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Protein-ligand docking is widely applied to structure-based virtual screening for drug discovery. This article presents a novel docking technique, PRL-Dock, based on hydrogen bond matching and probabilistic relaxation labeling. It deals with multiple hydrogen bonds and can match many acceptors and donors simultaneously. In the matching process, the initial probability of matching an acceptor with a donor is estimated by an efficient scoring function and the compatibility coefficients are assigned according to the coexisting condition of two hydrogen bonds. After hydrogen bond matching, the geometric complementarity of the interacting donor and acceptor sites is taken into account for displacement of the ligand. It is reduced to an optimization problem to calculate the optimal translation and rotation matrixes that minimize the root mean square deviation between two sets of points, which can be solved using the Kabsch algorithm. In addition to the van der Waals interaction, the contribution of intermolecular hydrogen bonds in a complex is included in the scoring function to evaluate the docking quality. A modified Lennard-Jones 12-6 dispersion-repulsion term is used to estimate the van der Waals interaction to make the scoring function fairly "soft" so that ligands are not heavily penalized for small errors in the binding geometry. The calculation of this scoring function is very convenient. The evaluation is carried out on 278 rigid complexes and 93 flexible ones where there is at least one intermolecular hydrogen bond. The experiment results of docking accuracy and prediction of binding affinity demonstrate that the proposed method is highly effective. 相似文献
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The complete mitochondrial genome (mitogenome) of Actias selene (Lepidoptera: Saturniidae) was determined to be 15,236 bp, including 13 protein-coding genes (PCGs), two rRNA genes, 22 tRNA genes and a control region. The arrangement of 13 PCGs was similar to that of other sequenced lepidopterans. The AT skew of the mitogenome of A. selene was slightly negative, indicating a higher number of T compared to A nucleotides. The nucleotide composition of the mitogenome of A. selene was also biased toward A+T nucleotides (78.91%). All PCGs were initiated by ATN codons, except for the gene encoding cytochrome c oxidase subunit 1 (cox1), which may be initiated by the TTAG, as observed in other lepidopterans. Three genes, including cox1, cox2, and nad5, had incomplete stop codons consisting of just a T. With an exception for trnS1(AGN), all the other tRNA genes displayed a typical clover-leaf structure of mitochondrial tRNA. The A+T-rich region of the mitogenome of A. selene was 339 bp in length, and contains several features common to the Lepidopteras, including non-repetitive sequences, a conserved structure combining the motif ATAGA and an 18-bp poly-T stretch and a poly-A element upstream of trnM gene. Phylogenetic analysis showed that A. selene was close to Saturniidae. 相似文献
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Patel AG Flatten KS Schneider PA Dai NT McDonald JS Poirier GG Kaufmann SH 《The Journal of biological chemistry》2012,287(6):4198-4210
Poly(ADP-ribose) polymerase-1 (PARP1) plays critical roles in the regulation of DNA repair. Accordingly, small molecule inhibitors of PARP are being developed as agents that could modulate the activity of genotoxic chemotherapy, such as topoisomerase I poisons. In this study we evaluated the ability of the PARP inhibitor veliparib to enhance the cytotoxicity of the topoisomerase I poisons topotecan and camptothecin (CPT). Veliparib increased the cell cycle and cytotoxic effects of topotecan in multiple cell line models. Importantly, this sensitization occurred at veliparib concentrations far below those required to substantially inhibit poly(ADP-ribose) polymer synthesis and at least an order of magnitude lower than those involved in selective killing of homologous recombination-deficient cells. Further studies demonstrated that veliparib enhanced the effects of CPT in wild-type mouse embryonic fibroblasts (MEFs) but not Parp1(-/-) MEFs, confirming that PARP1 is the critical target for this sensitization. Importantly, parental and Parp1(-/-) MEFs had indistinguishable CPT sensitivities, ruling out models in which PARP1 catalytic activity plays a role in protecting cells from topoisomerase I poisons. To the contrary, cells were sensitized to CPT in a veliparib-independent manner upon transfection with PARP1 E988K, which lacks catalytic activity, or the isolated PARP1 DNA binding domain. These results are consistent with a model in which small molecule inhibitors convert PARP1 into a protein that potentiates the effects of topoisomerase I poisons by binding to damaged DNA and preventing its normal repair. 相似文献
