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1

Modeling of solvent-dependent conformational transitions in Burkholderia cepacia lipase  

PubMed Central

Background The characteristic of most lipases is the interfacial activation at a lipid interface or in non-polar solvents. Interfacial activation is linked to a large conformational change of a lid, from a closed to an open conformation which makes the active site accessible for substrates. While for many lipases crystal structures of the closed and open conformation have been determined, the pathway of the conformational transition and possible bottlenecks are unknown. Therefore, molecular dynamics simulations of a closed homology model and an open crystal structure of Burkholderia cepacia lipase in water and toluene were performed to investigate the influence of solvents on structure, dynamics, and the conformational transition of the lid. Results The conformational transition of B. cepacia lipase was dependent on the solvent. In simulations of closed B. cepacia lipase in water no conformational transition was observed, while in three independent simulations of the closed lipase in toluene the lid gradually opened during the first 10–15 ns. The pathway of conformational transition was accessible and a barrier was identified, where a helix prevented the lid from opening to the completely open conformation. The open structure in toluene was stabilized by the formation of hydrogen bonds. In simulations of open lipase in water, the lid closed slowly during 30 ns nearly reaching its position in the closed crystal structure, while a further lid opening compared to the crystal structure was observed in toluene. While the helical structure of the lid was intact during opening in toluene, it partially unfolded upon closing in water. The closing of the lid in water was also observed, when with eight intermediate structures between the closed and the open conformation as derived from the simulations in toluene were taken as starting structures. A hydrophobic ?-hairpin was moving away from the lid in all simulations in water, which was not observed in simulations in toluene. The conformational transition of the lid was not correlated to the motions of the ?-hairpin structure. Conclusion Conformational transitions between the experimentally observed closed and open conformation of the lid were observed by multiple molecular dynamics simulations of B. cepacia lipase. Transitions in both directions occurred without applying restraints or external forces. The opening and closing were driven by the solvent and independent of a bound substrate molecule.

Trodler, Peter; Schmid, Rolf D; Pleiss, Jurgen

2009-01-01

2

Modeling of solvent-dependent conformational transitions in Burkholderia cepacia lipase  

Microsoft Academic Search

BACKGROUND: The characteristic of most lipases is the interfacial activation at a lipid interface or in non-polar solvents. Interfacial activation is linked to a large conformational change of a lid, from a closed to an open conformation which makes the active site accessible for substrates. While for many lipases crystal structures of the closed and open conformation have been determined,

Peter Trodler; Rolf D Schmid; Jürgen Pleiss

2009-01-01

3

Solvent-dependent transition states for decarboxylations.  

PubMed

The rate constants and kinetic isotope effects for decarboxylation of 4-pyridylacetic acid depend strongly on whether the solvent is water or dioxane, and the present paper interprets this finding. We calculate the solvent dependence of the free energy barrier and of the (13)C and (18)O kinetic isotope effects using a quantum mechanical solvation model based on class IV charges and semiempirical atomic surface tensions. The calculations provide a consistent interpretation of the experimental results, which provides a striking confirmation of the soundness of the solvation modeling. Even more significantly, the agreement of theory and experiment gives us confidence in the physical picture of the reaction provided by the model. This indicates that the location of the transition state, as measured by the length of the breaking C--C bond, is 0.24 A later than the gas phase in dioxane and 0.37 A later than the gas phase in water. Charge development at the transition state also depends strongly on the solvent; in particular the CO(2) moiety is 0.07 electronic charge units more negative at the transition state in dioxane than in water. PMID:11480991

Sicinska, D; Truhlar, D G; Paneth, P

2001-08-01

4

An experimental study of the solvent-dependent self-assembly/disassembly and conformer preferences of gramicidin A.  

PubMed

The solvent dependence of self-assembly/disassembly kinetics and conformer preferences of the gramicidin A (GA) dimer is investigated using a combination of techniques, viz., electrospray ionization-ion mobility-mass spectrometry (IM-MS), collision-induced dissociation (CID), and hydrogen/deuterium exchange (HDX)-MS. IM-MS measurements reveal that there are possibly three distinct GA dimeric species, detected as sodium ion adduct ions [2GA + 2Na](2+), and these are assigned as the parallel ?-helix, antiparallel ?-helix, and head-to-head dimer. The monomerization kinetics and equilibrium abundances of the dimer ions depend upon solvent polarity. The antiparallel ?-helix was the thermodynamically preferred species in less polar solvents. HDX measurements and collision-induced dissociation (CID) of the intermediate complex confirm the well-protected dimer geometry with strong intermolecular hydrogen bonds. This combined IM-HDX-CID methodology provides a comprehensive view of GA self-assembly/disassembly in low dielectric solutions, showing its potential utility in solving solution-phase protein self-assembly/disassembly kinetics and providing structural information of the multimers at the same time. PMID:23855712

Chen, Liuxi; Chen, Shu-Hua; Russell, David H

2013-08-20

5

Simulation of conformational transitions  

Microsoft Academic Search

Conformational transitions are essential for the functioning of many proteins, and understanding this dynamical behavior is a central goal in molecular biology. Computer simulations are playing an important role towards this aim by providing insights into how the conformational changes are induced, propagated and used. Popular methods for the simulation of conformational transitions will be reviewed, with a focus on

Arjan van der Vaart

2006-01-01

6

Conformational transition behavior around glass transition temperature  

NASA Astrophysics Data System (ADS)

The conformational transition behavior around the glass transition temperature has been studied by means of molecular dynamics through a model system, atactic polypropylene in bulk. Various criteria of the conformational transition were examined. A domain at barrier site is defined as the transition state of the conformers and the other conformational states are labeled in code. The transition is accepted when the code is changed. Variation of the width of the domain at barrier distinguishes the deep jumps of the torsion rotations from the shallow jumps that do not reach the well bottom within +/-20° from the minimum. The behavior of the deep jumps obeys the rate equation of the transition-state theory, being independent of Tg. The shallow jumps were found significant in the characterization of the motion of polymer chains through Tg. This study thus proves that the changes of properties of polymers resulting from the glass transition are predominately mastered by the shallow jumps.

Liang, Taining; Yang, Yong; Guo, Dawei; Yang, Xiaozhen

2000-01-01

7

Spurious conformational transitions in proteins?  

PubMed Central

Temperature-dependent dynamic processes in biological macromolecules can produce sharp and reversible transitions in spectroscopic properties that might be misinterpreted as evidence for thermally induced conformational changes. This provides a rational explanation for the paradoxical case of D-amino acid oxidase [D-amino-acid:oxygen oxidoreductase (deaminating), EC 1.4.3.3], for which a sharp fluorescence transition at 14 degrees C, not observed by sensitive calorimetry [Sturtevant, J. M. & Mateo, P. L. (1978) Proc. Natl. Acad. Sci. USA 75, 2584-2587], could be due to a dynamic quenching process of large activation energy, rather than a change in conformational state of the protein. Similar interpretations may be valid in other systems studied by experimental techniques that depend, directly or indirectly, on molecular relaxation processes.

Cooper, A

1981-01-01

8

Electroweak phase transition in nearly conformal technicolor  

Microsoft Academic Search

We examine the temperature-dependent electroweak phase transition in extensions of the standard model in which the electroweak symmetry is spontaneously broken via strongly coupled, nearly conformal dynamics. In particular, we focus on the low energy effective theory used to describe minimal walking technicolor at the phase transition. Using the one-loop effective potential with ring improvement, we identify significant regions of

James M. Cline; Matti Järvinen; Francesco Sannino

2008-01-01

9

Kinetics of conformational transitions in chain molecules  

Microsoft Academic Search

A theory is developed for the rate of conformational transitions (trans-->gauche) of bonds in chain molecules, such as alkanes and polymers. This is a multidimensional extension of Kramers' reaction rate theory. Central to the understanding of how changes in the chain's geometry affect transition rate is the determination and examination of the reaction coordinate. The reaction coordinate is a localized

Jeffrey Skolnick; Eugene Helfand

1980-01-01

10

Transition path sampling of protein conformational changes  

NASA Astrophysics Data System (ADS)

Conformational changes in proteins often take place on long time scales compared to the molecular timescale. These long time scales, related to high free energy barriers, make such processes difficult to access with a straightforward molecular dynamics approach. The transition path sampling technique has been developed to overcome such timescale differences without assuming a predefined reaction coordinate. We review the transition path sampling methodology with the application of protein conformational change in mind. Using three case studies, based on previous work, we elucidate the strengths and pitfalls of the method. First, the extensive work on the folding of Trp-cage reveals how to sample parallel pathways, how to obtain rate constants, and how to extract reaction coordinates. The second case-study, on the folding of Trpzip4 ?-hairpin, illustrates how to treat long-lived intermediates in a conformational change. The final example showcases the light-triggered conformational transition of Photo-active Yellow Protein into its signaling state, highlighting the wealth of insight that can be gathered from a transition path sampling approach, including new hypotheses for reaction mechanisms. We end with an outlook discussing future developments and application of the methodology.

Juraszek, Jarek; Vreede, Jocelyne; Bolhuis, Peter G.

2012-03-01

11

Electroweak phase transition in nearly conformal technicolor  

SciTech Connect

We examine the temperature-dependent electroweak phase transition in extensions of the standard model in which the electroweak symmetry is spontaneously broken via strongly coupled, nearly conformal dynamics. In particular, we focus on the low energy effective theory used to describe minimal walking technicolor at the phase transition. Using the one-loop effective potential with ring improvement, we identify significant regions of parameter space which yield a sufficiently strong first-order transition for electroweak baryogenesis. The composite particle spectrum corresponding to these regions can be produced and studied at the Large Hadron Collider experiment. We note the possible emergence of a second phase transition at lower temperatures. This occurs when the underlying technicolor theory possesses a nontrivial center symmetry.

Cline, James M.; Jaervinen, Matti; Sannino, Francesco [McGill University, Montreal, Quebec H3A 2T8 (Canada); High Energy Center, University of Southern Denmark, Campusvej 55, DK-5230 Odense M (Denmark)

2008-10-01

12

Pathway of the conformational transitions in flexible molecules  

Microsoft Academic Search

The pathways of the conformational transitions in flexible molecular systems were studied by the DDRP (Dynamically Determined Reaction Path) method implemented in TINKER molecular modelling package. Our first model systems were conformational transitions in small organic molecules (determination of rotational transitions, boat-chair transitions, etc.). The method was found to be very effective in finding such transitions and the location of

T. Körtvélyesi; L. L. Stacho?; Gy. Dömötör; B. Jójárt; M. I. Bán

2005-01-01

13

DNA conformational transitions induced by supercoiling control transcription in chromatin.  

PubMed

Regulation of transcription in eukaryotes is considered in the light of recent findings demonstrating the presence of negative and positive superhelical tension in chromatin. This tension induces conformational transitions in DNA duplex. Particularly, the transition into A-form renders DNA accessible and waylaying for initiation of transcription producing RNA molecules long known to belong to the A-conformation. Competition between conformational transitions in various DNA sequences for the energy of elastic spring opens a possibility for understanding of fine tuning of transcription at a distance. PMID:24653646

Luchnik, Andrey N

2014-01-01

14

Conformal invariance of the transition vertex 2 ? 4 gluons  

Microsoft Academic Search

We show that the transition vertex: two reggeized gluons ? four reggeized gluons in invariant under Möbius transformations. This provides an important step in defining a conformally invariant effective field theory for QCD in the Regge limit.

J. Bartels; L. N. Lipatov; M. Wüsthoff

1996-01-01

15

De Sitter Transitivity, Conformal Transformations and Conservation Laws  

NASA Astrophysics Data System (ADS)

Minkowski spacetime is transitive under ordinary translations, a transformation that do not have matrix representations. The de Sitter spacetime, on the other hand, is transitive under a combination of translations and proper conformal transformations, which do have a matrix representation. Such matrix, however, is not by itself a de Sitter generator: it gives rise to a conformal re-scaling of the metric, a transformation not belonging to the de Sitter group, and in general not associated with diffeomorphisms in spacetime. When dealing with variational principles and Noether's theorem in de Sitter spacetime, it is necessary to regularize the transformations in order to eliminate the conformal re-scaling of the metric.

Pereira, J. G.; Sampson, A. C.; Savi, L. L.

2014-04-01

16

Conformation transition kinetics ofBombyx mori silk protein  

Microsoft Academic Search

Time-resolved FTIR analysis was used to monitor the conformation transition induced by treating regenerated Bombyx mori silk fibroin films and solutions with different concentrations of ethanol. The resulting curves showing the kinetics of the transition for both films and fibroin solutions were influenced by the ethanol concentration. In addition, for silk fibroin solutions the protein con- centration also had an

Xin Chen; Zhengzhong Shao; David P. Knight; Fritz Vollrath

2007-01-01

17

Intermediate conformations during viral fusion glycoprotein structural transition.  

PubMed

Entry of enveloped viruses into cells requires the fusion of viral and cellular membranes, driven by conformational changes in viral glycoproteins. Three different classes of viral fusion proteins have been hitherto identified based on common structural elements. Crystal structures have provided static pictures of pre-fusion and post-fusion conformations of these proteins and have revealed the dramatic reorganization of the molecules, but the transition pathway remains elusive. In this review, we will focus on recent data aiming to characterize intermediate structures during the conformational change. All these data support the existence of a pre-hairpin intermediate, but its oligomeric status is still a matter of debate. PMID:23562213

Baquero, Eduard; Albertini, Aurélie A; Vachette, Patrice; Lepault, Jean; Bressanelli, Stéphane; Gaudin, Yves

2013-04-01

18

Conformational transition pathway in the allosteric process of human glucokinase  

PubMed Central

Glucokinase (GK) is an important enzyme for regulating blood glucose levels and a potentially attractive target for diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the conformational transition of GK from the closed state to the superopen state, a series of conventional molecular dynamics (MD) and target MD (TMD) simulations were performed on both the wild-type enzyme and its mutants. Two 10-ns conventional MD simulations showed that, although the allosteric site of GK is ?20 Å away from the active site, the activator is able to enhance the activity of the enzyme through conformational restriction. Fourteen TMD simulations on GK and five of its mutants revealed a reliably conformational transition pathway. The overall conformational transition includes three stages, and three likely stable intermediate states were identified by free energy scanning for the snapshots throughout the pathway. The conformational transition feature revealed by our TMD simulations rationalized several important mutagenesis and kinetic data. Remarkably, the TMD simulations predicted that Y61S, I159A, A201R, V203E, and V452S mutations, which have not been investigated so far, may facilitate the opening process of GK. These predictions also have been verified by mutagenesis and kinetic analyses in this study. These observations are beneficial to understanding the mechanism of GK regulation and designing the compounds for treating metabolic diseases.

Zhang, Jian; Li, Chenjing; Chen, Kaixian; Zhu, Weiliang; Shen, Xu; Jiang, Hualiang

2006-01-01

19

Conformational transitions in random heteropolymer models  

NASA Astrophysics Data System (ADS)

We study the conformational properties of heteropolymers containing two types of monomers A and B, modeled as self-attracting self-avoiding random walks on a regular lattice. Such a model can describe in particular the sequences of hydrophobic and hydrophilic residues in proteins [K. F. Lau and K. A. Dill, Macromolecules 22, 3986 (1989)] and polyampholytes with oppositely charged groups [Y. Kantor and M. Kardar, Europhys. Lett. 28, 169 (1994)]. Treating the sequences of the two types of monomers as quenched random variables, we provide a systematic analysis of possible generalizations of this model. To this end we apply the pruned-enriched Rosenbluth chain-growth algorithm, which allows us to obtain the phase diagrams of extended and compact states coexistence as function of both the temperature and fraction of A and B monomers along the heteropolymer chain.

Blavatska, Viktoria; Janke, Wolfhard

2014-01-01

20

Maximum Flux Transition Paths of Conformational Change.  

PubMed

Given two metastable states A and B of a biomolecular system, the problem is to calculate the likely paths of the transition from A to B. Such a calculation is more informative and more manageable if done for a reduced set of collective variables chosen so that paths cluster in collective variable space. The computational task becomes that of computing the "center" of such a cluster. A good way to define the center employs the concept of a committor, whose value at a point in collective variable space is the probability that a trajectory at that point will reach B before A. The committor "foliates" the transition region into a set of isocommittors. The maximum flux transition path is defined as a path that crosses each isocommittor at a point which (locally) has the highest crossing rate of distinct reactive trajectories. This path is based on the same principle as the minimum resistance path of Berkowitz et al (1983), but it has two advantages: (i) the path is invariant with respect to a change of coordinates in collective variable space and (ii) the differential equations that define the path are simpler. It is argued that such a path is nearer to an ideal path than others that have been proposed with the possible exception of the finite-temperature string method path. To make the calculation tractable, three approximations are introduced, yielding a path that is the solution of a nonsingular two-point boundary-value problem. For such a problem, one can construct a simple and robust algorithm. One such algorithm and its performance is discussed. PMID:20890401

Zhao, Ruijun; Shen, Juanfang; Skeel, Robert D

2010-08-10

21

Quantum Hall transitions: An exact theory based on conformal restriction  

NASA Astrophysics Data System (ADS)

We revisit the problem of the plateau transition in the integer quantum Hall effect. Here we develop an analytical approach for this transition, and for other two-dimensional disordered systems, based on the theory of “conformal restriction.” This is a mathematical theory that was recently developed within the context of the Schramm-Loewner evolution which describes the “stochastic geometry” of fractal curves and other stochastic geometrical fractal objects in two-dimensional space. Observables elucidating the connection with the plateau transition include the so-called point-contact conductances (PCCs) between points on the boundary of the sample, described within the language of the Chalker-Coddington network model for the transition. We show that the disorder-averaged PCCs are characterized by a classical probability distribution for certain geometric objects in the plane (which we call pictures), occurring with positive statistical weights, that satisfy the crucial so-called restriction property with respect to changes in the shape of the sample with absorbing boundaries; physically, these are boundaries connected to ideal leads. At the transition point, these geometrical objects (pictures) become fractals. Upon combining this restriction property with the expected conformal invariance at the transition point, we employ the mathematical theory of “conformal restriction measures” to relate the disorder-averaged PCCs to correlation functions of (Virasoro) primary operators in a conformal field theory (of central charge c=0). We show how this can be used to calculate these functions in a number of geometries with various boundary conditions. Since our results employ only the conformal restriction property, they are equally applicable to a number of other critical disordered electronic systems in two spatial dimensions, including for example the spin quantum Hall effect, the thermal metal phase in symmetry class D, and classical diffusion in two dimensions in a perpendicular magnetic field. For most of these systems, we also predict exact values of critical exponents related to the spatial behavior of various disorder-averaged PCCs.

Bettelheim, E.; Gruzberg, I. A.; Ludwig, A. W. W.

2012-10-01

22

Solutes Modify a Conformational Transition in a Membrane Transport Protein  

PubMed Central

The bacterial outer-membrane vitamin B12 transporter, BtuB, undergoes a dramatic order-to-disorder transition in its N-terminal energy-coupling motif (Ton box) upon substrate binding. Here, site-directed spin labeling (SDSL) is used to show that a range of solutes prevents this conformational change when ligand is bound to BtuB, resulting in a more ordered Ton box structure. For each solute examined, the data indicate that solutes effectively block this conformational transition through an osmotic mechanism. The molecular weight dependence of this solute effect has been examined for a series of polyethylene glycols, and a sharp molecular weight cutoff is observed. This cutoff indicates that solutes are preferentially excluded from a cavity within the protein as well as the protein surface. Furthermore, the sensitivity of the conformational change to solution osmolality is consistent with a structural model predicted by SDSL. When the Ton box is unfolded by detergents or mutations (rather than by ligand binding), solutes, such as polyethylene glycols and salts, also induce a more structured compacted conformation. These results suggest that conformational changes in this class of outer membrane transporters, which involve modest energy differences and changes in hydration, may be modulated by a range of solutes, including solutes typically used in protein crystallization.

Kim, Miyeon; Xu, Qi; Fanucci, Gail E.; Cafiso, David S.

2006-01-01

23

Unique Solvent-Dependent Atropisomerism of a Novel Cytotoxic Naphthoxanthene Antibiotic FD-594.  

PubMed

The absolute stereochemistry of FD-594 1, a new cytotoxic antibiotic, was determined by X-ray diffraction, and its conformation was studied by CD and NMR spectroscopy. The aglycon part of 1 was found to have (3R,6S,7S) configuration. Particularly interesting was the solvent-dependent atropisomerism of 1 and related compounds. The CD spectra of 1 exhibited in two solvent systems almost opposite mirror-image curves depending on the solvent. While a large negative Cotton effect (Deltaepsilon = -33.9, 279 nm) was observed in CHCl(3), a similar positive Cotton effect (Deltaepsilon = 38.9, 279 nm) appeared in methanol most probably due to dramatic conformational changes. Similar chiroptical reversal was observed in aglycon 2 and aglycon methyl ether 4. These results can be best described in terms of solvent-dependent atropisomerism. This constitutes the first observation of solvent-dependent atropisomerism of a natural product. The crucial factor that perturbs the stable conformation in different solvents is discussed on the basis of molecular mechanics calculations. PMID:11674595

Eguchi, Tadashi; Kondo, Katsuya; Kakinuma, Katsumi; Uekusa, Hidehiro; Ohashi, Yuji; Mizoue, Kazutoshi; Qiao, Ya-Fang

1999-07-23

24

Conformation transition kinetics of Bombyx mori silk protein.  

PubMed

Time-resolved FTIR analysis was used to monitor the conformation transition induced by treating regenerated Bombyx mori silk fibroin films and solutions with different concentrations of ethanol. The resulting curves showing the kinetics of the transition for both films and fibroin solutions were influenced by the ethanol concentration. In addition, for silk fibroin solutions the protein concentration also had an effect on the kinetics. At low ethanol concentrations (for example, less than 40% v/v in the case of film), films and fibroin solutions showed a phase in which beta-sheets slowly formed at a rate dependent on the ethanol concentration. Reducing the concentration of the fibroin in solutions also slowed the formation of beta-sheets. These observations suggest that this phase represents a nucleation step. Such a nucleation phase was not seen in the conformation transition at ethanol concentrations > 40% in films or > 50% in silk fibroin solutions. Our results indicate that the ethanol-induced conformation transition of silk fibroin in films and solutions is a three-phase process. The first phase is the initiation of beta-sheet structure (nucleation), the second is a fast phase of beta-sheet growth while the third phase represents a slow perfection of previously formed beta-sheet structure. The nucleation step can be very fast or relatively slow, depending on factors that influence protein chain mobility and intermolecular hydrogen bond formation. The findings give support to the previous evidence that natural silk spinning in silkworms is nucleation-dependent, and that silkworms (like spiders) use concentrated silk protein solutions, and careful control of the pH value and metallic ion content of the processing environment to speed up the nucleation step to produce a rapid conformation transition to convert the water soluble spinning dope to a tough solid silk fiber. PMID:17436322

Chen, Xin; Shao, Zhengzhong; Knight, David P; Vollrath, Fritz

2007-07-01

25

Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA  

PubMed Central

We develop a statistical mechanical model to analyze the competitive behavior of transitions to multiple alternate conformations in a negatively supercoiled DNA molecule of kilobase length and specified base sequence. Since DNA superhelicity topologically couples together the transition behaviors of all base pairs, a unified model is required to analyze all the transitions to which the DNA sequence is susceptible. Here we present a first model of this type. Our numerical approach generalizes the strategy of previously developed algorithms, which studied superhelical transitions to a single alternate conformation. We apply our multi-state model to study the competition between strand separation and B-Z transitions in superhelical DNA. We show this competition to be highly sensitive to temperature and to the imposed level of supercoiling. Comparison of our results with experimental data shows that, when the energetics appropriate to the experimental conditions are used, the competition between these two transitions is accurately captured by our algorithm. We analyze the superhelical competition between B-Z transitions and denaturation around the c-myc oncogene, where both transitions are known to occur when this gene is transcribing. We apply our model to explore the correlation between stress-induced transitions and transcriptional activity in various organisms. In higher eukaryotes we find a strong enhancement of Z-forming regions immediately 5? to their transcription start sites (TSS), and a depletion of strand separating sites in a broad region around the TSS. The opposite patterns occur around transcript end locations. We also show that susceptibility to each type of transition is different in eukaryotes and prokaryotes. By analyzing a set of untranscribed pseudogenes we show that the Z-susceptibility just downstream of the TSS is not preserved, suggesting it may be under selection pressure.

Zhabinskaya, Dina; Benham, Craig J.

2012-01-01

26

Cooperative Transition between Open and Closed Conformations in Potassium Channels  

PubMed Central

Potassium (K+) ion channels switch between open and closed conformations. The nature of this important transition was revealed by comparing the X-ray crystal structures of the MthK channel from Methanobacterium thermoautotrophicum, obtained in its open conformation, and the KcsA channel from Streptomyces lividans, obtained in its closed conformation. We analyzed the dynamic characteristics and energetics of these homotetrameric structures in order to study the role of the intersubunit cooperativity in this transition. For this, elastic models and in silico alanine-scanning mutagenesis were used, respectively. Reassuringly, the calculations manifested motion from the open (closed) towards the closed (open) conformation. The calculations also revealed a network of dynamically and energetically coupled residues. Interestingly, the network suggests coupling between the selectivity filter and the gate, which are located at the two ends of the channel pore. Coupling between these two regions was not observed in calculations that were conducted with the monomer, which emphasizes the importance of the intersubunit interactions within the tetrameric structure for the cooperative gating behavior of the channel.

2008-01-01

27

Conformational transition of H-shaped branched polymers  

NASA Astrophysics Data System (ADS)

We report dynamic Monte Carlo simulation on conformational transition of H-shaped branched polymers by varying main chain (backbone) and side chain (branch) length. H-shaped polymers in comparison with equivalent linear polymers exhibit a depression of theta temperature accompanying with smaller chain dimensions. We observed that the effect of branches on backbone dimension is more pronounced than the reverse, and is attributed to the conformational heterogeneity prevails within the molecule. With an increase in branch length, backbone is slightly stretched out in the coil and globule state. However, in the pre-collapsed (cf. crumpled globule) state, backbone size decreases with the increase of branch length. We attribute this non-monotonic behavior as the interplay between excluded volume interaction and intra-chain bead-bead attractive interaction during collapse transition. Structural analysis reveals that the inherent conformational heterogeneity promotes the formation of a collapsed structure with segregated backbone and branch units (resembles to "sandwich" or "Janus" morphology) rather an evenly distributed structure consisting of all the units. The shape of the collapsed globule becomes more spherical with increasing either backbone or branch length.

Dasmahapatra, Ashok Kumar; Sanka, Venkata Mahanth

2014-03-01

28

Conformational Transition Pathway in the Activation Process of Allosteric Glucokinase  

PubMed Central

Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins.

Shi, Ting; Zhao, Yaxue; Chen, Yingyi; Li, Xiaobai; Liu, Xinyi; Huang, Zhimin; Zhang, Jian

2013-01-01

29

From induced fit to conformational selection: a continuum of binding mechanism controlled by the timescale of conformational transitions.  

PubMed

In receptor-ligand binding, a question that generated considerable interest is whether the mechanism is induced fit or conformational selection. This question is addressed here by a solvable model, in which a receptor undergoes transitions between active and inactive forms. The inactive form is favored while unbound but the active form is favored while a ligand is loosely bound. As the active-inactive transition rates increase, the binding mechanism gradually shifts from conformational selection to induced fit. The timescale of conformational transitions thus plays a crucial role in controlling binding mechanisms. PMID:20303846

Zhou, Huan-Xiang

2010-03-17

30

Conformal invariance at a deconfinement phase transition in (2+1) dimensions.  

National Technical Information Service (NTIS)

The conformal dimension of the Polyakov line at the deconfinement phase transition of (2+1)-dimensional SU(2) lattice gauge theory is determined numerically using two-dimensional finite size conformal field theory. Excellent agreement with two-dimensional...

J. Christensen P. H. Damgaard

1990-01-01

31

Molecular dynamics studies on the conformational transitions of adenylate kinase: a computational evidence for the conformational selection mechanism.  

