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111.
The conformational characteristics of the deoxydinucleoside monophosphates with adenine and thymine bases in all possible sequences, namely, dApdA, dApdT, dTpdA, and dTpdT have been studied using an improved set of energy parameters to calculate the total potential energy and an improved set of energy parameters to calculate the total potential energy and an improved version of the minimization technique to minimize the total energy by allowing all seven dihedral angles of the molecular fragment to vary simultaneously. The results reveal that the most preferred conformation in all these units usually corresponds to one of the four helical conformations, namely, the A-DNA, B-DNA, C-DNA, and Watson-Crick DNA models. These helical conformations differ in energies by about 3 kcal/mol with respect to one another. The conformations which could promote a loop or bend in the backbone are, in general, less stable by about 3.5 kcal/mol with respect to the respective lowest-energy helical conformation. The results indicate that there is a definite influence of bases and their actual sequences on the preferred conformations of the deoxydinucleoside monophosphates. The lowest-energy structure, although corresponding to one of the four helical conformations, differ with the type of the deoxydinucleoside monophosphate. Good or reasonable base stacking is noted in dApdA and dTpdA with both C(3′)-endo and C(2′)-endo sugars and in dApdT and dTpdT with only C(3′)-endo sugar. The inversion of the base sequence in deoxydinucleoside monophosphates alters the order of preference of low-energy conformations as well as the base-stacking property of the unit. The paths linking the starting and final states in the (ω′, ω) plane show interesting features with regard to the energy spread, thus providing insight into the path of conformational movement ofthe molecule under slight perturbation. The stabilities of the A and B forms, including the internal energies of the C(3′)-endo ans C(2′)-endo sugar systems, indicate that for dTpdT the B → A transition is less probable. For dApdA, dApdT, and dTpdA this transition is probable in the same order of preference. We propose that the T-A sequence in the polynucleotide chain might serve as the site accessible for B ? A transitions. The theoretical predictions are in good agreement with the experimental observations. 相似文献
112.
Energy-minimization studies were carried out on the trinucleoside diphosphate d(ApApA). The potential energy contributions from nonbonded, electrostatic, hydrogen-bonding, and torsional interactions were minimized by treating the 13 relevant dihedral angles as simultaneous variables. For the C(3′)-endo trimer, 14 low-energy conformations are within 10 kcal/mol above the lowest energy found, compared to only 3 in the case of the C(2′)-endo trimer. This result shows the flexible character of the C(3′)-endo unit. The hairpin-type, loop-promoting conformer with (ω′,ω) = (101°, 59°) was found to be the most favored structure at the 3′-terminus of d(ApApA). The predicted U- and L-type bend conformers were found to lie within 5 kcal/mol, compared to the lowest energy B-DNA structure. The A-DNA and Watson-Crick DNA types of helical conformers also lie within very small energy barriers. The phosphate group at the 5′-end of the nucleotide residue has a definite influence on the base of the corresponding nucleotide, keeping it in the normal anti-region, and hence on the base-stacking property. The results are compared with the presently available experimental data, mainly with the tRNAPhe crystal. 相似文献
113.
Kalaimagal T Muthaiah A Rajarathinam S Malini S Nadarajan N Pechiammal I 《Journal of applied genetics》2008,49(3):221-227
Exploitation of hybrid vigour is quite possible in cross-pollinated crops. However, pigeonpea is a grain legume crop with a moderate level of cross-pollination (20-70%), which is mainly aided by insect pollinators. As a first step, hybrids based on genetic male sterility (GMS) were developed in pigeonpea, but the hybrid seed production technique is not farmer-friendly, because in the hybrid seed production plot 50% of the population, which are male-fertile in the female rows, have to be eliminated in time before contamination. This requires skilled labour and is a time-consuming process, which increases the cost of hybrid seed production. Therefore, the objective of this study was to develop cytoplasmic-genetic male-sterile (CGMS) lines in pigeonpea through wide hybridization, which would be very suitable for hybrid seed production. Two CGMS lines, viz. CORG 990052 A and CORG 990047, were developed by interspecific hybridization of Cajanus cajan and C. scarabaeoides. Restorers were identified and three CGMS-based pigeonpea hybrids were developed. The hybrid COPH 3 is found to be promising in Tamil Nadu State, India. 相似文献
114.
alpha-1,3-Galactosyltransferase (alpha3GT) catalyzes the transfer of galactose from UDP-galactose to form an alpha 1-3 link with beta-linked galactosides; it is part of a family of homologous retaining glycosyltransferases that includes the histo-blood group A and B glycosyltransferases, Forssman glycolipid synthase, iGb3 synthase, and some uncharacterized prokaryotic glycosyltransferases. In mammals, the presence or absence of active forms of these enzymes results in antigenic differences between individuals and species that modulate the interplay between the immune system and pathogens. The catalytic mechanism of alpha3GT is controversial, but the structure of an enzyme complex with the donor substrate could illuminate both this and the basis of donor substrate specificity. We report here the structure of the complex of a low-activity mutant alpha3GT with UDP-galactose (UDP-gal) exhibiting a bent configuration stabilized by interactions of the galactose with multiple residues in the enzyme including those in a highly conserved region (His315 to Ser318). Analysis of the properties of mutants containing substitutions for these residues shows that catalytic activity is strongly affected by His315 and Asp316. The negative charge of Asp316 is crucial for catalytic activity, and structural studies of two mutants show that its interaction with Arg202 is needed for an active site structure that facilitates the binding of UDP-gal in a catalytically competent conformation. 相似文献
115.
