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1.
Lowe SL Atkinson DM Waingeh VF Thomasson KA 《Journal of molecular recognition : JMR》2002,15(6):423-431
Previous Brownian dynamics (BD) simulations (Ouporov IG, Knull HR and Thomasson KA 1999. Biophys. J. 76: 17-27) of complex formation between rabbit aldolase and F-actin have identified three lysine residues (K288, K293 and K341) on aldolase and acidic residues (DEDE) at the N-terminus of actin as important to binding. BD simulations of computer models of aldolase mutants with any of these lysine residues replaced by alanine show reduced binding energy; the greatest effect of a single substitution is for K341A, and replacement of all three lysines greatly reduces binding. BD simulations of wild-type rabbit aldolase vs altered F-actin show that binding is decreased if any one of the four N-terminal acidic residues is replaced by alanine and binding is greatly reduced if three or more of the N-terminal acidic residues are replaced; none of the four actin residues appear more critical for binding than the others. 相似文献
2.
Brownian dynamics simulations of computer models of GAPDH mutants interacting with F-actin emphasized the electrostatic nature of such interactions, and confirmed the importance of four previously identified lysine residues on the GAPDH structure in these interactions. Mutants were GAPDH models in which one or more of the previously identified lysines had been replaced with alanine. Simulations showed reduced binding of these mutants to F-actin compared to wild-type GAPDH. Binding was significantly reduced by mutating the four lysines; the specific electrostatic interaction energy of the quadruple mutant was -7.3 +/- 1.0 compared to -11.4 +/- 0.5 kcal/mol for the wild enzyme. The BD simulations also reaffirmed the importance of quaternary structure for GAPDH binding F-actin. 相似文献
3.
Ding Li Tuong Thi Mai Luong Wen-Jia Dan Yanliang Ren Hoang Xuan Nien An-Ling Zhang Jin-Ming Gao 《Bioorganic & medicinal chemistry》2018,26(2):386-393
Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1H, 13C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27?μM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba. 相似文献
4.
Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate: mechanistic implications 下载免费PDF全文
Dalby A Dauter Z Littlechild JA 《Protein science : a publication of the Protein Society》1999,8(2):291-297
Fructose 1,6-bisphosphate aldolase catalyzes the reversible cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate to dihydroxyacetone phosphate and either glyceraldehyde 3-phosphate or glyceraldehyde, respectively. Catalysis involves the formation of a Schiff's base intermediate formed at the epsilon-amino group of Lys229. The existing apo-enzyme structure was refined using the crystallographic free-R-factor and maximum likelihood methods that have been shown to give improved structural results that are less subject to model bias. Crystals were also soaked with the natural substrate (fructose 1,6-bisphosphate), and the crystal structure of this complex has been determined to 2.8 A. The apo structure differs from the previous Brookhaven-deposited structure (1ald) in the flexible C-terminal region. This is also the region where the native and complex structures exhibit differences. The conformational changes between native and complex structure are not large, but the observed complex does not involve the full formation of the Schiff's base intermediate, and suggests a preliminary hydrogen-bonded Michaelis complex before the formation of the covalent complex. 相似文献
5.
We report the sequences of full-length cDNAs for the nuclear genes encoding the chloroplastic and cytosolic fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) from spinach. A comparison of the deduced amino-acid sequences with one another and with published cytosolic aldolase sequences of other plants revealed that the two enzymes from spinach share only 54% homology on their amino acid level whereas the homology of the cytosolic enzyme of spinach with the known sequences of cytosolic aldolases of maize, rice and Arabidopsis range from 67 to 92%. The sequence of the chloroplastic enzyme includes a stroma-targeting N-terminal transit peptide of 46 amino acid residues for import into the chloroplast. The transit peptide exhibits essential features similar to other chloroplast transit peptides. Southern blot analysis implies that both spinach enzymes are encoded by single genes. 相似文献
6.
7.
Alejandro M. Reyes Nicole Bravo Heide Ludwig Ana Iriarte Juan C. Slebe 《Journal of Protein Chemistry》1993,12(2):159-168
Treatment of fructose 1,6-bisphosphatase with N-ethylmaleimide was shown to abolish the inhibition by fructose 2,6-bisphosphate, which also protected the enzyme against this chemical modification [Reyes, A., Burgos, M. E., Hubert, E., and Slebe, J. C. (1987),J. Biol. Chem.