PubMed

Escherichia coli adenylate kinase (ADK) is a monomeric phosphotransferase enzyme that catalyzes reversible transfer of phosphoryl group from ATP to AMP with a large-scale domain motion. The detailed mechanism for this conformational transition remains unknown. In the current study, we performed long time-scale molecular dynamics simulations on both open and closed states of ADK. Based on the structural analyses of the simulation trajectories, we detected over 20 times conformational transitions between the open and closed states of ADK and identified two novel conformations as intermediate states in the catalytic processes. With these findings, we proposed a possible mechanism for the large-scale domain motion of Escherichia coli ADK and its catalytic process: (1) the substrate free ADK adopted an open conformation; (2) ATP bound with LID domain closure; (3) AMP bound with NMP domain closure; (4) phosphoryl transfer occurred with ATP, and AMP converted into two ADPs, and no conformational transition was detected in the enzyme; (5) LID domain opened with one ADP released; (6) another ADP released with NMP domain open. As both open and closed states sampled a wide range of conformation transitions, our simulation strongly supported the conformational selection mechanism for Escherichia coli ADK. PMID:23936827

Ping, Jie; Hao, Pei; Li, Yi-Xue; Wang, Jing-Fang

2013-01-01

32

Sequence Recognition of DNA by Protein-Induced Conformational Transitions  

SciTech Connect

The binding of proteins to specific sequences of DNA is an important feature of virtually all DNA transactions. Proteins recognize specific DNA sequences using both direct readout (sensing types and positions of DNA functional groups) and indirect readout (sensing DNA conformation and deformability). Previously we showed that the P22 c2 repressor N-terminal domain (P22R NTD) forces the central non-contacted 5{prime}-ATAT-3{prime} sequence of the DNA operator into the B{prime} state, a state known to affect DNA hydration, rigidity and bending. Usually the B{prime} state, with a narrow minor groove and a spine of hydration, is reserved for A-tract DNA (TpA steps disrupt A-tracts). Here, we have co-crystallized P22R NTD with an operator containing a central 5{prime}-ACGT-3{prime} sequence in the non-contacted region. C {center_dot} G base pairs have not previously been observed in the B{prime} state and are thought to prevent it. However, P22R NTD induces a narrow minor groove and a spine of hydration to 5{prime}-ACGT-3{prime}. We observe that C {center_dot} G base pairs have distinctive destabilizing and disordering effects on the spine of hydration. It appears that the reduced stability of the spine results in a higher energy cost for the B to B{prime} transition. The differential effect of DNA sequence on the barrier to this transition allows the protein to sense the non-contacted DNA sequence.

Watkins, Derrick; Mohan, Srividya; Koudelka, Gerald B.; Williams, Loren Dean (GIT); (SUNYB)

2010-11-09

33

Solvent-dependent gating motions of an extremophilic lipase from Pseudomonas aeruginosa.  

PubMed

Understanding how organic solvent-stable proteins can function in anhydrous and often complex solutions is essential for the study of the interaction of protein and molecular immiscible interfaces and the design of efficient industrial enzymes in nonaqueous solvents. Using an extremophilic lipase from Pseudomonas aeruginosa as an example, we investigated the conformational dynamics of an organic solvent-tolerant enzyme in complex solvent milieux. Four 100-ns molecular dynamics simulations of the lipase were performed in solvent systems: water, hexane, and two mixtures of hexane and water, 5% and 95% (w/w) hexane. Our results show a solvent-dependent structural change of the protein, especially in the region that regulates the admission of the substrate. We observed that the lipase is much less flexible in hexane than in aqueous solution or at the immiscible interface. Quantified by the size of the accessible channel, the lipase in water has a closed-gate conformation and no access to the active site, while in the hexane-containing systems, the lipase is at various degrees of open-gate state, with the immiscible interface setup being in the widely open conformation ensembles. The composition of explicit solvents in the access channel showed a significant influence on the conformational dynamics of the protein. Interestingly, the slowest step (bottleneck) of the hexane-induced conformational switch seems to be correlated with the slow dehydration dynamics of the channel. PMID:22830585

Johnson, Quentin R; Nellas, Ricky B; Shen, Tongye

2012-08-01

34

Conformational probes in glassy polymers: free volume and relaxation transitions (FT-IR spectroscopy)  

NASA Astrophysics Data System (ADS)

The method of conformational probes has been developed. The conformational mobility of probes introduced into poly(methyl methacrylate) (PMMA) and having different sizes of rotational fragments (Vp?) has been investigated. There is a correlation between the freezing temperature of probe conformational transitions (Tf) and Vp?. These data have been considered within the frameworks of the free volume theory and the relaxational transitions. Conformational mobility of probes in poly(vinyl trimethylsilane) (PVTMS) and poly(trimethylsilyl propyne) (PTMSP) with a large free volume fraction has been studied.

Kamalova, D. I.; Petrova, S. A.; Remizov, A. B.

2004-07-01

35

Solvent-dependent enantiodivergence in the chlorocyclization of unsaturated carbamates.  

PubMed

A remarkable solvent-controlled enantiodivergence is seen in the hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL)-catalyzed chlorocyclization of unsaturated carbamates. Eyring plot analyses of this previously unreported reaction are used to probe and compare the R- and S-selective pathways. In the CHCl3/hexanes solvent system, the pro-R process shows a surprising increase in selectivity with increasing temperature. These studies point to a strongly solvent-dependent entropy-enthalpy balance between the pro-R and pro-S pathways. PMID:23671005

Garzan, Atefeh; Jaganathan, Arvind; Salehi Marzijarani, Nastaran; Yousefi, Roozbeh; Whitehead, Daniel C; Jackson, James E; Borhan, Babak

2013-07-01

36

Multiscale Modeling of Complex Systems Conformational Transitions in Proteins.  

National Technical Information Service (NTIS)

This project concerns development of new simulation methods for modeling protein conformational changes. The purpose is to develop accurate methods for generating a coarse Hamiltonian for use in Monte Carlo simulation. Our method is unique in that we deri...

D. Rogers N. Wijesekera R. Petrenko T. Beck

2006-01-01

37

Towards Understanding the Early Events in the Conformational Transition of Amyloid Beta Peptides  

Microsoft Academic Search

It is experimentally known that oligomerization of amyloid beta peptides is accompanied by a conformational transition from mainly alpha or random coil to beta sheets. The aim of this study is to analyze and compare the spatial orientation of hydration water near the peptide surface during this conformational transition of amyloid-beta 42 (Ab42) and amyloid-beta 40 (Ab40) peptides. Therefore, molecular

Sikander Hayat; Volkhard Helms

38

Identification of key residues for protein conformational transition using elastic network model  

NASA Astrophysics Data System (ADS)

Proteins usually undergo conformational transitions between structurally disparate states to fulfill their functions. The large-scale allosteric conformational transitions are believed to involve some key residues that mediate the conformational movements between different regions of the protein. In the present work, a thermodynamic method based on the elastic network model is proposed to predict the key residues involved in protein conformational transitions. In our method, the key functional sites are identified as the residues whose perturbations largely influence the free energy difference between the protein states before and after transition. Two proteins, nucleotide binding domain of the heat shock protein 70 and human/rat DNA polymerase ?, are used as case studies to identify the critical residues responsible for their open-closed conformational transitions. The results show that the functionally important residues mainly locate at the following regions for these two proteins: (1) the bridging point at the interface between the subdomains that control the opening and closure of the binding cleft; (2) the hinge region between different subdomains, which mediates the cooperative motions between the corresponding subdomains; and (3) the substrate binding sites. The similarity in the positions of the key residues for these two proteins may indicate a common mechanism in their conformational transitions.

Su, Ji Guo; Jin Xu, Xian; Hua Li, Chun; Chen, Wei Zu; Wang, Cun Xin

2011-11-01

39

Conformational transitions of weak polyacids grafted to nanoparticles  

NASA Astrophysics Data System (ADS)

The charge distribution on polyelectrolytes is a key factor, which controls their conformation and interactions. In weak polyelectrolytes, this distribution is determined by a number of factors, including the solvent conditions and local environment. In this work, we investigate charge distributions of chains end-grafted on a spherical nanoparticle in a salt solution, using grand canonical titration Monte Carlo simulations of a coarse-grained polymer model. In this approach, the ionization state of each polymer bead fluctuates based on the dissociation constant, pH of the solution, and interactions with other particles in the system. We determine charge and polymer conformations as functions of the pH and solvent quality. We compare the results to a fixed charge model and also investigate the role of grafting density and the effect of curvature on the film morphologies.

Barr, S. A.; Panagiotopoulos, A. Z.

2012-10-01

40

Finite size scaling and conformal symmetry around the (2+1)-dimensional SU(2) deconfinement phase transition.  

National Technical Information Service (NTIS)

Conformal invariance at a 2nd order phase transition yields an exact finite size scaling theory on a 2-dimensional cylindrical geometry. We combine this two-dimensional conformal field theory with a numerical investigation of the deconfinement phase trans...

J. Christensen P. H. Damgaard

1990-01-01

41

Rotation Triggers Nucleotide-Independent Conformational Transition of the Empty ? Subunit of F1-ATPase.  

PubMed

F1-ATPase (F1) is the catalytic portion of ATP synthase, a rotary motor protein that couples proton gradients to ATP synthesis. Driven by a proton flux, the F1 asymmetric ? subunit undergoes a stepwise rotation inside the ?3?3 headpiece and causes the ? subunits' binding sites to cycle between states of different affinity for nucleotides. These concerted transitions drive the synthesis of ATP from ADP and phosphate. Here, we study the coupling between the mechanical progression of ? and the conformations of ?3?3. Using molecular dynamics simulations, we show that the nucleotide-free ? subunit, initially in the open, low-affinity state, undergoes a spontaneous closing transition to the half-open state in response to the ? rotation in the synthesis direction. We estimate the kinetics of this spontaneous conformational change and analyze its mechanism and driving forces. By computing free energy profiles, we find that the isolated empty ? subunit preferentially adopts the half-open conformation and that the transition to this conformation from the fully open state is accompanied by well-defined changes in the structure and interactions of the active site region. These results suggest that ADP binding to F1 occurs via conformational selection and is preceded by the transition of the active site to the half-open conformation, driven by the intrinsic elasticity of ?. Our results also indicate that opening of the nucleotide-free ? during hydrolysis is not spontaneous, as previously assumed. Rather, the fully open conformation observed in the F1 X-ray structure is enforced sterically by the ? subunit whose orientation is stabilized by interactions with the two other ? subunits in the completely closed state. This finding supports the notion that ? acts by coupling the extreme conformational states of ? subunits within the ?3?3 hexamer and therefore is responsible for high efficiency of the coordinated catalysis. PMID:24798048

Czub, Jacek; Grubmüller, Helmut

2014-05-14

42

Conformational Transition of Response Regulator RR468 in a Two-Component System Signal Transduction Process.  

PubMed

Signal transduction can be accomplished via a two-component system (TCS) consisting of a histidine kinase (HK) and a response regulator (RR). In this work, we simulate the response regulator RR468 from Thermotoga maritima, in which phosphorylation and dephosphorylation of a conserved aspartate residue acts as a switch via a large conformational change concentrated in three proximal loops. A detailed view of the conformational transition is obscured by the lack of stability of the intermediate states, which are difficult to detect using common structural biology techniques. Molecular dynamics (MD) trajectories of the inactive and active conformations were run, and show that the inactive (or active) trajectories do not exhibit sampling of the active (or inactive) conformations on this time scale. Targeted MD (TMD) was used to generate trajectories that span the inactive and active conformations and provide a view of how a localized event like phosphorylation can lead to conformational changes elsewhere in the protein, especially in the three proximal loops. The TMD trajectories are clustered to identify stages along the transition path. Residue interaction networks are identified that point to key residues having to rearrange in the process of transition. These are identified using both hydrogen bond analysis and residue interaction strength measurements. Potentials of mean force are generated for key residue rearrangements to ascertain their free energy barriers. We introduce methods that attempt to extrapolate from one conformation to the other and find that the most fluctuating proximal loop can transit part way from one to the other, suggesting that this conformational information is embedded in the sequence. PMID:24731214

Banerjee, Rahul; Yan, Honggao; Cukier, Robert I

2014-05-01

43

Conformational transitions in human translin enable nucleic acid binding  

PubMed Central

Translin is a highly conserved RNA- and DNA-binding protein that plays essential roles in eukaryotic cells. Human translin functions as an octamer, but in the octameric crystallographic structure, the residues responsible for nucleic acid binding are not accessible. Moreover, electron microscopy data reveal very different octameric configurations. Consequently, the functional assembly and the mechanism of nucleic acid binding by the protein remain unclear. Here, we present an integrative study combining small-angle X-ray scattering (SAXS), site-directed mutagenesis, biochemical analysis and computational techniques to address these questions. Our data indicate a significant conformational heterogeneity for translin in solution, formed by a lesser-populated compact octameric state resembling the previously solved X-ray structure, and a highly populated open octameric state that had not been previously identified. On the other hand, our SAXS data and computational analyses of translin in complex with the RNA oligonucleotide (GU)12 show that the internal cavity found in the octameric assemblies can accommodate different nucleic acid conformations. According to this model, the nucleic acid binding residues become accessible for binding, which facilitates the entrance of the nucleic acids into the cavity. Our data thus provide a structural basis for the functions that translin performs in RNA metabolism and transport.

Perez-Cano, Laura; Eliahoo, Elad; Lasker, Keren; Wolfson, Haim J.; Glaser, Fabian; Manor, Haim; Bernado, Pau; Fernandez-Recio, Juan

2013-01-01

44

Conformational transitions in human translin enable nucleic acid binding.  

PubMed

Translin is a highly conserved RNA- and DNA-binding protein that plays essential roles in eukaryotic cells. Human translin functions as an octamer, but in the octameric crystallographic structure, the residues responsible for nucleic acid binding are not accessible. Moreover, electron microscopy data reveal very different octameric configurations. Consequently, the functional assembly and the mechanism of nucleic acid binding by the protein remain unclear. Here, we present an integrative study combining small-angle X-ray scattering (SAXS), site-directed mutagenesis, biochemical analysis and computational techniques to address these questions. Our data indicate a significant conformational heterogeneity for translin in solution, formed by a lesser-populated compact octameric state resembling the previously solved X-ray structure, and a highly populated open octameric state that had not been previously identified. On the other hand, our SAXS data and computational analyses of translin in complex with the RNA oligonucleotide (GU)12 show that the internal cavity found in the octameric assemblies can accommodate different nucleic acid conformations. According to this model, the nucleic acid binding residues become accessible for binding, which facilitates the entrance of the nucleic acids into the cavity. Our data thus provide a structural basis for the functions that translin performs in RNA metabolism and transport. PMID:23980029

Pérez-Cano, Laura; Eliahoo, Elad; Lasker, Keren; Wolfson, Haim J; Glaser, Fabian; Manor, Haim; Bernadó, Pau; Fernández-Recio, Juan

2013-11-01

45

Molecular Dynamics Simulations of Forced Conformational Transitions in 1,6-Linked Polysaccharides  

PubMed Central

Recent atomic force microscopy stretching measurements of single polysaccharide molecules suggest that their elasticity is governed by force-induced conformational transitions of the pyranose ring. However, the mechanism of these transitions and the mechanics of the pyranose ring are not fully understood. Here we use steered molecular dynamics simulations of the stretching process to unravel the mechanism of forced conformational transitions in 1,6 linked polysaccharides. In contrast to most sugars, 1,6 linked polysaccharides have an extra bond in their inter-residue linkage, C5–C6, around which restricted rotations occur and this additional degree of freedom increases the mechanical complexity of these polymers. By comparing the computational results with the atomic force microscopy data we determine that forced rotations around the C5–C6 bond have a significant and different impact on the elasticity of ?- and ?-linked polysaccharides. ?-linkages of a polysaccharide pustulan force the rotation around the C5–C6 bonds and produce a Hookean-like elasticity but do not affect the conformation of the pyranose rings. However, ?-linkages of dextran induce compound conformational transitions that include simultaneous rotations around the C5–C6 bonds and chair-boat transitions of the pyranose rings. These previously not-recognized transitions are responsible for the characteristic plateau in the force-extension relationship of dextran.

Lee, Gwangrog; Nowak, Wieslaw; Jaroniec, Justyna; Zhang, Qingmin; Marszalek, Piotr E.

2004-01-01

46

?C Helix as a Switch in the Conformational Transition of Src/CDK-like Kinase Domains  

PubMed Central

One mechanism of regulating the catalytic activity of protein kinases is through conformational transitions. Despite great diversity in the structural changes involved in the transitions, a certain set of changes within the kinase domain (KD) has been observed for many kinases including Src and CDK2. We investigated this conformational transition computationally to identify the topological features that are energetically critical to the transition. Results from both molecular dynamics sampling and transition path optimization highlight the displacement of the ?C helix as the major energy barrier, mediating the switch of the KD between the active and down-regulated states. The critical role of the ?C helix is noteworthy by providing a rationale for a number of activation and deactivation mechanisms known to occur in cells. We find that kinases with the ?C helix displacement exist throughout the kinome, suggesting that this feature may have emerged early in evolution.

Huang, He; Zhao, Ruijun; Dickson, Bradley M.; Skeel, Robert D.; Post, Carol Beth

2013-01-01

47

Modeling conformational transitions in kinases by molecular dynamics simulations: achievements, difficulties, and open challenges  

PubMed Central

Protein kinases work because their flexibility allows to continuously switch from inactive to active form. Despite the large number of structures experimentally determined in such states, the mechanism of their conformational transitions as well as the transition pathways are not easily to capture. In this regard, computational methods can help to shed light on such an issue. However, due to the intrinsic sampling limitations, much efforts have been done to model in a realistic way the conformational changes occurring in protein kinases. In this review we will address the principal biological achievements and structural aspects in studying kinases conformational transitions and will focus on the main challenges related to computational approaches such as molecular modeling and MD simulations.

D'Abramo, Marco; Besker, Neva; Chillemi, Giovanni; Grottesi, Alessandro

2014-01-01

48

Temperature-induced conformational transition of bovine serum albumin in neutral aqueous solution by reversed-phase liquid chromatography.  

PubMed

The temperature-induced conformational transition of bovine serum albumin (BSA) in neutral aqueous solution was studied using intrinsic fluorescence emission spectrum, reversed-phase liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the conformation transition thermodynamic parameters were determined in the temperature range 12-50 °C. The results showed that, in the temperature range 12-20 °C, BSA only existed in a single conformation state A, while in the temperature range 22-50 °C, it existed in two different conformation states: A and B. The percentage of conformation state A decreased while that of conformation state B increased with the increase in temperatures, and when temperature approached 50 °C conformation state B accounted for approximately 25% of all conformation states of BSA. In the conformational transition of BSA from conformation state A to conformation state B, the positive enthalpy change, entropy change and free energy changes demonstrated that the conformational transition was endothermic, nonspontaneous and mainly entropy-driven. PMID:24037907

Bian, Liujiao; Wu, Dan; Hu, Wei

2014-02-01

49

The Preliminary Stretching Effect on Mechanical Properties of Natural and Synthetic Polyamide fibres and Conformational Transitions  

NASA Astrophysics Data System (ADS)

The preliminary stretching effect on mechanical properties of natural (wool, hair, and silk) and synthetic polyamide fibres (nylon, capron) and conformational transitions are investigated by using a tensile tester. It is shown that ?-keratin fibres (wool and hair) show silk-like properties and properties of synthetic polyamide fibres for preliminary extension of 18-24% and 34-38%, respectively.

Aksakal, Baki; Phoshkina, Svetlana P.; Darvish, Diana M.; Tsobkallo, Ekaterina S.; Alekberov, Vilayet

2007-04-01

50

Hierarchical analysis of conformational dynamics in biomolecules: Transition networks of metastable states  

Microsoft Academic Search

Molecular dynamics simulation generates large quantities of data that must be interpreted using physically meaningful analysis. A common approach is to describe the system dynamics in terms of transitions between coarse partitions of conformational space. In contrast to previous work that partitions the space according to geometric proximity, the authors examine here clustering based on kinetics, merging configurational microstates together

Frank Noé; Illia Horenko; Christof Schütte; Jeremy C. Smith

2007-01-01

51

Iterative cluster-NMA (icNMA): A tool for generating conformational transitions in proteins  

PubMed Central

Computational models provide insight into the structure-function relationship in proteins. These approaches, especially those based on normal mode analysis, can identify the accessible motion space around a given equilibrium structure. The large magnitude, collective motions identified by these methods are often well aligned with the general direction of the expected conformational transitions. However, these motions cannot realistically be extrapolated beyond the local neighborhood of the starting conformation. In this paper, the icNMA method is presented for traversing the energy landscape from a starting conformation to a desired goal conformation. This is accomplished by allowing the evolving geometry of the intermediate structures to define the local accessible motion space, and thus produce an appropriate displacement. Following the derivation of the icNMA method, a set of sample simulations are performed to probe the robustness of the model. A detailed analysis of ?1,4-galactosyltransferase-T1 is also given, to highlight many of the capabilities of icNMA. Remarkably, during the transition, a helix is seen to be extended by an additional turn, emphasizing a new unknown role for secondary structures to absorb slack during transitions. The transition pathway for adenylate kinase, which has been frequently studied in the literature, is also discussed.

Schuyler, Adam D.; Jernigan, Robert L.; Qasba, Pradman K.; Ramakrishnan, Boopathy; Chirikjian, Gregory S.

2010-01-01

52

Parallel cascade selection molecular dynamics (PaCS-MD) to generate conformational transition pathway  

NASA Astrophysics Data System (ADS)

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) is proposed as a molecular simulation method to generate conformational transition pathway under the condition that a set of ``reactant'' and ``product'' structures is known a priori. In PaCS-MD, the cycle of short multiple independent molecular dynamics simulations and selection of the structures close to the product structure for the next cycle are repeated until the simulated structures move sufficiently close to the product. Folding of 10-residue mini-protein chignolin from the extended to native structures and open-close conformational transition of T4 lysozyme were investigated by PaCS-MD. In both cases, tens of cycles of 100-ps MD were sufficient to reach the product structures, indicating the efficient generation of conformational transition pathway in PaCS-MD with a series of conventional MD without additional external biases. Using the snapshots along the pathway as the initial coordinates, free energy landscapes were calculated by the combination with multiple independent umbrella samplings to statistically elucidate the conformational transition pathways.

Harada, Ryuhei; Kitao, Akio

2013-07-01

53

The impact of N-terminal phosphorylation on LHCII conformation in state transition  

NASA Astrophysics Data System (ADS)

State transition is an important protection mechanism of plants for maintaining optimal efficiency through redistributing unbalanced excitation energy between photo-system II (PSII) and photosystem I (PSI). This process depends on the reversible phosphorylation/dephosphorylation of the major light-harvesting complex II (LHCII) and its bi-directional migration between PSII and PSI. But it remains unclear how phosphorylation/dephosphorylation modulates the LHCII conformation and further regulates its reversible migration. Here molecular dynamics simulations (MDS) were employed to elucidate the impact of phosphorylation on LHCII conformation. The results indicated that N-terminal phosphorylation loosened LHCII trimer with decreased hydrogen bond (H-bond) interactions and extended the distances between neighboring monomers, which stemmed from the conformational adjustment of each monomer itself. Global conformational change of LHCII monomer started from its stromal Nterminal (including the phosphorylation sites) by enhancing its interaction to lipid membrane and by adjusting the interaction network with surrounded inter-monomer and intra-monomer transmembrane helixes of B, C, and A, and finally triggered the reorientation of transmembrane helixes and transferred the conformational change to luminal side helixes and loops. These results further our understanding in molecular mechanism of LHCII migration during state transition from the phosphorylation-induced microstructural feature of LHCII.

Ding, Jin-Hong; Li, Ning; Wang, Man-Liu; Zhang, Yan; Lü, Shou-Qin; Long, Mian

2014-05-01

54

Cyclophilin A inhibition: targeting transition-state-bound enzyme conformations for structure-based drug design.  

PubMed

Human Cyclophilin A (CypA) catalyzes cis-trans isomerization of the prolyl peptide ?-bond in proteins and is involved in many subcellular processes. CypA has, therefore, been identified as a potential drug target in many diseases, and the development of potent inhibitors with high selectivity is a key objective. In computer-aided drug design, selectivity is improved by taking into account the inherent flexibility of the receptor. However, the relevant receptor conformations to focus on in order to develop highly selective inhibitors are not always obvious from available X-ray crystal structures or ensemble of conformations generated using molecular dynamics simulations. Here, we show that the conformation of the active site of CypA varies as the substrate configuration changes during catalytic turnover. We have analyzed the principal modes of the active site dynamics of CypA from molecular dynamics simulations to show that similar ensembles of enzyme conformations recognize diverse inhibitors and bind the different configurations of the peptide substrate. Small nonpeptidomimetic inhibitors with varying activity are recognized by enzyme ensembles that are similar to those that tightly bind the transition state and cis configurations of the substrate. Our results suggest that enzyme-substrate ensembles are more relevant in structure-based drug design for CypA than free enzyme. Of the vast conformational space of the free enzyme, the enzyme conformations of the tightly bound enzyme-substrate complexes are the most important for catalysis. Therefore, functionalizing lead compounds to optimize their interactions with the enzyme's conformational ensemble bound to the substrate in the cis or the transition state could lead to more potent inhibitors. PMID:23312027

Nagaraju, Mulpuri; McGowan, Lauren C; Hamelberg, Donald

2013-02-25

55

Features of large hinge-bending conformational transitions. Prediction of closed structure from open state.  

PubMed

We performed a detailed analysis of conformational transition pathways for a set of 10 proteins, which undergo large hinge-bending-type motions with 4-12 Å RMSD (root mean-square distance) between open and closed crystal structures. Anisotropic network model-Monte Carlo (ANM-MC) algorithm generates a targeted pathway between two conformations, where the collective modes from the ANM are used for deformation at each iteration and the conformational energy of the deformed structure is minimized via an MC algorithm. The target structure was approached successfully with an RMSD of 0.9-4.1 Å when a relatively low cutoff radius of 10 Å was used in ANM. Even though one predominant mode (first or second) directed the open-to-closed conformational transition, changes in the dominant mode character were observed for most cases along the transition. By imposing radius of gyration constraint during mode selection, it was possible to predict the closed structure for eight out of 10 proteins (with initial 4.1-7.1 Å and final 1.7-2.9 Å RMSD to target). Deforming along a single mode leads to most successful predictions. Based on the previously reported free energy surface of adenylate kinase, deformations along the first mode produced an energetically favorable path, which was interestingly facilitated by a change in mode shape (resembling second and third modes) at key points. Pathway intermediates are provided in our database of conformational transitions (http://safir.prc.boun.edu.tr/anmmc/method/1). PMID:24940783

Uyar, Arzu; Kantarci-Carsibasi, Nigar; Haliloglu, Turkan; Doruker, Pemra

2014-06-17

56

The energy profiles of atomic conformational transition intermediates of adenylate kinase  

PubMed Central

The elastic network interpolation (ENI)1 is a computationally efficient and physically realistic method to generate conformational transition intermediates between two forms of a given protein. However it can be asked whether these calculated conformations provide good representatives for these intermediates. In this study, we use ENI to generate conformational transition intermediates between the open form and the closed forms of adenylate kinase (AK). Based on C?-only intermediates, we construct atomic intermediates by grafting all the atoms of known AK structures onto the C? atoms and then perform CHARMM energy minimization to remove steric conflicts and optimize these intermediate structures. We compare the energy profiles for all intermediates from both the CHARMM force-field and from knowledge-based energy functions. We find that the CHARMM energies can successfully capture the two energy minima representing the open AK and closed AK forms, while the energies computed from the knowledge-based energy functions can detect the local energy minimum representing the closed AK form and show some general features of the transition pathway with a somewhat similar energy profile as the CHARMM energies. The combinatorial extension (CE) structural alignment2 and the k-means clustering algorithm are then used to show that known PDB structures closely resemble computed intermediates along the transition pathway.

Feng, Yaping; Yang, Lei; Kloczkowski, Andrzej; Jernigan, Robert L.

2009-01-01

57

Mechanistic picture for conformational transition of a membrane transporter at atomic resolution  

PubMed Central

During their transport cycle, ATP-binding cassette (ABC) transporters undergo large-scale conformational changes between inward- and outward-facing states. Using an approach based on designing system-specific reaction coordinates and using nonequilibrium work relations, we have performed extensive all-atom molecular dynamics simulations in the presence of explicit membrane/solvent to sample a large number of mechanistically distinct pathways for the conformational transition of MsbA, a bacterial ABC exporter whose structure has been solved in multiple functional states. The computational approach developed here is based on (i) extensive exploration of system-specific biasing protocols (e.g., using collective variables designed based on available low-resolution crystal structures) and (ii) using nonequilibrium work relations for comparing the relevance of the transition pathways. The most relevant transition pathway identified using this approach involves several distinct stages reflecting the complex nature of the structural changes associated with the function of the protein. The opening of the cytoplasmic gate during the outward- to inward-facing transition of apo MsbA is found to be disfavored when the periplasmic gate is open and facilitated by a twisting motion of the nucleotide-binding domains that involves a dramatic change in their relative orientation. These results highlight the cooperativity between the transmembrane and the nucleotide-binding domains in the conformational transition of ABC exporters. The approach introduced here provides a framework to study large-scale conformational changes of other membrane transporters whose computational investigation at an atomic resolution may not be currently feasible using conventional methods.

