19 naturally occurring amino acids excluding proline) as model systems. In addition, calculations were performed for selected fragments from protein GB3. The conducting polarizable continuum model was employed to include the effect of solvent in the density functional calculations. Our calculations for NMA show that the augmentation of the polarizable continuum model with the explicit water molecules in the first solvation shell has a significant influence on isotropic 15 N chemical shift but not as much on the chemical shift anisotropy. The difference in the isotropic chemical shift between the standard β-sheet and α-helical conformations ranges from 0.8 ppm to 6.2 ppm depending on the residue type, with the mean of 2.7 ppm. This is in good agreement with the experimental chemical shifts averaged over a database of 36 proteins containing >6100 amino acid residues. The orientation of the 15 N chemical shielding tensor as well as its anisotropy and asymmetry are also in the range of values experimentally observed for peptides and proteins.

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Section: Resultssupporting

confidence: 92%

Density functional calculations of 15N chemical shifts in solvated dipeptides

2008

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“…2A). The CЈ chemical shift is more sensitive to changes in the C-O bond length upon hydrogen bond formation than to changes in the backbone / angles (69). Thereby, the overall ␤-sheet topology that depends on the hydrogen bonding pattern as well as the tertiary structure in general is better predicted if the CЈ chemical shift information is included.…”

Section: Discussionmentioning

confidence: 99%

Structure, Dynamics, Lipid Binding, and Physiological Relevance of the Putative GTPase-binding Domain of Dictyostelium Formin C

Dames

Junemann

Sass

et al. 2011

Journal of Biological Chemistry

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Dictyostelium Formin C (ForC) is involved in the regulation of local actin cytoskeleton reorganization (e.g. during cellular adhesion or migration). ForC contains formin homology 2 and 3 (FH2 and -3) domains and an N-terminal putative GTPase-binding domain (GBD) but lacks a canonical FH1 region. To better understand the role of the GBD, its structure, dynamics, lipid-binding properties, and cellular functions were analyzed by NMR and CD spectroscopy and by in vivo fluorescence microscopy. Moreover, the program CS-Rosetta was tested for the structure prediction based on chemical shift data only. The ForC GBD adopts an ubiquitinlike ␣/␤-roll fold with an unusually long loop between ␤-strands 1 and 2. Based on the lipid-binding data, the presence of DPC micelles induces the formation of ␣-helical secondary structure and a rearrangement of the tertiary structure. Lipid-binding studies with a mutant protein and a peptide suggest that the ␤1-␤2 loop is not relevant for these conformational changes. Whereas small amounts of negatively charged phosphoinositides (1,2-dioctanoyl-sn-glycero-3-(phosphoinositol 4,5-bisphosphate) and 1,2-dihexanoyl-sn-glycero-3-(phosphoinositol 3,4,5-trisphosphate)) lower the micelle concentration necessary to induce the observed spectral changes, other negatively charged phospholipids (1,2-dihexanoyl-sn-glycero-3-(phospho-L-serine) and 1,2-dihexanoyl-snglycero-3-phospho-(1 -rac-glycerol)) had no such effect. Interestingly, bicelles and micelles composed of diacylphosphocholines had no effect on the GBD structure. Our data suggest a model in which part of the large positively charged surface area of the GBD mediates localization to specific membrane patches, thereby regulating interactions with signaling proteins. Our cellular localization studies show that both the GBD and the FH3 domain are required for ForC targeting to cell-cell contacts and early phagocytic cups and macropinosomes.Formins are widely expressed multidomain proteins that regulate the spatial and temporal organization of the actin and microtubule cytoskeleton, thereby affecting important cellular functions, such as cytokinesis and cell-cell adhesion (1-3). The defining element is the ϳ400-amino acid-encompassing "formin homology 2" (FH2) 2 domain that can tightly associate with the barbed end of elongating actin filaments (4). In nearly all formins, the FH2 domain is preceded by a prolinerich "formin homology 1" (FH1) region that varies in length and the number of binding sites for profilin and that is used to recruit profilin-actin complexes for filament elongation. The influence of the FH2 domain on the rate of filament elongation depends on the length and composition of the FH1 region and the connecting linker (2, 4, 5). Most formins contain additional regulatory domains. The N-terminal "formin homology 3" (FH3) domain mediates interactions with autoinhibitory regulatory elements in the C terminus as well as with other formin regulators. The FH3 domain can be further divided into functional subdomains, such as an armadill...

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“…Each nucleus has different susceptibilities to structural parameters. C ␣ chemical shifts depend largely on the structural environment (average backbone dihedral angles), whereas H N and N shifts do so to a much lesser extent and are also strongly influenced by the chemical environment, side-chain conformation and, in the case of H N nuclei, hydrogen bonding (49,50). The dynamics on the fast (nanosecond to picosecond) and slow (millisecond to second) timescales correlated well with the deviation of the C ␣ shifts from their random-coil positions (Fig.…”

Section: ␣-Synuclein Structure and Dynamicsmentioning

confidence: 99%

Structure and Dynamics of Micelle-bound Human α-Synuclein

Ulmer¹,

Bax²,

Cole

et al. 2005

Journal of Biological Chemistry

882

1,168

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Misfolding of the protein ␣-synuclein (aS), which associates with presynaptic vesicles, has been implicated in the molecular chain of events leading to Parkinson's disease. Here, the structure and dynamics of micelle-bound aS are reported. A dynamic variation in interhelical distance on the microsecond timescale is complemented by enhanced sub-nanosecond timescale dynamics, particularly in the remarkably glycine-rich segments of the helices. These unusually rich dynamics may serve to mitigate the effect of aS binding on membrane fluidity. The well ordered conformation of the helix-helix connector indicates a defined interaction with lipidic surfaces, suggesting that, when bound to larger diameter synaptic vesicles, it can act as a switch between this structure and a previously proposed uninterrupted helix.

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CHEMICALSHIFTS INAMINOACIDS, PEPTIDES,ANDPROTEINS: From Quantum Chemistry to Drug Design

Cited by 117 publications

References 80 publications

Density functional calculations of 15N chemical shifts in solvated dipeptides

Density functional calculations of 15N chemical shifts in solvated dipeptides

Structure, Dynamics, Lipid Binding, and Physiological Relevance of the Putative GTPase-binding Domain of Dictyostelium Formin C

Structure and Dynamics of Micelle-bound Human α-Synuclein

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