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991.
A quasi-harmonic approximation is described for studying very low frequency vibrations and flexible paths in proteins. The force constants of the empirical potential function are quadratic approximations to the potentials of mean force; they are evaluated from a molecular dynamics simulation of a protein based on a detailed anharmonic potential. The method is used to identify very low frequency (~1 cm?1) normal modes for the protein pancreatic trypsin inhibitor. A simplified model for the protein is used, for which each residue is represented by a single interaction center. The quasi-harmonic force constants of the virtual internal coordinates are evaluated and the normal-mode frequencies and eigenvectors are obtained. Conformations corresponding to distortions along selected low-frequency modes are analyzed. 相似文献
992.
Photokilling of bacteria by the natural dye curcumin 总被引:4,自引:0,他引:4
Thomas A. Dahl William M. McGowan Mark A. Shand Vakula S. Srinivasan 《Archives of microbiology》1989,151(2):183-185
Curcumin is a yellow-orange compound derived from the root of Curcuma longa (Zingiberaceae family), that has been used as a medicine, spice and coloring agent. Curcumin has proved nontoxic in a number of cell culture and whole animal studies. Curcumin has, however, been reported to have bactericidal effects at very high concentrations. When illuminated, curcumin exerted potent phototoxic effects in micromolar amounts. Gram-negative bacteria displayed greater resistance to curcumin phototoxicity relative to Gram-positive bacteria. Oxygen was required for curcumin phototoxicity. Curcumin binding to cells was not required for photokilling; the reactive intermediate therefore must be relatively long-lived. The mechanism(s) of curcumin phototoxicity may involve hydrogen peroxide production. Singlet excited oxygen was not detected.Publication no 35 of the Center for Photochemical Sciences 相似文献
993.
Two mechanisms have been postulated for the formation of bound alpha-iminoglutarate intermediate during the glutamate dehydrogenase-catalyzed reductive amination of alpha-ketoglutarate; one involves the nucleophilic attack of ammonia on a covalently bound Schiff base in the enzyme-NADPH-alpha-ketoglutarate complex, and the other involves the reaction of ammonia with the carbonyl group of alpha-ketoglutarate in the ternary complex. We have measured the rates of carbonyl oxygen exchange in the complex to unambiguously distinguish between these two mechanisms. We find that the loss of label in the carbonyl oxygen-labeled ternary complex is at least 10(5) times slower than the rate of the reductive amination reaction. Therefore, the former mechanism cannot be operative. We also find that (i) the carbonyl oxygen exchange in free alpha-ketoglutarate proceeds without any significant catalysis by its gamma-carboxylate group; (ii) this exchange reaction has energy parameters which are comparable to those observed for the hydration of simple aliphatic ketones; and (iii) the carbonyl oxygen exchange in bound alpha-ketoglutarate is slower than that in the free keto acid over a wide pH range. We conclude that the oxygen exchange in the free and bound alpha-ketoglutarate must occur via a gem-diol intermediate. The observation that the enzyme inhibits the reaction of water with alpha-ketoglutarate while it catalyzes the reaction of ammonia with the same keto acid points to an extraordinary recognition of ammonia by the enzyme. We interpret this observation by assuming that the enzyme-NADPH-alpha-ketoglutarate complex exists in two forms, a predominant form which is produced rapidly upon mixing the components together and an unstable form which is produced in trace amounts from the predominant form via a gem-diol intermediate. These two forms are presumed to differ in the spatial relationship of the carbonyl group to the enzyme functional groups. The carbonyl group in the unstable form is assumed to be surrounded by the same enzyme groups as the iminium ion is in the bound iminoglutarate complex. We ascribe the remarkable catalysis of the ammonia reaction and the inhibition of the water reaction by the enzyme to the opposing interactions of the iminium and carbonyl groups with these surrounding enzyme groups. 相似文献
994.
Delta 1-Piperidine 2-carboxylic acid, an alpha-imino acid, is reduced by 1,4-dihydropyridines to pipecolic acid, an alpha-amino acid, and the corresponding pyridinium ions. This nonenzymatic reaction occurs only in the direction of pipecolic acid production. Glutamate dehydrogenase catalyzes this reaction when the reductant is NADPH and gives as products L-pipecolic acid and NADP+. The reaction velocity for the enzyme-catalyzed reaction is measurable in either direction. The pH-independent equilibrium constant, Keq, for the reduction of the imino acid by NADPH to give pipecolic acid anion and NADP+ was determined from the equilibrium conditions and the pKa values of pipecolic acid (10.72) and of the cyclic imino acid (8.10). The value of Keq was found to be 175 +/- 30; the values of delta G0, delta H0 and delta S0 are -3.1 +/- 0.1 kcal/mol, 5 +/- 1 kcal/mol and 27 +/- 4 e.u., respectively. The data indicate that the reactants are far more solvated than the products and that there must be a large degree of solvent reorganization during the course of the reaction. If these thermodynamic parameters apply to the redox step of the enzyme-catalyzed glutamate reaction, then the burst phase which results upon mixing the enzyme, L-glutamate and NADP+ in stoichiometric amounts must contain a hidden nonredox step of large delta H0 value to account for the curved Arrhenius plot observed for this phase (A.H. Colen, R.T. Medary and H.F. Fisher, Biopolymers 20 (1981) 879). 相似文献
995.