Moradi, Mahmoud; Tajkhorshid, Emad

2013-01-01

58

The discontinuities of conformal transitions and mass spectra of V-QCD  

NASA Astrophysics Data System (ADS)

Zero temperature spectra of mesons and glueballs are analyzed in a class of holographic bottom-up models for QCD in the Veneziano limit, N c ? ?, N f ? ?, with x = N f /N c fixed(V-QCD).The back reaction of flavor on color is fully included. It is found that spectra are discrete and gapped (modulo the pions) in the QCD regime, for x below the critical value x c where the conformal transition takes place. The masses uniformly converge to zero in the walking region due to Miransky scaling. All the ratios of masses asymptote to non-zero constants as and therefore there is no "dilaton" in the spectrum. The S-parameter is computed and found to be of in units of N f N c in the walking regime, while it is always an increasing function of x. This indicates the presence of a subtle discontinuity of correlation functions across the conformal transition at x = x c .

Areán, Daniel; Iatrakis, Ioannis; Järvinen, Matti; Kiritsis, Elias

2013-11-01

59

Solid-to-hybrid transitioning armature railgun with non-conforming-to-prejudice bore profile  

DOEpatents

An improved railgun, railgun barrel, railgun projectile, and railgun system for accelerating a solid-to-hybrid transitioning armature projectile using a barrel having a bore that does not conform to a cross-sectional profile of the projectile, to contact and guide the projectile only by the rails in a low pressure bore volume so as to minimize damage, failure, and/or underperformance caused by plasma armatures, insulator ablation, and/or restrikes.

Solberg, Jerome Michael

2012-12-04

60

Conformational transitions of a confined lattice protein: A Wang-Landau study  

NASA Astrophysics Data System (ADS)

We use Wang-Landau sampling with suitable Monte Carlo trial moves to study a hydrophobic-polar (HP) lattice protein confined between two parallel, attractive walls. The density of states is determined iteratively by a random walk in energy space. Thermodynamic and structural properties, such as specific heat, number of surface contacts and number of H-H monomer pairs, are then calculated. When the surface attraction is comparable to the internal attraction among the hydrophobic monomers in the chain, two conformationaltransitions”, adsorption at higher temperature and collapse at lower temperature, have been analyzed based on these properties. This transition behavior depends on the variation of surface separation.

Pattanasiri, Busara; Li, Ying Wai; Landau, David P.; Wüst, Thomas; Triampo, Wannapong

2012-12-01

61

The methanol-induced transition and the expanded helical conformation in hen lysozyme.  

PubMed Central

Methanol-induced conformational transitions of hen egg white lysozyme were investigated with a combined use of far- and near-UV CD and NMR spectroscopies, ANS binding and small-angle X-ray scattering. Addition of methanol induced no global change in the native conformation itself, but induced a transition from the native state to the denatured state which was highly cooperative, as shown by the coincidence of transition curves monitored by the far- and near-UV CD spectroscopy, by isodichroic points in the far- and near-UV CD spectra and by the concomitant disappearance of individual 1H NMR signals of the native state. The ANS binding experiments could detect no intermediate conformer similar to the molten globule state in the process of the methanol denaturation. However, at high concentration of methanol, e.g., 60% (v/v) methanol/water, a highly helical state (H) was realized. The H state had a helical content much higher than the native state, monitored by far-UV CD spectroscopy, and had no specific tertiary structure, monitored both by near-UV CD and NMR spectroscopy. The radius of gyration in the H state, 24.9 angstroms, was significantly larger than that in the native state (15.7 angstroms). The Kratky plot for the H state did not show a clear peak and was quite similar to that for the urea-denatured state, indicating a complete lack of globularity. Thus we conclude that the H state has a considerably expanded, flexible broken rod-like conformation which is clearly distinguishable from the "molten globule" state. The stability of both N and H states depends on pH and methanol concentration. Thus a phase diagram involving N and H was constructed.

Kamatari, Y. O.; Konno, T.; Kataoka, M.; Akasaka, K.

1998-01-01

62

Many local motions cooperate to produce the adenylate kinase conformational transition.  

PubMed

Conformational transitions are functionally important in many proteins. In the enzyme adenylate kinase (AK), two small domains (LID and NMP) close over the larger CORE domain; the reverse (opening) motion limits the rate of catalytic turnover. Here, using double-well G? simulations of Escherichia coli AK, we elaborate on previous investigations of the AK transition mechanism by characterizing the contributions of rigid-body (Cartesian), backbone dihedral, and contact motions to transition-state (TS) properties. In addition, we compare an apo simulation to a pseudo-ligand-bound simulation to reveal insights into allostery. In Cartesian space, LID closure precedes NMP closure in the bound simulation, consistent with prior coarse-grained models of the AK transition. However, NMP-first closure is preferred in the apo simulation. In backbone dihedral space, we find that, as expected, backbone fluctuations are reduced in the O/C transition in parts of all three domains. Among these "quenching" residues, most in the CORE, especially residues 11-13, are rigidified in the TS of the bound simulation, while residues 42-44 in the NMP are flexible in the TS. In contact space, in both apo and bound simulations, one nucleus of closed-state contacts includes parts of the NMP and CORE; CORE-LID contacts are absent in the TS of the apo simulation but formed in the TS of the bound simulation. From these results, we predict mutations that will perturb the opening and/or closing transition rates by changing the entropy of dihedrals and/or the enthalpy of contacts. Furthermore, regarding allostery, the fully closed structure is populated in the apo simulation, but our contact results imply that ligand binding shifts the preferred O/C transition pathway, thus precluding a simple conformational selection mechanism. Finally, the analytical approach and the insights derived from this work may inform the rational design of flexibility and allostery in proteins. PMID:20471396

Daily, Michael D; Phillips, George N; Cui, Qiang

2010-07-16

63

The Conformational Transition Pathway of ATP Binding Cassette Transporter MsbA Revealed by Atomistic Simulations*  

PubMed Central

ATP binding cassette transporters are integral membrane proteins that use the energy released from ATP hydrolysis at the two nucleotide binding domains (NBDs) to translocate a wide variety of substrates through a channel at the two transmembrane domains (TMDs) across the cell membranes. MsbA from Gram-negative bacteria is a lipid and multidrug resistance ATP binding cassette exporter that can undergo large scale conformational changes between the outward-facing and the inward-facing conformations revealed by crystal structures in different states. Here, we use targeted molecular dynamics simulation methods to explore the atomic details of the conformational transition from the outward-facing to the inward-facing states of MsbA. The molecular dynamics trajectories revealed a clear spatiotemporal order of the conformational movements. The disruption of the nucleotide binding sites at the NBD dimer interface is the very first event that initiates the following conformational changes, verifying the assumption that the conformational conversion is triggered by ATP hydrolysis. The conserved x-loops of the NBDs were identified to participate in the interaction network that stabilizes the cytoplasmic tetrahelix bundle of the TMDs and play an important role in mediating the cross-talk between the NBD and TMD. The movement of the NBD dimer is transmitted through x-loops to break the tetrahelix bundle, inducing the packing rearrangements of the transmembrane helices at the cytoplasmic side and the periplasmic side sequentially. The packing rearrangement within each periplasmic wing of TMD that results in exposure of the substrate binding sites occurred at the end stage of the trajectory, preventing the wrong timing of the binding site accessibility.

Weng, Jing-Wei; Fan, Kang-Nian; Wang, Wen-Ning

2010-01-01

64

The 'order-to-disorder' conformational transition in CD44 protein: an umbrella sampling analysis.  

PubMed

The molecule of CD44, a membrane protein being the major cell surface receptor for hyaluronan, is postulated to undergo the conformational rearrangement called the 'order-to-disorder' transition. The experimental studies suggest that the Tyr161 residue is crucial for maintaining the equilibrium between the 'ordered' (O) and 'partially disordered' (PD) forms of CD44. The molecular modeling study based on the umbrella sampling protocol was carried out separately for the wild-type CD44 and Tyr161Ala mutant in order to gain more insight into the molecular mechanism of the O-PD transition and to clarify the role of the Tyr161 amino acid residue. The calculated free energy profiles associated with the initial stages of the O-PD conformational transition allow to identify the crucial steps of this process and their molecular details. The differences between the wild-type CD44 and the Tyr161Ala mutant are very insignificant which allows for speculating that, surprisingly, the role of Tyr161 in the O-PD transition is not connected with disrupting the attractive Glu48-Tyr161 and Leu52-Tyr161 interactions but with other types of (unknown yet) interactions located outside the ?7-?8 loop or with the existence of the PD-like structure in which the terminal lobe remains located under the ?7-?8 loop. PMID:24012974

Plazinski, Wojciech; Knys-Dzieciuch, Agnieszka

2013-09-01

65

Structural Basis of Lipid-Driven Conformational Transitions in the KvAP Voltage Sensing Domain  

PubMed Central

Voltage-gated ion channels respond to transmembrane electric fields through reorientations of the positively charged S4 helix within the voltage-sensing domain (VSD). Despite a wealth of structural and functional data, the details of this conformational change remain controversial. Recent electrophysiological evidence showed that equilibrium between the resting (Down) and activated (Up) conformations of KvAP-VSD from Aeropyrum pernix can be biased through reconstitution in lipids with or without phosphate groups. We investigated the structural transition between these functional states using site-directed spin labeling and EPR spectroscopic methods. Solvent accessibility and inter-helical distance determinations suggest that KvAP gates through S4 movements involving a ~3 Å upward tilt and simultaneous ~2 Å axial shift. This motion leads to large accessibly changes in the intracellular water-filled crevice and supports a novel model of gating that combines structural rearrangements and electric field remodeling.

Li, Qufei; Wanderling, Sherry; Somponspisut, Pornthep; Perozo, Eduardo

2013-01-01

66

Single tryptophan mutants of FtsZ: Nucleotide binding/exchange and conformational transitions.  

PubMed

Cell division protein FtsZ cooperatively self-assembles into straight filaments when bound to GTP. A set of conformational changes that are linked to FtsZ GTPase activity are involved in the transition from straight to curved filaments that eventually disassemble. In this work, we characterized the fluorescence of single Trp mutants as a reporter of the predicted conformational changes between the GDP- and GTP-states of Escherichia coli FtsZ. Steady-state fluorescence characterization showed the Trp senses different environments and displays low solvent accessibility. Time-resolved fluorescence data indicated that the main conformational changes in FtsZ occur at the interaction surface between the N and C domains, but also minor rearrangements were detected in the bulk of the N domain. Surprisingly, despite its location near the bottom protofilament interface at the C domain, the Trp 275 fluorescence lifetime did not report changes between the GDP and GTP states. The equilibrium unfolding of FtsZ features an intermediate that is stabilized by the nucleotide bound in the N-domain as well as by quaternary protein-protein interactions. In this context, we characterized the unfolding of the Trp mutants using time-resolved fluorescence and phasor plot analysis. A novel picture of the structural transition from the native state in the absence of denaturant, to the solvent-exposed unfolded state is presented. Taken together our results show that conformational changes between the GDP and GTP states of FtsZ, such as those observed in FtsZ unfolding, are restricted to the interaction surface between the N and C domains. PMID:24704635

Montecinos-Franjola, Felipe; James, Nicholas G; Concha-Marambio, Luis; Brunet, Juan E; Lagos, Rosalba; Monasterio, Octavio; Jameson, David M

2014-07-01

67

How and why do transition dipole moment orientations depend on conformer structure?  

PubMed

A remarkable influence of the orientation of a polar side chain on the direction of the S(1) ? S(0) transition dipole moment of monosubstituted benzenes was previously reported from high-resolution electronic spectroscopy. In search for a more general understanding of this non-Condon behavior, we investigated ethylamino-substituted indole and benzene (tryptamine and 2-phenylethylamine) using ab initio theory and compared the results to rotationally resolved laser-induced fluorescence measurements. The interaction of the ethylamino side chain with the benzene chromophore can evoke a rotation and a change of ordering of the molecular orbitals involved in the excitation, leading to state mixing and large changes in the orientation of the excited-state transition dipole moment. These changes are much less pronounced in tryptamine with the indole chromophore, where a rotation of the transition dipole moment is attributed to Rydberg contributions of the nitrogen atom of the chromophore. For phenylethylamine, a strong dependence of the oscillator strengths of the lowest two singlet states from the conformation of the side chain is found, which makes the use of experimental vibronic intensities for assessment of relative conformer stabilities at least questionable. PMID:21500787

Brand, Christian; Meerts, W Leo; Schmitt, Michael

2011-09-01

68

Methanol-induced conformation transition of gland fibroin monitored by FTIR spectroscopy and terahertz spectroscopy.  

PubMed

Silk fibroin extracted from the gland of Bombyx mori silkworm is employed as an ideal system to investigate its conformation transition in methanol/D2O solution. The transition process was monitored by Fourier transform infrared (FTIR) spectroscopy coupled with terahertz time domain spectroscopy (THz-TDS). Analysis of FTIR spectra suggests that, with increasing time of treatment, an increasing band at 1634 cm(-1) is observed indicating the formation of ?-pleated sheets coincident with the loss of intensity of a band at 1673 cm(-1) indicating decrease of the random coil structure. In addition, there is a burst phase of 33% occurring during the first 2 minutes when the gland fibroin membranes are immersed into methanol/D2O solution. THz spectra present distinct features for conformations of silk fibroin, in combination with the results obtained from FTIR; the peaks observed at 1.54 THz (51 cm(-1)), 1.67 THz (55 cm(-1)), and 1.84 THz (61 cm(-1)) can be attributed to a ?-pleated sheet, ?-helix, and random coil, respectively. Intensity change of bands centered at 1.54 THz and 1.84 THz confirms the formation of the ?-pleated sheet and the disappearance of the random coil. Kinetic curves obtained from THz spectra indicate that the methanol-induced conformation transition from the random coil to the ?-pleated sheet is fitted with an exponential function. The results suggest that THz-TDS presents great potential as a complementary approach in studying the secondary structure of a protein, providing significant insight into the silk-spinning process in vivo. PMID:24588004

Yan, Chao; Yang, Bin; Yu, Zhicheng

2014-04-21

69

Conformational transitions during FtsK translocase activation of individual XerCD-dif recombination complexes  

PubMed Central

Three single-molecule techniques have been used simultaneously and in tandem to track the formation in vitro of single XerCD–dif recombination complexes. We observed the arrival of the FtsK translocase at individual preformed synaptic complexes and demonstrated the conformational change that occurs during their activation. We then followed the reaction intermediate transitions as Holliday junctions formed through catalysis by XerD, isomerized, and were converted by XerC to reaction products, which then dissociated. These observations, along with the calculated intermediate lifetimes, inform the reaction mechanism, which plays a key role in chromosome unlinking in most bacteria with circular chromosomes.

Zawadzki, Pawel; May, Peter F. J.; Baker, Rachel A.; Pinkney, Justin N. M.; Kapanidis, Achillefs N.; Sherratt, David J.; Arciszewska, Lidia K.

2013-01-01

70

Effect of water on the temperatures of human immunoglobulin conformation transitions  

NASA Astrophysics Data System (ADS)

A differential thermal analysis of native and denaturated human immunoglobulin (G isotype) and mixtures of the native protein with water over the temperature range of 80-570 K is conducted. Temperatures of the protein conformational transitions and the effect of water on them are investigated. The limit of water solubility in the native protein is determined calorimetrically from the enthalpy of excess water phase melting. A physical state diagram of the immunoglobulin-water system over a wide range of temperatures and component concentrations is built and analyzed.

Ur'yash, V. F.; Kokurina, N. Yu.

2013-10-01

71

Modeling protein conformational transitions by a combination of coarse-grained normal mode analysis and robotics-inspired methods  

PubMed Central

Background Obtaining atomic-scale information about large-amplitude conformational transitions in proteins is a challenging problem for both experimental and computational methods. Such information is, however, important for understanding the mechanisms of interaction of many proteins. Methods This paper presents a computationally efficient approach, combining methods originating from robotics and computational biophysics, to model protein conformational transitions. The ability of normal mode analysis to predict directions of collective, large-amplitude motions is applied to bias the conformational exploration performed by a motion planning algorithm. To reduce the dimension of the problem, normal modes are computed for a coarse-grained elastic network model built on short fragments of three residues. Nevertheless, the validity of intermediate conformations is checked using the all-atom model, which is accurately reconstructed from the coarse-grained one using closed-form inverse kinematics. Results Tests on a set of ten proteins demonstrate the ability of the method to model conformational transitions of proteins within a few hours of computing time on a single processor. These results also show that the computing time scales linearly with the protein size, independently of the protein topology. Further experiments on adenylate kinase show that main features of the transition between the open and closed conformations of this protein are well captured in the computed path. Conclusions The proposed method enables the simulation of large-amplitude conformational transitions in proteins using very few computational resources. The resulting paths are a first approximation that can directly provide important information on the molecular mechanisms involved in the conformational transition. This approximation can be subsequently refined and analyzed using state-of-the-art energy models and molecular modeling methods.

2013-01-01

72

Nonequilibrium polymer chains induced by conformational transitions in densely interfacial layers  

NASA Astrophysics Data System (ADS)

Nonequilibrium poly(N-isopropylacrylamide) (PNIPAM) chains are generated by temperature-induced conformational transitions in the densely interfacial PNIPAM layer at high adsorbed amounts in aqueous solution. The interleaving chains relax in a spatially heterogeneous space of adsorbed layer which is filled with the domains via the hydrogen bonding and hydrophobic interactions. The relaxation dynamics of interleaving chains is changed from the weekly stretched exponential behaviour at the lower adsorbed amount to the strongly stretched exponential behaviour at the higher adsorbed amount. The kinetic constraints for the relaxation dynamics depend on the segment density of the adsorbed layer which is controlled by the temperature. The stretched exponential relaxation is related to an ensemble of relaxations confined in the domains with different physical origins for the heterogeneous dynamics. The range of energy barriers for the relaxation is estimated from the stretched exponent based on the random first order transition theory.

Zhu, Peng-Wei

2012-09-01

73

Translin binding to DNA: recruitment through DNA ends and consequent conformational transitions.  

PubMed

The human translin protein binds a variety of sequences (chromosomal breakpoint consensus sequences, their sequence variants, as well as nonbreakpoint sequences such as simple AT and GC repeats) at nanomolar protein concentration when short single strands ( approximately 20-30mers) are used as DNA targets. The protein, which is known to exist as an octamer in its free state, undergoes a conformational transition upon binding to short single strands leading either to a compaction or to the dissociation of the oligomer. Moreover, the protein oligomers tend to aggregate into complexes that get progressively larger as the length of the single-stranded DNA target increases. The protein loads onto duplexes via the free ends of DNA, generating higher oligomeric complexes as a function of protein concentration. Interestingly, the conformation of DNA targets encased by translin oligomer is significantly altered such that the single strand is rendered hypersensitive to DNase I. Furthermore, the loading of translin oligomers leads to tighter clamping of duplex ends. All of these observations, taken together, suggest that translin is a bona fide binder of DNA ends, thereby subjecting the DNA to a conformation conducive for repair steps during translocation events. We discuss the results in the perspective of translin biology. PMID:12484770

Sengupta, Kundan; Rao, Basuthkar J

2002-12-24

74

Conformational transitions as determinants of specificity for the DNA methyltransferase EcoRI.  

PubMed

Changes in DNA bending and base flipping in a previously characterized specificity-enhanced M.EcoRI DNA adenine methyltransferase mutant suggest a close relationship between precatalytic conformational transitions and specificity (Allan, B. W., Garcia, R., Maegley, K., Mort, J., Wong, D., Lindstrom, W., Beechem, J. M., and Reich, N. O. (1999) J. Biol. Chem. 274, 19269-19275). The direct measurement of the kinetic rate constants for DNA bending, intercalation, and base flipping with cognate and noncognate substrates (GAATTT, GGATTC) of wild type M.EcoRI using fluorescence resonance energy transfer and 2-aminopurine fluorescence studies reveals that DNA bending precedes both intercalation and base flipping, and base flipping precedes intercalation. Destabilization of these intermediates provides a molecular basis for understanding how conformational transitions contribute to specificity. The 3500- and 23,000-fold decreases in sequence specificity for noncognate sites GAATTT and GGATTC are accounted for largely by an approximately 2500-fold increase in the reverse rate constants for intercalation and base flipping, respectively. Thus, a predominant contribution to specificity is a partitioning of enzyme intermediates away from the Michaelis complex prior to catalysis. Our results provide a basis for understanding enzyme specificity and, in particular, sequence-specific DNA modification. Because many DNA methyltransferases and DNA repair enzymes induce similar DNA distortions, these results are likely to be broadly relevant. PMID:16845123

Youngblood, Ben; Reich, Norbert O

2006-09-15

75

Thermal stability and conformational transitions of scrapie amyloid (prion) protein correlate with infectivity.  

PubMed Central

The scrapie amyloid (prion) protein (PrP27-30) is the protease-resistant core of a larger precursor (PrPSc) and a component of the infectious scrapie agent; the potential to form amyloid is a result of posttranslational event or conformational abnormality. The conformation, heat stability, and solvent-induced conformational transitions of PrP27-30 were studied in the solid state in films by CD spectroscopy and correlated with the infectivity of rehydrated and equilibrated films. The exposure of PrP27-30 in films to 60 degrees C, 100 degrees C, and 132 degrees C for 30 min did not change the beta-sheet secondary structure; the infectivity slightly diminished at 132 degrees C and correlated with a decreased solubility of PrP27-30 in sodium dodecyl sulfate (SDS), probably due to cross-linking. Exposing PrP27-30 films to formic acid (FA), trifluoroacetic acid (TFA), trifluoroethanol (TFE), hexafluoro-2-propanol (HFIP), and SDS transformed the amide CD band, diminished the mean residue ellipticity of aromatic bands, and inactivated scrapie infectivity. The convex constraint algorithm (CAA) deconvolution of the CD spectra of the solvent-exposed and rehydrated solid state PrP27-30 identified five common spectral components. The loss of infectivity quantitatively correlated with a decreasing proportion of native, beta-pleated sheet-like secondary structure component, an increasing amount of alpha-helical component, and an increasingly disordered tertiary structure. The results demonstrate the unusual thermal stability of the beta-sheet secondary structure of PrP27-30 protein in the solid state. The conformational perturbations of PrP27-30 parallel the changes in infectivity and suggest that the beta-sheet structure plays a key role in the physical stability of scrapie amyloid and in the ability to propagate and replicate scrapie.

Safar, J.; Roller, P. P.; Gajdusek, D. C.; Gibbs, C. J.

1993-01-01

76

Thermodynamic and conformational insights into the phase transition of a single flexible homopolymer chain using replica exchange Monte Carlo method.  

PubMed

The phase transition of a single flexible homopolymer chain in the limit condition of dilute solution is systematically investigated using a coarse-grained model. Replica exchange Monte Carlo method is used to enhance the performance of the conformation space exploration, and thus detailed investigation of phase behavior of the system can be provided. With the designed potentials, the coil-globule transition and the liquid-solid-like transition are identified, and the transition temperatures are measured with the conformational and thermodynamic analyses. Additionally, by extrapolating the coil-globule transition temperature, T ? , and the liquid-solid-like transition temperature to the thermodynamic limit, N????, we found no "tri-critical" point in the current model. PMID:24961896

Wang, Lei; Li, Ningning; Xiao, Shiyan; Liang, Haojun

2014-07-01

77

Distinguishing unfolding and functional conformational transitions of calmodulin using ultraviolet resonance Raman spectroscopy.  

PubMed

Calmodulin (CaM) is a ubiquitous moderator protein for calcium signaling in all eukaryotic cells. This small calcium-binding protein exhibits a broad range of structural transitions, including domain opening and folding-unfolding, that allow it to recognize a wide variety of binding partners in vivo. While the static structures of CaM associated with its various binding activities are fairly well-known, it has been challenging to examine the dynamics of transition between these structures in real-time, due to a lack of suitable spectroscopic probes of CaM structure. In this article, we examine the potential of ultraviolet resonance Raman (UVRR) spectroscopy for clarifying the nature of structural transitions in CaM. We find that the UVRR spectral change (with 229 nm excitation) due to thermal unfolding of CaM is qualitatively different from that associated with opening of the C-terminal domain in response to Ca(2+) binding. This spectral difference is entirely due to differences in tertiary contacts at the interdomain tyrosine residue Tyr138, toward which other spectroscopic methods are not sensitive. We conclude that UVRR is ideally suited to identifying the different types of structural transitions in CaM and other proteins with conformation-sensitive tyrosine residues, opening a path to time-resolved studies of CaM dynamics using Raman spectroscopy. PMID:24895328

Jones, Eric M; Balakrishnan, Gurusamy; Squier, Thomas C; Spiro, Thomas G

2014-08-01

78

Exploring the thermodynamic landscape, kinetics, and structural evolution of a protein conformational transition with a microscopic double-well model.  

PubMed

Functional conformational transition in the glutamine-binding protein (GlnBP) is known to be the key to bind and transfer ligand glutamine. Here, we developed a structure-based double-well model to investigate the thermodynamic and kinetic natures of the GlnBP conformational transition. We uncovered the underlying free-energy landscape of the conformational transition with different temperatures. The analysis shows that below the melting temperature, two basins of attractions emerge, corresponding to the open state and the closed state of the protein. We explored the kinetic property of the conformational switch through the mean and distribution of the first passage time as well as the autocorrelation function. The kinetics implies the complexity and the hierarchical structure of the underlying energy landscape. We built the contact maps of the structures to probe the structural evolution of the conformational transition. Finally, the ? values of the residues were calculated to identify the important residues (hot spots) of the transition state. PMID:21425801

Lai, Zai-Zhi; Lu, Qiang; Wang, Jin

2011-04-14

79

Conformational Sampling and Nucleotide-Dependent Transitions of the GroEL Subunit Probed by Unbiased Molecular Dynamics Simulations  

PubMed Central

GroEL is an ATP dependent molecular chaperone that promotes the folding of a large number of substrate proteins in E. coli. Large-scale conformational transitions occurring during the reaction cycle have been characterized from extensive crystallographic studies. However, the link between the observed conformations and the mechanisms involved in the allosteric response to ATP and the nucleotide-driven reaction cycle are not completely established. Here we describe extensive (in total long) unbiased molecular dynamics (MD) simulations that probe the response of GroEL subunits to ATP binding. We observe nucleotide dependent conformational transitions, and show with multiple 100 ns long simulations that the ligand-induced shift in the conformational populations are intrinsically coded in the structure-dynamics relationship of the protein subunit. Thus, these simulations reveal a stabilization of the equatorial domain upon nucleotide binding and a concomitant “opening” of the subunit, which reaches a conformation close to that observed in the crystal structure of the subunits within the ADP-bound oligomer. Moreover, we identify changes in a set of unique intrasubunit interactions potentially important for the conformational transition.

Skjaerven, Lars; Grant, Barry; Muga, Arturo; Teigen, Knut; McCammon, J. Andrew; Reuter, Nathalie; Martinez, Aurora

2011-01-01

80

Kinetics of anesthetic-induced conformational transitions in a four-alpha-helix bundle protein.  

