Theoretical analysis of conformational possibilities of Z-DNA.
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DNA↗
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Analysis of conformational changes in bacteriorhodopsin upon retinal removal.
The conformation of bacterioopsin in the apomembrane has been studied by Fourier transform infrared spectroscopy. Resolution enhancement techniques and curve-fitting procedures have been used to determine the secondary structural components from the amide I region. Bacterioopsin contains about 54% helicoidal structure (alpha I and alpha II helices + 3(10) turns), 21% sheets, 16% reverse turns, and 9% unordered structure. Thus, after retinal removal, all of the secondary structural types of bacteriorhodopsin remain present, and only slight quantitative differences appear. On the other hand, H/D exchange studies show that there is a higher degree of exchange for reverse turns and protonated carboxylic lateral chains in bacterioopsin as compared to bacteriorhodopsin. This gives further support to the idea of a more open tertiary structure of bacterioopsin, and to the consideration of the retinal molecule as an important element in complementing the interhelical interactions in bacteriorhodopsin folding.
Bacteriorhodopsins↗
Simplified normal mode analysis of conformational transitions in DNA-dependent polymerases: the elastic network model.
The Elastic Network Model is used to investigate the open/closed transition in all DNA-dependent polymerases whose structure is known in both forms. For each structure the model accounts well for experimental crystallographic B-factors. It is found in all cases that the transition can be well described with just a handful of the normal modes. Usually, only the lowest and/or the second lowest frequency normal modes deduced from the open form give rise to calculated displacement vectors that have a correlation coefficient larger than 0.50 with the observed difference vectors between the two forms. This is true for every structural class of DNA-dependent polymerases where a direct comparison with experimental structural data is available. In cases where only one form has been observed by X-ray crystallography, it is possible to make predictions concerning the possible existence of another form in solution by carefully examining the vector displacements predicted for the lowest frequency normal modes. This simple model, which has the advantage to be computationally inexpensive, could be used to design novel kind of drugs directed against polymerases, namely drugs preventing the open/closed transition from occurring in bacterial or viral DNA-dependent polymerases.
Computer Simulation↗
Nuclear magnetic resonance spectral analysis and conformational properties of 11-benzoyl-9,9a,10,11-tetrahydro-4H-indolo[4,3-ab]carbazole.
The structure of 11-benzoyl-9,9a,10,11-tetrahydro-4H-indolo [4,3-ab] carbazole, a candidate molecule to possess significant antitumor or antimicrobial activity, was elucidated using a combination of one-dimensional and two-dimensional nuclear magnetic resonance (NMR) techniques. Its conformational properties were studied using a combination of two-dimensional NOESY spectroscopy and molecular modeling. Such information will be of aid to synthetic chemists who aim to develop derivatives of this structure. It may also provide information about the stereoelectronic requirements that govern their activities.
Anti-Infective Agents↗
Nuclear magnetic resonance analysis and conformational characterization of a cyclic decapeptide antagonist of gonadotropin-releasing hormone.
Two-dimensional proton nuclear magnetic resonance spectroscopy at 500 MHz has been carried out on the cyclic decapeptide antagonist of gonadotropin-releasing hormone: cyclo-(delta 3-Pro1-D-pClPhe2-D-Trp3-Ser4-Tyr5-D-Trp6-NMeLeu7-Arg8- Pro9-beta-Ala 10). The antagonist exists in two slowly interconverting conformations. All data are consistent with the conclusion that one form has all-trans peptide bonds and the other has a cis beta-Ala10-delta3-Pro1 bond. With the use of sequential assignment methods, chemical shift assignments were obtained for all backbone and side-chain protons of both conformational isomers except for the serine and tyrosine hydroxyl groups and the C gamma, C delta, and guanidinium group protons of the arginine. Temperature dependence of spectral parameters and magnitudes of observed nuclear Overhauser effects support the interpretation that both conformers of the antagonist consist of two beta-turns (type II', D-Trp6-NMeLeu7; type II, delta 3-Pro1-D-pClPhe2) connected by extended antiparallel beta-like strands.
Gonadotropin-Releasing Hormone↗
The cytochrome c oxidase-cytochrome c complex: spectroscopic analysis of conformational changes in the protein-protein interaction domain.