Erythrina cristagalli lectin (ECL) is a galactose-specific legume lectin. Although its biological function in the legume is unknown, ECL exhibits hemagglutinating activity in vitro and is mitogenic for T lymphocytes. In addition, it has been recently shown that ECL forms a novel conjugate when coupled to a catalytically active derivative of the type A neurotoxin from Clostridium botulinum, thus providing a therapeutic potential. ECL is biologically active as a dimer in which each protomer contains a functional carbohydrate-combining site. The crystal structure of native ECL was recently reported in complex with lactose and 2'-fucosyllactose. ECL protomers adopt the legume lectin fold but form non-canonical dimers via the handshake motif as was previously observed for Erythrina corallodendron lectin. Here we report the crystal structures of native and recombinant forms of the lectin in three new crystal forms, both unliganded and in complex with lactose. For the first time, the detailed structure of the glycosylated hexasaccharide for native ECL has been elucidated. The structure also shows that in the crystal lattice the glycosylation site and the carbohydrate binding site are involved in intermolecular contacts through water-mediated interactions. 相似文献
116.
Pressure-jump small-angle x-ray scattering detected kinetics of staphylococcal nuclease folding
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Woenckhaus J Köhling R Thiyagarajan P Littrell KC Seifert S Royer CA Winter R 《Biophysical journal》2001,80(3):1518-1523
The kinetics of chain disruption and collapse of staphylococcal nuclease after positive or negative pressure jumps was monitored by real-time small-angle x-ray scattering under pressure. We used this method to probe the overall conformation of the protein by measuring its radius of gyration and pair-distance-distribution function p(r) which are sensitive to the spatial extent and shape of the particle. At all pressures and temperatures tested, the relaxation profiles were well described by a single exponential function. No fast collapse was observed, indicating that the rate limiting step for chain collapse is the same as that for secondary and tertiary structure formation. Whereas refolding at low pressures occurred in a few seconds, at high pressures the relaxation was quite slow, approximately 1 h, due to a large positive activation volume for the rate-limiting step for chain collapse. A large increase in the system volume upon folding implies significant dehydration of the transition state and a high degree of similarity in terms of the packing density between the native and transition states in this system. This study of the time-dependence of the tertiary structure in pressure-induced folding/unfolding reactions demonstrates that novel information about the nature of protein folding transitions and transition states can be obtained from a combination of small-angle x-ray scattering using high intensity synchrotron radiation with the high pressure perturbation technique. 相似文献
117.
118.
Anandarajan Thiyagarajan Mohammed T.A. Salim Tuniki Balaraju Chandralata Bal Masanori Baba Ashoke Sharon 《Bioorganic & medicinal chemistry letters》2012,22(24):7742-7747
The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure–activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement of the amino group. The ligand conformation, binding mode studies and drug like properties were major determinant for selection of molecules for final synthesis. The replacement of amino group with methyl restored the interactions with RNA-template (Tem 799) through bifurcated weak H-bond (C–H…O). This is an interesting finding observed from molecular modeling studies. It was found that 6c–e has anti-HCV activity (EC50 in 37–46 μM) while 6a, 6b and 6g were inactive. The compound 6f (EC50 28 μM) was the most active among the series however it also showed some cytotoxicity (CC50 52.8 μM). Except 6f, none of the compounds were found to be cytotoxic (CC50 > 100 μM). The present study discloses structure–based approach for novel anti-HCV lead discovery and opens a future scope of lead optimization. 相似文献
119.
Ramadevi Subramani Rebecca Lopez-Valdez Arunkumar Arumugam Sushmita Nandy Thiyagarajan Boopalan Rajkumar Lakshmanaswamy 《PloS one》2014,9(5)
Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer. 相似文献
120.
Solvent accessibility study on tRNAPhe 总被引:4,自引:0,他引:4
In order to assess the solvent–solute association in the tRNAPhe molecule, solvent accessibility calculations were carried out for its crystalline and completely extended states following the method of Lee and Richards. To do this, results from the calculations on model trinucleotide systems pApXpA with different bases at position X were used. In the folded form of the molecule, it was found that the oxygen atoms O(I) and O(II) of almost all the phosphate groups and the O(2′) atoms of the sugar rings situated throughout the backbone were highly exposed to the solvent. The amount of reduction found in the solvent accessibilities of the various atoms in going from the extended state to the folded state of the molecule indicates the kind of compactness of the tertiary structure in tRNAPhe. The results give quantitative support to many characteristics of the tRNA molecule, such as loop sections, buried/exposed residues, hydrophobic interactions, etc., which were thought to be due to other factors. 相似文献