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At least 127 records · Page 7Linked to original sources
PubMed2003

Conformational dynamics of a bispyridinium cyclophane.

A complete study of the conformational behavior of 4,8-diaza-3(1,4),9(4,1)-dipyridina-1,6(1,4)-dibenzenacyclodecaphan-3(1),9(1)-bis(ilium) bishexafluorophosphate is described. This study allows us to conclude that the process observed by which the different chemical shifts of the pyridinium protons show coalescence at a high-temperature 1H NMR is the rotation around the C-N bond, whereas the conformational equilibrium between the four conformers is produced at low temperature.

Journal Article↗
PubMed2004

Slow conformational dynamics in the hamster prion protein.

Although the mechanism of the conformational conversion from the cellular (PrP(C)) to the scrapie (PrP(Sc)) form of animal prion proteins has yet to be elucidated, evidence is accumulating that may provide insight into the conversion process at atomic resolution. Here we show critical aspects of the slow fluctuation dynamics of the recombinant hamster prion protein, rPrP(90-231), based on NMR relaxation analysis using Carr-Purcell-Meiboom-Gill (CPMG) experiments, and compare them in detail with results from high-pressure NMR. Residues exhibiting slow fluctuations on the time scale of microseconds to milliseconds are mainly localized on helices B and C (172-193 and 200-227), which include locally disordered regions in an intermediate conformer, PrP*, identified previously by high-pressure NMR [Kuwata, K., et al., (2002) Biochemistry 41, 12277-12283]. Moreover, chemical shift differences between two putative exchanging conformers obtained by the CPMG relaxation analysis and the linear component of the pressure-induced chemical shift changes are reasonably correlated at individual residue sites. These observations suggest that both the CMPG relaxation and the pressure shifts reflect slow conformational fluctuations and that these slow motions in PrP(C) are related to the trajectories leading to the transition to PrP*.

Animals↗
PubMedDate not supplied

Studies of biomolecular conformations and conformational dynamics by mass spectrometry.

In the post-genomic era, a wealth of structural information has been amassed for proteins from NMR and crystallography. However, static protein structures alone are not a sufficient description: knowledge of the dynamic nature of proteins is essential to understand their wide range of functions and behavior during the life cycle from synthesis to degradation. Furthermore, few proteins have the ability to act alone in the crowded cellular environment. Assemblies of multiple proteins governed by complex signaling pathways are often required for the tasks of target recognition, binding, transport, and function. Mass spectrometry has emerged over the past several years as a powerful tool to address many of these questions. Recent improvements in "soft" ionization techniques have enabled researchers to study proteins and biomolecular complexes, both directly and indirectly. Likewise, continuous improvements in instrumental design in recent years have resulted in a dramatic expansion of the m/z range and resolution, enabling observation of large multi-protein assemblies whose structures are retained in the gas phase. In this article, we discuss some of the mass spectrometric techniques applied to investigate the nature of the conformations and dynamical properties that govern protein function.

Amino Acid Sequence↗
PubMed2005

Conformational dynamics of sialyl Lewisx in aqueous solution and its interaction with selectinE. A study by molecular dynamics.

Three dimensional structures of sialyl Lewis(x) (SLe(x)) in aqueous solution and bound to selectinE are described based on an exhaustive conformational analysis and several long molecular dynamics simulations using different glycosidic regions as starting conformations. It appears from this study that when the oligosaccharide is free in solution the NeuNAcalpha(2-3)Gal segment favors glycosidic conformation in three different regions in the (Phi,Psi) plane with propensity of populations in the ratio 1:8:1. Each one of these structures is characteristically stabilized by specific hydrogen bonding interaction between NeuNAc and Gal. On the other hand, the Gal-GlcNAc-Fuc segment can exist in four different conformational states. Based on the topology of SLe(x) we are able to predict that out of all the allowed conformations in solution only two of these structures possess a geometry that would fit without steric clashes into the binding location of selectinE. In both of these binding modes, segment Gal-GlcNAc-Fuc adopts a unique conformation. The only difference between the two SLe(x) conformers that can successfully bind to selectinE is given by two possible regions in glycosidic space in the fragment NeuNAcalpha(2-3)Gal. A large conformational departure from the crystallographic data is observed for two lysine residues at the binding site of selectinE. These two residues play an important role when SLe(x) binds selectinE in aqueous solution. These findings help reconcile the X-ray data, in which these residues appear to be 1 nm away from SLe(x), with recent liquid NMR data reporting couplings between these protein residues and the sugar.