PubMed

Inhaled anesthetics are thought to alter the conformational states of Cys-loop ligand-gated ion channels (LGICs) by binding within discrete cavities that are lined by portions of four alpha-helical transmembrane domains. Because Cys-loop LGICs are complex molecules that are notoriously difficult to express and purify, scaled-down models have been used to better understand the basic molecular mechanisms of anesthetic action. In this study, stopped-flow fluorescence spectroscopy was used to define the kinetics with which inhaled anesthetics interact with (Aalpha(2)-L1M/L38M)(2), a four-alpha-helix bundle protein that was designed to model anesthetic binding sites on Cys-loop LGICs. Stopped-flow fluorescence traces obtained upon mixing (Aalpha(2)-L1M/L38M)(2) with halothane revealed immediate, fast, and slow components of quenching. The immediate component, which occurred within the mixing time of the spectrofluorimeter, was attributed to direct quenching of tryptophan fluorescence upon halothane binding to (Aalpha(2)-L1M/L38M)(2). This was followed by a biexponential fluorescence decay containing fast and slow components, reflecting anesthetic-induced conformational transitions. Fluorescence traces obtained in studies using sevoflurane, isoflurane, and desflurane, which poorly quench tryptophan fluorescence, did not contain the immediate component. However, these anesthetics did produce the fast and slow components, indicating that they also alter the conformation of (Aalpha(2)-L1M/L38M)(2). Cyclopropane, an anesthetic that acts with unusually low potency on Cys-loop LGICs, acted with low apparent potency on (Aalpha(2)-L1M/L38M)(2). These results suggest that four-alpha-helix bundle proteins may be useful models of in vivo sites of action that allow the use of a wide range of techniques to better understand how anesthetic binding leads to changes in protein structure and function. PMID:16445285

Solt, Ken; Johansson, Jonas S; Raines, Douglas E

2006-02-01

81

Mapping the structure and conformational movements of proteins with transition metal ion FRET  

PubMed Central

SUMMARY Visualizing conformational dynamics in proteins has been difficult, and the atomic-scale motions responsible for the behavior of most allosteric proteins are unknown. Here, we report that FRET between a small fluorescent dye and a nickel ion bound to a di-histidine motif can be used to monitor small structural rearrangements in proteins. This method provides several key advantages over classical FRET including the ability to measure the dynamics of close range interactions, the use of small probes with short linkers, a low orientation dependence, and the ability to add and remove unique tunable acceptors. We used this ‘transition metal ion FRET’ approach along with x-ray crystallography to determine the structural changes of the gating-ring of the mouse hyperpolarization-activated cyclic nucleotide-regulated ion channel HCN2. Binding of cAMP to the isolated carboxyl-terminal region of HCN2 caused a structural rearrangement involving a movement of the C-helix towards the ?-roll of the cAMP-binding domain and a movement of the F? helix of the C-linker, along with a stabilization of the secondary structure of the helices. Our results suggest a general model for the conformational switch in the cyclic nucleotide-binding site of cyclic nucleotide-regulated ion channels.

Taraska, Justin W.; Puljung, Michael C.; Olivier, Nelson B.; Flynn, Galen E.; Zagotta, William N.

2009-01-01

82

Native ordered structure of welan polysaccharide: conformational transitions and gel formation in aqueous dimethyl sulphoxide.  

PubMed

Welan, in aqueous solution, has "weak gel" properties analogous to those of ordered xanthan but, unlike xanthan, shows no evidence of conformational change between 0 and 100 degrees C. When the polymer is dissolved in dimethyl sulphoxide (Me2SO) rather than in water, however, there is a massive decrease in viscosity and total loss of gel-like character. In mixtures of the two solvents, the change in rheology occurs over a narrow range of composition (approximately 85-90% v/v Me2SO for 0.5% welan). On heating and cooling in a solvent close to the lower end of the critical range (86% Me2SO), the polymer shows typical order-disorder and disorder-order transitions [as monitored by optical rotation, differential scanning calorimetry, and temperature-course of rheological change]. When solutions of disordered welan in Me2SO are poured into excess water they form cohesive strings of gel. We interpret these results as showing that: (1) the stable conformation of welan in water is the double helix structure identified by X-ray fibre diffraction in the solid state; (2) in native welan, as biosynthesised, the strands are perfectly paired, and ordered along their full length; (3) on exposure to high concentrations of Me2SO, the native structure is dissociated into disordered coils; (4) rapid renaturation from the disordered state gives shorter helices, with exchange of partners to form a stable cross-linked network. PMID:8137361

Hember, M W; Richardson, R K; Morris, E R

1994-01-15

83

Reversible conformational transitions of a polymer brush containing boronic acid and its interaction with mucin glycoprotein.  

PubMed

Reversible changes of the height of a polymer brush containing phenylboronic acid were studied. The polymer brush thickness underwent reversible changes of 0.5-1?nm, in response to the changes in composition of the contacting aqueous phase from deionized water to bicarbonate buffer and vice versa, apparently due to the conformational transition of the weak polyelectrolyte to the more extended electrically charged state. Adsorption of mucin glycoprotein to the polymer brush took place due to boronate/sugar interactions between the glycoprotein and the graft copolymer and resulted in further increase of the brush height by ca. 1.5?nm, as observed by means of spectral correlation spectroscopy and ellipsometry. PMID:21136536

Ivanov, Alexander E; Solodukhina, Nadezda; Wahlgren, Marie; Nilsson, Lars; Vikhrov, Alexander A; Nikitin, Maxim P; Orlov, Alexey V; Nikitin, Petr I; Kuzimenkova, Marina V; Zubov, Vitali P

2011-02-11

84

MM/PBSA analysis of molecular dynamics simulations of bovine beta-lactoglobulin: free energy gradients in conformational transitions?  

PubMed

The pH-driven opening and closure of beta-lactoglobulin EF loop, acting as a lid and closing the internal cavity of the protein, has been studied by molecular dynamics (MD) simulations and free energy calculations based on molecular mechanics/Poisson-Boltzmann (PB) solvent-accessible surface area (MM/PBSA) methodology. The forms above and below the transition pH differ presumably only in the protonation state of residue Glu89. MM/PBSA calculations are able to reproduce qualitatively the thermodynamics of the transition. The analysis of MD simulations using a combination of MM/PBSA methodology and the colony energy approach is able to highlight the driving forces implied in the transition. The analysis suggests that global rearrangements take place before the equilibrium local conformation is reached. This conclusion may bear general relevance to conformational transitions in all lipocalins and proteins in general. PMID:15690343

Fogolari, Federico; Moroni, Elisabetta; Wojciechowski, Marcin; Baginski, Maciej; Ragona, Laura; Molinari, Henriette

2005-04-01

85

Nucleotide-free MalK Drives the Transition of the Maltose Transporter to the Inward-facing Conformation.  

PubMed

The complex MalFGK2 hydrolyzes ATP and alternates between inward- and outward-facing conformations during maltose transport. It has been shown that ATP promotes closure of MalK2 and opening of MalFG toward the periplasm. Yet, why the transporter rests in a conformation facing the cytosol in the absence of nucleotide and how it returns to this state after hydrolysis of ATP is unknown. The membrane domain MalFG may be naturally stable in the inward-facing conformation, or the ABC domain may catalyze the transition. We address this question by analyzing the conformation of MalFG in nanodiscs and in proteoliposomes. We find that MalFG alone exists in an intermediate state until MalK binds and converts the membrane domain to the inward-facing state. We also find that MalK, if overly-bound to MalFG, blocks the transition of the transporter, whereas suppressor mutations that weaken this association restore transport. MalK therefore exploits hydrolysis of ATP to reverse the conformation of MalFG to the inward-facing conformation, a step essential for release of maltose in the cytosol. PMID:24526688

Bao, Huan; Duong, Franck

2014-04-01

86

Detection of an en masse and reversible B- to A-DNA conformational transition in prokaryotes in response to desiccation.  

PubMed

The role that DNA conformation plays in the biochemistry of cells has been the subject of intensive research since DNA polymorphism was discovered. B-DNA has long been considered the native form of DNA in cells although alternative conformations of DNA are thought to occur transiently and along short tracts. Here, we report the first direct observation of a fully reversible en masse conformational transition between B- and A-DNA within live bacterial cells using Fourier transform infrared (FTIR) spectroscopy. This biospectroscopic technique allows for non-invasive and reagent-free examination of the holistic biochemistry of samples. For this reason, we have been able to observe the previously unknown conformational transition in all four species of bacteria investigated. Detection of this transition is evidence of a previously unexplored biological significance for A-DNA and highlights the need for new research into the role that A-DNA plays as a cellular defence mechanism and in stabilizing the DNA conformation. Such studies are pivotal in understanding the role of A-DNA in the evolutionary pathway of nucleic acids. Furthermore, this discovery demonstrates the exquisite capabilities of FTIR spectroscopy and opens the door for further investigations of cell biochemistry with this under-used technique. PMID:24898023

Whelan, Donna R; Hiscox, Thomas J; Rood, Julian I; Bambery, Keith R; McNaughton, Don; Wood, Bayden R

2014-08-01

87

Fourier Imaging Correlation Spectroscopy for Studies of Sub-Cellular Dynamics and Biomolecular Conformation Transition Pathways  

NASA Astrophysics Data System (ADS)

Novel high signal-to-noise spectroscopic experiments that probe the dynamics of fluorescently labeled macromolecules have the potential to reveal complex intracellular biochemical mechanisms, or the slow relaxations of soft matter systems. Fourier imaging correlation spectroscopy (FICS) is a phase-selective approach to fluorescence fluctuation spectroscopy that employs a unique route to elevate signal levels while acquiring detailed information about microscopic coordinate trajectories. In this talk, I will illustrate the broad applicability of this approach by discussing two recent studies. The anomalous sub-diffusive dynamics of mitochondria in budding yeast are characterized using FICS, and provide detailed, length-scale dependent information about the influence of specific cytoskeletal elements on the movements of this organelle. We find that non-equilibrium forces associated with actin polymerization lead to a 1.5-fold enhancement of the long-time mitochondrial diffusion coefficient, and a transient sub-diffusive temporal scaling of the mean-square displacement. These non-equilibrium dynamics are a predominant factor in driving mitochondrial transport. In another set of experiments, polarization-modulated FICS simultaneously captures information about the internal conformation fluctuations and molecular translational dynamics of the fluorescent protein DsRed. By implementing a four-point correlation analysis, we construct two-dimensional spectral densities and joint distribution functions that determine temporal correlations of center-of-mass and anisotropy coordinates over successive time intervals. These four-point functions reveal statistically meaningful transition pathways between different optical conformations of the DsRed protein. The FICS method is well suited to investigate the dynamics of a broad range of heterogeneous systems, which include the molecular motions of glass forming liquids.

Marcus, Andrew

2010-03-01

88

Transitions between closed and open conformations of TolC: the effects of ions in simulations.  

PubMed

Bacteria, such as Escherichia coli, use multidrug efflux pumps to export toxic substrates through their cell membranes. Upon formation of an efflux pump, the aperture of its outer membrane protein TolC opens and thereby enables the extrusion of substrate molecules. The specialty of TolC is its ability to dock to different transporters, making it a highly versatile export protein. Within this study, the transition between two conformations of TolC that are both available as crystal structures was investigated using all-atom molecular dynamics simulations. To create a partially open conformation from a closed one, the stability of the periplasmic aperture was weakened by a double point mutation at the constricting ring, which removes some salt bridges and hydrogen bonds. These mutants, which showed partial opening in previous experiments, did not spontaneously open during a 20-ns equilibration at physiological values of the KCl solution. Detailed analysis of the constricting ring revealed that the cations of the solvent were able to constitute ionic bonds in place of the removed salt bridges, which inhibited the opening of the aperture in simulations. To remove the ions from these binding positions within the available simulation time, an extra force was applied onto the ions. To keep the effect of this additional force rather flexible, it was applied in form of an artificial external electric field perpendicular to the membrane. Depending on the field direction and the ion concentration, these simulations led to a partial opening. In experiments, this energy barrier for the ions can be overcome by thermal fluctuations on a longer timescale. PMID:19383457

Schulz, Robert; Kleinekathöfer, Ulrich

2009-04-22

89

The alpha-to-beta conformational transition of Alzheimer's Abeta-(1-42) peptide in aqueous media is reversible: a step by step conformational analysis suggests the location of beta conformation seeding.  

PubMed

Current views of the role of beta-amyloid (Abeta) peptide fibrils range from regarding them as the cause of Alzheimer's pathology to having a protective function. In the last few years, it has also been suggested that soluble oligomers might be the most important toxic species. In all cases, the study of the conformational properties of Abeta peptides in soluble form constitutes a basic approach to the design of molecules with "antiamyloid" activity. We have experimentally investigated the conformational path that can lead the Abeta-(1-42) peptide from the native state, which is represented by an alpha helix embedded in the membrane, to the final state in the amyloid fibrils, which is characterized by beta-sheet structures. The conformational steps were monitored by using CD and NMR spectroscopy in media of varying polarities. This was achieved by changing the composition of water and hexafluoroisopropanol (HFIP). In the presence of HFIP, beta conformations can be observed in solutions that have very high water content (up to 99 % water; v/v). These can be turned back to alpha helices simply by adding the appropriate amount of HFIP. The transition of Abeta-(1-42) from alpha to beta conformations occurs when the amount of water is higher than 80 % (v/v). The NMR structure solved in HFIP/H2O with high water content showed that, on going from very apolar to polar environments, the long N-terminal helix is essentially retained, whereas the shorter C-terminal helix is lost. The complete conformational path was investigated in detail with the aid of molecular-dynamics simulations in explicit solvent, which led to the localization of residues that might seed beta conformations. The structures obtained might help to find regions that are more affected by environmental conditions in vivo. This could in turn aid the design of molecules able to inhibit fibril deposition or revert oligomerization processes. PMID:16444756

Tomaselli, Simona; Esposito, Veronica; Vangone, Paolo; van Nuland, Nico A J; Bonvin, Alexandre M J J; Guerrini, Remo; Tancredi, Teodorico; Temussi, Piero A; Picone, Delia

2006-02-01

90

Solvent-dependent divergent functions of Sc(OTf)? in stereoselective epoxide-opening spiroketalizations.  

PubMed

A stereocontrolled synthesis of benzannulated spiroketals has been developed using solvent-dependent Sc(OTf)3-mediated spirocyclizations of exo-glycal epoxides having alcohol side chains. In THF, the reaction proceeds via Lewis acid catalysis under kinetic control with inversion of configuration at the anomeric carbon. In contrast, in CH2Cl2, Brønsted acid catalysis under thermodynamic control leads to retention of configuration. The reactions accommodate a variety of aryl substituents and ring sizes and provide stereochemically diverse spiroketals. PMID:24742081

Sharma, Indrajeet; Wurst, Jacqueline M; Tan, Derek S

2014-05-01

91

An analysis of stable forms of CL-20: A DFT study of conformational transitions, infrared and Raman spectra  

NASA Astrophysics Data System (ADS)

The most stable forms of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) were analyzed at the B3LYP/6-31G+(d,p) level of theory. The mechanism of conformational transformations was clarified. The activation energies of those transitions were found to be quite low and lie in the range 1.2-4.0 kcal mol -1. IR and Raman spectra of the studied CL-20 forms were simulated. The predicted vibrational modes were used for comparison with the experimental values. The unique peaks for each of the conformers in IR and Raman spectra were found. These peaks can be used as the "signatures" of the studied conformers and for identification of different polymorphs of CL-20 in mixtures.

Kholod, Yana; Okovytyy, Sergiy; Kuramshina, Gulnara; Qasim, Mohammad; Gorb, Leonid; Leszczynski, Jerzy

2007-10-01

92

Glutamate dehydrogenase of the unicellular green alga Scenedesmus acutus : Substrate-induced conformational transition.  

PubMed

The coenzyme-non-specific glutamate dehydrogenase (EC 1.4.1.3) from Scenedesmus acutus in inhibited by p-hydroxymercuribenzoate only in the deamination reaction. From this result and from its stability in the presence of urea it is concluded that this enzyme exhibits and equilibrium between three conformations: aminating and deaminating conformations induced by NADH-2-oxoglutarate and NAD(+)-glutamate, respectively, and the "native" conformation in the absence of substrates. PMID:24264271

Shatilov, V R; Sund, H

1983-07-01

93

All-or-none switching of transcriptional activity on single DNA molecules caused by a discrete conformational transition  

NASA Astrophysics Data System (ADS)

Recently, it has been confirmed that long duplex DNA molecules with a size larger than several tens of kilo-base pairs (kbp), exhibit a discrete conformational transition from an unfolded coil state to a folded compact state upon the addition of various kinds of chemical species that usually induce DNA condensation. In this study, we performed a single-molecule observation on a large DNA, Lambda ZAP II DNA (~41 kbp), in a solution containing RNA polymerase and substrates along with spermine, a tetravalent cation, at different concentrations, by use of fluorescence staining of both DNA and RNA. We found that transcription, or RNA production, is completely inhibited in the compact globule state, but is actively performed in the unfolded coil state. Such an all-or-none effect on transcriptional activity induced by the discrete conformational transition of single DNA molecules is discussed in relation to the mechanism of the regulation of large-scale genetic activity.

Yamada, Ayako; Kubo, Koji; Nakai, Tonau; Yoshikawa, Kenichi; Tsumoto, Kanta

2005-05-01

94

Free energy of conformational transition paths in biomolecules: The string method and its application to myosin VI  

PubMed Central

A set of techniques developed under the umbrella of the string method is used in combination with all-atom molecular dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI. The challenges specific to the application of these techniques to such a large and complex biomolecule are addressed in detail. These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition. A detailed description of the PPS?R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion. The methodology developed here is expected to be useful more generally in studies of conformational transitions in complex biomolecules.

Ovchinnikov, Victor; Karplus, Martin; Vanden-Eijnden, Eric

2011-01-01

95

Free energy of conformational transition paths in biomolecules: the string method and its application to myosin VI.  

PubMed

A set of techniques developed under the umbrella of the string method is used in combination with all-atom molecular dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI. The challenges specific to the application of these techniques to such a large and complex biomolecule are addressed in detail. These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition. A detailed description of the PPS?R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion. The methodology developed here is expected to be useful more generally in studies of conformational transitions in complex biomolecules. PMID:21361558

Ovchinnikov, Victor; Karplus, Martin; Vanden-Eijnden, Eric

2011-02-28

96

Ion-Controlled Conformational Dynamics in the Outward-Open Transition from an Occluded State of LeuT  

PubMed Central

Neurotransmitter:sodium symporter (NSS) proteins are secondary Na+-driven active transporters that terminate neurotransmission by substrate uptake. Despite the availability of high-resolution crystal structures of a bacterial homolog of NSSs—Leucine Transporter (LeuT)—and extensive computational and experimental structure-function studies, unanswered questions remain regarding the transport mechanisms. We used microsecond atomistic molecular-dynamics (MD) simulations and free-energy computations to reveal ion-controlled conformational dynamics of LeuT in relation to binding affinity and selectivity of the more extracellularly positioned Na+ binding site (Na1 site). In the course of MD simulations starting from the occluded state with bound Na+, but in the absence of substrate, we find a spontaneous transition of the extracellular vestibule of LeuT into an outward-open conformation. The outward opening is enhanced by the absence of Na1 and modulated by the protonation state of the Na1-associated Glu-290. Consistently, the Na+ affinity for the Na1 site is inversely correlated with the extent of outward-open character and is lower than in the occluded state with bound substrate; however, the Na1 site retains its selectivity for Na+ over K+ in such conformational transitions. To the best of our knowledge, our findings shed new light on the Na+-driven transport cycle and on the symmetry in structural rearrangements for outward- and inward-open transitions.

Zhao, Chunfeng; Stolzenberg, Sebastian; Gracia, Luis; Weinstein, Harel; Noskov, Sergei; Shi, Lei

2012-01-01

97

Large scale conformational transitions in ?-structural motif of gramicidin A: kinetic analysis based on CD and FT-IR data.  

PubMed

Gramicidin A (gA) is a polypeptide antibiotic, which forms dimeric channels specific for monovalent cations in artificial and biological membranes. It is a polymorphic molecule that adopts a unique variety of helical conformations, including antiparallel double-stranded ???5.6 or ???7.2 helices (number of residues per turn) and a single-stranded ?6.3 helix (the 'channel form'). The behavior of gA-Cs(+) complex in the micelles of TX-100 was studied in this work. Transfer of the complex into the micelles activates a cascade of sequential conformational transitions monitored by CD and FT-IR spectroscopy: [Formula: see text] At the first step after Cs(+) removal, the RH ???5.6 helix is formed, which has been discussed so far only hypothetically. Kinetics of the transitions was measured, and the activation parameters were determined. The activation energies of the ???5.6????-helical monomer transition in dioxane and dioxane/water solutions were also measured for comparison. The presence of water raises the transition rate constant ~10(3) times but does not lead to crucial fall of the activation energy. All activation energies were found in the 20-25?kcal/mol range, i.e. much lower than would be expected for unwinding of the double helix (when 28 H-bonds are broken simultaneously). These results can be accounted for in the light of local unfolding (or 'cracking') model for large scale conformational transitions developed by the P.?G.Wolynes team [Miyashita O, Onuchic JN, Wolynes PG. Proc. Natl. Acad. Sci. USA 2003; 100: 12570-12575.]. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd. PMID:24788525

Sychev, Sergei V; Ivanov, Vadim T

2014-08-01

98

Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin.  

PubMed

The popular targeted molecular dynamics (TMD) method for generating transition paths in complex biomolecular systems is revisited. In a typical TMD transition path, the large-scale changes occur early and the small-scale changes tend to occur later. As a result, the order of events in the computed paths depends on the direction in which the simulations are performed. To identify the origin of this bias, and to propose a method in which the bias is absent, variants of TMD in the restraint formulation are introduced and applied to the complex open ? closed transition in the protein calmodulin. Due to the global best-fit rotation that is typically part of the TMD method, the simulated system is guided implicitly along the lowest-frequency normal modes, until the large spatial scales associated with these modes are near the target conformation. The remaining portion of the transition is described progressively by higher-frequency modes, which correspond to smaller-scale rearrangements. A straightforward modification of TMD that avoids the global best-fit rotation is the locally restrained TMD (LRTMD) method, in which the biasing potential is constructed from a number of TMD potentials, each acting on a small connected portion of the protein sequence. With a uniform distribution of these elements, transition paths that lack the length-scale bias are obtained. Trajectories generated by steered MD in dihedral angle space (DSMD), a method that avoids best-fit rotations altogether, also lack the length-scale bias. To examine the importance of the paths generated by TMD, LRTMD, and DSMD in the actual transition, we use the finite-temperature string method to compute the free energy profile associated with a transition tube around a path generated by each algorithm. The free energy barriers associated with the paths are comparable, suggesting that transitions can occur along each route with similar probabilities. This result indicates that a broad ensemble of paths needs to be calculated to obtain a full description of conformational changes in biomolecules. The breadth of the contributing ensemble suggests that energetic barriers for conformational transitions in proteins are offset by entropic contributions that arise from a large number of possible paths. PMID:22409258

Ovchinnikov, Victor; Karplus, Martin

2012-07-26

99

Symmetry- and solvent-dependent photophysics of fluorenes containing donor and acceptor groups.  

PubMed

Three two-photon absorption (2PA) dyes (donor-?-donor (DPA2F), donor-?-acceptor (AF240), and acceptor-?-acceptor (BT2F); specifically, D is Ph2N-, A is 2-benzothiazoyl, and the ?-linker is 9,9-diethylfluorene) are examined in a variety of aprotic solvents. Because the 2PA cross section is sensitive to the polarity of the local environment, this report examines the solvent-dependent linear photophysics of the dyes, which are important to understand before probing more complex solid-state systems. The symmetrical dyes show little solvent dependence; however, AF240 has significant solvatochromism observed in the fluorescence spectra and lifetimes and also the transient absorption spectra. A 114 nm bathochromic shift is observed in the fluorescence maximum when going from n-hexane to acetonitrile, whereas the lifetimes increase from 1.25 to 3.12 ns. The excited-state dipole moment for AF240 is found to be 20.1 D using the Lippert equation, with smaller values observed for the symmetrical dyes. Additionally, the femtosecond transient absorption (TA) spectra at time zero show little solvent dependence for DPA2F or BT2F, but AF240 shows a 52 nm hypsochromic shift from n-hexane to acetonitrile. Coupled with the solvatochromism in the fluorescence and large excited-state dipole moment, this is attributed to formation of an intramolecular charge-transfer (ICT) state in polar solvents. By 10 ps in AF240, the maximum TA in acetonitrile has shifted 30 nm, providing direct evidence of a solvent-stabilized ICT state, whose formation occurs in 0.85-2.71 ps, depending on solvent. However, AF240 in nonpolar solvents and the symmetrical dyes in all solvents show essentially no shifts due to a predominantly locally excited (LE) state. Preliminary temperature-dependent fluorescence using frozen glass media supports significant solvent reorganization around the AF240 excited state in polar solvents, and may also support a twisted intramolecular charge-transfer (TICT)-state contribution to the stabilization. Finally, time-dependent density functional theory calculations support ICT in AF240 in polar media and also allow prediction of the 2PA cross sections in the 0-0 band, which are much larger for AF240 than the symmetrical dyes. PMID:24972335

Stewart, David J; Dalton, Matthew J; Swiger, Rachel N; Fore, Jennifer L; Walker, Mark A; Cooper, Thomas M; Haley, Joy E; Tan, Loon-Seng

2014-07-17

100

Molecular Dynamics Simulation on the Conformational Transition of the Mad2 Protein from the Open to the Closed State  

PubMed Central

The Mad2 protein, with two distinct conformations of open- and closed-states, is a key player in the spindle checkpoint. The closed Mad2 state is more active than the open one. We carried out conventional and targeted molecular dynamics simulations for the two stable Mad2 states and their conformational transition to address the dynamical transition mechanism from the open to the closed state. The intermediate structure in the transition process shows exposure of the ?6 strand and an increase of space around the binding sites of ?6 strand due to the unfolding of the ?7/8 sheet and movement of the ?6/4/5 sheet close to the ?C helix. Therefore, Mad2 binding to the Cdc20 protein in the spindle checkpoint is made possible. The interconversion between these two states might facilitate the functional activity of the Mad2 protein. Motion correlation analysis revealed the allosteric network between the ?1 strand and ?7/8 sheet via communication of the ?5-?C loop and the ?6/4/5 sheet in this transition process.

Li, Chaoqun; Zhu, Yanyan; Wang, Yan; Chen, Guangju

2014-01-01

101

Conformational transitions of a free amino-acid-functionalized polythiophene induced by different buffer systems  

NASA Astrophysics Data System (ADS)

A chiral, 3-substituted polythiophene with an amino-acid function shows pH-dependent visible, emission and circular dichroism spectra in buffered aqueous solution. At pH equal to the pI of the amino-acid, the backbone adopts a nonplanar right-handed helical conformation and the polymer chains are separated from each other. Increasing pH leads to a more planar conformation of the backbone and an aggregation of the polymer chains occurs. A lower pH will also lead to a more planar conformation of the backbone, but aggregation of the polymer chains appears to be absent. The aggregates are disrupted by increasing ionic strength in alkaline buffer systems, indicating hydrogen bonding is important for aggregation. On the other hand, ions containing an amino group and one or more hydroxyl groups induce a more planar conformation of the polymer backbone.

Nilsson, K. P. R.; Andersson, M. R.; Inganäs, O.

2002-10-01

102

A conformational transition in the myosin VI converter contributes to the variable step size.  

PubMed

Myosin VI (MVI) is a dimeric molecular motor that translocates backwards on actin filaments with a surprisingly large and variable step size, given its short lever arm. A recent x-ray structure of MVI indicates that the large step size can be explained in part by a novel conformation of the converter subdomain in the prepowerstroke state, in which a 53-residue insert, unique to MVI, reorients the lever arm nearly parallel to the actin filament. To determine whether the existence of the novel converter conformation could contribute to the step-size variability, we used a path-based free-energy simulation tool, the string method, to show that there is a small free-energy difference between the novel converter conformation and the conventional conformation found in other myosins. This result suggests that MVI can bind to actin with the converter in either conformation. Models of MVI/MV chimeric dimers show that the variability in the tilting angle of the lever arm that results from the two converter conformations can lead to step-size variations of ?12 nm. These variations, in combination with other proposed mechanisms, could explain the experimentally determined step-size variability of ?25 nm for wild-type MVI. Mutations to test the findings by experiment are suggested. PMID:22098742

Ovchinnikov, V; Cecchini, M; Vanden-Eijnden, E; Karplus, M

2011-11-16

103

Solvent-dependent luminescent Cu(I) framework based on 5-(4-pyridyl)tetrazole  

NASA Astrophysics Data System (ADS)

A new Cu(?) coordination compound, Cu 4(L) 4·2EtOH ( 1), has been obtained from the solvothermal reaction of CuBr, HL (L=5-(4-pyridyl) tetrazole), EtOH and NH 3·H 2O. The structure determination reveals that 1 has a 2D network, where each Cu(I) atom adopts a trigonal coordination mode. The 2D networks stacked in an ABAB sequence through the ?-? interaction to form a 3D supramolecular framework, giving a 1D channel along the b-axis. The TGA and powder XRD measurements reveal that the framework is stable after removal of the guest molecules. Gas (N 2) adsorption measurement was carried out for the framework. Framework 1 shows II sorption profile with N 2, which indicates that N 2 molecules cannot diffuse into the micropore and only surface adsorption occurs. The photoluminescent research shows that compound 1 displays an interesting solvent-dependent luminescence.

Wang, Fei; Yu, Rongmin; Zhang, Qi-Sheng; Zhao, Zhen-Guo; Wu, Xiao-Yuan; Xie, Yi-Ming; Qin, Li; Chen, Shan-Ci; Lu, Can-Zhong

2009-09-01

104

Cooperative symmetric to asymmetric conformational transition of the apo-form of scavenger decapping enzyme revealed by simulations.  

