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1.
T P Lybrand S C Brown S Creighton R H Shafer P A Kollman 《Journal of molecular biology》1986,191(3):495-507
We have performed molecular mechanical calculations on intercalation complexes of actinomycin D with a series of base-paired hexanucleoside pentaphosphates; d(GCGCGC)2, d(GCCGGC)2, d(GCATGC)2, d(GCTAGC)2 and d(ATGCAT)2. Our results are in good agreement with previous experimental work on sequence selectivity. The results provide a rationalization for the strong preference of actinomycin D to intercalate on the 3' side of guanine residues, consistent with previously proposed models. Finally, the computed structures for d(ATGCAT)2-actinomycin D complexes have been compared with two-dimensional nuclear magnetic resonance nuclear Overhauser effect experimental results. To our knowledge, this is the first extensive comparison of molecular mechanical model structures for a drug-DNA complex with experimental solution phase data. We find generally good agreement between our computational models and the experimental solution phase structures. 相似文献
2.
Energetics of protein structure and folding 总被引:7,自引:0,他引:7
The available experimental date on the kinetics of unfolding and refolding of small proteins are reviewed. Excluding slow transitions in the unfolded protein due to cis–trans isomerization of peptide bonds, the rate-limiting transition state in both unfolding and refolding is concluded to be a high-energy distortion of the fully folded state. Partially folded intermediates are undoubtedly important for folding, but their formation is normally not rate limiting. A simple model is used to illustrate some of the aspects of protein-folding energetics. 相似文献
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Circular dichroism spectra of the partially folded trapped intermediates were measured in order to aid in the elucidation of the conformational forces which determine a nonrandom, nonsequential pathway of disulfide bond formation upon refolding of bovine pancreatic trypsin inhibitor. Whatever conformation was responsible for the kinetic rates of the intermediates should be stabilized by the presence of their trapped disulfide bonds. The near-ultraviolet spectra provide considerable information about the environments of the aromatic and disulfide side chains. The predominant single-disulfide intermediate has significant nonrandom conformation not present in the fully reduced protein, with aromatic rings and the disulfide bond in stabilized asymmetric environments. Forming either of the two nonnative, but kinetically important, second disulfides in this intermediate does not produce unequivocably different conformations. Forming a second native, but kinetically unproductive, disulfide produces a substantial decrease in randomness, which may hinder formation of the third disulfide. The largest conformational changes occur upon disulfide rearrangement to the stable, correctly refolded, two- and three-disulfide species. Interpretation of the far-ultraviolet spectra in terms of the secondary structure of the intermediates is uncertain, due to the atypical spectra of the folded forms of the protein. Consequently, we are unable to determine unambiguously the secondary structure of the intermediates. However, all the spectra show that nonrandom conformations of the polypeptide chain gradually appear as disulfide bond formation progresses, as expected from the nonrandom pathway of the latter. 相似文献
5.
Comparison of the tryptophan synthetase alpha-subunits of several species of Enterobacteriaceae 总被引:13,自引:9,他引:4
Creighton, T. E. (Stanford University, Stanford), D. R. Helinski, R. L. Somerville, and C. Yanofsky. Comparison of the tryptophan synthetase alpha subunits of several species of Enterobacteriaceae. J. Bacteriol. 91:1819-1826. 1966.-The tryptophan synthetase alpha subunits of Escherichia coli K-12, E. coli B, Shigella dysenteriae, Salmonella typhimurium, and Aerobacter aerogenes have been purified and their structures compared. Each of these alpha subunits exhibits a sedimentation coefficient of about 2.7S. Peptide patterns of trypsin plus chymotrypsin digests of the alpha subunits have indicated that all of the alpha subunits have peptide regions in common. The patterns of E. coli K-12, E. coli B, and S. dysenteriae alpha subunits appear to be nearly identical, whereas the alpha subunits from S. typhimurium and A. aerogenes differ from those of E. coli and from each other. It has also been shown that the E. coli structural gene for the alpha subunit is translated identically in E. coli and S. typhimurium. 相似文献
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Thomas E. Creighton 《Journal of molecular biology》1977,113(2):313-328
Concentrated solutions of urea and of guanidine · HCl produced a random spectrum of single-disulphide forms of the polypeptide chain of the pancreatic trypsin inhibitor. Guanidine · HCl also unfolded completely, with accompanying interchange of disulphide bonds, the two-disulphide form of this protein in the native-like conformation; urea produced an equilibrium mixture in which one-quarter of the molecules had the native-like conformation and disulphide bonds. The unfolded forms of the protein in the denaturants were very flexible polypeptide chains. The observations suggest that urea and guanidine · HCl are denaturants because they produce essentially equally favourable solvation of all portions of a polypeptide.The energetics of the conformational transitions involved in folding and unfolding of the inhibitor were determined in urea and compared with those observed in its absence. The denaturant lowers the stability of the native, folded inhibitor relative to that of the reduced, unfolded state by 6.5 kilocalories per mole; the greatest part of this apparent free-energy difference was expressed at the two-disulphide stage of folding. The results are consistent with other indications that most of the favourable interactions stabilizing the native conformation of this protein are not encountered until the final stage of folding, when all may occur simultaneously.The unfolded one- and two-disulphide species produced in guanidine · HCl were trapped, and their rearrangement to the normal intermediates followed after removal of the denaturant. The random single-disulphide species, with one exception, reverted very rapidly to the non-random spectrum of intermediates normally observed during folding; this confirms that these species are normally rapidly interconverted and that normal refolding of the reduced protein is not dependent kinetically upon residual stable conformation in the reduced protein. The unfolded two-disulphide species refolded to the native-like conformation more slowly, but appeared to pass through the same intermediates normally observed during refolding from the fully reduced state. 相似文献
8.
An analogue of the BPT1 folding intermediate that contains only the disulphide bond between Cys-5 and Cys-55 has been prepared by mutation of the other four Cys residues to Ser. On the basis of its circular dichroism and 1H-nuclear magnetic resonance spectra and its electrophoretic mobility, this intermediate is shown to be at least partially folded at low temperatures. This probably accounts for several of the unique properties of this intermediate observed during folding. 相似文献
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10.
The effect of neurotensin on submaximally-stimulated hepatobiliary and pancreatic secretion was studied in 6 healthy subjects. An intravenous infusion of neurotensin 1.4 ± 0.3 pmol/kg/min, designed to reproduce plasma neurotensin immunoreactivity levels within the physiological range, produced a significant increase in pancreatic bicarbonate output. Plasma concentrations of pancreatic polypeptide rose by 83 ± 16 pmol/l and were associated with a small reduction in trypsin, but no significant change in bilirubin outputs. 相似文献