Binding to cytochrome c oxidase induces a conformational change in the cytochrome c molecule. This conformational change has been characterized by comparing the binding of native cytochrome c and chemically modified cytochrome c derivatives to bovine cytochrome c oxidase by using absorption, circular dichroism (CD), and magnetic circular dichroism (MCD) spectroscopy. The following derivatives were analyzed: (i) cytochrome c modified at all 19 lysine residues to yield the (N epsilon-acetimidyl)19 cytochrome c, (N epsilon-isopropyl)19 cytochrome c, and (N epsilon,N epsilon-dimethyl)19 cytochrome c; (ii) cytochrome c in which Met65 and Met80 are converted to the methionine sulfoxide; (iii) cytochrome c with a single break in the polypeptide chain at Arg38 or Gly37. The derivatives bind to cytochrome c oxidase at a ratio of one heme c per heme aa3. The association constants are similar to that of native cytochrome c except for (N epsilon-isopropyl)19 and (N epsilon,N epsilon-dimethyl)19 cytochromes c, which bind respectively four times and six times less strongly. The derivatives are good substrates for the cytochrome c oxidase reaction. The spectral changes accompanying the binding of the modified cytochromes c to cytochrome c oxidase are quite different from the spectral changes observed with native cytochrome c. The different optical absorption and MCD changes are explained by a polarity change around the exposed heme edge in the cytochrome c-cytochrome c oxidase complex. The CD changes indicate a conformational rearrangement restricted to the surface area surrounding the exposed heme edge. The rearrangement may involve a movement of the evolutionarily conserved Phe82 out of the vicinity of the heme.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Structural flexibility of non-nucleoside HIV-1 reverse transcriptase inhibitor: 9-Cl TIBO as explained by potential energy surface and (13)C and (1)H NMR calculations, based on ab initio and density functional study.
The conformational analysis of the HIV-1 reverse transcriptase inhibitor, (+)-(s)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazol[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione or 9-Cl TIBO, has been investigated using high level of calculations, ab initio, and DFT theory. The potential energy surface as the function of two important rotatable dihedral angles of the 9-Cl TIBO side chain was generated by the Hartree-Fock method at the 3-21G basis set. Eight pronounced local minima were found to exist within an energy difference of less than 10 kJ/mol. The energy barriers between the different local minima are lower than 15 kJ/mol. A second derivative (frequency) analysis showed that all conformers are stable at this level of theory. These structures were used as starting points for full geometry optimizations at the HF/6-31G and B3LYP/6-31G levels of theory to obtain the absolute geometries and structural information. The comparisons of calculated conformers with the bound conformer in the X-ray structure were sequentially considered. Additionally, to obtain some structural information and to correlate between calculated structures and the structure in solution, NMR chemical shift calculations were also performed on all eight local minimum structures at B3LYP/6-311++G level, using the GIAO approach. The calculated (1)H NMR and (13)C NMR chemical shifts for the lowest energetic conformer give the greatest correspondence with the experimental results.
Benzodiazepines↗
MIMUMBA revisited: torsion angle rules for conformer generation derived from X-ray structures.
A method has been developed which automatically generates SMARTS patterns for four-atomic torsional fragments, searches experimental structures in the Cambridge Crystallographic Database, and obtains rules for preferred torsion angles in drug-size molecules. These rules can be used for exhaustive conformational analysis using the popular conformer generator OMEGA. This approach results in an overall improvement of quality and coverage of conformational space when comparing conformer ensembles generated by this method with results obtained by using the default OMEGA setup. In particular, the percentage of structures with at least one conformation closer than 0.5 A to the X-ray structure improves from 84% to 92% in a test set of 11 027 experimental structures from the CSD. Moreover, the average RMS distance of the closest conformation to the X-ray structure improves from 0.30 to 0.22 A.
Chemistry↗
X-ray analysis reveals conformational adaptation of the linker in functional calmodulin mutants.
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Calcium-Calmodulin-Dependent Protein Kinase Type 2↗
Characterization of the T cell receptor repertoire of neonatal T cells by RT-PCR and single strand conformation polymorphism analysis.
