Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “conformational dynamics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 379 records · Page 21Linked to original sources
PubMed2000

Thymosin-beta(4) changes the conformation and dynamics of actin monomers.

Thymosin-beta(4) (Tbeta(4)) binds actin monomers stoichiometrically and maintains the bulk of the actin monomer pool in metazoan cells. Tbeta(4) binding quenches the fluorescence of N-iodoacetyl-N'-(5-sulfo-1-naphthyl)ethylenediamine (AEDANS) conjugated to Cys(374) of actin monomers. The K(d) of the actin-Tbeta(4) complex depends on the cation and nucleotide bound to actin but is not affected by the AEDANS probe. The different stabilities are determined primarily by the rates of dissociation. At 25 degrees C, the free energy of Tbeta(4) binding MgATP-actin is primarily enthalpic in origin but entropic for CaATP-actin. Binding is coupled to the dissociation of bound water molecules, which is greater for CaATP-actin than MgATP-actin monomers. Proteolysis of MgATP-actin, but not CaATP-actin, at Gly(46) on subdomain 2 is >12 times faster when Tbeta(4) is bound. The C terminus of Tbeta(4) contacts actin near this cleavage site, at His(40). By tritium exchange, Tbeta(4) slows the exchange rate of approximately eight rapidly exchanging amide protons on actin. We conclude that Tbeta(4) changes the conformation and structural dynamics ("breathing") of actin monomers. The conformational change may reflect the unique ability of Tbeta(4) to sequester actin monomers and inhibit nucleotide exchange.

Actins↗
PubMed2006

Conformational structure, dynamics, and solvation energies of small alanine peptides in water and carbon tetrachloride.

The rate-limiting barrier for peptide transport across lipid bilayers is the nonpolar hydrocarbon interior. Permeating peptides may undergo conformational changes during their transfer from an aqueous solution into the barrier domain, thus facilitating peptide transport. To test this hypothesis, all-atom and explicit-solvent molecular dynamics (MD) simulations have been conducted on a series of small peptides, p-toluyl-Ala(n) (n = 0-3) used previously in transport experiments, to explore their conformational structures, dynamics and solvation free energies in water and carbon tetrachloride (CCl(4)). The conformations of the p-toluyl alanine di- and tri-peptides in water were found to be far from random coils, with P(II) and alpha(R) dominating but with smaller populations of seven-membered (c(7)) and five-membered rings (c(5)). In contrast, the seven-membered ring, c(7), along with c(5) dominated in CCl(4). These results indicate that the conformational preferences of the alanine peptides are highly sensitive to solvent. Dynamically, stable seven-membered ring formation occurred on a time scale of 10 ps while larger ring-sizes (e.g., 10-membered rings) were observed much less frequently. The values of adjacent torsional angles (phi(1), psi(1)) were dependent on neighboring torsional angles. Thermal motions of neighboring torsions leading to transitions between c(7), c(5), alpha(R), and P(II) conformers were highly cooperative while longer range correlations between transitions of adjacent sets of torsions (phi(1), psi(1)) and (phi(2), psi(2)) were less evident. Peptide folding in CCl(4) lowers the intramolecular electrostatic energies. This, along with hydrophobic interactions, favors partitioning into CCl(4). These effects only partially offset other types of intramolecular interactions and peptide-solvent polar interactions that are more favorable in water, leading to net transfer free energies (3-7 kcal/mol) that disfavor peptide transfer from water into carbon tetrachloride.

Alanine↗
PubMed2004

Kv channel S6 helix as a molecular switch: simulation studies.