262, 8451–8454]. On the basis of these results, it was suggested that a single reactive sulfhydryl group was essential for the inhibition. We have isolated a peptide bearing the N-ethylmaleimide target site and the modified residue has been identified as cysteine-128. We have further examined the reactivity of this group and demonstrated that when reagents with bulky groups are used to modify the protein at the reactive sulfhydryl [e.g., N-ethylmaleimide or 5,5-dithiobis-(2-nitrobenzoate)], most of the fructose 2,6-bisphosphate inhibition potential is lost. However, there is only partial or no loss of inhibition when smaller groups (e.g., cyanate or cyanide) are introduced. Kinetic and ultraviolet difference spectroscopy-binding studies show that the treatment of fructose 1,6-bisphosphatase with N-ethylmaleimide causes a considerable reduction in the affinity of the enzyme for fructose 2,6-bisphosphate while affinity for fructose 1,6-bisphosphate does not change. We can conclude that modification of this reactive sulfhydryl affects the enzyme sensitivity to fructose 2,6-bisphosphate inhibition by sterically interfering with the binding of this sugar bisphosphate, although this residue does not seem to be essential for the inhibition to occur. The results also suggest that fructose 1,6-bisphosphate and fructose 2,6-bisphosphate may interact with the enzyme in a different way. 相似文献
8.
Weimin Ma Lanzhen Wei Quanxi Wang Dingji Shi Haibao Chen 《Journal of applied phycology》2007,19(3):207-213
Non-regulated enzymes in the Calvin cycle are generally presumed to be less important for the regulation of photosynthetic
yield. Here, to investigate the relationship between the activity of non-regulated enzymes and photosynthetic yield, two non-regulated
enzymes in the Calvin cycle—a rice cytosolic fructose-1,6-bisphosphate aldolase (FBA) and a spinach chloroplast triosephosphate
isomerase (TPI)—were cloned and co-expressed in cells of the cyanobacterium Anabaena sp. strain PCC 7120. The activity of FBA and TPI and the photosynthetic yield reflected by photosynthetic O2 evolution and cell dry weight were measured and compared between wild-type and transgenic cells. Our results demonstrated
that the activity of FBA and TPI were increased in transgenic cells relative to wild-type cells, and that activity was further
increased in a transgenic strain harboring two sets of FBA-TPI tandem genes relative to cells containing one copy of the FBA-TPI
tandem gene. The increased activity of FBA and TPI in Anabaena sp. strain PCC 7120 increased photosynthetic yield, with increased activity levels correlating closely with the degree of
changes in photosynthetic yield. This implies that the photosynthetic yield is limited by the activity of the non-regulated
enzymes FBA and TPI, and that the endogenous activity of non-regulated enzymes is not sufficient to increase photosynthetic
yield. We discuss the various roles of FBA and TPI, and regulated and non-regulated enzymes, in modulating photosynthetic
yield.
W. Ma and L. Wei contributed equally to this work. 相似文献
9.
The zinc-coordinated protein motifs known as RING-finger domains, present on a class of ubiquitin ligases (E3's), recruit ubiquitin-conjugating enzymes (E2s), tethering them to substrate proteins for covalent modification with ubiquitin. Each RING-finger domain can recruit different E2s, and these interactions are frequently selective, in that certain RING-finger domains associate preferentially with certain E2s. This selectivity acquires particular biological relevance when the recruited E2s exert specialized functions. We have explored the determinants that specify the presence or absence of experimentally detectable interaction between two RING-finger domains, those on RNF11 and RNF103, and two E2s, UBC13, a specialized E2 that catalyzes ubiquitin chain elongation through Lys63 of ubiquitin, and UbcH7, which mediates polyubiquitylation through Lys48. Through the iterative use of computational predictive tools and experimental validations, we have found that these interactions and their selectivity are partly governed by the combinations of electrostatic interactions linking specific residues of the contact interfaces. Our analysis also predicts that the main determinants of selectivity of these interactions reside on the RING-finger domains, rather than on the E2s. The application of some of these rules of interaction selectivity has permitted us to experimentally manipulate the selectivity of interaction of the RING-finger domain-E2 pairs under study. 相似文献
10.
Human cellular protein LEDGF/p75 (lens epithelium-derived growth factor) is an important binding partner of human immunodeficiency virus type 1 (HIV-1) integrase (IN). Without LEDGF/p75, HIV-1 can not complete its life cycle. To study the detailed interactions between LEDGF/p75 and HIV-1 IN, and then obtain the hotspots at the binding interface, 13 ns molecular dynamics simulations were carried out here. One-hundred snapshots extracted from the last 4 ns trajectories were used for calculation of binding free energy and decomposition of the energy by residue. First, the structural changes and their dynamic interactions were investigated focused on the production stage. And then, the free energy was discussed. On the basis of the above results, it could be suggested that residues Gln168, Glu170, and Thr174 in chain A of IN, Thr125, and Trp131 in chain B of IN as well as Ile365, Asp366, Phe406, and Val408 in LEDGF/p75 were responsible for their binding. These results might be helpful for discovery and design of small molecules to interrupt the interaction between HIV-1 IN and LEDGF/p75. 相似文献
11.