Crystallography, X-Ray↗
PubMed2005

Slow protein conformational dynamics from multiple experimental structures: the helix/sheet transition of arc repressor.

Conformational transitions underlie the function of many biomolecular systems. Resolving intermediate structural changes, however, is challenging for both experiments and all-atom simulations because the duration of transitions is short relative to the lifetime of the stable species. Simplified descriptions based on a single experimental structure, such as elastic network models or Gō models, are not immediately applicable. Here, we develop a general method that combines multiple coarse-grained models to capture slow conformational transitions. Individually, each model describes one of the experimental structures; together, they approximate the complete energy surface. We demonstrate the method for the helix-to-sheet transition in Arc repressor N11L. We find that the transition involves the partial unfolding of the switch region, and rapid refolding into the alternate structure. Transient local unfolding is consistent with the low hydrogen exchange protection factors of the switch region. Also in agreement with experiment, the isomerization occurs independently of the global folding/dimerization transition.

Dimerization↗
PubMed2006

Conformational dynamics of hSGLT1 during Na+/glucose cotransport.

This study examines the conformations of the Na(+)/glucose cotransporter (SGLT1) during sugar transport using charge and fluorescence measurements on the human SGLT1 mutant G507C expressed in Xenopus oocytes. The mutant exhibited similar steady-state and presteady-state kinetics as wild-type SGLT1, and labeling of Cys507 by tetramethylrhodamine-6-maleimide had no effect on kinetics. Our strategy was to record changes in charge and fluorescence in response to rapid jumps in membrane potential in the presence and absence of sugar or the competitive inhibitor phlorizin. In Na(+) buffer, step jumps in membrane voltage elicited presteady-state currents (charge movements) that decay to the steady state with time constants tau(med) (3-20 ms, medium) and tau(slow) (15-70 ms, slow). Concurrently, SGLT1 rhodamine fluorescence intensity increased with depolarizing and decreased with hyperpolarizing voltages (DeltaF). The charge vs. voltage (Q-V) and fluorescence vs. voltage (DeltaF-V) relations (for medium and slow components) obeyed Boltzmann relations with similar parameters: zdelta (apparent valence of voltage sensor) approximately 1; and V(0.5) (midpoint voltage) between -15 and -40 mV. Sugar induced an inward current (Na(+)/glucose cotransport), and reduced maximal charge (Q(max)) and fluorescence (DeltaF(max)) with half-maximal concentrations (K(0.5)) of 1 mM. Increasing [alphaMDG](o) also shifted the V(0.5) for Q and DeltaF to more positive values, with K(0.5)'s approximately 1 mM. The major difference between Q and DeltaF was that at saturating [alphaMDG](o), the presteady-state current (and Q(max)) was totally abolished, whereas DeltaF(max) was only reduced 50%. Phlorizin reduced both Q(max) and DeltaF(max) (K(i) approximately 0.4 microM), with no changes in V(0.5)'s or relaxation time constants. Simulations using an eight-state kinetic model indicate that external sugar increases the occupancy probability of inward-facing conformations at the expense of outward-facing conformations. The simulations predict, and we have observed experimentally, that presteady-state currents are blocked by saturating sugar, but not the changes in fluorescence. Thus we have isolated an electroneutral conformational change that has not been previously described. This rate-limiting step at maximal inward Na(+)/sugar cotransport (saturating voltage and external Na(+) and sugar concentrations) is the slow release of Na(+) from the internal surface of SGLT1. The high affinity blocker phlorizin locks the cotransporter in an inactive conformation.

Animals↗
PubMed1983

Understanding DNA conformational dynamics: answering questions and questioning answers.