PubMed

Decapping is a central step in eukaryotic mRNA turnover and in gene expression regulation. The human scavenger decapping enzyme, DcpS, catalyses cap hydrolysis following mRNA degradation. DcpS is a dimeric enzyme, with two active sites. Crystal structures suggest that DcpS must undergo significant conformational changes upon ligand binding, but the mechanism of this transition is unknown. Here, we report two long timescale (20 ns) molecular dynamics simulations of the apo-form of DcpS. The dimer is observed to undergo a strikingly cooperative motion, with one active site closing while the other opens. The amplitude of the conformational change is 6-21 A and the apparent timescale is 4-13 ns. These findings indicate that the crystallographically observed symmetric conformation of apo-form of DcpS is only a minor conformation in solution. The simulations also show that active sites are structurally connected via the domain-swapped dimer structure of the N-terminal domain, even in the absence of a bound ligand. These findings suggest a functional reason for the enzyme existing as a dimer, and may be widely relevant, also for other dimeric proteins. PMID:17705275

Pentikäinen, Ulla; Pentikäinen, Olli T; Mulholland, Adrian J

2008-02-01

105

Conformational transitions in RNA single uridine and adenosine bulge structures: a molecular dynamics free energy simulation study.  

PubMed

Extra unmatched nucleotides (single base bulges) are common structural motifs in folded RNA molecules and can participate in RNA-ligand binding and RNA tertiary structure formation. Often these processes are associated with conformational transitions in the bulge region such as flipping out of the bulge base from an intrahelical stacked toward a looped out state. Knowledge of the flexibility of bulge structures and energetics of conformational transitions is an important prerequisite to better understand the function of this RNA motif. Molecular dynamics simulations were performed on single uridine and adenosine bulge nucleotides at the center of eight basepair RNA molecules and indicated larger flexibility of the bulge bases compared to basepaired regions. The umbrella sampling method was applied to study the bulge base looping out process and accompanying conformational and free energy changes. Looping out toward the major groove resulted in partial disruption of adjacent basepairs and was found to be less favorable compared to looping out toward the minor groove. For both uridine and adenosine bulges, a positive free energy change for full looping out was obtained which was approximately 1.5 kcal mol-1 higher in the case of the adenosine compared to the uridine bulge system. The simulations also indicated stable partially looped out states with the bulge bases located in the RNA minor groove and forming base triples with 5'-neighboring basepairs. In the case of the uridine bulge this state was more stable than the intrahelical stacked bulge structure. Induced looping out toward the minor groove involved crossing of an energy barrier of approximately 3.5 kcal mol-1 before reaching the base triple state. A continuum solvent analysis of intermediate bulge states indicated that electrostatic interactions stabilize looped out and base triple states, whereas van der Waals interactions and nonpolar contributions favor the stacked bulge conformation. PMID:16399833

Barthel, André; Zacharias, Martin

2006-04-01

106

Exploring transition pathway and free-energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics.  

PubMed

Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38? kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38? leads to a large change in free-energy barrier (??G ? 7 kcal/mol), promoting the transition from DFG-in to DFG-out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38? is also studied, which reduces the free-energy difference between the two functional states of p38? and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions. PMID:24350625

Wang, Jinan; Shao, Qiang; Xu, Zhijian; Liu, Yingtao; Yang, Zhuo; Cossins, Benjamin P; Jiang, Hualiang; Chen, Kaixian; Shi, Jiye; Zhu, Weiliang

2014-01-01

107

Conformance Testing with Labelled Transition Systems: Implementation Relations and Test Generation  

Microsoft Academic Search

This paper studies testing based on labelled transition systems, presenting two test generation algorithms with their corresponding implementation relations. The first algorithm assumes that implementations communicate with their environment via symmetric, synchronous interactions. It is based on the theory of testing equivalence and preorder, as is most of the testing theory for labelled transition systems, and it is found in

Jan Tretmans

1996-01-01

108

Phosphorylation Induces a Conformational Transition near the Lipid-Water Interface of Phospholamban Reconstituted with the Ca-ATPase  

SciTech Connect

We have measured conformational changes of phospholamban (PLB) induced both by its interaction with the SR Ca-ATPase and by phosphorylation of Ser-16 by cAMP-dependent protein kinase (PKA) using an engineered PLB having a single cysteine (Cys-24) derivatized with the fluorophore 2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid (ANSmal). This modified mutant PLB is fully functional when co-reconstituted with the affinity-purified Ca-ATPase in liposomes. ANSmal emission properties and its solvent accessibility indicate that Cys-24 is in an aqueous environment outside the membrane. Fluorescence quenching and time-resolved anisotropy measurements of ANSmal-PLB demonstrate distinct structures for PLB in the free and Ca-ATPase-bound state. Both solvent exposure and probe motions of ANSmal are enhanced upon interaction of PLB with the Ca-ATPase. This conformational transition entails conversion of free PLB in a conformation which is insensitive to one which is sensitive to the phosphorylation state of PLB. Upon phosphorylation of Ca-ATPase-bound PLB, a decreased level of solvent exposure of ANSmal is observed, suggesting that the amino acid sequence of PLB near the lipid-water interface acts as a conformational switch in response to the phosphorylation of PLB. A longer correlation time, resolved by anisotropy measurements, corresponding to polypeptide chain fluctuations, is substantially restricted by interaction of PLB with the Ca-ATPase. This restriction is not reversed by phosphorylation of PLB, indicating that the region around Cys-24 near the lipid-water interface does not undergo dissociation from the Ca-ATPase. These results suggest that the phosphorylation by PKA induces a redistribution of PLB-Ca-ATPase protein contacts to relieve the inhibitory effect of PLB for the activation of calcium transport.

Chen, Baowei; Bigelow, Diana J.

2002-11-26

109

The Substrate-Driven Transition to an Inward-Facing Conformation in the Functional Mechanism of the Dopamine Transporter  

PubMed Central

Background The dopamine transporter (DAT), a member of the neurotransmitter:Na+ symporter (NSS) family, terminates dopaminergic neurotransmission and is a major molecular target for psychostimulants such as cocaine and amphetamine, and for the treatment of attention deficit disorder and depression. The crystal structures of the prokaryotic NSS homolog of DAT, the leucine transporter LeuT, have provided critical structural insights about the occluded and outward-facing conformations visited during the substrate transport, but only limited clues regarding mechanism. To understand the transport mechanism in DAT we have used a homology model based on the LeuT structure in a computational protocol validated previously for LeuT, in which steered molecular dynamics (SMD) simulations guide the substrate along a pathway leading from the extracellular end to the intracellular (cytoplasmic) end. Methodology/Principal Findings Key findings are (1) a second substrate binding site in the extracellular vestibule, and (2) models of the conformational states identified as occluded, doubly occupied, and inward-facing. The transition between these states involve a spatially ordered sequence of interactions between the two substrate-binding sites, followed by rearrangements in structural elements located between the primary binding site and the cytoplasmic end. These rearrangements are facilitated by identified conserved hinge regions and a reorganization of interaction networks that had been identified as gates. Conclusions/Significance Computational simulations supported by information available from experiments in DAT and other NSS transporters have produced a detailed mechanistic proposal for the dynamic changes associated with substrate transport in DAT. This allosteric mechanism is triggered by the binding of substrate in the S2 site in the presence of the substrate in the S1 site. Specific structural elements involved in this mechanism, and their roles in the conformational transitions illuminated here describe, a specific substrate-driven allosteric mechanism that is directly amenable to experiment as shown previously for LeuT.

Shan, Jufang; Javitch, Jonathan A.; Shi, Lei; Weinstein, Harel

2011-01-01

110

Reentrant conformation transition in poly( N, N-dimethylacrylamide) hydrogels in water–organic solvent mixtures  

Microsoft Academic Search

Conformational changes in poly(N,N-dimethylacrylamide) (PDMA) networks swollen in aqueous solutions of organic solvents are studied both experimentally and theoretically. PDMA hydrogels of various charge densities were prepared by free-radical crosslinking copolymerization. Swelling behavior of the hydrogels was investigated in aqueous organic solvent mixtures as functions of solvent species and the concentration. With increasing volume fraction ? of acetone, tetrahydrofuran, or

Nermin Orakdogen; Oguz Okay

2006-01-01

111

Turn-Directed ?-? Conformational Transition of ?-syn12 Peptide at Different pH Revealed by Unbiased Molecular Dynamics Simulations  

PubMed Central

The transition from ?-helical to ?-hairpin conformations of ?-syn12 peptide is characterized here using long timescale, unbiased molecular dynamics (MD) simulations in explicit solvent models at physiological and acidic pH values. Four independent normal MD trajectories, each 2500 ns, are performed at 300 K using the GROMOS 43A1 force field and SPC water model. The most clustered structures at both pH values are ?-hairpin but with different turns and hydrogen bonds. Turn9-6 and four hydrogen bonds (HB9-6, HB6-9, HB11-4 and HB4-11) are formed at physiological pH; turn8-5 and five hydrogen bonds (HB8-5, HB5-8, HB10-3, HB3-10 and HB12-1) are formed at acidic pH. A common folding mechanism is observed: the formation of the turn is always before the formation of the hydrogen bonds, which means the turn is always found to be the major determinant in initiating the transition process. Furthermore, two transition paths are observed at physiological pH. One of the transition paths tends to form the most-clustered turn and improper hydrogen bonds at the beginning, and then form the most-clustered hydrogen bonds. Another transition path tends to form the most-clustered turn, and turn5-2 firstly, followed by the formation of part hydrogen bonds, then turn5-2 is extended and more hydrogen bonds are formed. The transition path at acidic pH is as the same as the first path described at physiological pH.

Liu, Lei; Cao, Zanxia

2013-01-01

112

A Conformational Transition in the Adenylyl Cyclase Catalytic Site Yields Different Binding Modes for Ribosyl-Modified and Unmodified Nucleotide Inhibitors  

PubMed Central

Adenylyl cyclases (ACs) are promising pharmacological targets for treating heart failure, cancer and psychosis. Ribose-substituted nucleotides have been reported as a potent family of AC inhibitors. In silico analysis of the docked conformers of such nucleotides in AC permits assembly of a consistent, intuitive QSAR model with strong correlation relative to measured pKi values. Energy decomposition suggests that the MANT group effects an AC conformational transition upon ligand binding.

Wang, Jenna L.; Guo, Jian-Xin; Zhang, Qi-Yuan; Wu, Jay J-Q.; Seifert, Roland; Lushington, Gerald H.

2007-01-01

113

dNTP-dependent Conformational Transitions in the Fingers Subdomain of Klentaq1 DNA Polymerase  

PubMed Central

DNA polymerases are responsible for the accurate replication of DNA. Kinetic, single-molecule, and x-ray studies show that multiple conformational states are important for DNA polymerase fidelity. Using high precision FRET measurements, we show that Klentaq1 (the Klenow fragment of Thermus aquaticus DNA polymerase 1) is in equilibrium between three structurally distinct states. In the absence of nucleotide, the enzyme is mostly open, whereas in the presence of DNA and a correctly base-pairing dNTP, it re-equilibrates to a closed state. In the presence of a dNTP alone, with DNA and an incorrect dNTP, or in elevated MgCl2 concentrations, an intermediate state termed the “nucleotide-binding” state predominates. Photon distribution and hidden Markov modeling revealed fast dynamic and slow conformational processes occurring between all three states in a complex energy landscape suggesting a mechanism in which dNTP delivery is mediated by the nucleotide-binding state. After nucleotide binding, correct dNTPs are transported to the closed state, whereas incorrect dNTPs are delivered to the open state.

Rothwell, Paul J.; Allen, William J.; Sisamakis, Evangelos; Kalinin, Stanislav; Felekyan, Suren; Widengren, Jerker; Waksman, Gabriel; Seidel, Claus A. M.

2013-01-01

114

Regulatory interplay between TFIID's conformational transitions and its modular interaction with core promoter DNA  

PubMed Central

Recent structural and biochemical studies of human TFIID have significantly increased our understanding of the mechanisms underlying the recruitment of TFIID to promoter DNA and its role in transcription initiation. Structural studies using cryo-EM revealed that modular interactions underlie TFIID’s ability to bind simultaneously multiple promoter motifs and to define a DNA state that will facilitate transcription initiation. Here we propose a general model of promoter binding by TFIID, where co-activators, activators, and histone modifications promote and/or stabilize a conformational state of TFIID that results in core promoter engagement. Within this high affinity conformation, we propose that TFIID’s extensive interaction with promoter DNA leads to topological changes in the DNA that facilitate the eventual loading of RNAP II. While more work is required to dissect the individual contributions of activators and repressors to TFIID’s DNA binding, the recent cryo-EM studies provide a physical framework to guide future structural, biophysical, and biochemical experiments.

Cianfrocco, Michael A; Nogales, Eva

2013-01-01

115

Principal component analysis of the pH-dependent conformational transitions of bovine ?-lactoglobulin monitored by heteronuclear NMR  

PubMed Central

To clarify the pH-dependent conformational transitions of proteins, we propose an approach in which structural changes monitored by heteronuclear sequential quantum correlation (HSQC) spectroscopy were analyzed by using a principal component analysis (PCA). We use bovine ?-lactoglobulin, a protein widely used in protein folding studies, as a target. First, we measured HSQC spectra at various pH values and subjected them to a PCA. The analysis revealed three apparent transitions with pKa values of 2.9, 4.9, and 6.8, consistent with previous reports using different methods. Next, Gdn-HCl-induced unfolding was examined by measuring tryptophan fluorescence at various pH values. Between pH 2 and 8, ?-lactoglobulin exhibited a number of structural transitions as well as changes in stability represented by the free energy change of unfolding, ?GU. By combining the NMR and fluorescence results, the change in ?GU was suggested to result from the decreased pKa of some acidic residues. Notably, the native state at neutral pH is destabilized by deprotonation of Glu-89, leading to an increase in the relative population of the intermediate. Thus, the PCA of pH-dependent HSQC spectra provides a more comprehensive understanding of the stability and function of proteins.

Sakurai, Kazumasa; Goto, Yuji

2007-01-01

116

Structures of the xylose-water complex: Energetics, transitions between conformers and spectroscopy  

NASA Astrophysics Data System (ADS)

Structure optimization, ab initio molecular dynamics (AIMD) simulation of transitions between structures, vibrational self-consistent field (VSCF) calculations of vibrational spectra and infrared ion dip (IRID) experiments have been used to explore the potential energy landscape of isomeric xylose·H 2O (and D 2O). The VSCF predictions are in close correspondence with the experimental data but the spectra associated with their two low energy isomers are too similar to permit an unequivocal structural assignment. At cryogenic temperatures several low energy isomers could be 'frozen in' but at 300 K the AIMD simulations predict rapid transitions between them and in consequence, a highly fluxional system.

Jin, Lin; Simons, John P.; Gerber, R. Benny

2011-12-01

117

Spectroscopic signatures of the T to R conformational transition in the insulin hexamer.  

PubMed

The cobalt(II)-substituted human insulin hexamer has been shown to undergo the phenol-induced T6 to R6 structural transition in solution. The accompanying octahedral to tetrahedral change in ligand field geometry of the cobalt ions results in dramatic changes in the visible region of the electronic spectrum and thus represents a useful spectroscopic method for studying the T to R transition. Changes in the Co2+ spectral envelope show that the aqua ligand associated with each tetrahedral Co2+ center can be replaced by SCN-, CN-, OCN-, N3-, Cl-, and NO2-. 19F NMR experiments show that the binding of m-trifluorocresol stabilizes the R6 state of zinc insulin. The chemical shift and line broadening of the CF3 singlet, which occur due to binding, provide a useful probe of the T6 to R6 transition. Due to the appearance of new resonances in the aromatic region, the 500 MHz 1H NMR spectrum of the phenol-induced R6 hexamer is readily distinguishable from that of the T6 form. 1H NMR studies show that phenol induces the T6 to R6 transition, both in the (GlnB13)6(Zn2+)2 hexamer and in the metal-free GlnB13 species; we conclude that metal binding is not a prerequisite for formation of the R state in this mutant. PMID:2681208

Roy, M; Brader, M L; Lee, R W; Kaarsholm, N C; Hansen, J F; Dunn, M F

1989-11-15

118

Conformational transitions in phosvitin with pH variation. Vibrational circular dichroism study.  

PubMed

The vibrational circular dichroism (VCD) spectra of metal-free phosvitin are presented as a function of pH and analyzed both qualitatively and by using a factor analysis approach referenced to a protein data set. The qualitative pattern of both the IR and VCD changes is consistent with a coil-to-sheet transition occurring as pH is progressively decreased to values lower than 3. A similar transition was seen in commercial preparation of phosvitin which still contained metal ions, but there the transition was more gradual and occurred at somewhat different pH values. Such a gradual change is also evident in the solution phase absorption band profile but is made clearer using Fourier deconvolution. Based on VCD results, the low pH transition appears to occur with two distinct manifestations of the beta-sheet form. However, at the lowest pH values the sample may precipitate. These two forms are not distinguishable with Fourier transform infrared alone and may be due to a twist of the beta-sheet form or to aggregation. PMID:2154489

Yasui, S C; Pancoska, P; Dukor, R K; Keiderling, T A; Renugopalakrishnan, V; Glimcher, M J; Clark, R C

1990-03-01

119

The ?1 72-96 Loop Controls Conformational Transitions during Reovirus Cell Entry  

PubMed Central

The reovirus outer capsid protein ?1 forms a lattice surrounding the viral core. In the native state, ?1 determines the environmental stability of the viral capsid. Additionally, during cell entry, ?1 undergoes structural rearrangements that facilitate delivery of the viral cores across the membrane. To determine how the capsid-stabilizing functions of ?1 impinge on the capacity of ?1 to undergo conformational changes required for cell entry, we characterized viruses with mutations engineered at charged residues within the ?1 loop formed by residues 72 to 96 (72-96 loop). This loop is proposed to stabilize the capsid by mediating interactions between neighboring ?1 trimers and between trimers and the core. We found that mutations at Glu89 (E89) within this loop produced viruses with compromised efficiency for completing their replication cycle. ISVPs of E89 mutants converted to ISVP*s more readily than those of wild-type viruses. The E89 mutants yielded revertants with second-site substitutions within regions that mediate interaction between ?1 trimers at a site distinct from the 72-96 loop. These viruses also contained changes in regions that control interactions within ?1 trimers. Viruses containing these second-site changes displayed restored plaque phenotypes and were capable of undergoing ISVP-to-ISVP* conversion in a regulated manner. These findings highlight regions of ?1 that stabilize the reovirus capsid and demonstrate that an enhanced propensity to form ISVP*s in an unregulated manner compromises viral fitness.

Sarkar, Payel

2013-01-01

120

Single-Molecule Analysis of Protein Large-Amplitude Conformational Transitions  

NASA Astrophysics Data System (ADS)

Proteins have evolved to harness thermal fluctuations, rather than frustrated by them, to carry out chemical transformations and mechanical work. What are, then, the operation and design principles of protein machines? To frame the problem in a tractable way, several basic questions have been formulated to guide the experimental design: (a) How many conformational states can a protein sample on the functionally important timescale? (b) What are the inter-conversion rates between states? (c) How do ligand binding or interactions with other proteins modulate the motions? (d) What are the structural basis of flexibility and its underlying molecular mechanics? Guided by this framework, we have studied protein tyrosine phosphatase B, PtpB, from M. tuberculosis (a virulence factor of tuberculosis and a potential drug target) and adenylate kinase, AK, from E. coli (a ubiquitous energy-balancing enzyme in cells). These domain movements have been followed in real time on their respective catalytic timescales using high-resolution single-molecule F"orster resonance energy transfer (FRET) spectroscopy. It is shown quantitatively that both PtpB and AK are capable of dynamically sampling two distinct states that correlate well with those observed by x-ray crystallography. Integrating these microscopic dynamics into macroscopic kinetics allows us to place the experimentally measured free-energy landscape in the context of enzymatic turnovers.

Yang, Haw

2011-03-01

121

Janus-like squaramide-based hosts: dual mode of binding and conformational transitions driven by ion-pair recognition.  

PubMed

New tripodal squaramide-based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5?% (v/v) [D(6)]DMSO in CDCl(3), compound 4 formed dimeric assemblies [log?K(dim)=3.68(8)] as demonstrated by (1)H?NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C(3)-symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N-H???X(-) hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C=O???H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi-regression analysis. The formation of high-order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR(4)I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4. The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion-pair complementary substrates. The results presented herein identify and fully describe two different modes of ion-pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion-pair recognition. PMID:22532395

Soberats, Bartomeu; Martínez, Luis; Sanna, Elena; Sampedro, Angel; Rotger, Carmen; Costa, Antoni

2012-06-11

122

Na(+) transport, and the E(1)P-E(2)P conformational transition of the Na(+)/K(+)-ATPase.  

PubMed Central

We have used admittance analysis together with the black lipid membrane technique to analyze electrogenic reactions within the Na(+) branch of the reaction cycle of the Na(+)/K(+)-ATPase. ATP release by flash photolysis of caged ATP induced changes in the admittance of the compound membrane system that are associated with partial reactions of the Na(+)/K(+)-ATPase. Frequency spectra and the Na(+) dependence of the capacitive signal are consistent with an electrogenic or electroneutral E(1)P <--> E(2)P conformational transition which is rate limiting for a faster electrogenic Na(+) dissociation reaction. We determine the relaxation rate of the rate-limiting reaction and the equilibrium constants for both reactions at pH 6.2-8.5. The relaxation rate has a maximum value at pH 7.4 (approximately 320 s(-1)), which drops to acidic (approximately 190 s(-1)) and basic (approximately 110 s(-1)) pH. The E(1)P <--> E(2)P equilibrium is approximately at a midpoint position at pH 6.2 (equilibrium constant approximately 0.8) but moves more to the E(1)P side at basic pH 8.5 (equilibrium constant approximately 0.4). The Na(+) affinity at the extracellular binding site decreases from approximately 900 mM at pH 6.2 to approximately 200 mM at pH 8.5. The results suggest that during Na(+) transport the free energy supplied by the hydrolysis of ATP is mainly used for the generation of a low-affinity extracellular Na(+) discharge site. Ionic strength and lyotropic anions both decrease the relaxation rate. However, while ionic strength does not change the position of the conformational equilibrium E(1)P <--> E(2)P, lyotropic anions shift it to E(1)P.

Babes, A; Fendler, K

2000-01-01

123

DNA binding induces conformational transition within human DNA topoisomerase I in solution.  

PubMed

We employed Raman and circular dichroism (CD) spectroscopy to probe the molecular structure of 68-kDa recombinant human DNA topoisomerase I (TopoI) in solution, in a complex with a 16-bp DNA fragment containing a camptothecin-enhanced TopoI cleavage site, and in a ternary complex with this oligonucleotide and topotecan. Raman spectroscopy reveals a TopoI secondary structure transition and significant changes in the hydrogen bonding of the tyrosine residues induced by the DNA binding. CD spectroscopy confirms the Raman data and identifies a DNA-induced (>7%) decrease of the TopoI alpha helix accompanied by at least a 6% increase of the beta structure. The Raman DNA molecular signatures demonstrated a bandshift that is expected for a net change in the environment of guanine C6 [double bond] O groups from pairing to solvent exposure. The formation of a ternary cleavage complex with TopoI, DNA, and topotecan as probed by CD spectroscopy reveals neither additional modifications of the TopoI secondary structure nor of the oligonucleotide structure, compared to the TopoI-oligonucleotide complex. PMID:12209444

Oleinikov, Vladimir; Sukhanova, Alyona; Mochalov, Konstantin; Ustinova, Olga; Kudelina, Irina; Bronstein, Igor; Nabiev, Igor

2002-01-01

124

Protein conformational transitions at the liquid-gas interface as studied by dilational surface rheology.  

PubMed

Experimental results on the dynamic dilational surface elasticity of protein solutions are analyzed and compared. Short reviews of the protein behavior at the liquid-gas interface and the dilational surface rheology precede the main sections of this work. The kinetic dependencies of the surface elasticity differ strongly for the solutions of globular and non-globular proteins. In the latter case these dependencies are similar to those for solutions of non-ionic amphiphilic polymers and have local maxima corresponding to the formation of the distal region of the surface layer (type I). In the former case the dynamic surface elasticity is much higher (>60 mN/m) and the kinetic dependencies are monotonical and similar to the data for aqueous dispersions of solid nanoparticles (type II). The addition of strong denaturants to solutions of bovine serum albumin and ?-lactoglobulin results in an abrupt transition from the type II to type I dependencies if the denaturant concentration exceeds a certain critical value. These results give a strong argument in favor of the preservation of the protein globular structure in the course of adsorption without any denaturants. The addition of cationic surfactants also can lead to the non-monotonical kinetic dependencies of the dynamic surface elasticity indicating destruction of the protein tertiary and secondary structures. The addition of anionic surfactants gives similar results only for the protein solutions of high ionic strength. The influence of cationic surfactants on the local maxima of the kinetic dependencies of the dynamic surface elasticity for solutions of a non-globular protein (?-casein) differs from the influence of anionic surfactants due to the heterogeneity of the charge distribution along the protein chain. In this case one can use small admixtures of ionic surfactants as probes of the adsorption mechanism. The effect of polyelectrolytes on the kinetic dependencies of the dynamic surface elasticity of protein solutions is weaker than the effect of conventional surfactants but exceeds the error limits. PMID:24238394

Noskov, Boris A

2014-04-01

125

Lecithin cholesterol acyltransferase (LCAT) activity in the presence of Apo-AI-derived peptides exposed to disorder-order conformational transitions.  

PubMed

Although the association of Apo AI with HDLs has been proposed to activate LCAT activity, the detailed molecular mechanisms involved in the process are not known. Therefore, in this study we have investigated how conformational changes in several exposed regions of Apo-AI might cause LCAT activation and for this purpose, designed a strategy to investigate three Apo AI-derived peptides. Since these peptides present the ability to adopt several secondary structure conformations, they were used to determine whether LCAT activity could be modulated in the presence of a particular conformation. Circular dichroism experiments showed that Apo AI-derived peptides in PBS displayed a disordered arrangement, with a strong tendency to adopt ?-sheet and random conformational structures as a function of concentration. However, in the presence of Lyso-C12PC, maximal percentages of ?-helical structures were observed. Performed in human plasma, time-course experiments of LCAT activity under control conditions reached the highest level of (3)H-cholesteryl esters after 2.5 h incubation. In the presence of Apo AI-derived peptides, a significant increase in the production of (3)H-cholesteryl esters was observed. The present study provides an important insight into the potential interactions between LCAT and lipoproteins and also suggests that peptides, initially present in a disordered conformation, are able to sense the lipid environment provided by lipoproteins of plasma and following a disorder-to-order transition, change their conformation to an ordered ?-helix. PMID:24383078

Aguilar-Espinosa, S L; Mendoza-Espinosa, P; Delgado-Coello, B; Mas-Oliva, J

2013-11-15

126

Unusually Strong Dependence of Conformation on Solvent  

Microsoft Academic Search

Relative partition coefficients between aqueous methanol and pentane of the two stereoisomers of a series of 4-tert-butylcyclohexylamines were measured by NMR. The cis isomer shows a larger partition coefficient, with a ¢¢G°orgfaq up to 1.4 kcal\\/mol. A thermodynamic cycle relates these values to a solvent dependence of the A value for conformational equilibrium of an amino substituent. The variation with

Charles L. Perrin; Miles A. Fabian; Ignacio A. Rivero

1998-01-01

127

Solvent dependence of structure, charge distribution, and absorption spectrum in the photochromic merocyanine-spiropyran pair.  