Nishith Saurav Topno Muthu Kannan 《Journal of biomolecular structure & dynamics》2018,36(7):1834-1852
12.
E. A. Ermakova 《Biophysics》2006,51(2):202-208
A comparative study of the interaction of two RNases (binase and barnase) with the polypeptide inhibitor barstar was performed by Brownian dynamics simulation. It was demonstrated that this method adequately reproduced the dependence of the association rate on the pH of solution as well as the effect of mutations at individual amino acid residues on the inhibition of barnase by barstar. Two types of energy-favorable binase-barstar encounter complexes were found. In type I complex, the amino acid residues of the binase active center are involved in formation of the complex; in type II complex, the active center remains free. It is suggested that temporary binding of free barstar into type II complex competes with the inhibition reaction. Presumably, this explains the decrease in the rate of binase inhibition by barstar as compared with the analogous reaction of barnase. 相似文献
13.
Many examples exist of charged amino acids that play a role in attracting or holding a charged ligand toward or inside an oppositely charged binding pocket of the protein. For example, the enzymes superoxide dismutase, triose-phosphate isomerase, and acetylcholinesterase can steer ligands toward their oppositely charged binding pockets or gorges. Interestingly, in our Brownian dynamics simulations of a phosphate-binding protein, we discovered that negatively charged phosphate (HPO(2-)(4)) could make its way into the negatively charged binding pocket. In fact, the phosphate-binding protein exhibits counterintuitive kinetics of association. That is, one would expect that the rate of association would increase on increases to the ionic strength since the interaction between the ligand, with a charge of -2, and the electronegative binding pocket would be repulsive and greater screening should reduce this repulsion and increase the rate of association. However, the opposite is seen-i.e., the rate of association decreases on increases in the ionic strength. We used Brownian dynamics techniques to compute the diffusion limited association rate constants between the negatively charged phosphate ligand and several open forms of PBP (wild-type and several mutants based on an x-ray structure of open-form PBP, mutant T141D). With the appropriate choices of reaction criteria and molecular parameters, the ligand was able to diffuse into the binding pocket. A number of residues influence binding of the ligand within the pocket via hydrogen bonds or salt bridges. Arg135 partially neutralizes the charges on the HPO(2-)(4) ligand in the binding pocket, allowing it to enter. It is also found that the positive electrostatic patches above and below the binding entrance of PBP contribute the major attractive forces that direct the ligand toward the surface of the protein near the binding site. 相似文献
14.
The interaction between like-charged amino acid residues has been proposed to stabilize the folded state of peptides and proteins, and to modulate the substrate binding and the action mechanism of enzymes. We have used an alanine- and lysine-based peptide as a model system to study the interaction between like charges, and we have performed a 16-nsec molecular dynamics simulation in solution. The calculated potential of mean force for the approach of the lysine's Nzeta atoms showed a minimum at a distance of 0.7 nm, in agreement with the separation probabilities obtained from analysis of protein crystal structures. The analysis of the individual energy components showed that the solvent polarization pays for the approach of the like charges and that the van der Waals energies do not contribute significantly. The entropic contributions have been divided in conformational and desolvation terms. Both terms favor the formation of the charge pair. A 10-fold increase in counterion concentration was observed-with respect to its bulk concentration-next to the peptide charges, which helps to stabilize the peptide charges at a close distance. 相似文献
15.
Loss of intramolecular electrostatic interactions and limited conformational ensemble may promote self‐association of cis–tau peptide 下载免费PDF全文
Self‐association of proteins can be triggered by a change in the distribution of the conformational ensemble. Posttranslational modification, such as phosphorylation, can induce a shift in the ensemble of conformations. In the brain of Alzheimer's disease patients, the formation of intra‐cellular neurofibrillary tangles deposition is a result of self‐aggregation of hyper‐phosphorylated tau protein. Biochemical and NMR studies suggest that the cis peptidyl prolyl conformation of a phosphorylated threonine‐proline motif in the tau protein renders tau more prone to aggregation than the trans isomer. However, little is known about the role of peptidyl prolyl cis/trans isomerization in tau aggregation. Here, we show that intra‐molecular electrostatic interactions are better formed in the trans isomer. We explore the conformational landscape of the tau segment containing the phosphorylated‐Thr231‐Pro232 motif using accelerated molecular dynamics and show that intra‐molecular electrostatic interactions are coupled to the isomeric state of the peptidyl prolyl bond. Our results suggest that the loss of intra‐molecular interactions and the more restricted conformational ensemble of the cis isomer could favor self‐aggregation. The results are consistent with experiments, providing valuable complementary atomistic insights and a hypothetical model for isomer specific aggregation of the tau protein. Proteins 2015; 83:436–444. © 2014 Wiley Periodicals, Inc. 相似文献
16.
