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PubMed2004

Dynamic conformational heterogeneities of carcinogen-DNA adducts and their mutagenic relevance.

Arylamines and polycyclic aromatic hydrocarbons (PAHs), which are known as "bulky" carcinogens, have been studied extensively and upon activation in vivo, react with cellular DNA to form DNA-adducts. The available structure data accumulated thus far has revealed that conformational heterogeneity is a common theme among duplex DNA modified with these carcinogens. Several conformationally diverse structures have been elucidated and found to be in equilibrium in certain cases. The dynamics of the heterogeneity appear to be modulated by the nature of the adduct structure and the base sequences neighboring the lesion site. These can be termed as "adduct- and sequence-induced conformational heterogeneities," respectively. Due to the small energy differences, the population levels of these conformers could readily be altered within the active sites of repair or replicate enzymes. Thus, the complex role of "enzyme-induced conformational heterogeneity" must also be taken into consideration for the establishment of a functional structure-mutation relationship. Ultimately, a major challenge in mutation structural biology is to carry out adduct- and site-specific experiments in a conformationally specific manner within biologically relevant environments. Results from such experiments should provide an accurate account of how a single chemically homogenous adduct gives rise to complex multiple mutations, the earliest step in the induction of cancer.

Carcinogens↗
PubMed2006

Helical conformational dynamics and photoisomerism of alternating pyridinedicarboxamide/m-(phenylazo)azobenzene oligomers.

Alternating sequences of pyridine-2,6-dicarboxamides and meta-(phenylazo)azobenzenes have been assembled into oligomers composed of four (8) and eight (9) azobenzene linkages. X-ray crystallography confirmed that oligomer 8 adopts a two-turn helical conformation with a helical pitch of approximately 3.4 Angstroms in the solid state. The presence of a two- and four-turn helical conformation of 8 and 9, respectively, in polar and nonpolar solvents was elucidated by the anisotropic upfield shifting of protons located within the helices, NOE enhancements between protons oriented toward the helix interior, and the diastereotopicity of the terminal benzyloxycarbonyl (CBz) methylene protons. (1)H NMR line shape analysis of the CBz methylene hydrogens at the chain ends revealed a dynamic equilibria interconverting M and P helical conformations with energetic barriers (DeltaG) of 11.1 (DeltaS = -19.4 +/- 1.6 cal mol(-1) K(-1); DeltaH = 6.5 +/- 0.4 kcal/mol) for 8 and 13.8 kcal/mol (DeltaS = -6.6 +/- 6.2 cal mol(-1) K(-1); DeltaH = 11.8 +/- 1.8 kcal/mol) for 9. Irradiation of the oligomers with 350 nm light induces an E --> Z isomerization of the azo linkages that decreases in efficacy at longer helix lengths. The suppression of E --> Z isomerization is a consequence of the contrasting behavior of the azo linkages located at the helix termini, which afford Z/E ratios similar to those of model compound 7d, and the internal azo groups, which undergo significantly lower Z/E conversion ratios compared with 7e.

Journal Article↗
PubMed2003

Conformational dynamics of the F1-ATPase beta-subunit: a molecular dynamics study.

According to the different nucleotide occupancies of the F(1)-ATPase beta-subunits and due to the asymmetry imposed through the central gamma-subunit, the beta-subunit adopts different conformations in the crystal structures. Recently, a spontaneous and nucleotide-independent closure of the open beta-subunit upon rotation of the gamma-subunit has been proposed. To address the question whether this closure is dictated by interactions to neighbored subunits or whether the open beta-subunit behaves like a prestressed "spring," we report multinanosecond molecular dynamics simulations of the isolated beta-subunit with different start conformations and different nucleotide occupancies. We have observed a fast, spontaneous closure motion of the open beta(E)-subunit, consistent with the available x-ray structures. The motions and kinetics are similar to those observed in simulations of the full (alpha beta)(3)gamma-complex, which support the view of a prestressed "spring," i.e., that forces internal to the beta(E)-subunit dominate possible interactions from adjacent alpha-subunits. Additionally, nucleotide removal is found to trigger conformational transitions of the closed beta(TP)-subunit; this provides evidence that the recently resolved half-closed beta-subunit conformation is an intermediate state before product release. The observed motions provide a plausible explanation why ADP and P(i) are required for the release of bound ATP and why gamma-depleted (alpha beta)(3) has a drastically reduced hydrolysis rate.

Adenosine Diphosphate↗
PubMed1991

Investigating protein conformation, dynamics and folding with monoclonal antibodies.