We have analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) the individual non-germ line configurations of the T cell receptor (TCR) Vbeta chains expressed by T cells from eight individual cord blood specimens. cDNA from each cord blood was amplified using a common primer coupled with a primer specific for each of 22 variable elements of the Vbeta chain family and the amplified fragments were separated under high resolution conditions. With cDNA from adult blood (as a control), all of the TCR chains were amplified as a smear consistent with the extensive polyclonality of adult T cells. In contrast, a heterogeneous pattern of amplification was observed with cDNAs from cord blood: only 26.7+/-21.9% of the 22 Vbeta chains analyzed were amplified as a smear. The majority of them were amplified as a discrete number of bands (up to 10) (in 68.2 +/-18.7% of samples) and some of them as a single fragment (4.0+/-7.8%). Only one of the eight samples analyzed expressed the majority (72.7%) of its Vbeta chains as a smear, consistent with an adult-like TCR repertoire. In conclusion, cord blood expressed, on average, a less complex TCR repertoire than adult blood.
Adult↗
Analysis of conformation of mutant proteins by studying in vitro translation products.
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Animals↗
Conformation of analysis of macromolecules. IV. Helical structures of poly-L-alanine, poly-L-valine, poly-beta-methyl-L-aspartate, poly-gamma-methyl-L-glutamate, and poly-L-tyrosine.
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Alanine↗
On the analysis of conformational dynamics in polymers with several rotational isomers.
The ability of different correlation functions to shed some light onto the conformational dynamics of an amorphous polymer has been analyzed. The study has been performed on a polyethylene model polymer, which has been simulated at decreasing temperatures towards its glass transition, via the molecular dynamics technique. Three rotational isomers are allowed by the considered torsional potential. The correlation times associated with the evaluated transition rates have shown to be Arrhenius in nature, with activation energies resulting basically from internal rotation barriers. Overall torsional autocorrelation functions have been calculated. We have observed that they are dominated by slow events. Alternatively, a set of torsional autocorrelation functions associated with every isomeric state has been evaluated. Stretched exponential fits lead to correlation times that display Vogel-Fulcher temperature dependence.
Journal Article↗
Fast kinetic analysis of conformational changes in mutants of the Ca(2+)-ATPase of sarcoplasmic reticulum.
Rapid quench experiments at 25 degrees C were carried out on selected mutants of the sarco(endo)plasmic reticulum Ca(2+)-ATPase to assess the kinetics of the conformational changes of the dephosphoenzyme associated with ATP binding/phosphoryl transfer and the binding and dissociation of Ca(2+) at the cytoplasmically facing transport sites. The mutants Gly(233) --> Glu, Gly(233) --> Val, Pro(312) --> Ala, Leu(319) --> Arg, and Lys(684) --> Arg differed conspicuously with respect to the behavior of the dephosphoenzyme, although they were previously shown to display a common block of the transformation of the phosphoenzyme from an ADP-sensitive to an ADP-insensitive form. The maximum rate of the ATP binding/phosphoryl transfer reaction was reduced 3.6-fold in mutant Gly(233) --> Glu and more than 50-fold in mutant Lys(684) --> Arg, relative to wild type. In mutant Leu(319) --> Arg, the rate of the Ca(2+)-binding transition was reduced as much as 10-30-fold depending on the presence of ATP. In mutants Gly(233) --> Glu, Gly(233) --> Val, and Pro(312) --> Ala, the rate of the Ca(2+)-binding transition was increased at least 2-3-fold at acid pH but not significantly at neutral pH, suggesting a destabilization of the protonated form. The rate of Ca(2+) dissociation was reduced 12-fold in mutant Pro(312) --> Ala and 3.5-fold in Leu(319) --> Arg, and increased at least 4-fold in a mutant in which the putative Ca(2+) liganding residue Glu(309) was replaced by aspartate. The data support a model in which Pro(312) and Leu(319) are closely associated with the cation binding pocket, Gly(233) is part of a long-range signal transmission pathway between the ion-binding sites and the catalytic site, and Lys(684) is an essential catalytic residue that may function in the same way as its counterpart in the soluble hydrolases belonging to the haloacid dehalogenase superfamily.
Adenosine Triphosphate↗
Simultaneous analysis of conformation and transcription of A and B groups of vitellogenin genes in male and female Xenopus during primary and secondary activation by estrogen.