Ion channels form pores of nanoscopic dimensions in biological membranes and play a key role in the physiology of cells. The majority of ion channels are gated, i.e. they contain a molecular switch that allows a transition between a closed (functionally 'off') and open (functionally 'on') state. Comparison of crystal structures of potassium channels suggest that the gating mechanism of voltage-gated potassium (Kv) channels involves a key role for the pore-lining S6 helix. There is a conserved PVP sequence motif in the S6 helix. Molecular dynamics simulations are used here to explore the conformational dynamics of the S6 helix hinge in models of fragments of a Kv channel, namely an S5-P-S6 monomer and an (S5-P-S6)4 tetramer. The latter is a model of the complete pore-forming domain of a Kv channel. All models were simulated embedded in an octane slab (a simple membrane mimetic). The results of these simulations indicate that the PVP motif may form a molecular hinge, even when the S6 helix forms part of a more complex model. The conformational dynamics of S6 are modulated by the remainder of protein, but it remains flexible. These simulation results are compatible with a channel gating model in which S6 bends in the vicinity of the PVP motif in addition to the region around the conserved glycine (G466) that is N-terminal to the PVP motif. This model is supported by comparison of the Kv S6 models with the S6 helix of the bacterial KvAP channel crystal structure. Thus, K channel gating may depend on a complex nanoswitch with three rigid helical sections linked by two molecular hinges.

Journal Article↗
PubMed2004

Treatment planning for dose escalation in non-small cell lung cancer (NSCLC).

This study was performed to examine potential field arrangements for irradiating non-small cell lung cancer (NSCLC) on a dose escalation study. An example patient was chosen and 7 coplanar treatment plans were created to treat a NSCLC. Two plans included prophylactic nodal irradiation (PNRT) and 5 did not. Four plans used 4 fields, 2 plans used 5 fields, and 1 plan included dynamic conformal 360 degrees rotational therapy. All plans delivered 80 Gy to the isocenter with 10-MV x-rays. Each plan was initially created without dose inhomogeneity corrections and then was recalculated with these corrections, maintaining the same weighting and number of monitor units. Avoiding PNRT spared a considerable volume of normal tissue from radiation. Plans with 5 fields generally spared normal tissues better than 4-field plans. There was no benefit to the dynamic conformal 360 degrees rotational plan. Inhomogeneity corrections revealed that higher doses were delivered to both the tumor and normal structures. Seven beam arrangements for the treatment of NSCLC were compared to develop potential beam arrangements that would be applicable to treating NSCLC on a multi-institutional dose escalation study. We favor the use of at least 5 beams in most situations. It is possible that the use of more fields would further improve plans up to a point of diminishing returns, as exemplified by the lack of benefit seen with the dynamic conformal 360 degrees rotational plan. It is possible that the use of noncoplanar fields or intensity-modulated radiation therapy (IMRT) may further improve the therapeutic ratio.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Three hydrolases and a transferase: comparative analysis of active-site dynamics via the BioSimGrid database.

Comparative molecular dynamics (MD) simulations enable us to explore the conformational dynamics of the active sites of distantly related enzymes. We have used the BioSimGrid (http://www.biosimgrid.org) database to facilitate such a comparison. Simulations of four enzymes were analyzed. These included three hydrolases and a transferase, namely acetylcholinesterase, outer-membrane phospholipase A, outer-membrane protease T, and PagP (an outer-membrane enzyme which transfers a palmitate chain from a phospholipid to lipid A). A set of 17 simulations were analyzed corresponding to a total of approximately 0.1 micros simulation time. A simple metric for active-site integrity was used to demonstrate the existence of clusters of dynamic conformational behaviour of the active sites. Small (i.e. within a cluster) fluctuations appear to be related to the function of an enzymatically active site. Larger fluctuations (i.e. between clusters) correlate with transitions between catalytically active and inactive states. Overall, these results demonstrate the potential of a comparative MD approach to analysis of enzyme function. This approach could be extended to a wider range of enzymes using current high throughput MD simulation and database methods.

Acetylcholinesterase↗
PubMed1996

Characterization of conformation and dynamics of CD4 Fragment (81-92) TYICEVEDQKEE and its benzylated derivative by 1H NMR spectroscopy and molecular modeling: Relevance of conformation to biological function.