Monoclonal antibodies with thoroughly characterized target specificities can be used as powerful probes of protein conformation. In addition to providing information on the relative arrangement of the domains in the native molecule, they can also be used to monitor both early and late stages of protein folding and conformational changes related to enzyme action.

Antibodies, Monoclonal↗
PubMedDate not supplied

[The conformational dynamics of the tetramer hemoglobin molecule as revealed by hydrogen exchange. III. Influence of the heme removal].

Two main types of conformational fluctuations--local and global are characteristic of the native protein structure and revealed by hydrogen exchange. The probability of those fluctuations changes to a different extent upon hemoglobin oxygenation, changing of pH, splitting of the intersubunit contacts. To compare with the influence of the heme removal the rate of the H-D exchange of the peptide NH atoms of the human apoHb was studied at the pH range 5.5-9.0 and temperature 10-38 degrees C by the IR spectroscopy. The removal of the heme increases the rate of the H-D exchange of the 80% peptide NH atoms with the factor retardation of the exchange rate (P) in the range approximately 10(2)-10(8). For the most of the peptide NH atoms the probability of the local fluctuations weakly depends on the temperature, the enthalpy changes upon all such local conformational transitions deltaH(op) degrees are 0-15 kcal/M. Characterized by the stronger temperature dependence the global fluctuations are not arised upon the temperature increases up to 38 degrees C at pH 7.0 inspite of in these conditions the slow denaturation and aggregation of apoHb begin to occur. Upon the destabilization of the apoHb structure by the simultaneous decreasing of pH to 5.5 and temperature to 10 degrees C the global fluctuations of the apoHb native structure described by deltaH(op)o < 0 begin to intensify. The mechanism of the overall intensification of the local fluctuations upon the heme removal, the peculiarity of the heat denaturation of apoHb in conditions, close to that existing upon the selfassembly of Hb in vivo, and analogy between low temperature global fluctuations and cold denaturation of globular proteins are discussed.

Apoproteins↗
PubMed2006

Odorant binding and conformational dynamics in the odorant-binding protein.

In mammals, the olfactory epithelium secretes odorant-binding proteins (OBPs), which are lipocalins found freely dissolved in the mucus layer protecting the olfactory neurons. OBPs may act as passive transporters of predominantly hydrophobic odorant molecules across the aqueous mucus layer, or they may play a more active role in which the olfactory neuronal receptor recognizes the OBP-ligand complex. To better understand the molecular events accompanying the initial steps in the olfaction process, we have performed molecular dynamics studies of rat and pig OBPs with the odorant molecule thymol. These calculations provide an atomic level description of conformational changes and pathway intermediates that remain difficult to study directly. A series of eight independent molecular dynamics trajectories of rat OBP permitted the observation of a consensus pathway for ligand unbinding and the calculation of the potential of mean force (PMF) along this path. Titration microcalorimetry confirmed the specific binding of thymol to this protein with a strong hydrophobic component. In both rat and pig OBPs we observed lipocalin strand pair opening in the presence of ligand, consistent with potential roles of these proteins in olfactive receptor recognition.

Animals↗
PubMed2004

Conformational dynamics of single molecules visualized in real time by scanning force microscopy: macromolecular mobility on a substrate surface in different vapours.

We describe a technique to visualize and effect in real time motion and conformational transitions of single macromolecules. Two steps are involved. First, scanning force microscopy (SFM) was applied to detect in situ conformational transitions of single polymer molecules adsorbed on a substrate surface. Secondly, these changes were induced by controlled variations of environmental conditions in a microscope environmental chamber. In particular, we have revealed that exposure of a substrate with adsorbed macromolecules to vapours of different nature was able to increase molecular mobility and to stimulate conformational transitions of the polymer chains on the surface. Realization of SFM observation in a variable vapour environment was not as difficult as in liquid media. Variations of the vapour composition affected the oscillation dynamics of the cantilever with the scanning probe only to a small extent, and did not impede continuation of the scanning procedure. In fact, the characteristic times of the observed conformational changes were large enough (minutes to dozens of minutes) for sampling images repeatedly. Although recording of an SFM image was slow and required several minutes, we were able to visualize step-by-step the successive stages of the slow conformational transformation of the macromolecules adhering to the substrate, i.e. to investigate a molecular response to the environment changes in real time. Here, we studied the reversible collapse-decollapse transitions of cylindrical poly(methacrylate)-graft-poly(n-butyl acrylate) brush-like macromolecules exposed to different vapours. Single macromolecules on mica tended to assume a compacted globular conformation when exposed to the vapour of compounds, which due to their amphiphilic nature adsorb on mica and lower the surface energy of the substrate (e.g. alcohols). By contrast, the macromolecules adopted extended two-dimensional worm-like conformations in the vapours of compounds having high values of surface tension (such as water). In our opinion, the reason for the observed tendency was a competition in spreading on the substrate surface between the macromolecules and the co-adsorbed vapour molecules. If the brush-like macromolecules succeeded in the spreading, they acquired an extended conformation. Otherwise they collapsed to globuli in order to reduce the surface area per macromolecule. Thus, the enhanced mobility of synthetic macromolecules on a substrate observed in a vapour environment in combination with the possibility to manipulate the macromolecular conformation via changes in a vapour phase and the ability to visualize the transitions of the macromolecules individually, provides challenging prospects for SFM studies on the dynamics of single molecules under applied external stimuli.