Phosphorus-31 and especially Carbon-13 NMR measurements have recently become primary input to the understanding of DNA solution dynamics. While the 31P measurements are inherently easier, the quality of 31P dynamics information is suspect and therefore 13C measurements are preferred. In fact, it is necessary to obtain several kinds of 13C data (T1s, NOE's, linewidths, integrated peak intensities) over a wide range of magnetic fields (13C NMR frequencies) in order to identify major features of DNA internal motions. Further information comes from variation of temperature and DNA fragment length and/or concentration. Most of our 13C measurements have been performed at 37.7-90.6 MHz on fully double stranded monomer size (147 base pair) DNA at concentrations in phosphate buffer of approximately less than 10 to approximately greater than 200 mg ml-1; temperatures studied range from 6 to 55 degrees C. Other measurements have been performed on monomer-size single-stranded DNA at 85 and 92 degrees. The large data set we have acquired appears to answer some important questions about the nature and extent of DNA overall and internal motional dynamics. However, the picture remains incomplete and a number of questions arise from these results: 1. Overall motion of the double stranded DNA fragments follows expected hydrodynamic behavior; 2. Restricted but rapid internal motion along the DNA structure is well represented by a spaghetti-like wobbling-in-a-cone model; 3. DNA-DNA Interactions and solvent ordering, present at relatively low DNA concentrations, partially quench the internal motion, consistent with hinge-model structural changes (and the spaghetti model above) but not as compatible with in-plane torsional motion models; 4. The deoxyribose C-2' sites undergo additional motion which is partially uncoupled from the internal wobbling motions: 5. At high DNA concentrations, a phase transition occurs, resulting in ordered structures which drastically affect DNA internal dynamics; 6. DNA interacting with ethidium does not greatly change its conformational mobility; 7. DNA interacting with Hg2+ ions shows less than anticipated change in internal DNA dynamics. The remaining challenge is to interpret our current results in terms of specific conformational processes and to understand why the conformational mobility of double stranded DNA is relatively unhindered by major structural perturbants such as intercalating ethidium and mercury ion.

DNA↗
PubMed2005

Dominant features of protein reaction dynamics: conformational relaxation and ligand migration.

Here, we review the dominant aspects of protein dynamics as revealed by studying hemoproteins using the combination of laser flash photolysis, kinetic spectroscopy and low temperature. The first breakthrough was the finding that geminate ligand rebinding with myoglobin is highly non-exponential at temperature T<200 K, providing evidence for the trapping of a large number of protein statistical substates. Another major advance was the introduction of a "model free" approach to analyze polychromatic kinetics in terms of their rate spectrum rather than to fit the data to some arbitrarily predefined kinetic scheme. Kinetic processes are identified and quantified directly from the rate spectrum without a priori assumptions. In recent years, further progresses were achieved by using xenon gas as a soft external perturbing agent that competes with ligand rebinding pathways by occupying hydrophobic protein cavities. The first part of this paper introduces several basic principles that are spread throughout a vast literature. The second part describes the main conclusions regarding conformational relaxation and ligand migration in hemoproteins obtained by combining these approaches.

Animals↗
PubMed2000

Conformal dynamics of fractal growth patterns without randomness

Many models of fractal growth patterns (such as diffusion limited aggregation and dielectric breakdown models) combine complex geometry with randomness; this double difficulty is a stumbling block to their elucidation. In this paper we introduce a wide class of fractal growth models with highly complex geometry but without any randomness in their growth rules. The models are defined in terms of deterministic itineraries of iterated conformal maps, generating the function Phi((n))(omega) which maps the exterior of the unit circle to the exterior of an n-particle growing aggregate. The complexity of the evolving interfaces is fully contained in the deterministic dynamics of the conformal map Phi((n))(omega). We focus attention on a class of growth models in which the itinerary is quasiperiodic. Such itineraries can be approached via a series of rational approximants. The analytic power gained is used to introduce a scaling theory of the fractal growth patterns and to identify the exponent that determines the fractal dimension.

Journal Article↗
PubMedDate not supplied

[Conformational dynamics of proteins and the simplest molecular "machines"].

A mathematical model is developed for conformational motions of proteins. The mechanism is shown to be by local jump diffusion via conformational substrates. The model is analysed in terms of experimental data obtained by Mössbauer spectroscopy and X-ray scattering. From comparative analysis the validity of a continual model is deduced. The correlation between electron transport activity and protein conformation motions is discussed within the local jump mechanism. An equation is established to describe the relationship between electron tunneling rate and correlation time of conformational movement.

Mathematics↗
PubMed2005

Dynamic conformational states of DNA containing T.T or BrdU.T mispaired bases: wobble H-bond pairing versus cross-strand inter-atomic contacts.