Two-dimensional 1H nuclear magnetic resonance (NMR) spectroscopy experiments were carried out to determine the conformation of a CD4 fragment (81-92) TYICEVEDQKEE and its di-benzylated analogue in aqueous solution. The refined structures obtained by use of distance geometry and simulated annealing for both peptides revealed a marked departure from that of the corresponding sequence within the D1D2 fragment of CD4 determined by x-ray crystal studies. Near the amino terminus of both peptides, a distinct loop exists that is stabilized by the hydrophobic interaction between the side chains of the amino acids in the region. For the parent peptide and Cys84 and Glu85 dibenzylated analogues, the orientation of the loop is different with respect to the reverse turn formed by Val86 through Gln89. In particular, the side chains of Val86 point in different directions for these two peptide analogues. The C- terminus of both peptide analogues exhibits a faster motional characteristic. The deuterium-proton exchange experiment showed a very slowly exchanged Gln89 backbone NH for the di-benzylated peptide, suggesting its participation in the hydrogen bond to Val86 C=O. The negatively charged side chains of Glu87 and Asp88 are found to jut out, similar to the crystal structure. The difference between the two peptides in inhibiting the syncytium formation is postulated to arise from the more defined Val86-Gln89 turn and the orientation of the apolar side chains of the residues in the stretch thought to participate in the cell-fusion process.

Amino Acid Sequence↗
PubMed2000

Studies on the solution conformation and dynamics of a polysaccharide from Sinorhizobium fredii HH103 and its monosaccharide repeating unit.

The conformational behavior of the homopolysaccharide isolated from Sinorhizobium fredii HH103 and its monosaccharide repeating unit (5-acetamido-3,5,7,9-tetradeoxy-7-(3-hydroxybutyramido)-L-glycero- L- manno-nonulosonic acid) was analyzed by nuclear magnetic resonance (NMR) spectroscopy and extensive molecular dynamics simulations (MD). The results indicate that the glycosidic linkages and lateral chains may adopt a variety of conformations. MD simulations using the generalized Born solvent-accessible surface area (GB/SA) continuum solvent model for water and the MM3* force field provide a population distribution of conformers that satisfactorily agrees with the experimental NMR data for the torsional degrees of freedom of the molecule.

Carbohydrate Conformation↗
PubMed1992

Conformation and dynamics of drug-DNA intercalation.

Molecular dynamics simulations have been undertaken for a B-form dodecanucleotide duplex in solution with and without an intercalated proflavine molecule between the central C.G base pairs. The introduction of this simple intercalator affects both the conformational features and dynamic properties of the oligonucleotide double helix. Changes are seen in the rms atomic fluctuations and anisotropy of phosphate, sugar and base atoms. The backbone conformation is slightly changed on average and more sugars adopt the C3' endo conformation in the simulation of the complex compared with the simulation of the oligonucleotide alone. Both major and minor grooves becomes wider on average with the addition of the intercalating drug. Flanking A.T base pairs on both sides of the intercalation site have undergone an increase in flexibility, with the base pairs, especially at the 5' side, having the N1...N3 hydrogen bonds being broken.

Base Composition↗
PubMed2000

Intramolecular dynamics and conformational transition in proteins studied by biophysical labelling methods. Common and specific features of proteins from thermophylic micro-organisms.

A general survey is carried out on the theoretical grounds for methods of spin, luminescence and Mössbauer labels, as well as their application in the study of protein intramolecular dynamics. When combined, these methods allow the protein dynamics to be investigated within a wide range of correlation times (tau c = 10(2) - 10(-10) s) and amplitudes. The purposeful application of the methods to various proteins at different temperatures (30-330 K), water content, substrate addition, etc., revealed a number of dynamical processes and conformational transitions in proteins. The experiments indicated correlations between the local segmental mobility of protein globules in a nanosecond temporal scale and biochemical reactions, such as long-distance electron transfer, hydrolysis and photoreactions. The biophysical labelling methods results were analysed together with the data on dynamics obtained using complementary physico-chemical methods and theoretical calculations. Special emphasis is given to recent results on proteins from thermophylic micro-organisms. The mechanisms of protein intramolecular dynamics and their role in the stability and functions of proteins and enzymes are discussed.