PubMed

We have studied the structures and absorption spectra of merocyanine, the photoresponsive isomer of the spiropyran (SP)-merocyanine (MC) pair, in chloroform and in water solvents using a combined hybrid QM/MM Car-Parrinello molecular dynamics (CP-QM/MM) and ZINDO approach. We report remarkable differences in the molecular structure and charge distribution of MC between the two solvents; the molecular structure of MC remains in neutral form in chloroform while it becomes charge-separated, zwitterionic, in water. The dipole moment of MC in water is about 50% larger than in chloroform, while the value for SP in water is in between, suggesting that the solvent is more influential than the conformation itself in deciding the dipole moment for the merocyanine-spiropyran pair. The calculations could reproduce the experimentally reported blue shift in the absorption spectra of MC when going from the nonpolar to the polar solvent, though the actual value of the absorption maximum is overestimated in chloroform solvent. We find that the CP-QM/MM approach is appropriate for structure modeling of solvatochromic and thermochromic molecules as this approach is able to capture the solvent and thermal-induced structural changes within the solute important for an accurate assessment of the properties. PMID:21417244

Murugan, N Arul; Chakrabarti, Swapan; Ågren, Hans

2011-04-14

128

Conformality lost  

SciTech Connect

We consider zero-temperature transitions from conformal to nonconformal phases in quantum theories. We argue that there are three generic mechanisms for the loss of conformality in any number of dimensions: (i) fixed point goes to zero coupling, (ii) fixed point runs off to infinite coupling, or (iii) an IR fixed point annihilates with a UV fixed point and they both disappear into the complex plane. We give both relativistic and nonrelativistic examples of the last case in various dimensions and show that the critical behavior of the mass gap behaves similarly to the correlation length in the finite temperature Berezinskii-Kosterlitz-Thouless (BKT) phase transition in two dimensions, {xi}{approx}exp(c/|T-T{sub c}|{sup 1/2}). We speculate that the chiral phase transition in QCD at large number of fermion flavors belongs to this universality class, and attempt to identify the UV fixed point that annihilates with the Banks-Zaks fixed point at the lower end of the conformal window.

Kaplan, David B.; Lee, Jong-Wan; Son, Dam T.; Stephanov, Mikhail A. [Institute for Nuclear Theory, University of Washington, Seattle, Washington 98195-1550 (United States); Department of Physics, University of Illinois, Chicago, Illinois 60607-7059 (United States)

2009-12-15

129

Conformation Transition in Silk Protein Films Monitored by Time-Resolved Fourier Transform Infrared Spectroscopy:  Effect of Potassium Ions on Nephila Spidroin Films †  

Microsoft Academic Search

We used time-resolved Fourier transform infrared spectroscopy (FTIR) to follow a conformation transition in Nephila spidroin film from random coil and\\/or helical structures to ‚-sheet induced by the addition of KCl from 0.01 to 1.0 mol\\/L in D2O. Time series difference spectra showed parallel increases in absorption at 1620 and 1691 cm-1, indicating formation of ‚-sheet, together with a coincident

Xin Chen; David P. Knight; Zhengzhong Shao; Fritz Vollrath

2002-01-01

130

Metal-free and transition-metal tetraferrocenylporphyrins part 1: synthesis, characterization, electronic structure, and conformational flexibility of neutral compounds.  

PubMed

H(2)TFcP [TFcP = 5,10,15,20-tetraferrocenyl porphyrin(2-)] was prepared by a direct tetramerization reaction between pyrrole and ferrocene carbaldehyde in the presence of a BF(3) catalyst, while the series of MTFcP (M = Zn, Ni, Co and Cu) were prepared by a metallation reaction between H(2)TFcP and respective metal acetates. All compounds were characterized by UV-vis and MCD spectroscopy, APCI MS and MS/MS methods, high-resolution ESI MS and XPS spectroscopy. Diamagnetic compounds were additionally characterized using (1)H and (13)C NMR methods, while the presence of low-spin iron(ii) centers in the neutral compounds was confirmed by Mössbauer spectroscopy and by analysis of the XPS Fe 2p peaks, revealing equivalent Fe sites. XPS additionally showed the influence on Fe 2p binding energies exerted by the distinct central metal ions. The conformational flexibility of ferrocene substituents in H(2)TFcP and MTFcP, was confirmed using variable-temperature NMR and computational methods. Density functional theory predicts that alpha,beta,alpha,beta atropisomers with ruffled porphyrin cores represent minima on the potential energy surfaces of both H(2)TFcP and MTFcP. The degree of non-planarity is central-metal dependent and follows the trend: ZnTFcP < H(2)TFcP approximately CuTFcP < CoTFcP < NiTFcP. In all cases, a set of occupied, predominantly ferrocene-based molecular orbitals were found between the highest occupied and the lowest unoccupied, predominantly porphyrin-based molecular orbitals. The vertical excitation energies of H(2)TFcP were calculated at the TDDFT level and confirm the presence of numerous predominantly metal-to-ligand charge-transfer bands coupled via configurational interaction with expected intra-ligand pi-pi* transitions. PMID:18682862

Nemykin, Victor N; Galloni, Pierluca; Floris, Barbara; Barrett, Christopher D; Hadt, Ryan G; Subbotin, Roman I; Marrani, Andrea G; Zanoni, Robertino; Loim, Nikolay M

2008-08-28

131

Retinoic acid biosynthesis catalyzed by retinal dehydrogenases relies on a rate-limiting conformational transition associated with substrate recognition.  

PubMed

Retinoic acid (RA), a metabolite of vitamin A, exerts pleiotropic effects throughout life in vertebrate organisms. Thus, RA action must be tightly regulated through the coordinated action of biosynthetic and degrading enzymes. The last step of retinoic acid biosynthesis is irreversibly catalyzed by the NAD-dependent retinal dehydrogenases (RALDH), which are members of the aldehyde dehydrogenase (ALDH) superfamily. Low intracellular retinal concentrations imply efficient substrate molecular recognition to ensure high affinity and specificity of RALDHs for retinal. This study addresses the molecular basis of retinal recognition in human ALDH1A1 (or RALDH1) and rat ALDH1A2 (or RALDH2), through the comparison of the catalytic behavior of retinal analogs and use of the fluorescence properties of retinol. We show that, in contrast to long chain unsaturated substrates, the rate-limiting step of retinal oxidation by RALDHs is associated with acylation. Use of the fluorescence resonance energy transfer upon retinol interaction with RALDHs provides evidence that retinal recognition occurs in two steps: binding into the substrate access channel, and a slower structural reorganization with a rate constant of the same magnitude as the kcat for retinal oxidation: 0.18 vs. 0.07 and 0.25 vs. 0.1 s(-1) for ALDH1A1 and ALDH1A2, respectively. This suggests that the conformational transition of the RALDH-retinal complex significantly contributes to the rate-limiting step that controls the kinetics of retinal oxidation, as a prerequisite for the formation of a catalytically competent Michaelis complex. This conclusion is consistent with the general notion that structural flexibility within the active site of ALDH enzymes has been shown to be an integral component of catalysis. PMID:23220587

Bchini, Raphaël; Vasiliou, Vasilis; Branlant, Guy; Talfournier, François; Rahuel-Clermont, Sophie

2013-02-25

132

Accounting for conformational flexibility and torsional anharmonicity in the H + CH3CH2OH hydrogen abstraction reactions: A multi-path variational transition state theory study  

NASA Astrophysics Data System (ADS)

This work reports a detailed theoretical study of the hydrogen abstraction reactions from ethanol by atomic hydrogen. The calculated thermal rate constants take into account torsional anharmonicity and conformational flexibility, in addition to the variational and tunneling effects. Specifically, the kinetics calculations were performed by using multi-path canonical variational transition state theory with least-action path tunneling corrections, to which we have added the two-dimensional non-separable method to take into account torsional anharmonicity. The multi-path thermal rate constant is expressed as a sum over conformational reaction channels. Each of these channels includes all the transition states that can be reached by internal rotations. The results show that, in the interval of temperatures between 250 and 2500 K, the account for multiple paths leads to higher thermal rate constants with respect to the single path approach, mainly at low and at high temperatures. In addition, torsional anharmonicity enhances the slope of the Arrhenius plot in this range of temperatures. Finally, we show that the incorporation of tunneling into the hydrogen abstraction reactions substantially changes the contribution of each of the transition states to the conformational reaction channel.

Meana-Pañeda, Rubén; Fernández-Ramos, Antonio

2014-05-01

133

Solvent Dependence of the N-Methylacetamide Structure and Force Field  

NASA Astrophysics Data System (ADS)

The N-methylacetamide molecule (NMA) is an important model for peptide and protein vibrational spectroscopy as it contains the main amide chromophore. In the past, some observed NMA geometry and spectral features could not be entirely explained at the harmonic level or by a single-conformer model. In particular, the spectra were found to be very dependent on molecular environment. In this work NMA Raman and infrared (IR) spectra in a variety of conditions were remeasured and simulated theoretically to separate the fundamental, dimer, and anharmonic bands. Under vacuum the MP2, MP4, and CCSD(T) wave function methods predicted a broad anharmonic potential energy well or even a double-well for the amide nitrogen out of plane motion, which density functional methods failed to reproduce. However, eventual nonplanar minima cannot support an asymmetric quantum state or explain band splittings observed in some experiments. In polar solvents the potential becomes more harmonic and the amide plane more rigid. On the other hand, solvent polarity enhances other anharmonic phenomena, such as the coupling between the carbonyl stretching (amide I) and lower frequency amide bending modes. The amide I band splitting is commonly observed experimentally. The influence of the CH3 group rotations modeled by a rigid rotor model was found to be important for explaining some features of the spectra in a solid parahydrogen matrix. At room temperature the methyl rotation contributes to a nonspecific inhomogeneous band broadening. The dependence of the amide group flexibility on the environment polarity may have interesting consequences for peptide and protein folding studies.

Andrushchenko, Valery; Pavel, Mat?jka; Anderson, David T.; Kaminský, Jakub; Horní?ek, Jan; Paulson, Leif O.; Bou?, Petr

2009-08-01

134

Solvent-dependent spectral diffusion in a hydrogen bonded "vibrational aggregate".  

PubMed

Two-dimensional infrared spectroscopy (2DIR) is used to measure the viscosity-dependent spectral diffusion of a model vibrational probe, Mn(2)(CO)(10) (dimanganese decacarbonyl, DMDC), in a series of alcohols with time scales ranging from 2.67 ps in methanol to 5.33 ps in 1-hexanol. Alcohol-alkane solvent mixtures were found to produce indistinguishable linear IR spectra, while still demonstrating viscosity-dependent spectral diffusion. Using a vibrational exciton model to characterize the inhomogeneous energy landscape, several analogies emerge with multichromophoric electronic systems, such as J-aggregates and light-harvesting protein complexes. An excitonic, local vibrational mode Hamiltonian parametrized to reproduce the vibrational structure of DMDC serves as a starting point from which site energies (i.e., local carbonyl frequencies) are given Gaussian distributed disorder. The model gives excellent agreement with both the linear IR spectrum and the inhomogeneous widths extracted from 2DIR, indicating the system can be considered to be a "vibrational aggregate." This model naturally leads to exchange narrowing due to disorder-induced exciton localization, producing line widths consistent with our 1D and 2D measurements. Further, the diagonal disorder alone effectively reduces the molecular symmetry, leading to the appearance of Raman bands in the IR spectrum in accord with the measurements. Here, we show that the static inhomogeneity of the excitonic model with disorder successfully captures the essential details of the 1D spectrum while predicting the degree of IR activity of forbidden modes as well as the inhomogeneous widths and relative magnitudes of the transition moments. PMID:20831231

King, John T; Baiz, Carlos R; Kubarych, Kevin J

2010-10-01

135

The highly conserved layer-3 component of the HIV-1 gp120 inner domain is critical for CD4-required conformational transitions.  

PubMed

The trimeric envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) mediates virus entry into host cells. CD4 engagement with the gp120 exterior envelope glycoprotein subunit represents the first step during HIV-1 entry. CD4-induced conformational changes in the gp120 inner domain involve three potentially flexible topological layers (layers 1, 2, and 3). Structural rearrangements between layer 1 and layer 2 have been shown to facilitate the transition of the envelope glycoprotein trimer from the unliganded to the CD4-bound state and to stabilize gp120-CD4 interaction. However, our understanding of CD4-induced conformational changes in the gp120 inner domain remains incomplete. Here, we report that a highly conserved element of the gp120 inner domain, layer 3, plays a pivot-like role in these allosteric changes. In the unliganded state, layer 3 modulates the association of gp120 with the Env trimer, probably by influencing the relationship of the gp120 inner and outer domains. Importantly, layer 3 governs the efficiency of the initial gp120 interaction with CD4, a function that can also be fulfilled by filling the Phe43 cavity. This work defines the functional importance of layer 3 and completes a picture detailing the role of the gp120 inner domain in CD4-induced conformational transitions in the HIV-1 Env trimer. PMID:23255784

Désormeaux, Anik; Coutu, Mathieu; Medjahed, Halima; Pacheco, Beatriz; Herschhorn, Alon; Gu, Christopher; Xiang, Shi-Hua; Mao, Youdong; Sodroski, Joseph; Finzi, Andrés

2013-03-01

136

Insights into the potential functionality of single-chain force-induced conformational transitions in polymer networks: Implications for polysaccharide signaling in the plant cell wall  

NASA Astrophysics Data System (ADS)

The behavior of biopolymer networks comprised of clickable polysaccharide chains that can undergo force-induced conformational transitions was investigated during straining using a simulation technique. The simulation was carried out both using an affine deformation field and alternatively using Lees-Edwards boundary conditions as an example of a nonaffine case. In the affine situation the simulated stress-strain curves were found to be consistent with results obtained by evaluating the molecular force-extension curve at a single average extension and calculating the bulk modulus as an average over all possible orientations with respect to the deformation. While in all cases examined the macroscopic mechanical responses of networks of randomly oriented chains, consisting either of simple extensible wormlike chains or their clickable analogs, were found to be indistinguishable, the simulation additionally allowed the number of chains containing sugar rings in different conformational states to be monitored, and this was found to change significantly during straining. This supports the hypothesis that in networks of randomly oriented clickable polysaccharide chains, such conformational transitions could have biological significance as stress switches in signaling processes but that they are unlikely to affect the bulk rheological properties of tissue.

Schuster, E.; Lundin, L.; Williams, M. A. K.

2010-11-01

137

Substrate-induced conformational transition in human phenylalanine hydroxylase as studied by surface plasmon resonance analyses: the effect of terminal deletions, substrate analogues and phosphorylation.  

PubMed Central

The optical biosensor technique, based on the surface plasmon resonance (SPR) phenomenon, was used for real-time measurements of the slow conformational transition (isomerization) which occurs in human phenylalanine hydroxylase (hPAH) on the binding/dissociation of L-phenylalanine (L-Phe). The binding to immobilized tetrameric wt-hPAH resulted in a time-dependent increase in the refractive index (up to approx. 3 min at 25 degrees C) with an end point of approx. 75 RU (resonance units)/(pmol subunit/mm(2)). By contrast, the contribution of binding the substrate (165 Da) to its catalytic core enzyme [DeltaN(1-102)/DeltaC(428-452)-hPAH] was only approx. 2 RU/(pmol subunit/mm(2)). The binding isotherm for tetrameric and dimeric wt-hPAH revealed a [S](0.5)-value of 98+/-7 microM (h =1.0) and 158+/-11 microM, respectively, i.e. for the tetramer it is slightly lower than the value (145+/-5 microM) obtained for the co-operative binding (h =1.6+/-0.4) of L-Phe as measured by the change in intrinsic tryptophan fluorescence. The responses obtained by SPR and intrinsic tryptophan fluorescence are both considered to be related to the slow reversible conformational transition which occurs in the enzyme upon L-Phe binding, i.e. by the transition from a low-activity state ('T-state') to a relaxed high-activity state ('R-state') characteristic of this hysteretic enzyme, however, the two methods reflect different elements of the transition. Studies on the N- and C-terminal truncated forms revealed that the N-terminal regulatory domain (residues 1-117) plus catalytic domain (residues 118-411) were required for the full signal amplitude of the SPR response. Both the on- and off-rates for the conformational transition were biphasic, which is interpreted in terms of a difference in the energy barrier and the rate by which the two domains (catalytic and regulatory) undergo a conformational change. The substrate analogue 3-(2-thienyl)-L-alanine revealed an SPR response comparable with that of L-Phe on binding to wild-type hPAH.

Stokka, Anne J; Flatmark, Torgeir

2003-01-01

138

Are density functional theory predictions of the Raman spectra accurate enough to distinguish conformational transitions during amyloid formation?  

PubMed

We report density functional theory (DFT) calculations of the Raman spectra for hexapeptides of glutamic acid and lysine in three different conformations (alpha, beta and PPII). The wave numbers of amide I, amide II and amide III bands of all three conformations predicted at B3LYP/6-31G and B3LYP/6-31G* are in good agreement with previously reported experimental values of polyglutamic acid and polylysine. Agreement with experiment improves when polarization functions are included in the basis set. Explicit water molecules, H-bonded to the backbone amide groups were found to be absolutely necessary to obtain this agreement. Our results indicate that DFT is a promising tool for assignment of the spectral data on kinetics of conformational changes for peptides during amyloid formation. PMID:19924452

Berhanu, Workalemahu Mikre; Mikhailov, Ivan A; Masunov, Artëm E

2010-06-01

139

Conformational transitions regulate the exposure of a DNA-binding domain in the RuvBL1-RuvBL2 complex  

PubMed Central

RuvBL1 and RuvBL2, also known as Pontin and Reptin, are AAA+ proteins essential in small nucleolar ribonucloprotein biogenesis, chromatin remodelling, nonsense-mediated messenger RNA decay and telomerase assembly, among other functions. They are homologous to prokaryotic RuvB, forming single- and double-hexameric rings; however, a DNA binding domain II (DII) is inserted within the AAA+ core. Despite their biological significance, questions remain regarding their structure. Here, we report cryo-electron microscopy structures of human double-ring RuvBL1–RuvBL2 complexes at ?15 Å resolution. Significantly, we resolve two coexisting conformations, compact and stretched, by image classification techniques. Movements in DII domains drive these conformational transitions, extending the complex and regulating the exposure of DNA binding regions. DII domains connect with the AAA+ core and bind nucleic acids, suggesting that these conformational changes could impact the regulation of RuvBL1–RuvBL2 containing complexes. These findings resolve some of the controversies in the structure of RuvBL1–RuvBL2 by revealing a mechanism that extends the complex by adjustments in DII.

Lopez-Perrote, Andres; Munoz-Hernandez, Hugo; Gil, David; Llorca, Oscar

2012-01-01

140

Catalytic activation of human glucokinase by substrate binding: residue contacts involved in the binding of D-glucose to the super-open form and conformational transitions.  

PubMed

alpha-D-Glucose activates glucokinase (EC 2.7.1.1) on its binding to the active site by inducing a global hysteretic conformational change. Using intrinsic tryptophan fluorescence as a probe on the alpha-D-glucose induced conformational changes in the pancreatic isoform 1 of human glucokinase, key residues involved in the process were identified by site-directed mutagenesis. Single-site W-->F mutations enabled the assignment of the fluorescence enhancement (DeltaF/F(0)) mainly to W99 and W167 in flexible loop structures, but the biphasic time course of DeltaF/F(0) is variably influenced by all tryptophan residues. The human glucokinase-alpha-D-glucose association (K(d) = 4.8 +/- 0.1 mm at 25 degrees C) is driven by a favourable entropy change (DeltaS = 150 +/- 10 J.mol(-1).K(-1)). Although X-ray crystallographic studies have revealed the alpha-d-glucose binding residues in the closed state, the contact residues that make essential contributions to its binding to the super-open conformation remain unidentified. In the present study, we combined functional mutagenesis with structural dynamic analyses to identify residue contacts involved in the initial binding of alpha-d-glucose and conformational transitions. The mutations N204A, D205A or E256A/K in the L-domain resulted in enzyme forms that did not bind alpha-D-glucose at 200 mm and were essentially catalytically inactive. Our data support a molecular dynamic model in which a concerted binding of alpha-D-glucose to N204, N231 and E256 in the super-open conformation induces local torsional stresses at N204/D205 propagating towards a closed conformation, involving structural changes in the highly flexible interdomain connecting region II (R192-N204), helix 5 (V181-R191), helix 6 (D205-Y215) and the C-terminal helix 17 (R447-K460). PMID:18397317

Molnes, Janne; Bjørkhaug, Lise; Søvik, Oddmund; Njølstad, Pål R; Flatmark, Torgeir

2008-05-01

141

Conformational transitions in the Ca2+ + Mg2+-activated ATPase and the binding of Ca2+ ions.  

PubMed Central

We have studied the fluorescence of the Ca2+ + Mg2+-activated ATPase of sarcoplasmic reticulum labelled with fluorescein isothiocyanate. The change in intensity of fluorescein fluorescence caused by addition of Ca2+ to the labelled ATPase can be interpreted in terms of a two-conformation model for the ATPase, one conformation (E1) having a high affinity for Ca2+, the other (E2) a low affinity. Effects of Ca2+ as a function of pH allow an estimate of the effect of pH on the E1/E2 ratio, consistent with kinetic studies. A model is presented for binding of Ca2+ to the ATPase as a function of pH that is consistent both with the data on the E1/E2 equilibrium and with literature data on Ca2+ binding.

Froud, R J; Lee, A G

1986-01-01

142

Time-resolved infrared absorption studies of the solvent-dependent vibrational relaxation dynamics of chlorine dioxide  

NASA Astrophysics Data System (ADS)

We report a series of time-resolved infrared absorption studies on chlorine dioxide (OClO) dissolved in H2O, D2O, and acetonitrile. Following the photoexcitation at 401 nm, the evolution in optical density for frequencies corresponding to asymmetric stretch of OClO is measured with a time resolution of 120+/-50 fs. The experimentally determined optical-density evolution is compared with theoretical models of OClO vibrational relaxation derived from collisional models as well as classical molecular-dynamics (MD) studies. The vibrational relaxation rates in D2O are reduced by a factor of 3 relative to H2O consistent with the predictions of MD. This difference reflects modification of the frequency-dependent solvent-solute coupling accompanying isotopic substitution of the solvent. Also, the geminate-recombination quantum yield for the primary photofragments resulting in the reformation of ground-state OClO is reduced in D2O relative to H2O. It is proposed that this reduction reflects enhancement of the dissociation rate accompanying vibrational excitation along the asymmetric-stretch coordinate. In contrast to H2O and D2O, the vibrational-relaxation dynamics in acetonitrile are not well described by the theoretical models. Reproduction of the optical-density evolution in acetonitrile requires significant modification of the frequency-dependent solvent-solute coupling derived from MD. It is proposed that this modification reflects vibrational-energy transfer from the asymmetric stretch of OClO to the methyl rock of acetonitrile. In total, the results presented here provide a detailed description of the solvent-dependent geminate-recombination and vibrational-relaxation dynamics of OClO in solution.

Bolinger, Joshua C.; Bixby, Teresa J.; Reid, Philip J.

2005-08-01

143

Solvent-dependent cage dynamics of small nonpolar radicals: lessons from the photodissociation and geminate recombination of alkylcobalamins.  

PubMed

Time-resolved transient absorption spectroscopy was used to investigate the primary geminate recombination and cage escape of alkyl radicals in solution over a temperature range from 0 to 80 degrees C. Radical pairs were produced by photoexcitation of methyl, ethyl, propyl, hexylnitrile, and adenosylcobalamin in water, ethylene glycol, mixtures of water and ethylene glycol, and sucrose solutions. In contrast to previous studies of cage escape and geminate recombination, these experiments demonstrate that cage escape for these radical pairs occurs on time scales ranging from a hundred picoseconds to over a nanosecond as a function of solvent fluidity and radical size. Ultrafast cage escape (<100 ps) is only observed for the methyl radical where the radical pair is produced through excitation to a directly dissociative electronic state. The data are interpreted using a unimolecular model with competition between geminate recombination and cage escape. The escape rate constant, k(e), is not a simple function of the solvent fluidity (T/eta) but depends on the nature of the solvent as well. The slope of k(e) as a function of T/eta for the adenosyl radical in water is in near quantitative agreement with the slope calculated using a hydrodynamic model and the Stokes-Einstein equation for the diffusion coefficients. The solvent dependence is reproduced when diffusion constants are calculated taking into account the relative volume and mass of both solvent and solute using the expression proposed by Akgerman (Akgerman, A.; Gainer, J. L. Ind. Eng. Chem. Fundam. 1972, 11, 373-379). Rate constants for cage escape of the other radicals investigated are consistently smaller than the calculated values suggesting a systematic correction for radical size or coupled radical pair motion. PMID:19585970

Stickrath, Andrew B; Carroll, Elizabeth C; Dai, Xiaochuan; Harris, D Ahmasi; Rury, Aaron; Smith, Broc; Tang, Kuo-Chun; Wert, Jonathan; Sension, Roseanne J

2009-07-30

144

Solvent dependent structural perturbations of chemical reaction intermediates visualized by time-resolved x-ray diffraction  

SciTech Connect

Ultrafast time-resolved wide angle x-ray scattering from chemical reactions in solution has recently emerged as a powerful technique for determining the structural dynamics of transient photochemical species. Here we examine the structural evolution of photoexcited CH{sub 2}I{sub 2} in the nonpolar solvent cyclohexane and draw comparisons with a similar study in the polar solvent methanol. As with earlier spectroscopic studies, our data confirm a common initial reaction pathway in both solvents. After photoexcitation, CH{sub 2}I{sub 2} dissociates to form CH{sub 2}I{center_dot}+I{center_dot}. Iodine radicals remaining within the solvent cage recombine with a nascent CH{sub 2}I{center_dot} radical to form the transient isomer CH{sub 2}I-I, whereas those which escape the solvent cage ultimately combine to form I{sub 2} in cyclohexane. Moreover, the transient isomer has a lifetime approximately 30 times longer in the nonpolar solvent. Of greater chemical significance is the property of time-resolved wide angle x-ray diffraction to accurately determine the structure of the of CH{sub 2}I-I reaction intermediate. Thus we observe that the transient iodine-iodine bond is 0.07 A {+-}0.04 A shorter in cyclohexane than in methanol. A longer iodine-iodine bond length for the intermediate arises in methanol due to favorable H-bond interaction with the polar solvent. These findings establish that time-resolved x-ray diffraction has sufficient sensitivity to enable solvent dependent structural perturbations of transient chemical species to be accurately resolved.

Vincent, Jonathan; Eklund, Mattias; Davidsson, Jan [Department of Photochemistry and Molecular Science, Uppsala University, P.O. Box 523, S-751 20 Uppsala (Sweden); Andersson, Magnus; Woehri, Annemarie B. [Department of Chemical and Biological Engineering, Chalmers University of Technology, P.O. Box 462, S-405 30 Gothenburg (Sweden); Odelius, Michael [FYSIKUM, Stockholm University, Albanova, S-106 91 Stockholm (Sweden); Malmerberg, Erik; Neutze, Richard [Department of Chemistry, Biochemistry and Biophysics, Gothenburg University, P.O. Box 462, S-405 30 Gothenburg (Sweden); Kong, Qingyu; Wulff, Michael [European Synchrotron Radiation Facility, BP 220, F-38043 Grenoble (France)

2009-04-21

145

Conformational and hydrational properties during the L ?- to L ?- and L ?- to H II-phase transition in phosphatidylethanolamine  

Microsoft Academic Search

Differential scanning calorimetry (DSC) measurements have been carried out simultaneously with small- and wide-angle X-ray scattering recordings on liposomal dispersions of stearoyl-oleoyl-phosphatidylethanolamine (PE) in a temperature range from 20 to 80°C. The main transition temperature, Tm, was determined at 30.9°C with an enthalpy of 28.5kJ\\/mol and the lamellar-to-inverse hexagonal phase transition temperature, Thex, at 61.6°C with an enthalpy of 3.8kJ\\/mol.

Michael Rappolt; Aden Hodzic; Barbara Sartori; Michel Ollivon; Peter Laggner

2008-01-01

146

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State  

PubMed Central

Structure analysis of the cell-penetrating peptide transportan 10 (TP10) revealed an exemplary range of different conformations in the membrane-bound state. The bipartite peptide (derived N-terminally from galanin and C-terminally from mastoparan) was found to exhibit prominent characteristics of (i) amphiphilic ?-helices, (ii) intrinsically disordered peptides, as well as (iii) ?-pleated amyloid fibrils, and these conformational states become interconverted as a function of concentration. We used a complementary approach of solid-state 19F-NMR and circular dichroism in oriented membrane samples to characterize the structural and dynamical behaviour of TP10 in its monomeric and aggregated forms. Nine different positions in the peptide were selectively substituted with either the L- or D-enantiomer of 3-(trifluoromethyl)-bicyclopent-[1.1.1]-1-ylglycine (CF3-Bpg) as a reporter group for 19F-NMR. Using the L-epimeric analogs, a comprehensive three-dimensional structure analysis was carried out in lipid bilayers at low peptide concentration, where TP10 is monomeric. While the N-terminal region is flexible and intrinsically unstructured within the plane of the lipid bilayer, the C-terminal ?-helix is embedded in the membrane with an oblique tilt angle of ?55° and in accordance with its amphiphilic profile. Incorporation of the sterically obstructive D-CF3-Bpg reporter group into the helical region leads to a local unfolding of the membrane-bound peptide. At high concentration, these helix-destabilizing C-terminal substitutions promote aggregation into immobile ?-sheets, which resemble amyloid fibrils. On the other hand, the obstructive D-CF3-Bpg substitutions can be accommodated in the flexible N-terminus of TP10 where they do not promote aggregation at high concentration. The cross-talk between the two regions of TP10 thus exerts a delicate balance on its conformational switch, as the presence of the ?-helix counteracts the tendency of the unfolded N-terminus to self-assemble into ?-pleated fibrils.