Journal Article↗
PubMed2005

A conformational dynamics study of alpha-l-Rhap-(1-->2)[alpha-l-Rhap-(1-->3)]-alpha-l-Rhap-OMe in solution by NMR experiments and molecular simulations.

The conformational preference of alpha-l-Rhap-(1-->2)[alpha-l-Rhap-(1-->3)]-alpha-l-Rhap-OMe in solution has been studied by NMR spectroscopy using one-dimensional (1)H,(1)H T-ROESY experiments and measurement of trans-glycosidic (3)J(C,H) coupling constants. Molecular dynamics (MD) simulations with a CHARMM22 type of force field modified for carbohydrates were performed with water as the explicit solvent. The homonuclear cross-relaxation rates, interpreted as effective proton-proton distances, were compared to those obtained from simulation. Via a Karplus torsional relationship, (3)J(C,H) values were calculated from simulation and compared to experimental data. Good agreement was observed between experimental data and the MD simulation, except for one inter-residue T-ROE between protons in the terminal sugar residues. The results show that the trisaccharide exhibits substantial conformational flexibility, in particular along the psi glycosidic torsion angles. Notably, for these torsions, a high degree of correlation (77%) was observed in the MD simulation revealing either psi(2)(+) psi(3)(+) or psi(2)(-)psi(3)(-) states. The simulations also showed that non-exoanomeric conformations were present at the phi torsion angles, but to a limited extent, with the phi(3) state populated to a larger extent than the phi(2) state. Further NMR analysis of the trisaccharide by translational diffusion measurements and (13)C T(1) relaxation experiments quantified global reorientation using an anisotropic model together with interpretation of the internal dynamics via the "model-free" approach. Fitting of the dynamically averaged states to experimental data showed that the psi(2)(+)psi(3)(+) state is present to approximately 49%, psi(2)(-) psi(3)(-) to approximately 39%, and phi(3) (non-exo) to approximately 12%. Finally, using a dynamic and population-averaged model, (1)H,(1)H T-ROE buildup curves were calculated using a full relaxation matrix approach and were found to be in excellent agreement with experimental data, in particular for the above inter-residue proton-proton interaction between the terminal residues.

Carbohydrate Conformation↗
PubMed2006

A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases.

Eph receptor tyrosine kinases (RTKs) mediate numerous developmental processes. Their activity is regulated by auto-phosphorylation on two tyrosines within the juxtamembrane segment (JMS) immediately N-terminal to the kinase domain (KD). Here, we probe the molecular details of Eph kinase activation through mutational analysis, X-ray crystallography and NMR spectroscopy on auto-inhibited and active EphB2 and EphA4 fragments. We show that a Tyr750Ala gain-of-function mutation in the KD and JMS phosphorylation independently induce disorder of the JMS and its dissociation from the KD. Our X-ray analyses demonstrate that this occurs without major conformational changes to the KD and with only partial ordering of the KD activation segment. However, conformational exchange for helix alphaC in the N-terminal KD lobe and for the activation segment, coupled with increased inter-lobe dynamics, is observed upon kinase activation in our NMR analyses. Overall, our results suggest that a change in inter-lobe dynamics and the sampling of catalytically competent conformations for helix alphaC and the activation segment rather than a transition to a static active conformation underlies Eph RTK activation.

Amino Acid Substitution↗
PubMed2001

Conformational dynamics underlie the activity of the auxin-binding protein, Nt-abp1.