Chemistry, Physical↗
PubMed2000

NMR evidence for base dynamics at all TpA steps in DNA.

NMR evidence is presented indicating that the exceptional conformational dynamics found at TpA steps in DNA is general to all immediate sequence contexts. One easily tractable NMR parameter that is sensitive to TpA base dynamics is the resonance linewidth of the TpA adenine H2 proton. This resonance experiences a temperature-dependent broadening due to conformational dynamics. Unusual dynamics at TpA steps were originally observed in the sequence context (T)pTpTpApAp(A). We have since shown that the evidence for TpA dynamics persists when either the thymine preceding the TpA step or the adenine following the TpA step is preserved [McAteer et al., Nucleic Acids Res. 23, 3962-3966 (1995)]. Here, in order establish whether or not exceptional TpA dynamics occurs in all DNA sequence contexts, we investigated a series of DNA sequences of the form GCNaTANbNbTANaGC, where N=A,T,C,G. In this family of sequences, all 16 possible immediate sequence context environments of the form NaTANb were examined using 10 DNA sequences. Our NMR results show that the TpA adenine H2 resonance contains a temperature dependent excess linewidth indicative of dynamics in all 16 sequence context environments. By studying a complete set of sequence contexts, it was possible to recognize trends relating resonance parameters and sequence environment. For example, the magnitude of the maximum linewidth is largely determined by the identity of the nucleotide following the TpA step and the magnitude of the linewidth maximum is moderately correlated (r=0.56) with the temperature of the linewidth maximum. The physical basis for these correlations is discussed.

Adenine↗
PubMed1999

Solution conformation and dynamics of the trisaccharide fragments of the O-antigen of Vibrio cholerae O1, serotypes Inaba and Ogawa.

The conformational behavior of the trisaccharide fragments of the Ogawa and Inaba Vibrio cholera serotypes has been studied using NMR and molecular dynamics (MD). The obtained results indicate that there are no significant differences in the major conformation and in the extent of motion of the glycosidic torsions of these molecules. The differences in biological activity are probably not due to conformational effects but to van der Waals and/or hydrogen bonding interactions between the antigens and the biological receptor.

Carbohydrate Conformation↗
PubMed2001

Conformational studies by dynamic NMR. 84.(1) structure, conformation, and stereodynamics of the atropisomers of N-aryl-tetrahydropyrimidines.

The existence of stereolabile atropisomers for a number of N-aryl-tetrahydropyrimidines in solution has been deduced from the observation of the anisochronous NMR signals of prochiral methylene groups. The interconversion barriers for these atropisomers have been measured by line shape analysis of dynamic NMR spectra at various temperatures: a Molecular Mechanics modeling resulted in good agreement with these values. In an appropriate case, distinct NMR signals for the two enantiomeric forms could be observed at ambient temperature in a chiral environment. Evidence was also obtained for an exchange process occurring between two conformers experiencing a very biased equilibrium. Single-crystal X-ray diffraction of one such compound yielded a molecular structure in good agreement with the results obtained by ab initio calculations.

Anti-Infective Agents↗
PubMed1984

Mechanism and dynamics of conformational ordering in xanthan polysaccharide.