Strandberg, Erik; Verdurmen, Wouter P. R.; Burck, Jochen; Ehni, Sebastian; Mykhailiuk, Pavel K.; Afonin, Sergii; Gerthsen, Dagmar; Komarov, Igor V.; Brock, Roland; Ulrich, Anne S.

2014-01-01

147

Distinct Docking and Stabilization Steps of the Pseudopilus Conformational Transition Path Suggest Rotational Assembly of Type IV Pilus-like Fibers.  

PubMed

The closely related bacterial type II secretion (T2S) and type IV pilus (T4P) systems are sophisticated machines that assemble dynamic fibers promoting protein transport, motility, or adhesion. Despite their essential role in virulence, the molecular mechanisms underlying helical fiber assembly remain unknown. Here, we use electron microscopy and flexible modeling to study conformational changes of PulG pili assembled by the Klebsiella oxytoca T2SS. Neural network analysis of 3,900 pilus models suggested a transition path toward low-energy conformations driven by progressive increase in fiber helical twist. Detailed predictions of interprotomer contacts along this path were tested by site-directed mutagenesis, pilus assembly, and protein secretion analyses. We demonstrate that electrostatic interactions between adjacent protomers (P-P+1) in the membrane drive pseudopilin docking, while P-P+3 and P-P+4 contacts determine downstream fiber stabilization steps. These results support a model of a spool-like assembly mechanism for fibers of the T2SS-T4P superfamily. PMID:24685147

Nivaskumar, Mangayarkarasi; Bouvier, Guillaume; Campos, Manuel; Nadeau, Nathalie; Yu, Xiong; Egelman, Edward H; Nilges, Michael; Francetic, Olivera

2014-05-01

148

Observation of the A-x electronic transition of the isomers and conformers of pentyl peroxy radical using cavity ringdown spectroscopy.  

PubMed

Cavity ringdown spectra of the A-X electronic transition of all eight isomers of the pentyl peroxy radical are reported. Using the corresponding assignments from previously studied smaller alkyl peroxy radicals, assignments of origin bands are made for the pentyl peroxy isomers including some conformer-specific assignments for bands of a given isomer. Ab initio calculations also were performed to aid in the spectral assignments for neopentyl, t-butyl, and t-pentyl peroxies. In addition to the origins, vibrational bands have also been assigned for some species. Using the analyzed spectra, the relative reactivity of the primary, secondary, and tertiary hydrogen atoms in isopentane could be determined semiquantitatively. PMID:18211043

Sharp, Erin N; Rupper, Patrick; Miller, Terry A

2008-02-21

149

Structural basis of conformational transitions in the active site and 80?s loop in the FK506-binding protein FKBP12  

PubMed Central

The extensive set of NMR doublings exhibited by the immunophilin FKBP12 (FK506-binding protein 12) arose from a slow transition to the cis-peptide configuration at Gly89 near the tip of the 80?s loop, the site for numerous protein-recognition interactions for both FKBP12 and other FKBP domain proteins. The 80?s loop also exhibited linebroadening, indicative of microsecond to millisecond conformational dynamics, but only in the trans-peptide state. The G89A variant shifted the trans–cis peptide equilibrium from 88:12 to 33:67, whereas a proline residue substitution induced fully the cis-peptide configuration. The 80?s loop conformation in the G89P crystal structure at 1.50 Å resolution differed from wild-type FKBP12 primarily at residues 88, 89 and 90, and it closely resembled that reported for FKBP52. Structure-based chemical-shift predictions indicated that the microsecond to millisecond dynamics in the 80?s loop probably arose from a concerted main chain (?88 and ?89) torsion angle transition. The indole side chain of Trp59 at the base of the active-site cleft was reoriented ~90o and the adjacent backbone was shifted in the G89P crystal structure. NOE analysis of wild-type FKBP12 demonstrated that this indole populates the perpendicular orientation at 20%. The 15N relaxation analysis was consistent with the indole reorientation occurring in the nanosecond timeframe. Recollection of the G89P crystal data at 1.20 Å resolution revealed a weaker wild-type-like orientation for the indole ring. Differences in the residues that underlie the Trp59 indole ring and altered interactions linking the 50?s loop to the active site suggested that reorientation of this ring may be disfavoured in the other six members of the FKBP domain family that bear this active-site tryptophan residue.

Mustafi, Sourajit M.; Brecher, Matthew; Zhang, Jing; Li, Hongmin; Lemaster, David M.; Hernandez, Griselda

2014-01-01

150

Trifluoroethanol-induced conformational transitions of proteins: insights gained from the differences between alpha-lactalbumin and ribonuclease A.  

PubMed Central

The trifluoroethanol (TFE)-induced structural changes of two proteins widely used in folding experiments, bovine alpha-lactalbumin, and bovine pancreatic ribonuclease A, have been investigated. The experiments were performed using circular dichroism spectroscopy in the far- and near-UV region to monitor changes in the secondary and tertiary structures, respectively, and dynamic light scattering to measure the hydrodynamic dimensions and the intermolecular interactions of the proteins in different conformational states. Both proteins behave rather differently under the influence of TFE: alpha-lactalbumin exhibits a molten globule state at low TFE concentrations before it reaches the so-called TFE state, whereas ribonuclease A is directly transformed into the TFE state at TFE concentrations above 40% (v/v). The properties of the TFE-induced states are compared with those of equilibrium and kinetic intermediate states known from previous work to rationalize the use of TFE in yielding information about the folding of proteins. Additionally, we report on the properties of TFE/water and TFE/buffer mixtures derived from dynamic light scattering investigations under conditions used in our experiments.

Gast, K.; Zirwer, D.; Muller-Frohne, M.; Damaschun, G.

1999-01-01

151

Binding, conformational transition and dimerization of amyloid-? peptide on GM1-containing ternary membrane: insights from molecular dynamics simulation.  

PubMed

Interactions of amyloid-? (A?) with neuronal membrane are associated with the progression of Alzheimer's disease (AD). Ganglioside GM1 has been shown to promote the structural conversion of A? and increase the rate of peptide aggregation; but the exact nature of interaction driving theses processes remains to be explored. In this work, we have carried out atomistic-scale computer simulations (totaling 2.65 µs) to investigate the behavior of A? monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for A?-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a ?-hairpin motif was formed at the C-terminus of the GM1-bound A?-monomer; that didn't appear in absence of GM1 (both in fluid POPC and liquid-ordered cholesterol/POPC bilayers and also in aqueous medium) within the simulation time span. For A?-dimers, the ?-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of A? to aggregate into higher-ordered structures. The salt-bridges and inter-peptide hydrogen bonds were found to account for dimer stability. We observed spontaneous formation of intra-peptide D(23)-K(28) salt-bridge and a turn at V(24)GSN(27) region - long been accepted as characteristic structural-motifs for amyloid self-assembly. Altogether, our results provide atomistic details of A?-GM1 and A?-A? interactions and demonstrate their importance in the early-stages of GM1-mediated A?-oligomerisation on membrane surface. PMID:23951128

Manna, Moutusi; Mukhopadhyay, Chaitali

2013-01-01

152

Role of cytochrome B5 in modulating peroxide-supported cyp3a4 activity: evidence for a conformational transition and cytochrome P450 heterogeneity.  

PubMed

The role of cytochrome b(5) (b(5)) in the alpha-naphthoflavone (alpha-NF)-mediated inhibition of H(2)O(2)-supported 7-benzyloxyquinoline (7-BQ) debenzylation by heterologously expressed and purified cytochrome P450 3A4 (CYP3A4) was studied. Although alpha-NF showed negligible effect in an NADPH-dependent reconstituted system, inhibition of 7-BQ oxidation was observed in the H(2)O(2) system. Analysis of the effect of various constituents of a standard reconstituted system on H(2)O(2)-supported activity showed that b(5) alone resulted in a 2.5-fold increase in the k(cat) value and reversed the inhibitory effect of alpha-NF. In addition, titration with b(5) suggested that only 65% of the CYP3A4 participated in the interaction with b(5), consistent with cytochrome P450 (P450) heterogeneity. Study of the influence of b(5) on the kinetics of H(2)O(2)-dependent destruction of the P450 heme moiety suggested two distinct conformers of CYP3A4 with different sensitivity to heme loss. In the absence of b(5), 66% of the wild-type enzyme was bleached in the fast phase, whereas the addition of b(5) decreased the fraction of the fast phase to 16%. Finally, to locate amino acid residues that might influence b(5) action, several active site mutants were tested. Substitution of Ser-119, Ile-301, Ala-305, Ile-369, or Ala-370 with the larger Phe or Trp decreased or even abolished the activation by b(5). Ser-119 is in the B'-C loop, a predicted b(5)-P450 interaction site, and Ile-301 and Ala-305 are closest to the heme. In conclusion, the interaction of b(5) with P450 apparently leads to a conformational transition, which results in redistribution of the CYP3A4 pool. PMID:15870379

Kumar, Santosh; Davydov, Dmitri R; Halpert, James R

2005-08-01

153

Gradual change of conformational disorder  

SciTech Connect

The basic step of crystallization of linear macromolecules is conformational ordering. If the ordering is completed during crystallization, the entropy of fusion is a measure of the gain of conformational disorder on melting. In this lecture the possibility is discussed that in some cases conformational order changes below the glass or disordering transitions (T{sub g} and T{sub d}, respectively). Changes in conformational order below T{sub g} were observed for some flexible macromolecules without side-chains, like polyethylene. Changes below T{sub d} are found among main-chain liquid-crystalline polymers, conformationally disordered (condis) crystals, and related small-molecule model-compounds.

Wunderlich, B

1994-12-31

154

Transits  

Microsoft Academic Search

Transits of the planets Mercury and especially Venus have been exciting events in the development of astronomy over the past few hundred years. Just two years ago the first transiting extra-solar planet, HD 209458b, was discovered, and subsequent studies during transit have contributed fundamental new knowledge. From the photometric light curve during transit one obtains a basic confirmation that the

Ronald L. Gilliland

2005-01-01

155

310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State  

PubMed Central

The activation of voltage-gated ion channels is controlled by the S4 helix, with arginines every third residue. The x-ray structures are believed to reflect an open-inactivated state, and models propose combinations of translation, rotation, and tilt to reach the resting state. Recently, experiments and simulations have independently observed occurrence of 310-helix in S4. This suggests S4 might make a transition from ?- to 310-helix in the gating process. Here, we show 310-helix structure between Q1 and R3 in the S4 segment of a voltage sensor appears to facilitate the early stage of the motion toward a down state. We use multiple microsecond-steered molecular simulations to calculate the work required for translating S4 both as ?-helix and transformed to 310-helix. The barrier appears to be caused by salt-bridge reformation simultaneous to R4 passing the F233 hydrophobic lock, and it is almost a factor-two lower with 310-helix. The latter facilitates translation because R2/R3 line up to face E183/E226, which reduces the requirement to rotate S4. This is also reflected in a lower root mean-square deviation distortion of the rest of the voltage sensor. This supports the 310 hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.

Schwaiger, Christine S.; Bjelkmar, Par; Hess, Berk; Lindahl, Erik

2011-01-01

156

A conformation change in the carboxyl terminus of Alzheimer's Abeta (1-40) accompanies the transition from dimer to fibril as revealed by fluorescence quenching analysis.  

PubMed

Alzheimer's disease is characterized by the presence of insoluble, fibrous deposits composed principally of amyloid beta (Abeta) peptide. A number of studies have provided information on the fibril structure and on the factors affecting fiber formation, but the details of the fibril structure are not known. We used fluorescence quenching to investigate the solvent accessibility and surface charge of the soluble Abeta(1-40) dimer and amyloid fibrils. Analogs of Abeta(1-40) containing a single tryptophan were synthesized by substituting residues at positions 4, 10, 34, and 40 with tryptophan. Quenching measurements in the dimeric state indicate that the amino-terminal analogs (AbetaF4W and AbetaY10W) are accessible to polar quenchers, and the more carboxyl-terminal analog AbetaV34W is less accessible. AbetaV40W, on the other hand, exhibits a low degree of quenching, indicating that this residue is highly shielded from the solvent in the dimeric state. Correcting for the effect of reduced translational and rotational diffusion, fibril formation was associated with a selective increase in solvent exposure of residues 34 and 40, suggesting that a conformation change may take place in the carboxyl-terminal region coincident with the dimer to fibril transition. PMID:10806193

Garzon-Rodriguez, W; Vega, A; Sepulveda-Becerra, M; Milton, S; Johnson, D A; Yatsimirsky, A K; Glabe, C G

2000-07-28

157

Analytical model and multiscale simulations of A? peptide aggregation in lipid membranes: towards a unifying description of conformational transitions, oligomerization and membrane damage.  

PubMed

The mechanisms underlying the formation of extracellular amyloid plaques on neuronal membranes, a major hallmark of Alzheimer's disease, are the subject of intense debate. Here we use multiscale simulations and analytical theory to unveil the early steps of the spontaneous self-assembly of membrane-embedded ?-helical A? (1-40) peptides. Based on a simple analytical model describing the electrostatic repulsions among water-exposed charged residues, the presence of distorted structures called "frustrated helices" is predicted. Large scale (20 ?s) Coarse Grained simulations of 36 replicas of A? (1-40) performed within a POPC lipid matrix confirmed the formation of supramolecular assemblies which resemble a twisted ribbon. Fully atomistic simulations have demonstrated the stability of these helical structures. Concomitant to the formation of these large assemblies, CG simulations evidenced membrane curvature and substantiate the view that these assemblies may entail mechanical stress on membrane structure. We think that these findings provide an alternative view to the traditional models that consider a conformational transition towards ?-sheet rich structures as a prerequisite for triggering membrane damage and, eventually, neurotoxicity. PMID:23588697

Pannuzzo, Martina; Milardi, Danilo; Raudino, Antonio; Karttunen, Mikko; La Rosa, Carmelo

2013-06-21

158

Transition.  

ERIC Educational Resources Information Center

This "feature issue" focuses on transition from school to adult life for persons with disabilities. Included are "success stories," brief program descriptions, and a list of resources. Individual articles include the following titles and authors: "Transition: An Energizing Concept" (Paul Bates); "Transition Issues for the 1990s" (William Halloran…

Thompson, Sandy, Ed.; And Others

1990-01-01

159

Solvent dependent frequency shift and Raman noncoincidence effect of Sdbnd O stretching mode of Dimethyl sulfoxide in liquid binary mixtures  

NASA Astrophysics Data System (ADS)

The isotropic and anisotropic Raman peak frequencies of Sdbnd O stretching mode of Dimethyl sulfoxide (DMSO) have been discussed in different chemical and isotopic solvent molecules using different mechanisms. The shifting of peak frequency in further dilution of DMSO with solvent molecule is observed for all solvents. Transition dipole - transition dipole interaction and hydrogen bonding may play a major role in shifting of peak frequencies. The non-coincidence effect (NCE) of DMSO was determined for all the solvents and compared with four theoretical models such as McHale's model, Mirone's modification of McHale's model, Logan's model and Onsager-Fröhlich dielectric continuum model respectively. Most of the theoretical models are largely consistent with our experimental data.

Upadhyay, Ganesh; Devi, Th. Gomti; Singh, Ranjan K.; Singh, A.; Alapati, P. R.

2013-05-01

160

[Conformal radiotherapy].  

PubMed

Conformal radiotherapy is a new irradiation technique made possible by technological improvements, especially progress in imaging and 3D dosimetry. By conforming the volume irradiated as closely as possible to the clinical anatomical target volume, conformal radiotherapy is designed to deliver a higher dose to the tumour volume, while more effectively sparing the adjacent tissues from the adverse effects of irradiation. Conformal radiotherapy may therefore constitute a progress comparable to the contribution of high-energy radiotherapy in the 1960s or the impact of computer-assisted dosimetry in the 1970s. Evaluation of the results, definition of its indications, standardisation of practices, and study of the impact of dose escalation require further studies in the field of prostate cancer, as the superiority of this new technique over conventional radiotherapy has not been formally established due to the limited follow-up. PMID:10434334

Hubert, J; Rossi, D; Beckendorf, V

1999-06-01

161

Temperature-/solvent-dependent low-dimensional compounds based on quinoline-2,3-dicarboxylic acid: structures and fluorescent properties.  

PubMed

A series of 0-D, 1-D, and 2-D metal-organic compounds through reactions of quinoline-2,3-dicarboxylic acid (2,3-H(2)qldc) with transition metal salts MCl(2), namely, M(2,3-Hqldc)(2)(H(2)O)(2) (M = Co(1), Zn(4) and Cd(7)), [M(3-qlc)(2)(H(2)O)(2)](n) (M = Co(2), Zn(5) and Cd(8)), M(2-qldc-3-OCH(3))(2)(CH(3)OH)(2) (M = Co(3) and Zn(6)) and [Cd(2,3-qldc-OCH(3))(?(2)-Cl)](2n) (9) (where, 3-Hqlc = quinoline-3-carboxylic acid and 2-qldc-3-OCH(3) = 3-(methoxycarbonyl)quinoline-2-carboxylic acid), were synthesized and characterized by elemental analysis, IR, thermogravimetric analysis (TG), and single-crystal X-ray diffraction. When the temperature ranged from room temperature to 70 °C, three isomorphous mononuclear complexes 1, 4 and 7 were obtained in H(2)O/H(2)O + CH(3)OH. As the temperature rose further to above 90 °C, due to the decomposition of 2-position carboxyl group in ligand 2,3-H(2)qldc, the same reactions, respectively, produced three isomorphous 2-D layer-like structures 2, 5 and 8 with 4(4) topology in water. By contrast, when the mixed solvent of H(2)O + CH(3)OH at a 1 : 1 ratio (v/v) was applied, the three above-mentioned reactions respectively gave compounds 3, 6 and 9 with the 3-position esterification of 2,3-H(2)qldc. Compounds 3 and 6 are mononuclear and isomorphous, while complex 9 has a 1-D double-stranded chain-like structure connected by two ?(2)-Cl bridges. Obviously, these results reveal that the reaction temperature and solvent play a critical role in structural direction of these low-dimensional compounds. Meanwhile, the photoluminescent property of the selected compounds is also investigated. PMID:22914814

Wang, Ming-Fang; Hong, Xu-Jia; Zhan, Qing-Guang; Jin, Hong-Guang; Liu, Yi-Ting; Zheng, Zhi-Peng; Xu, Shi-Hai; Cai, Yue-Peng

2012-10-14

162

Förster resonance energy transfer confirms the bacterial-induced conformational transition in highly-branched poly(N-isopropyl acrylamide with vancomycin end groups on binding to Staphylococcus aureus.  

PubMed

We describe a series of experiments designed to investigate the conformational transition that highly-branched polymers with ligands undergo when interacting with bacteria, a process that may provide a new sensing mechanism for bacterial detection. Fluorescent highly-branched poly(N-isopropyl acrylamide)s (HB-PNIPAM) were prepared by sequential self-condensing radical copolymerizations, using anthrylmethyl methacrylate (AMMA) and fluorescein-O-acrylate (FA) as fluorescent comonomers and 4-vinylbenzyl pyrrole carbodithioate as a branch forming monomer. Differences in reactivity necessitated to first copolymerize AMMA then react with FA in a separate sequential monomer feed step. Modifications of the chain ends produced vancomycin-functional derivatives (HB-PNIPAM-Van). The AMMA and FA labels allow probing of the conformational behaviour of the polymers in solution via Förster resonance energy transfer experiments. It was shown that interaction of this polymer's end groups with Staphylococcus aureus induced a macromolecular collapse. The data thus provide conclusive evidence for a conformational transition that is driven by binding to a bacterium. PMID:24974819

Sarker, Prodip; Swindells, Kathryn; Douglas, C W Ian; MacNeil, Sheila; Rimmer, Stephen; Swanson, Linda

2014-08-21

163

Detection and characterization of large-scale protein conformational transitions in solution using charge-state distribution analysis in ESI-MS.  

PubMed

Ion charge-state distribution analysis in electro-spray ionization mass spectrometry (ESI-MS) is a robust and fast technique for direct detection and characterization of coexisting protein conformations in solution. Compact folded proteins give rise to ESI-generated ions carrying a relatively small number of charges, whereas less compact conformers accommodate upon ESI a larger number of charges depending on the extent of their unfolding. A chemometric approach [1] based upon factor analysis is applied to determine contributions from individual conformers to the overall CSD. Here we present basic guidelines for the use of this MS-based technique: from the preparation of suitable solutions for ESI-MS to the acquisition of reliable MS data and their subsequent analysis. PMID:22821537

Abzalimov, Rinat R; Frimpong, Agya K; Kaltashov, Igor A

2012-01-01

164

Conformal technicolor  

Microsoft Academic Search

We point out that the flavor problem in theories with dynamical electroweak symmetry breaking can be effectively decoupled if the physics above the TeV scale is strongly conformal, and the electroweak order parameter has a scaling dimension d = 1+epsilon with epsilon simeq 1\\/few. There are many restrictions on small values of epsilon: for epsilon << 1, electroweak symmetry breaking

Markus A. Luty; Takemichi Okui

2006-01-01

165

Conformational changes in biopolymers  

NASA Astrophysics Data System (ADS)

Biopolymer conformational changes are involved in many biological processes. This thesis summarizes some theoretical and experimental approaches which I have taken at UCLA to explore conformational changes in biopolymers. The reversible thermal denaturation of the DNA double helix is, perhaps, the simplest example of biopolymer conformational change. I have developed a statistical mechanics model of DNA melting with reduced degrees of freedom, which allows base stacking interaction to be taken into account and treat base pairing and stacking separately. Unlike previous models, this model describes both the unpairing and unstacking parts of the experimental melting curves and explains the observed temperature dependence of the effective thermodynamic parameters used in models of the nearest neighbor type. I developed a basic kinetic model for irreversible thermal denaturation of F-actin, which incorporates depolymerization of F-actin from the ends and breaking of F-actin fiber in the middle. The model explains the cooperativity of F-actin thermal denaturation observed by D. Pavlov et al. in differential calorimetry measurements. CG-rich DNA sequences form left-handed Z-DNA at high ionic strength or upon binding of polyvalent ions and some proteins. I studied experimentally the B-to-Z transition of the (CG)6 dodecamer. Improvement of the locally linearized model used to interpret the data gives evidence for an intermediate state in the B-to-Z transition of DNA, contrary to previous research on this subject. In the past 15 years it has become possible to study the conformational changes of biomolecules using single-molecule techniques. In collaboration with other lab members I performed a single-molecule experiment, where we monitored the displacement of a micrometer-size bead tethered to a surface by a DNA probe undergoing the conformational change. This technique allows probing of conformational changes with subnanometer accuracy. We applied the method to detect, for the first time, single hybridization events of label-free target oligomers. This demonstrates a new paradigm of molecule detection where, hybridization of the target is detected through the conformational change of the probe.

Ivanov, Vassili

2005-12-01

166

Conformable seal  

DOEpatents

Sealing apparatus and method, comprising first and second surfaces or membranes, at least one of which surfaces is deformable, placed in proximity to one another. Urging means cause these surfaces to contact one another in a manner such that the deformable surface deforms to conform to the geometry of the other surface, thereby creating a seal. The seal is capable of undergoing multiple cycles of sealing and unsealing.

Neef, W.S.; Lambert, D.R.

1982-08-10

167

Modeling conformational changes in cyclosporin A.  

PubMed Central

NMR and X-ray structures for the immunosuppressant cyclosporin A (CsA) reveal a remarkable difference between the unbound (free) conformation in organic solvents and the conformation bound to cyclophilin. We have performed computer simulations of the molecular dynamics of CsA under a variety of conditions and confirmed the stability of these two conformations at room temperature in water and in vacuum. However, when the free conformation was modeled in vacuum at 600 K, a transition pathway leading to the bound conformation was observed. This involved a change in the cis MeLeu-9 peptide bond to a trans conformation and the movement of the side chains forming the dominant hydrophobic cluster (residues MeBmt-1, MeLeu-4, MeLeu-6, and MeLeu-10) to the opposite side of the plane formed by the backbone atoms in the molecular ring. The final conformation had a backbone RMS deviation from the bound conformation of 0.53 A and was as stable in dynamics simulations as the bound conformation. Our calculations allowed us to make a detailed analysis of a transition pathway between the free and the bound conformations of CsA and to identify two distinct regions of coordinated movement in CsA, both of which underwent transitions independently.

O'Donohue, M. F.; Burgess, A. W.; Walkinshaw, M. D.; Treutlein, H. R.

1995-01-01

168

Conformational fluctuations in single DNA molecules  

PubMed Central

Measurement of fluorescent lifetimes of dye-tagged DNA molecules reveal the existence of different conformations. Conformational fluctuations observed by fluorescence correlation spectroscopy give rise to a relaxation behavior that is described by “stretched” exponentials and indicates the presence of a distribution of transition rates between two conformations. Whether this is an inhomogeneous distribution, where each molecule contributes with its own reaction rate to the overall distribution, or a homogeneous distribution, where the reaction rate of each molecule is time-dependent, is not yet known. We used a tetramethylrhodamine-linked 217-bp DNA oligonucleotide as a probe for conformational fluctuations. Fluorescence fluctuations from single DNA molecules attached to a streptavidin-coated surface directly show the transitions between two conformational states. The conformational fluctuations typical for single molecules are similar to those seen in single ion channels in cell membranes.

Wennmalm, Stefan; Edman, Lars; Rigler, Rudolf

1997-01-01

169

Dissociation of different conformations of ubiquitin ions  

Microsoft Academic Search

The fragmentation pathways of different conformations of three charge states of ubiquitin ions are examined using ion mobility\\/collisional\\u000a activation\\/time-of-flight techniques. Mass spectra for fragments for different conformers of a single charge state appear\\u000a to be identical (within the experimental reproducibility). These results are consistent with a mechanism in which different\\u000a conformers of each charge state rearrange to similar dissociation transition

Ethan R. Badman; Cherokee S. Hoaglund-Hyzer; David E. Clemmer

2002-01-01

170

A quantitative measure for protein conformational heterogeneity  

NASA Astrophysics Data System (ADS)

Conformational heterogeneity is a defining characteristic of proteins. Intrinsically disordered proteins (IDPs) and denatured state ensembles are extreme manifestations of this heterogeneity. Inferences regarding globule versus coil formation can be drawn from analysis of polymeric properties such as average size, shape, and density fluctuations. Here we introduce a new parameter to quantify the degree of conformational heterogeneity within an ensemble to complement polymeric descriptors. The design of this parameter is guided by the need to distinguish between systems that couple their unfolding-folding transitions with coil-to-globule transitions and those systems that undergo coil-to-globule transitions with no evidence of acquiring a homogeneous ensemble of conformations upon collapse. The approach is as follows: Each conformation in an ensemble is converted into a conformational vector where the elements are inter-residue distances. Similarity between pairs of conformations is quantified using the projection between the corresponding conformational vectors. An ensemble of conformations yields a distribution of pairwise projections, which is converted into a distribution of pairwise conformational dissimilarities. The first moment of this dissimilarity distribution is normalized against the first moment of the distribution obtained by comparing conformations from the ensemble of interest to conformations drawn from a Flory random coil model. The latter sets an upper bound on conformational heterogeneity thus ensuring that the proposed measure for intra-ensemble heterogeneity is properly calibrated and can be used to compare ensembles for different sequences and across different temperatures. The new measure of conformational heterogeneity will be useful in quantitative studies of coupled folding and binding of IDPs and in de novo sequence design efforts that are geared toward controlling the degree of heterogeneity in unbound forms of IDPs.

Lyle, Nicholas; Das, Rahul K.; Pappu, Rohit V.

2013-09-01

171

A conformational ensemble derived using NMR methyl chemical shifts reveals a mechanical clamping transition that gates the binding of the HU protein to DNA.  