The dynamic structure of 11-mer DNA duplexes of different sequences with or without homopyrimidine (T.T, or BrdU.T) mismatches was studied by molecular dynamics (MD) simulations on a time scale from 200 ps to 1 ns. The conformational analysis suggests that in mismatched duplexes the formation of classical T.T wobble H-bonding pairing is nearest-neighbor sequence-dependent and, in most cases, three-centered H-bonds and numerous alternative close cross-strand interatomic contacts exist. Thus, in duplex W1, where the central triplet is 5'd(CTA).d(TTG), two wobble conformations W upward arrow (alphabeta) and W downward arrow (betaalpha) are formed and exchange rapidly at 300 K. In contrast, when the central triplet is 5'd(TTT).d(ATA) (W2 duplex) wobble conformations are rarely observed at 300 K, and the T.T mispair most often adopts a "twisted" conformation with one largely persistent normal H-bond, plus a stable cross-strand contact involving a T flanking base. However, at elevated temperature (400 K) the same W2 duplex shows frequent exchange between the two classical wobble conformations (alphabeta<-->betaalpha), as is in the case when the central triplet is 5'd(TBrdUT).d(ATA) (W3 duplex at 300 K). It is suggested that in the W2 sequence, restrictions due to thymine-methyl/pi interactions prevent the formation of wobble pairing and thermal activation energy, and/or the chemical replacement of T by BrdU are required in order for the T(BrdU).T mismatch to adopt and exchange between wobble conformations. The specific short and/or long-lived (double/triple) cross-strand dynamic interactions in W1, W2 and W3 duplexes are throughout characterized. These frequent atomic encounters exemplify possible inter-strand charge transfer pathways in the studied DNA molecules.

Base Composition↗
PubMed1995

Conformational dynamism in d-(GAATTCCGTTATT) containing the complementary Myb responsive element d-CCGTTA: NMR and MD investigations.

Conformational features of the DNA segment d-(GAATTCCGTTATT) containing the complementary Myb responsive element CCGTTA has been studied by NMR and molecular dynamics calculations with a view to see the role of 3D structure in specific DNA recognition. From the low field imino proton NMR spectra, the DNA sequence is seen to exist as a duplex with pyrimidine mismatches in the centre. The 2D NMR spectra however show that teh molecule exhibits substantial dynamism even at 1 degree C. Several extra cross peaks, more than the expected number, are seen in particular regions in all the spectra. These observations indicate that the duplex undergoes slow transitions between base-paired and unbase-paired states due to mismatches in the centre. Hence, to characterise those transitions a restrained verlet dynamics has been performed for 50ps using X-PLOR force field. Structural intermediates at regular intervals have been analysed, and we see that the dynamism in the molecule results in substantial fluctuations in the different torsion angles. The mismatch sites are seen to exhibit the highest degree of fluctuations, with the bases stacking in and looping out of the duplex. The sugar geometry is seen to be fairly steady around the S domain for most of the residues.

Base Sequence↗
PubMed2003

Structures and conformational dynamics of gold(I) halide complexes of resorcinarene tetraphosphinite ligands.

Gold(I) halide derivatives of several tetrakis(diphenylphosphinite) tetraester resorcinarene compounds have been prepared. The complexes are shown to exist in boat conformations, and two different boat conformations were characterized by X-ray structure determinations; the structural characterization of both boat conformations of the same parent resorcinarene is unprecedented. Intramolecular Au.Au interactions were observed in the solid state for both boat conformers and could cause twisting of the resorcinarene skeleton. Several of the complexes exist in solution as an equilibrium mixture of the two different boat conformers, and the equilibrium and dynamics of exchange were studied by variable-temperature NMR.

Journal Article↗
PubMed2003

Insights into nucleic acid conformational dynamics from massively parallel stochastic simulations.

The helical hairpin is one of the most ubiquitous and elementary secondary structural motifs in nucleic acids, capable of serving functional roles and participating in long-range tertiary contacts. Yet the self-assembly of these structures has not been well-characterized at the atomic level. With this in mind, the dynamics of nucleic acid hairpin formation and disruption have been studied using a novel computational tool: large-scale, parallel, atomistic molecular dynamics simulation employing an inhomogeneous distributed computer consisting of more than 40,000 processors. Using multiple methodologies, over 500 micro s of atomistic simulation time has been collected for a large ensemble of hairpins (sequence 5'-GGGC[GCAA]GCCU-3'), allowing characterization of rare events not previously observable in simulation. From uncoupled ensemble dynamics simulations in unperturbed folding conditions, we report on 1), competing pathways between the folded and unfolded regions of the conformational space; 2), observed nonnative stacking and basepairing traps; and 3), a helix unwinding-rewinding mode that is differentiated from the unfolding and folding dynamics. A heterogeneous transition state ensemble is characterized structurally through calculations of conformer-specific folding probabilities and a multiplexed replica exchange stochastic dynamics algorithm is used to derive an approximate folding landscape. A comparison between the observed folding mechanism and that of a peptide beta-hairpin analog suggests that although native topology defines the character of the folding landscape, the statistical weighting of potential folding pathways is determined by the chemical nature of the polymer.

Computer Simulation↗
PubMed2026

EWS-RNA Binding Protein 1: Structural Insights into Ewing Sarcoma by Conformational Dynamics Investigations.