The thermally induced order-disorder transition of xanthan (extracellular bacterial polysaccharide from Xanthomonas campestris) has been investigated by optical rotation, differential scanning calorimetry, stopped-flow reaction kinetics and low-angle laser light scattering, and the results have been analysed in terms of Zimm -Bragg helix-coil transition theory. The reciprocal of the transition midpoint temperature (Tm) varies linearly with the logarithm of cation (K+) the salt dependence of Tm, is in agreement with Manning polyelectrolyte theory the ordered structure. The associated increase in cation binding, calculated from the salt dependence of tm, is in agreement with the Manning polyelectrolyte theory for one of the candidate structures from X-ray diffraction, a 5(1) single helix stabilized by packing of side-chains along the polymer backbone, but not for the alternative double-helix structure that has also been proposed. At each salt concentration, the two fundamental parameters of the Zimm -Bragg theory, s and sigma, were calculated. The equilibrium constant for growth of the ordered structure (s) is derived directly from calorimetric measurement of transition enthalpy (delta Hcal ), and sigma, which quantifies the relative instability of the helix nucleus, is derived from the ratio of delta Hcal to the apparent transition enthalpy (delta Happ ) obtained by van't Hoff analysis of the optical rotation data. The temperature course of conformational ordering calculated theoretically is in good quantitative agreement with experimental results from both optical rotation and scanning calorimetry. The calculated average length of stable, ordered chain-sequences increases with decreasing temperature, but equals or exceeds the total chain length from light scattering only at temperatures more than approximately equal to 70 K below Tm, suggesting that ordered and disordered regions may co-exist within the same xanthan molecule. Consistent with this interpretation, the observed rate of conformational ordering increases sharply under conditions where the starting solution for dynamic measurements is partially ordered, suggesting that ordered sequences within each chain may act as helix nuclei for adjacent disordered regions, so that helix growth, rather than the slower nucleation process, becomes rate limiting.

Calorimetry, Differential Scanning↗
PubMed2005

Theory of glassy dynamics in conformationally anisotropic polymer systems.

A mode coupling theory for the ideal glass transition temperature, or crossover temperature to highly activated dynamics in the deeply supercooled regime, T(c), has been developed for anisotropic polymer liquids. A generalization of a simplified mode coupling approach at the coarse-grained segment level is employed which utilizes structural and thermodynamic information from the anisotropic polymer reference interaction site model theory. Conformational alignment or/and coil deformation modifies equilibrium properties and constraining interchain forces thereby inducing anisotropic segmental dynamics. For liquid-crystalline polymers a small suppression of T(c) with increasing nematic or discotic orientational order is predicted. The underlying mechanism is reduction of the degree of coil interpenetration and intermolecular repulsive contacts due to segmental alignment. For rubber networks chain deformation results in an enhanced bulk modulus and a modest elevation of T(c) is predicted. The theory can also be qualitatively applied to systems that undergo nonuniversal local deformation and alignment, such as polymer thin films and grafted brush layers, and large elevations or depressions of T(c) are possible. Extension to treat directionally dependent collective barrier formation and activated hopping is possible.

Algorithms↗
PubMed2004

Insights into conformation and dynamics of protein GB1 during folding and unfolding by NMR.

Understanding protein stability requires characterization of structural determinants of the folded and unfolded states. Many proteins are capable of populating partially folded states under specific solution conditions. Occasionally, coexistence of the folded and an unfolded state under non- or mildly denaturing conditions can be observed by NMR, allowing us to structurally probe these states under identical conditions. Here we report on a destabilized mutant of the B1 domain of protein G (GB1) whose equilibrium unfolding was systematically investigated. Backbone amide residual dipolar couplings (RDCs), the tryptophan Nepsilon-H resonance and the amide nitrogen transverse relaxation rates (R2s) for varying pH values and different temperatures were measured. The backbone amide RDCs indicate that prior to complete unfolding, two melting hot spots are formed at the turn around T11, L12 and K13 and the N terminus of the helix at A24 and T25. The RDCs for the low pH, thermally unfolded state of GB1 are very small and do not indicate the presence of any native-like structure. Amide nitrogen transverse relaxation rates for GB1 in the folded state at different temperatures exhibit large contributions from exchange processes and the associated dynamics display considerable heterogeneity. Our data provide clear evidence for intermediate conformations and multi-state equilibrium un/folding for this GB1 variant.

Antigens, Bacterial↗
PubMed1999

Structural dynamics in the C-terminal domain of calmodulin at low calcium levels.