The auxin-binding protein 1 (ABP1) has been proposed to be involved in the perception of the phytohormone at the plasma membrane. Site-directed mutagenesis was performed on highly conserved residues at the C terminus of ABP1 to investigate their relative importance in protein folding and activation of a functional response at the plasma membrane. Detailed analysis of the dynamic interaction of the wild-type ABP1 and mutated proteins with three distinct monoclonal antibodies recognizing conformation-dependent epitopes was performed by surface plasmon resonance. The influence of auxin on these interactions was also investigated. The Cys(177) as well as Asp(175) and Glu(176) were identified as critical residues for ABP1 folding and action at the plasma membrane. On the contrary, the C-terminal KDEL sequence was demonstrated not to be essential for auxin binding, interaction with the plasma membrane, or activation of the transduction cascade although it does appear to be involved in the stability of ABP1. Taken together, the results confirmed that ABP1 conformational change is the critical step for initiating the signal from the plasma membrane.

Amino Acid Sequence↗
PubMed2000

Comparison of interpolated vs. calculated micromultileaf settings in dynamic conformal arc treatment.

Stereotactic radiosurgery has developed into a technique where patient positioning and treatment delivery can be performed with submillimeter precision. Achievement of this level of precision has allowed margins to be significantly reduced, and in some cases, removed altogether. Joined with these reductions in treatment margin has come a desire to shape the radiation beam, further limiting dose to normal tissues. Initial applications of shaped radiosurgery fields utilized circular blocking apertures in an attempt to shape the beam to these small volumes. The resultant dose distributions conformed well to spherical treatment volumes but were inadequate for situations where the volume of interest was irregular in shape. Other techniques, such as applying these circular apertures through multiple isocenter positions to a single volume, have been investigated as possible ways to better conform dose distributions to these irregularly-shaped volumes. Recent technological advances allow the use of micromultileaf collimators which dynamically shape the beam by adjustment of individual leaves as the gantry rotates through the are. With margins potentially so tight, accurate evaluation of these dynamically adjusting treatment parameters becomes critical. Our current treatment planning software evaluates adjustments of the leaf positions in increments of 10 degrees and then does a linear interpolation between increments. Treatment delivery, however, is performed with adjustment in leaf position more consistent with a 1 degree increment. This paper compares the individual position of each leaf as determined for the 10 degrees interpolation to required changes in leaf position when the calculation is performed at increments of less than 10 degrees. Our data suggest that there are instances where improvements can be seen when corrections in leaf positions are made at these smaller increments.

Humans↗
PubMed2002

Mode-coupling theory for structural and conformational dynamics of polymer melts.

A mode-coupling theory for dense polymeric systems is developed which unifyingly incorporates the segmental cage effect relevant for structural slowing down and polymer chain conformational degrees of freedom. An ideal glass transition of polymer melts is predicted which becomes molecular-weight independent for large molecules. The theory provides a microscopic justification for the use of the Rouse theory in polymer melts, and the results for Rouse-mode correlators and mean-squared displacements are in good agreement with computer simulation results.

Journal Article↗
PubMed2005

Real-time monitoring of conformational dynamics of the epsilon subunit in F1-ATPase.

It has been proposed that C-terminal two alpha-helices of the epsilon subunit of F1-ATPase can undergo conformational transition between retracted folded-hairpin form and extended form. Here, using F(1) from thermophilic Bacillus PS3, we monitored this transition in real time by fluorescence resonance energy transfer (FRET) between a donor dye and an acceptor dye attached to N terminus of the gamma subunit and C terminus of the epsilon subunit, respectively. High FRET (extended form) of F1 turned to low FRET (retracted form) by ATP, which then reverted as ATP was hydrolyzed to ADP. 5'-Adenyl-beta,gamma-imidodiphosphate, ADP + AlF4-, ADP + NaN3, and GTP also caused the retracted form, indicating that ATP binding to the catalytic beta subunits induces the transition. The ATP-induced transition from high FRET to low FRET occurred in a similar time scale to the ATP-induced activation of ATPase from inhibition by the epsilon subunit, although detailed kinetics were not the same. The transition became faster as temperature increased, but the extrapolated rate at 65 degrees C (physiological temperature of Bacillus PS3) was still too slow to assign the transition as an obligate step in the catalytic turnover. Furthermore, binding affinity of ATP to the isolated epsilon subunit was weakened as temperature increased, and the dissociation constant extrapolated to 65 degrees C reached to 0.67 mm, a consistent value to assume that the epsilon subunit acts as a sensor of ATP concentration in the cell.

Adenosine Diphosphate↗