996.
997.
Maya Srinivasan Sebastien G.M. Uzel Alfonso Gautieri Sinan Keten Markus J. Buehler 《Journal of structural biology》2009,168(3):503-510
Alport Syndrome is a genetic disease characterized by breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to kidney failure in most patients. It is the second most inherited kidney disease in the US, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level structure–property relationships of this disease using a bottom-up computational materiomics approach implemented through large-scale molecular dynamics simulation. Since the GBM is under constant mechanical loading due to blood flow, changes in mechanical properties due to amino acid mutations may be critical in the symptomatic GBM breakdown seen in Alport Syndrome patients. Through full-atomistic simulations in explicit solvent, the effects of single-residue glycine substitution mutations of varying clinical severity are studied in short segments of type IV tropocollagen molecules. The segments with physiological amino acid sequences are equilibrated and then subjected to tensile loading. Major changes are observed at the single molecule level of the mutated sequence, including a bent shape of the structures after equilibration (with the kink located at the mutation site) and a significant alteration of the molecules’ stress–strain responses and stiffnesses. These results suggest that localized structural changes at amino acid level induce severe alterations of the molecular properties. Our study opens a new approach in pursuing a bottom-up multi-scale analysis of this disease. 相似文献
998.
Jose L. Herrera Ravi Srinivasan John S. Brownstein Alison P. Galvani Lauren Ancel Meyers 《PLoS computational biology》2016,12(7)
As infectious disease surveillance systems expand to include digital, crowd-sourced, and social network data, public health agencies are gaining unprecedented access to high-resolution data and have an opportunity to selectively monitor informative individuals. Contact networks, which are the webs of interaction through which diseases spread, determine whether and when individuals become infected, and thus who might serve as early and accurate surveillance sensors. Here, we evaluate three strategies for selecting sensors—sampling the most connected, random, and friends of random individuals—in three complex social networks—a simple scale-free network, an empirical Venezuelan college student network, and an empirical Montreal wireless hotspot usage network. Across five different surveillance goals—early and accurate detection of epidemic emergence and peak, and general situational awareness—we find that the optimal choice of sensors depends on the public health goal, the underlying network and the reproduction number of the disease (R0). For diseases with a low R0, the most connected individuals provide the earliest and most accurate information about both the onset and peak of an outbreak. However, identifying network hubs is often impractical, and they can be misleading if monitored for general situational awareness, if the underlying network has significant community structure, or if R0 is high or unknown. Taking a theoretical approach, we also derive the optimal surveillance system for early outbreak detection but find that real-world identification of such sensors would be nearly impossible. By contrast, the friends-of-random strategy offers a more practical and robust alternative. It can be readily implemented without prior knowledge of the network, and by identifying sensors with higher than average, but not the highest, epidemiological risk, it provides reasonably early and accurate information. 相似文献
999.
1000.
Tzer-Min Kuo Srinivasan Nithiyanantham Chi-Pin Lee Hui-Ting Hsu Shun-Yuan Luo You-Zhe Lin Kun-Tu Yeh Ying-Chin Ko 《Journal of cellular physiology》2019,234(8):13984-13993
Areca nut has been evaluated as a group I carcinogen to humans. However, the exact compounds of areca nut causing oral cancer remain unproven. Previous findings from our lab revealed that arecoline N-oxide (ANO), a metabolite of arecoline, exhibits an oral fibrotic effect in immune-deficient NOD/SCID mice. The aim of this study is to investigate the oral potentially malignant disorders (OPMD) inductive activity between areca-alkaloid arecoline and its metabolite ANO in C57BL/6 mice. Our findings show that ANO showed higher activity in inducing hyperplasia with leukoplakia and collagen deposition in C57BL/6 mice compared with the arecoline treated groups. Importantly, immunohistochemical studies showed significant upregulation of NOTCH1, HES1, FAT1, PCNA, and Ki67 expressions in the pathological hyperplastic part. In addition, in vitro studies showed that upregulation of NOTCH1 and FAT1 expressions in ANO treated HGF-1 and DOK cell models. We found that NOTCH1 regulates TP53 expression from NOTCH1 knockdown oral cancer cells. The DNA damage was significantly increased after arecoline and ANO treatment. Further, we found that arecoline-induced H2AX expression was regulated by FMO3. Altogether, our findings show that ANO exhibited higher toxicity in OPMD activity and play a significant role in the induction of areca nut mediated oral tumorigenesis. 相似文献