Calmodulin undergoes Ca2+-induced structural rearrangements that are intimately coupled to the regulation of numerous cellular processes. The C-terminal domain of calmodulin has previously been observed to exhibit conformational exchange in the absence of Ca2+. Here, we characterize further the conformational dynamics in the presence of low concentrations of Ca2+ using 15N spin relaxation experiments. The analysis included 1H-15N dipolar/15N chemical shift anisotropy interference cross-correlation relaxation rates to improve the description of the exchange processes, as well as the picosecond to nanosecond dynamics. Conformational transitions on microsecond to millisecond time scales were revealed by exchange contributions to the transverse auto-relaxation rates. In order to separate the effects of Ca2+ exchange from intramolecular conformational exchange processes in the apo state, transverse auto-relaxation rates were measured at different concentrations of free Ca2+. The results reveal a Ca2+-dependent contribution due mainly to exchange between the apo and (Ca2+)1 states with an apparent Ca2+ off-rate of approximately 5115 s(-1), as well as Ca2+-independent contributions due to conformational exchange within the apo state. 15N chemical shift differences estimated from the exchange data suggest that the first Ca2+ binds preferentially to loop IV. Thus, characterization of chemical exchange as a function of Ca2+ concentration has enabled the extraction of unique information on the rapidly exchanging and weakly populated (<10 %) (Ca2+)1 state that is otherwise inaccessible to direct study due to strongly cooperative Ca2+ binding. The conformational exchange within the apo state appears to involve transitions between a predominantly populated closed conformation and a smaller population of more open conformations. The picosecond to nanosecond dynamics of the apo state are typical of a well-folded protein, with reduced amplitudes of motions in the helical segments, but with significant flexibility in the Ca2+-binding loops. Comparisons with order parameters for skeletal troponin C and calbindin D9k reveal key structural and dynamical differences that correlate with the different Ca2+-binding properties of these proteins.

Amino Acid Sequence↗
PubMed1995

Human type-alpha transforming growth factor undergoes slow conformational exchange between multiple backbone conformations as characterized by nitrogen-15 relaxation measurements.

Human type-alpha transforming growth factor (hTGF alpha) is a small mitogenic protein containing 50 amino acids and three disulfide bonds. It has both sequence and structural homology with epidermal growth factor (EGF). While the three-dimensional structures of hTGF alpha and other EGF-like proteins have been studied extensively, relatively little is known about conformational dynamics of these molecules. In this paper we describe nuclear relaxation measurements which probe the molecular dynamics of hTGF alpha in aqueous solution at neutral pH. In order to characterize conformational dynamics of hTGF alpha on both the fast (i.e., sub-nanosecond) and intermediate nitrogen-15 chemical-exchange (i.e., microsecond) time scales, we measured nitrogen-15 relaxation parameters at pH 7.1 +/- 0.1 and a temperature of 30 +/- 0.5 degrees C. Measurements of nitrogen-15 longitudinal (R1) and transverse (R2) relaxation rates, and 1H-15N heteronuclear NOE effects, were then interpreted using an extended Lipari-Szabo analysis [Lipari, G., & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559; Clore, G. M., Szabo, A., Bax, A., Kay, L. E., Driscoll, P. C., & Gronenborn, A. M. (1990) J. Am. Chem. Soc. 112, 4989-4991] to provide estimates of the locations and amplitudes of fast internal motions and the locations of nitrogen-15 chemical-exchange line broadening. These results demonstrate that, under conditions of pH and temperature at which it is tightly bound by the EGF receptor, hTGF alpha is a highly dynamic molecule. Indeed, some 40% of the backbone amide groups of hTGF alpha, including many at the interface between the two subdomains, exhibit significant nitrogen-15 chemical-exchange line broadening indicative of interconversions between multiple protein conformations on the microsecond time scale. The distribution of these sites on the three-dimensional protein structure suggests that these dynamic fluctuations are due to (i) partial unfolding of the core beta-sheet, (ii) hinge-bending motions between the N- and C-terminal subdomains, and/or (iii) disulfide bond isomerization in the solution structure of hTGF alpha at neutral pH.

Amino Acid Sequence↗