In male Xenopus, primary estradiol administration results in noncoordinate activation in the liver of the A and B groups of vitellogenin genes, both as judged by transcription and DNase I sensitivity in isolated nuclei, B group genes being activated preferentially in the first 20 hr. Secondary induction in males or "primary" induction in females results in a coordinate and equal transcription of these two groups of genes. The elevated transcriptional activity following primary estrogen stimulation returns to low levels rapidly but the high DNase I sensitivity of these genes persists for 2-3 months. A non-coordinate activation of the A and B groups of vitellogenin genes is however re-established in response to a second administration of estradiol 8 months after primary stimulation of male Xenopus.
Animals↗
Analysis of conformational parameters in nucleic acid fragments. IV. Intercalating drug complexes of very short chain oligonucleotides.
Studies have been made of base-pairing conformational parameters in single crystal structures of very short chain oligonucleotide structures complexed with drug molecules, using data extracted from the Cambridge structural database. The planar portion of the drug has a tendency to intercalate between two bases, utilising strong stacking interactions to stabilise the configuration. The effect of the existence of a formative backbone is seen in the high occurrence of standard base-pairing schemes and a consistent C1'-C1' separation, although the choice of compounds studied does tend to emphasise complementary pairing. In addition to the modulation of the general magnitude which is reduced from that in uncomplexed oligonucleotides, there appears to be some correlation of propeller twist value with the presence of planar groups sandwiching a base-pair. The average twist in such sandwiched pairs is lower than in any other group studied to date.
Base Composition↗
Analysis of conformational changes at the unique loop adjacent to the ATP binding site of smooth muscle myosin using a fluorescent probe.
Recent crystallographic studies have shown that smooth muscle myosin has three highly conserved unique loops, loop B (320-327), loop M (687-699), and loop N (125-134), similar to other myosins, skeletal muscle and dictyostelium myosins. We previously demonstrated that the effect of actin is mediated by a conformational change in one of the loops, loop M comprising amino acids 677 to 689 of skeletal muscle myosin [Maruta and Homma (1998) J. Biochem. 124, 528-533]. In the present study, in order to clarify the role of these smooth muscle myosin loops in energy transduction, we specifically labeled the loops with a fluorescent photoreactive ADP analogue, 3'-O-(N-methylanthraniloyl)-8-azido-ADP (Mant-8-N(3)-ADP), and then measured the fluorescent polarization. When Mant-8-N(3)-ADP was trapped by aluminium fluoride or vanadate into the ATPase site, Mant-8-N(3)-ADP was covalently incorporated into loop N (125-134). In contrast, Mant-8-N(3)-ADP trapped by beryllium fluoride was covalently incorporated into both loop M (687-699) and loop N (125-134) at an almost equimolar ratio. Actin binding to smooth muscle myosin S1 (SMO-S1) labeled at only loop N (125-134) increased the polarization due to the viscosity of actin. In contrast, S1 labeled at both loops N and M showed a much smaller increase in polarization. Our results indicate that the probe at loop M (687-699) of smooth muscle myosin moved to a less hindered region, suggesting that actin binding induces conformational changes at loop M (687-699) similar to those of the corresponding loop (677-689) in skeletal muscle myosin, as previously demonstrated in our laboratory.
Adenosine Diphosphate↗
An analysis of conformational changes on protein-protein association: implications for predictive docking.
Conformational changes on complex formation have been measured for 39 pairs of structures of complexed proteins and unbound equivalents, averaged over interface and non-interface regions and for individual residues. We evaluate their significance by comparison with the differences seen in 12 pairs of independently solved structures of identical proteins, and find that just over half have some substantial overall movement. Movements involve main chains as well as side chains, and large changes in the interface are closely involved with complex formation, while those of exposed non-interface residues are caused by flexibility and disorder. Interface movements in enzymes are similar in extent to those of inhibitors. All eight of the complexes (six enzyme-inhibitor and two antibody-antigen) that have structures of both components in an unbound form available show some significant interface movement. However, predictive docking is successful even when some of the largest changes occur. We note however that the situation may be different in systems other than the enzyme-inhibitors which dominate this study. Thus the general model is induced fit but, because there is only limited conformational change in many systems, recognition can be treated as lock and key to a first approximation.
Algorithms↗