Application of Ring Current Calculations to the Proton NMR of Proteins and Transfer RNA

Perkins, Stephen J.

doi:10.1007/978-1-4615-6540-6_4

Cited by 82 publications

(29 citation statements)

References 230 publications

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“…In fact, all the nicotine NMR signals shift downfield, with the 5-R-CH′ and 5--CH′ signals having the largest shifts of 0.24 and 0.31 ppm (Table 1). This deshielding was rationalized in terms of a ring-current contribution from the His aromatic rings (Perkins, 1982). The downfield shifts are consistent with 5′CH 2 protons located in the plane of the His rings.…”

Section: Biological Functions Of Nicotine and Its Relevance To Alzheimentioning

confidence: 66%

Nicotine Inhibits Amyloid Formation by the β-Peptide

et al. 1996

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The 42-residue -(1-42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic -(1-42) peptide readily aggregates and precipitates as oligomeric -sheet structures, a process that occurs during amyloid formation in Alzheimer's disease. Using circular dichroism (CD) and ultraviolet spectroscopic techniques, we show that nicotine, a major component in cigarette smoke, inhibits amyloid formation by the -(1-42) peptide. The related compound cotinine, the major metabolite of nicotine in humans, also slows down amyloid formation, but to a lesser extent than nicotine. In contrast, control substances pyridine and Nmethylpyrrolidine accelerate the aggregation process. Nuclear magnetic resonance (NMR) studies demonstrate that nicotine binds to the 1-28 peptide region when folded in an R-helical conformation. On the basis of chemical shift data, the binding primarily involves the N-CH 3 and 5′CH 2 pyrrolidine moieties of nicotine and the histidine residues of the peptide. The binding is in fast exchange, as shown by single averaged NMR peaks and the lack of nuclear Overhauser enhancement data between nicotine and the peptide in two-dimensional NOESY spectra. A mechanism is proposed, whereby nicotine retards amyloidosis by preventing an R-helix f -sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.

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Section: Biological Functions Of Nicotine and Its Relevance To Alzheimentioning

confidence: 66%

Nicotine Inhibits Amyloid Formation by the β-Peptide

et al. 1996

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“…The average distance from the emethyl protons and the closest &proton of Tyr 97 is 2.8 A . (Johnson & Bovey, 1958;Perkins, 1982;Gao et al, 1991b) C102T 'H 6, ppm nitude of chemical-shift changes. The standard deviation is +O.lOppm when the FlOM;C102T and F10CsM,;C102T variants are compared individually to the C102T variant.…”

Section: Chemical Shiftsmentioning

confidence: 99%

“…obs. ), suggesting that these groups are near the edge of an aromatic ring (Johnson & Bovey, 1958;Perkins, 1982;Wiithrich, 1986). Analysis of NOE and scalar coupling data shows that the aromatic ring belongs to Tyr 97.…”

Section: Comparing the Structure Of The Fiom;ci02t And Fiocsme;c102t mentioning

confidence: 99%

Probing weakly polar interactions in cytochrome c

et al. 1993

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Theoretical, statistical, and model studies suggest that proteins are stabilized by weakly polar attractions between sulfur atoms and properly oriented aromatic rings. The two sulfur-containing amino acids, methionine and cysteine, occur frequently among functional alleles in random mutant libraries of Saccharomyces cerevisiue iso-lcytochrome c genes at positions that form a weakly polar aromatic-aromatic interaction in the wild-type protein.To determine if a weakly polar sulfur-aromatic interaction replaced the aromatic-aromatic interaction, the structure and stability of two variants were examined. Phenylalanine 10, which interacts with tyrosine 97, was replaced by methionine and cysteine. The cysteine was modified to form the methionine and cystine analog, S-methyl cysteine (CysSMe). Proton NMR studies indicate that changing Phe 10 to Met or CysSMe affects only local structure and that the structures of sulfur-containing variants are nearly identical. Analysis of chemical shifts and nuclear Overhauser effect data indicates that both sulfur-containing side chains are in position to form a weakly polar interaction with Tyr 97. The FlOM and FlOCsM, variants are 2-3 kcal mol-' less stable than iso-I-cytochrome c at 3 0 0 K. Comparison of the stabilities of the FlOM and FlOCsM, variants allows evaluation of the potential weakly polar interaction between the additional sulfur atom of FlOCsM, and the aromatic moiety of Tyr 97. The F I O C~M , ; C~~~T variant is 0.7 * 0.3 kcal mol-' more stable than the FIOM;C102T protein. The increased stability is explained by the difference in hydrophobicity of the sulfur-containing side chains. We conclude that any weakly polar interaction between the additional sulfur and the aromatic ring is too weak to detect or is masked by destabilizing contributions to the free energy of denaturation.

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“…In diamagnetic proteins the shifts are generally less than about 1 ppm, but may be as large as 5 ppm, and 3 mechanisms are thought to be important. Shifts can arise from the anisotropy of the magnetic susceptibility associated with ring currents in aromatic groups, from the local anisotropy associated with other groups (e.g., carbonyls) or atoms, and from the perturbations to electron distributions arising from the electric fields associated with charged groups [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Theoretical models for calculating the magnitude of ring current shifts for a given molecular conformation are well developed [2]. Provided that resonance assignments are known, these predictions can be compared with experimental values of secondary shifts.…”

Section: Introductionmentioning

confidence: 99%

Chemical shifts of aromatic protons in protein NMR spectra

Redfield

Hoch

Dobson³

1983

FEBS Letters

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Experimental secondary shifts have been compared with calculated ring current shifts for the aromatic protons of lysozyme. The root mean square differences were calculated for all possible permutations of the assignment scheme. The experimentally determined assignment scheme was found to give the best agreement with the ring current shift calculations. Similar results were obtained in the case of bovine pancreatic trypsin inhibitor and cytochrome c. The use of the degree of correlation between experimental and predicted NMR parameters as a basis for making assignments is examined.

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Application of Ring Current Calculations to the Proton NMR of Proteins and Transfer RNA

Cited by 82 publications

References 230 publications

Nicotine Inhibits Amyloid Formation by the β-Peptide

Nicotine Inhibits Amyloid Formation by the β-Peptide

Probing weakly polar interactions in cytochrome c

Chemical shifts of aromatic protons in protein NMR spectra

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