BACKGROUND: Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ewsing Sarcoma by interaction with RNA molecules. AIMS: The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma. OBJECTIVE: The current study explores the complexity of EWSR1 structure and its conformational interactions with RNA in relation to Ewing sarcoma. METHODS: Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes. RESULTS: The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression. CONCLUSION: Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.

Sarcoma, Ewing↗
PubMed2002

Conformational dynamics of tetraisopropylmethane and of tetracyclopropylmethane.

Tetraisopropylmethane (1) exists in solution as a mixture of two types of conformers (D2d and S4 time-averaged symmetry) in the ratio 93:7 at -110 degrees C, interconverting with a barrier of 9.7 kcal mol-1. Molecular mechanics calculations and the multiplicity of NMR signals at low temperature allow the assignment of these conformations. The only conformation populated in tetracyclopropylmethane (2) is the same type as the minor conformation (S4 time-averaged symmetry) populated in 1. 13C NMR spectra at about -180 degrees C show that degenerate versions of this conformation interconvert with a barrier of 4.5 kcal mol-1. Molecular mechanics calculations that characterize the six possible conformational types for these molecules, and the most important interconversion pathways, are reported. Calculated and experimental barriers match satisfactorily well.

Journal Article↗
PubMed1990

Anaplastic astrocytoma and glioblastoma: pion irradiation with the dynamic conformation technique at the Swiss Institute for Nuclear Research (SIN).

Clinical phase I/II studies have been performed at the Swiss Institute for Nuclear Research (SIN) since February 1982. Fifty-two out of 249 patients accepted for pion treatment by the end of 1986 were treated for malignant glioma with high dose pion irradiation. A substantial influence of their radioresistance was expected from increased radiation quality due to the contribution of high LET particles from pion capture, and by the possibility of target volume shaping and dose distribution related to the dynamic spot-scan conformation technique. The patients' treatment followed a dose escalation program with total doses from 2720-3420 cGy, fraction sizes from 170 to 205 cGy (90% isodose, minimum target dose), and treatment times from 4 to 5 weeks. 12/52 patients received an accelerated treatment with 3280 cGy in 14-22 days. 49/52 patients are eligible: 3 with astrocytoma of clinical aggressive behaviour, 14 with anaplastic astrocytoma (median age 42 years), and 32 patients with glioblastoma (median age 52 years). 8/49 patients had total/subtotal tumour resection, 19 patients a stereotactic biopsy. The patients were divided into three groups according to total dose, and a fourth group which received the accelerated treatment. There was no statistically significant difference in the median survival rate between the four groups, which was 13 months for the non-glioblastoma patients and 9 months for the glioblastoma patients. No radiation necrosis and no demyelination was found in 17 patients (6 recraniotomies, 11 autopsies). In 10/17 patients, clearly identifiable tumour cells were not demonstrated. NMR findings showed the tumour-surrounding oedema mostly stimulated by tumour necrosis and tumour progression. From these findings, further dose escalation programs, together with a shaping of the target volume close to the tumour, are not contraindicated.

Adult↗
PubMed2006

Rapid conformational dynamics of cytochrome P450 2E1 in a natural biological membrane environment.

Among the members of the cytochrome P450 superfamily, P450 2E1 is most often associated with the production of reactive oxygen species and subsequent cellular toxicity. We sought to identify a structural basis for this distinguishing feature of P450 2E1 by examining its carbon monoxide binding kinetics as a probe of conformation/dynamics. We employed liver microsomes from wild-type and P450 2E1 knockout mice in order to characterize this P450 in a natural membrane environment. The CO binding kinetics of the P450s of wild-type microsomes had a rapid component that was absent in the knockout microsomes. Data analysis using the maximum entropy method (MEM) correspondingly identified two distinct kinetic components in the wild-type microsomes and only one component in the knockout microsomes. The rapid kinetic component in wild-type microsomes was attributed to endogenous P450 2E1, while the slower component was derived from the remaining P450s. In addition, rapid binding kinetics and a single component were also observed for human P450 2E1 in a baculovirus expression system, in the absence of other P450s. Binding kinetics of both mouse and human P450 2E1 were slowed in the presence of ethanol, a modulator of this P450. The unusually rapid CO binding kinetics of P450 2E1 indicate that it is more dynamically mobile than other P450s and thus able to more readily interconvert among alternate conformations. This suggests that conformational switching during the catalytic cycle may promote substrate release from a short-lived binding site, allowing activated oxygen to attack other targets with toxic consequences.

Animals↗