Optimization of the electrostatic interactions between ionized groups and peptide dipoles in proteins. 总被引:1,自引:3,他引:1 下载免费PDF全文
V. Z. Spassov R. Ladenstein A. D. Karshikoff 《Protein science : a publication of the Protein Society》1997,6(6):1190-1196
The three-dimensional optimization of the electrostatic interactions between the charged amino acid residues and the peptide partial charges was studied by Monte-Carlo simulations on a set of 127 nonhomologous protein structures with known atomic coordinates. It was shown that this type of interaction is very well optimized for all proteins in the data set, which suggests that they are a valuable driving force, at least for the native side-chain conformations. Similar to the optimization of the charge-charge interactions (Spassov VZ, Karshikoff AD, Ladenstein R, 1995, Protein Sci 4:1516-1527), the optimization effect was found more pronounced for enzymes than for proteins without enzymatic function. The asymmetry in the interactions of acidic and basic groups with the peptide dipoles was analyzed and a hypothesis was proposed that the properties of peptide dipoles are a factor contributing to the natural selection of the basic amino acids in the chemical composition of proteins. 相似文献
17.
Asalapuram R. Pavankumar Rajarathinam Kayathri Natarajan A. Murugan Qiong Zhang Vaibhav Srivastava Chuka Okoli 《Journal of biomolecular structure & dynamics》2013,31(3):406-415
Many proteins exist in dimeric and other oligomeric forms to gain stability and functional advantages. In this study, the dimerization property of a coagulant protein (MO2.1) from Moringa oleifera seeds was addressed through laboratory experiments, protein–protein docking studies and binding free energy calculations. The structure of MO2.1 was predicted by homology modelling, while binding free energy and residues-distance profile analyses provided insight into the energetics and structural factors for dimer formation. Since the coagulation activities of the monomeric and dimeric forms of MO2.1 were comparable, it was concluded that oligomerization does not affect the biological activity of the protein. 相似文献
18.
Saravanan Manjula 《Journal of biomolecular structure & dynamics》2020,38(12):3533-3543
AbstractDengue virus (DENV) is one of the most dangerous mosquito-borne human pathogens known to the mankind. Currently, no vaccines or standard therapy is avaliable to treate DENV infection. This makes the drug development against DENV more significant and challenging. The MTase domain of DENV RNA RdRp NS5 is a promising drug target, because this domain hosts the RNA capping process of DENV RNA to escape from human immune system. In the present study, we have analysed the RNA intervention mechanism exerted by flavoniod molecules against NS5 MTase RNA capping site by using molecular docking, molecular dynamics simulation and the binding free energy calculations. The results from the docking analysis confirmed that the RNA intervention mecanism is exerted by the quercetagetin (QGN) molecule with all necessary intermolecular interactions and high binding affinity. Notably, QGN forms strong hydrogen bonding interactions with Asn18, Leu20 and Ser150 residues and π???π stacking interaction with Phe25 residue. The apo and QGN bound NS5 MTase and QGN-NS5 MTase complex were used for MD simulation. The results of MD simulation reveal that the RMSD and RMSF values of QGN-MTase complex have increased on comparing the apo protein due to the effect of ligand binding. The binding free energy calulation includes prediction of total binding free energy of ligand-protein complex and per-residue free energy decomposition. The QGN binding to NS5 MTase affects it’s native motion, this result is found from Principal component analysis.Communicated by Ramaswamy H. Sarma 相似文献
19.
Giuseppe Lazzarino Barbara Tavazzi Donato Di Pierro Bruno Giardina 《Free radical research》1992,16(5):325-339
Several lines of evidence indicating a close relationship among ischemia, concentration of high-energy metabolites and onset of the “oxygen paradox” in reperfused tissues have been published. In this framework, we have recently studied the effects of exogenous fructose-1,6-bisphosphate on energy metabolism and on oxygen free radical damages of isolated rat heart subjected to anoxia and reoxygenation. In comparison with control groups, hearts perfused in the presence of 5mM fructose-1,6-bisphosphate throughout the different perfusion conditions showed higher concentrations of energy metabolites at the end of anoxia, most of which were normalized after reperfusion. Furthermore, in comparison with control hearts, a reduction of tissue malondialdehyde and of lactate dehydrogenase release in the perfusate was observed in fructose-1,6-bisphosphate-perfused hearts. In this article we review most of the available data concerning the ability of fructose-1,6-bisphosphate to protect from ischemia and reperfusion damage outlining those recent findings which contributed both to clarify the pharmacological profile of the drug and to give an insight in its probable mechanism of action. 相似文献
20.
Joel L. Asenjo Heide C. Ludwig Cristian A. Droppelmann Juan G. Cárcamo Ilona I. Concha Alejandro J. Yáñez María L. Cárdenas Athel Cornish-Bowden Juan C. Slebe 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014