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? Premise of the study: Microsatellite primers were developed for the endangered Davidia involucrata to assess the population genetics and infer its evolutionary history. ? Methods and Results: Using both the modified magnetic bead hybridization method and the dual-suppression PCR method, we isolated and characterized 12 polymorphic microsatellite loci using 134 individuals from five populations in southwestern China. The number of alleles per locus ranged from six to 21 (mean = 10.8). The expected heterozygosity per locus ranged from 0.404 to 0.918 and observed heterozygosity ranged from 0.015 to 0.821. ? Conclusions: All of the 12 microsatellite markers developed for D. involucrata are polymorphic, and lay a solid foundation for further studies of the population genetics of this famous tree. 相似文献
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W. J. Duan T. Z. Yang Y. Dai D. L. Li X. Q. Zhang H. B. Liu N. Li C. G. Wang 《Biologia Plantarum》2012,56(4):771-774
We compared stomatal ammonia compensation point (χs) and its metabolic regulation in tobacco (Nicotiana tabacum) leaves of a quick-leaf-senescence phenotype ZY90 and a slow-leaf-senescence phenotype NC89. Compared with NC89, ZY90 had significantly higher χs values between 40 and 60 d after leaf sprouting in spite of its lower nitrogen content. During the same time, a steeper decline in glutamine synthetase activity was detected in ZY90 leaves, simultaneously with a steep increase in χs. These results suggested that the quick leaf senescence phenotype exhibited high NH3 emission potential due to efficient nitrogen recycling and remobilization, and glutamine synthetase played a key role in regulating χs in ZY90. 相似文献
890.
Metabolic engineering of microorganisms is an alternative and attractive route for production of valuable terpenoids that are usually extracted from plant sources. Tanshinones are the bioactive components of Salvia miltiorrhizha Bunge, which is a well‐known traditional Chinese medicine widely used for treatment of many cardiovascular diseases. As a step toward microbial production of tanshinones, copalyl diphosphate (CPP) synthase, and normal CPP kaurene synthase‐like genes, which convert the universal diterpenoid precursor geranylgeranyl diphosphate (GGPP) to miltiradiene (an important intermediate of the tanshinones synthetic pathway), was introduced into Saccharomyces cerevisiae, resulting in production of 4.2 mg/L miltiradiene. Improving supplies of isoprenoid precursors was then investigated for increasing miltiradiene production. Although over‐expression of a truncated 3‐hydroxyl‐3‐methylglutaryl‐CoA reductase (tHMGR) and a mutated global regulatory factor (upc2.1) gene did improve supply of farnesyl diphosphate (FPP), production of miltiradiene was not increased while large amounts of squalene (78 mg/L) were accumulated. In contrast, miltiradiene production increased to 8.8 mg/L by improving supply of GGPP through over‐expression of a fusion gene of FPP synthase (ERG20) and endogenous GGPP synthase (BTS1) together with a heterologous GGPP synthase from Sulfolobus acidocaldarius (SaGGPS). Auxotrophic markers in the episomal plasmids were then replaced by antibiotic markers, so that engineered yeast strains could use rich medium to obtain better cell growth while keeping plasmid stabilities. Over‐expressing ERG20‐BTS1 and SaGGPS genes increased miltiradiene production from 5.4 to 28.2 mg/L. Combinatorial over‐expression of tHMGR‐upc2.1 and ERG20‐BTS1‐SaGGPS genes had a synergetic effects on miltiradiene production, increasing titer to 61.8 mg/L. Finally, fed‐batch fermentation was performed, and 488 mg/L miltiradiene was produced. The yeast strains engineered in this work provide a basis for creating an alternative way for production of tanshinones in place of extraction from plant sources. Biotechnol. Bioeng. 2012; 109: 2845–2853. © 2012 Wiley Periodicals, Inc. 相似文献