PubMed

Recent improvements in the accuracy of structure-based methods for the prediction of nuclear magnetic resonance chemical shifts have inspired numerous approaches for determining the secondary and tertiary structures of proteins. Such advances also suggest the possibility of using chemical shifts to characterize the conformational fluctuations of these molecules. Here we describe a method of using methyl chemical shifts as restraints in replica-averaged molecular dynamics (MD) simulations, which enables us to determine the conformational ensemble of the HU dimer and characterize the range of motions accessible to its flexible ?-arms. Our analysis suggests that the bending action of HU on DNA is mediated by a mechanical clamping mechanism, in which metastable structural intermediates sampled during the hinge motions of the ?-arms in the free state are presculpted to bind DNA. These results illustrate that using side-chain chemical shift data in conjunction with MD simulations can provide quantitative information about the free energy landscapes of proteins and yield detailed insights into their functional mechanisms. PMID:24517490

Kannan, Arvind; Camilloni, Carlo; Sahakyan, Aleksandr B; Cavalli, Andrea; Vendruscolo, Michele

2014-02-12

172

Effects of pH and Calcium Ions on the Conformational Transitions in Silk Fibroin Using 2D Raman Correlation Spectroscopy and 13 C Solid-State NMR †  

Microsoft Academic Search

Silk fibroin exists in a number of different states, such as silk I and silk II, with different properties largely defined by differences in secondary structure composition. Numerous attempts have been made to control the transitions from silk I to silk II in vitro to produce high-performance materials. Of all the factors influencing the structural compositions, pH and some metal

Ping Zhou; Xun Xie; David P. Knight; Xiao-Hong Zong; Feng Deng; Wen-Hua Yao

2004-01-01

173

Combined Use of Residual Dipolar Couplings and Solution X-ray Scattering To Rapidly Probe Rigid-Body Conformational Transitions in a Non-phosphorylatable Active-Site Mutant of the 128 kDa Enzyme I Dimer  

SciTech Connect

The first component of the bacterial phosphotransferase system, enzyme I (EI), is a multidomain 128 kDa dimer that undergoes large rigid-body conformational transitions during the course of its catalytic cycle. Here we investigate the solution structure of a non-phosphorylatable active-site mutant in which the active-site histidine is substituted by glutamine. We show that perturbations in the relative orientations and positions of the domains and subdomains can be rapidly and reliably determined by conjoined rigid-body/torsion angle/Cartesian simulated annealing calculations driven by orientational restraints from residual dipolar couplings and shape and translation information afforded by small- and wide-angle X-ray scattering. Although histidine and glutamine are isosteric, the conformational space available to a Gln side chain is larger than that for the imidazole ring of His. An additional hydrogen bond between the side chain of Gln189 located on the EIN{sup {alpha}/{beta}} subdomain and an aspartate (Asp129) on the EIN{sup {alpha}} subdomain results in a small ({approx}9{sup o}) reorientation of the EIN{sup {alpha}} and EIN{sup {alpha}/{beta}} subdomains that is in turn propagated to a larger reorientation ({approx}26{sup o}) of the EIN domain relative to the EIC dimerization domain, illustrating the positional sensitivity of the EIN domain and its constituent subdomains to small structural perturbations.

Takayama, Yuki; Schwieters, Charles D.; Grishaev, Alexander; Ghirlando, Rodolfo; Clore, G. Marius (NIH)

2012-10-23

174

Jumping out of the light-Higgs conformal window  

NASA Astrophysics Data System (ADS)

We investigate generic properties of the conformal phase transition in gauge theories featuring Higgs-like fundamental particles. These theories provide an excellent arena to properly investigate conformal dynamics and discover novel features. We show that the phase transition at the boundary of the Higgs conformal window is not smooth but a jumping one for the known perturbative examples. In addition, the general conditions under which the transition is either jumping or smooth are provided. Jumping implies that the massive spectrum of the theory will jump at the phase transition. It, however, still allows for one of the states, the would-be dilaton of the theory, to be lighter than the heaviest states in the broken phase. Finally, we exhibit a calculable Higgs model in which we can, in perturbation theory, determine the Higgs conformal window, the spectrum in the conformally broken phase, and demonstrate it to possess a jumping-type conformal phase transition.

Antipin, Oleg; Mojaza, Matin; Sannino, Francesco

2013-05-01

175

Conformational characteristics of the N-acetyl-N'-methylamides of the four (Lys, Tyr) dipeptides.  

PubMed

The conformational properties of the N-acetyl-N'-methylamides of the dipeptides lysyl-lysine, lysyl-tyrosine, tyrosyl-lysine, and tyrosyl-tyrosine were studied by means of conformational energy calculations, by n.m.r. measurements in deuterated dimethylsulfoxide, and by circular dichroism in water, methanol, dioxane-water, and trifluoroethanol. Since these four dipeptides occur occasionally as bends in proteins, it was of interest to see whether short-range interactions, acting within the terminally blocked dipeptides, are sufficient to stabilize bend conformations significantly over other conformations. It was found that the four dipeptides exist as ensembles of conformations in solution. Therefore, it appears that longer-range interactions, such as those present in proteins, are required if bend conformations of these dipeptide sequences are to exist as stable conformations. Three of the dipeptides behave rather similarly. Both the CD and the n.m.r. experiments and computations indicate that the fourth (Lys-Tyr) differs from the others. It has a preference for compact conformations that appear to be stabilized by strong favorable interactions, primarily hydrogen bonds, between the tyrosyl and the lysyl side chains. The computations suggest that the presence of these interactions, and hence the existence of preferred conformations, is strongly solvent-dependent, and that these interactions are weakened in aqueous solution. PMID:7309363

Rae, I D; Leach, S J; Minasian, E; Smith, J A; Zimmerman, S S; Weigold, J A; Hodes, Z I; Némethy, G; Woody, R W; Scheraga, H A

1981-05-01

176

Theoretical modeling of UV-Vis absorption and emission spectra in liquid state systems including vibrational and conformational effects: Explicit treatment of the vibronic transitions  

NASA Astrophysics Data System (ADS)

Here, we extend a recently introduced theoretical-computational procedure [M. D'Alessandro, M. Aschi, C. Mazzuca, A. Palleschi, and A. Amadei, J. Chem. Phys. 139, 114102 (2013)] to include quantum vibrational transitions in modelling electronic spectra of atomic molecular systems in condensed phase. The method is based on the combination of Molecular Dynamics simulations and quantum chemical calculations within the Perturbed Matrix Method approach. The main aim of the presented approach is to reproduce as much as possible the spectral line shape which results from a subtle combination of environmental and intrinsic (chromophore) mechanical-dynamical features. As a case study, we were able to model the low energy UV-vis transitions of pyrene in liquid acetonitrile in good agreement with the experimental data.

D'Abramo, Marco; Aschi, Massimiliano; Amadei, Andrea

2014-04-01

177

Theoretical modeling of UV-Vis absorption and emission spectra in liquid state systems including vibrational and conformational effects: Explicit treatment of the vibronic transitions.  

PubMed

Here, we extend a recently introduced theoretical-computational procedure [M. D'Alessandro, M. Aschi, C. Mazzuca, A. Palleschi, and A. Amadei, J. Chem. Phys. 139, 114102 (2013)] to include quantum vibrational transitions in modelling electronic spectra of atomic molecular systems in condensed phase. The method is based on the combination of Molecular Dynamics simulations and quantum chemical calculations within the Perturbed Matrix Method approach. The main aim of the presented approach is to reproduce as much as possible the spectral line shape which results from a subtle combination of environmental and intrinsic (chromophore) mechanical-dynamical features. As a case study, we were able to model the low energy UV-vis transitions of pyrene in liquid acetonitrile in good agreement with the experimental data. PMID:24784250

D'Abramo, Marco; Aschi, Massimiliano; Amadei, Andrea

2014-04-28

178

Conformational dynamics through an intermediate  

NASA Astrophysics Data System (ADS)

The self-assembly of biological and synthetic nanostructures commonly proceeds via intermediate states. In living systems in particular, the intermediates have the capacity to tilt the balance between functional and potentially fatal behavior. This work develops a statistical mechanical treatment of conformational dynamics through an intermediate under a variable force. An analytical solution is derived for the key experimentally measurable quantity—the distribution of forces at which a conformational transition occurs. The solution reveals rich kinetics over a broad range of parameters and enables one to locate the intermediate and extract the activation barriers and rate constants.

Garai, Ashok; Zhang, Yaojun; Dudko, Olga K.

2014-04-01

179

Conformation changes and folding of proteins mediated by Davydov's soliton  

Microsoft Academic Search

We suggest that Davydov's solitons, propagating through the backbone of a protein, can mediate conformational transition and folding of a protein to its native state. A simple toy model is presented in which a non-linear Schrödinger (NLS) field interacts with another field ? corresponding to the conformation angles of the protein. The interaction provides the conformation field with the energy

Shay Caspi; Eshel Ben-Jacob

2000-01-01

180

Time-resolved fluorescence studies of tryptophan mutants of Escherichia coli glutamine synthetase: conformational analysis of intermediates and transition-state complexes.  

PubMed Central

Single tryptophan-containing mutants of low adenylylation state Escherichia coli glutamine synthetase have been studied by frequency-domain fluorescence spectroscopy in the presence of various substrates and inhibitors. At pH 6.5, the Mn-bound wild-type enzyme (wild type has two tryptophans/subunit) and the mutant enzymes exhibit heterogeneous fluorescence decay kinetics; the individual tryptophans are adequately described by a triple exponential decay scheme. The recovered lifetime values are 5.9 ns, 2.6 ns, and 0.4 ns for Trp-57 and 5.8 ns, 2.3 ns, and 0.4 ns for Trp-158. These values are nearly identical to the previously reported results at pH 7.5 (Atkins, W.M., Stayton, P.S., & Villafranca, J.J., 1991, Biochemistry 30, 3406-3416). In addition, Trp-57 and Trp-158 both exhibit an ATP-induced increase in the relative fraction of the long lifetime component, whereas only Trp-57 is affected by this ligand at pH 7.5. The transition-state analogue L-methionine-(R,S)-sulfoximine (MSOX) causes a dramatic increase in the fractional intensity of the long lifetime component of Trp-158. This ligand has no effect on the W158S mutant protein and causes a small increase in the fractional intensity of the long lifetime component of the W158F mutant protein. Addition of glutamate to the ATP complex, which affords the gamma-glutamylphosphate-ADP complex, results in the presence of new lifetime components at 7, 3.2, and 0.5 ns for Trp-158, but has no effect on Trp-57. Similar results were obtained when ATP was added to the MSOX complex; Trp-57 exhibits heterogeneous fluorescence decay with lifetimes of 7, 3.5, and 0.8 ns. Decay kinetics of Trp-158 are best fit to a nearly homogeneous decay with a lifetime of 5.5 ns in the MSOX-ATP inactivated complex. These results provide a model for the sequence of structural and dynamic changes that take place at the Trp-57 loop and the central loop (Trp-158) during several intermediate stages of catalysis.

Atkins, W. M.; Villafranca, J. J.

1992-01-01

181

Solvent dependent frequency shift and Raman noncoincidence effect of S=O stretching mode of Dimethyl sulfoxide in liquid binary mixtures.  

PubMed

The isotropic and anisotropic Raman peak frequencies of S=O stretching mode of Dimethyl sulfoxide (DMSO) have been discussed in different chemical and isotopic solvent molecules using different mechanisms. The shifting of peak frequency in further dilution of DMSO with solvent molecule is observed for all solvents. Transition dipole - transition dipole interaction and hydrogen bonding may play a major role in shifting of peak frequencies. The non-coincidence effect (NCE) of DMSO was determined for all the solvents and compared with four theoretical models such as McHale's model, Mirone's modification of McHale's model, Logan's model and Onsager-Fröhlich dielectric continuum model respectively. Most of the theoretical models are largely consistent with our experimental data. PMID:23542514

Upadhyay, Ganesh; Devi, Th Gomti; Singh, Ranjan K; Singh, A; Alapati, P R

2013-05-15

182

Side-Chain Conformational Changes upon Protein-Protein Association  

PubMed Central

Conformational changes upon protein-protein association are the key element of the binding mechanism. The study presents a systematic large-scale analysis of such conformational changes in the side chains. The results indicate that short and long side chains have different propensities for the conformational changes. Long side chains with three or more dihedral angles are often subject to large conformational transition. Shorter residues with one or two dihedral angles typically undergo local conformational changes not leading to a conformational transition. The relationship between the local readjustments and the equilibrium fluctuations of a side chain around its unbound conformation is suggested. Most of the side chains undergo larger changes in the dihedral angle most distant from the backbone. The frequencies of the core-to-surface interface transitions of six nonpolar residues and Tyr are larger than the frequencies of the opposite, surface-to-core transitions. The binding increases both polar and nonpolar interface areas. However, the increase of the nonpolar area is larger for all considered classes of protein complexes, suggesting that the protein association perturbs the unbound interfaces to increase the hydrophobic contribution to the binding free energy. To test modeling approaches to side-chain flexibility in protein docking, conformational changes in the X-ray set were compared with those in the docking decoys sets. The results lead to a better understanding of the conformational changes in proteins and suggest directions for efficient conformational sampling in docking protocols.

Ruvinsky, Anatoly M.; Kirys, Tatsiana; Tuzikov, Alexander V.; Vakser, Ilya A.

2011-01-01

183

Protein conformational populations and functionally relevant substates.  

PubMed

Functioning proteins do not remain fixed in a unique structure, but instead they sample a range of conformations facilitated by motions within the protein. Even in the native state, a protein exists as a collection of interconverting conformations driven by thermodynamic fluctuations. Motions on the fast time scale allow a protein to sample conformations in the nearby area of its conformational landscape, while motions on slower time scales give it access to conformations in distal areas of the landscape. Emerging evidence indicates that protein landscapes contain conformational substates with dynamic and structural features that support the designated function of the protein. Nuclear magnetic resonance (NMR) experiments provide information about conformational ensembles of proteins. X-ray crystallography allows researchers to identify the most populated states along the landscape, and computational simulations give atom-level information about the conformational substates of different proteins. This ability to characterize and obtain quantitative information about the conformational substates and the populations of proteins within them is allowing researchers to better understand the relationship between protein structure and dynamics and the mechanisms of protein function. In this Account, we discuss recent developments and challenges in the characterization of functionally relevant conformational populations and substates of proteins. In some enzymes, the sampling of functionally relevant conformational substates is connected to promoting the overall mechanism of catalysis. For example, the conformational landscape of the enzyme dihydrofolate reductase has multiple substates, which facilitate the binding and the release of the cofactor and substrate and catalyze the hydride transfer. For the enzyme cyclophilin A, computational simulations reveal that the long time scale conformational fluctuations enable the enzyme to access conformational substates that allow it to attain the transition state, therefore promoting the reaction mechanism. In the long term, this emerging view of proteins with conformational substates has broad implications for improving our understanding of enzymes, enzyme engineering, and better drug design. Researchers have already used photoactivation to modulate protein conformations as a strategy to develop a hypercatalytic enzyme. In addition, the alteration of the conformational substates through binding of ligands at locations other than the active site provides the basis for the design of new medicines through allosteric modulation. PMID:23988159

Ramanathan, Arvind; Savol, Andrej; Burger, Virginia; Chennubhotla, Chakra S; Agarwal, Pratul K

2014-01-21

184

Conformational Properties of ?-PrP*  

PubMed Central

Prion propagation involves a conformational transition of the cellular form of prion protein (PrPC) to a disease-specific isomer (PrPSc), shifting from a predominantly ?-helical conformation to one dominated by ?-sheet structure. This conformational transition is of critical importance in understanding the molecular basis for prion disease. Here, we elucidate the conformational properties of a disulfide-reduced fragment of human PrP spanning residues 91–231 under acidic conditions, using a combination of heteronuclear NMR, analytical ultracentrifugation, and circular dichroism. We find that this form of the protein, which similarly to PrPSc, is a potent inhibitor of the 26 S proteasome, assembles into soluble oligomers that have significant ?-sheet content. The monomeric precursor to these oligomers exhibits many of the characteristics of a molten globule intermediate with some helical character in regions that form helices I and III in the PrPC conformation, whereas helix II exhibits little evidence for adopting a helical conformation, suggesting that this region is a likely source of interaction within the initial phases of the transformation to a ?-rich conformation. This precursor state is almost as compact as the folded PrPC structure and, as it assembles, only residues 126–227 are immobilized within the oligomeric structure, leaving the remainder in a mobile, random-coil state.

Hosszu, Laszlo L. P.; Trevitt, Clare R.; Jones, Samantha; Batchelor, Mark; Scott, David J.; Jackson, Graham S.; Collinge, John; Waltho, Jonathan P.; Clarke, Anthony R.

2009-01-01

185

On conformal biharmonic immersions  

Microsoft Academic Search

This paper studies conformal biharmonic immersions. We first study the transformations of Jacobi operator and the bitension\\u000a field under conformal change of metrics. We then obtain an invariant equation for a conformal biharmonic immersion of a surface\\u000a into Euclidean 3-space. As applications, we construct a two-parameter family of non-minimal conformal biharmonic immersions\\u000a of cylinder into $${\\\\mathbb{R}^3}$$ and some examples of

Ye-Lin Ou

2009-01-01

186

A free-energy perturbation method based on Monte Carlo simulations using quantum mechanical calculations (QM/MC/FEP method): application to highly solvent-dependent reactions.  

PubMed

This study describes the framework of the quantum mechanical (QM)/Monte Carlo (MC)/free-energy perturbation (FEP) method, a FEP method based on MC simulations using quantum chemical calculations. Because a series of structures generated by interpolating internal coordinates between transition state and reactant did not produce smooth free-energy profiles, we used structures from the intrinsic reaction coordinate calculations. This method was first applied to the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene and produced ?G(?sol)‡ values of 20.1 and 21.4 kcal mol(-1) in aqueous and methanol solutions, respectively. They are very consistent with the experimentally observed values. The other two applications were the free-energy surfaces for the Cope elimination of N,N-dimethyl-3-phenylbutan-2-amine oxide in aqueous, dimethyl sulfoxide, and tetrahydrofuran solutions, and the Kemp decarboxylation of 6-hydroxybenzo-isoxazole-3-carboxylic acid in aqueous, dimethyl sulfoxide, and CH(3) CN solutions. The calculated activation free energies differed by less than 1.8 kcal mol(-1) from the experimental values for these reactions. Although we used droplet models for the QM/MC/FEP simulations, the calculated results for three reactions are very close to the experimental data. It was confirmed that most of the interactions between the solute and solvents can be described using small numbers of solvent molecules. This is because a few solvent molecules can produce large portions of the solute-solvent interaction energies at the reaction centers. When we confirmed the dependency on the droplet sizes of solvents, the QM/MC/FEP for a large droplet with 106 water molecules produced a ?G?(sol)‡ value similar to the experimental values, as well as that for a small droplet with 34 molecules. PMID:21341291

Hori, Kenji; Yamaguchi, Toru; Uezu, Keita; Sumimoto, Michinori

2011-04-15

187

Toward TeV Conformality  

SciTech Connect

We study the chiral properties of an SU(3) gauge theory with N{sub f} massless Dirac fermions in the fundamental representation when N{sub f} is increased from 2 to 6. For N{sub f}=2, our lattice simulations lead to a value of /F{sup 3}, where F is the Nambu-Goldstone-boson decay constant and is the chiral condensate, which agrees with the measured QCD value. For N{sub f}=6, this ratio shows significant enhancement, presaging an even larger enhancement anticipated as N{sub f} increases further, toward the critical value for transition from confinement to infrared conformality.

Appelquist, T.; Fleming, G. T.; Neil, E. T. [Department of Physics, Sloane Laboratory, Yale University, New Haven, Connecticut 06520 (United States); Avakian, A.; Babich, R.; Brower, R. C.; Cohen, S. D.; Rebbi, C.; Schaich, D. [Department of Physics, Boston University, Boston, Massachusetts 02215 (United States); Cheng, M.; Vranas, P. [Physical Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550 (United States); Clark, M. A. [Harvard-Smithsonian Center for Astrophysics, Cambridge, Massachusetts 02138 (United States); Initiative in Innovative Computing, Harvard University School of Engineering and Applied Sciences, Cambridge, Massachusetts 02138 (United States); Kiskis, J. [Department of Physics, University of California, Davis, California 95616 (United States); Osborn, J. C. [Argonne Leadership Computing Facility, Argonne, Illinois 60439 (United States)

2010-02-19

188

Toward TeV Conformality  

SciTech Connect

We study the chiral condensate <{bar {psi}}{psi}> for an SU(3) gauge theory with N{sub f} massless Dirac fermions in the fundamental representation when N{sub f} is increased from 2 to 6. For N{sub f} = 2, our lattice simulations of <{bar {psi}}{psi}>/F{sup 3}, where F is the Nambu-Goldstone-boson decay constant, agree with the measured QCD value. For N{sub f} = 6, this ratio shows significant enhancement, presaging an even larger enhancement anticipated as N{sub f} increases further, toward the critical value for transition from confinement to infrared conformality.

Appelquist, T; Avakian, A; Babich, R; Brower, R C; Cheng, M; Clark, M A; Cohen, S D; Fleming, G T; Kiskis, J; Neil, E T; Osborn, J C; Rebbi, C; Schaich, D; Soltz, R; Vranas, P

2009-11-30

189

Mapping Conformational Dynamics of Proteins Using Torsional Dynamics Simulations  

PubMed Central

All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein’s experimentally established conformational substates. Conformational transition of calmodulin from the Ca2+-bound to the Ca2+-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins.

Gangupomu, Vamshi K.; Wagner, Jeffrey R.; Park, In-Hee; Jain, Abhinandan; Vaidehi, Nagarajan

2013-01-01

190

Solvent dependent branching between C-I and C-Br bond cleavage following 266 nm excitation of CH2BrI.  

PubMed

It is well known that ultraviolet photoexcitation of halomethanes results in halogen-carbon bond cleavage. Each halogen-carbon bond has a dominant ultraviolet (UV) absorption that promotes an electron from a nonbonding halogen orbital (nX) to a carbon-halogen antibonding orbital (?*C-X). UV absorption into specific transitions in the gas phase results primarily in selective cleavage of the corresponding carbon-halogen bond. In the present work, broadband ultrafast UV-visible transient absorption studies of CH2BrI reveal a more complex photochemistry in solution. Transient absorption spectra are reported spanning the range from 275 nm to 750 nm and 300 fs to 3?ns following excitation of CH2BrI at 266 nm in acetonitrile, 2-butanol, and cyclohexane. Channels involving formation of CH2Br + I radical pairs, iso-CH2Br-I, and iso-CH2I-Br are identified. The solvent environment has a significant influence on the branching ratios, and on the formation and stability of iso-CH2Br-I. Both iso-CH2Br-I and iso-CH2I-Br are observed in cyclohexane with a ratio of ~2.8:1. In acetonitrile this ratio is 7:1 or larger. The observation of formation of iso-CH2I-Br photoproduct as well as iso-CH2Br-I following 266 nm excitation is a novel result that suggests complexity in the dissociation mechanism. We also report a solvent and concentration dependent lifetime of iso-CH2Br-I. At low concentrations the lifetime is >4 ns in acetonitrile, 1.9 ns in 2-butanol and ~1.4 ns in cyclohexane. These lifetimes decrease with higher initial concentrations of CH2BrI. The concentration dependence highlights the role that intermolecular interactions can play in the quenching of unstable isomers of dihalomethanes. PMID:24320326

Anderson, Christopher P; Spears, Kenneth G; Wilson, Kaitlynn R; Sension, Roseanne J

2013-11-21

191

Solvent dependent branching between C-I and C-Br bond cleavage following 266 nm excitation of CH{sub 2}BrI  

SciTech Connect

It is well known that ultraviolet photoexcitation of halomethanes results in halogen-carbon bond cleavage. Each halogen-carbon bond has a dominant ultraviolet (UV) absorption that promotes an electron from a nonbonding halogen orbital (n{sub X}) to a carbon-halogen antibonding orbital (?*{sub C-X}). UV absorption into specific transitions in the gas phase results primarily in selective cleavage of the corresponding carbon-halogen bond. In the present work, broadband ultrafast UV-visible transient absorption studies of CH{sub 2}BrI reveal a more complex photochemistry in solution. Transient absorption spectra are reported spanning the range from 275 nm to 750 nm and 300 fs to 3 ns following excitation of CH{sub 2}BrI at 266 nm in acetonitrile, 2-butanol, and cyclohexane. Channels involving formation of CH{sub 2}Br + I radical pairs, iso-CH{sub 2}Br-I, and iso-CH{sub 2}I-Br are identified. The solvent environment has a significant influence on the branching ratios, and on the formation and stability of iso-CH{sub 2}Br-I. Both iso-CH{sub 2}Br-I and iso-CH{sub 2}I-Br are observed in cyclohexane with a ratio of ?2.8:1. In acetonitrile this ratio is 7:1 or larger. The observation of formation of iso-CH{sub 2}I-Br photoproduct as well as iso-CH{sub 2}Br-I following 266 nm excitation is a novel result that suggests complexity in the dissociation mechanism. We also report a solvent and concentration dependent lifetime of iso-CH{sub 2}Br-I. At low concentrations the lifetime is >4 ns in acetonitrile, 1.9 ns in 2-butanol and ?1.4 ns in cyclohexane. These lifetimes decrease with higher initial concentrations of CH{sub 2}BrI. The concentration dependence highlights the role that intermolecular interactions can play in the quenching of unstable isomers of dihalomethanes.

Anderson, Christopher P.; Spears, Kenneth G.; Wilson, Kaitlynn R.; Sension, Roseanne J. [Department of Chemistry and Department of Physics, University of Michigan, Ann Arbor, Michigan 48109 (United States)] [Department of Chemistry and Department of Physics, University of Michigan, Ann Arbor, Michigan 48109 (United States)

2013-11-21

192

Conformations of Substituted Ethanes.  

ERIC Educational Resources Information Center

Reviews state-of-the-art of conformational analysis and factors which affect it. Emphasizes sp-3 hybridized acrylic molecules. Provides examples on the importance of certain factors in determining conformation. Purpose, is to provide examples for examination questions. (Author/SA)

Kingsbury, Charles A.

1979-01-01

193

Structure and Conformation of Carbohydrates  

NASA Astrophysics Data System (ADS)

The conformational analysis of monosaccharides, disaccharides, and oligosaccharides is reviewed. Conformational terms are introduced through examination of the conformations of cyclohexane and cyclopentane then applied to the pyranose, furanose , and septanose rings. Concepts such as the anomeric effect are discussed. Topics of current interest, such as hydroxymethyl group and hydroxyl group rotation and disaccharide conformations are summarized. Physical methods for studying conformation are outlined.

Grindley, T. Bruce

194

Solvent dependent photophysical properties of dimethoxy curcumin  

NASA Astrophysics Data System (ADS)

Dimethoxy curcumin (DMC) is a methylated derivative of curcumin. In order to know the effect of ring substitution on photophysical properties of curcumin, steady state absorption and fluorescence spectra of DMC were recorded in organic solvents with different polarity and compared with those of curcumin. The absorption and fluorescence spectra of DMC, like curcumin, are strongly dependent on solvent polarity and the maxima of DMC showed red shift with increase in solvent polarity function (?f), but the above effect is prominently observed in case of fluorescence maxima. From the dependence of Stokes' shift on solvent polarity function the difference between the excited state and ground state dipole moment was estimated as 4.9 D. Fluorescence quantum yield (?f) and fluorescence lifetime (?f) of DMC were also measured in different solvents at room temperature. The results indicated that with increasing solvent polarity, ?f increased linearly, which has been accounted for the decrease in non-radiative rate by intersystem crossing (ISC) processes.

Barik, Atanu; Indira Priyadarsini, K.

2013-03-01

195

Solvent dependence of 7-azaindole dimerization.  

PubMed

We have investigated 7-azaindole (AI) in a variety of solvents including CCl4, CHCl3, CH2Cl2, acetone, CH3CN, and DMSO by femtosecond Raman-induced Kerr effect spectroscopy. In differential low-frequency Kerr spectra between the solutions and the respective neat solvents, vibrational bands of the AI hydrogen-bonding (HB) dimer have been observed at ca. 90 and 105 cm(-1) in CHCl3 and CH2Cl2, as well as CCl4: the standard solvent for the AI dimer. In contrast, a broad monomodal band at ca. 80 cm(-1) characterizes an HB mode between the AI monomer and solvent in acetone, CH3CN, and DMSO. The overdamped Kerr transients in the picosecond region show evidence of both the AI monomer and dimer reorientations in CHCl3, CH2Cl2, acetone, and CH3CN, but only the monomer reorientation has been confirmed in DMSO. The clear intermolecular HB bands have not been observed in acetone, CH3CN, and DMSO because these solvents are sufficiently strong HB acceptors, which form HB AI-solvent complexes, thus preventing quantitative AI dimerization. In addition, it is plausible that the HB band of between AI and solvent obscures the intermolecular bands of the AI dimer when the concentration of the AI dimer is much lower than the AI monomer. For comparison, we have employed NMR to study the concentration-dependent chemical shift of the proton attached to the N at the 7-position of AI and to estimate the dimerization constant: 356, 13.3, 14.7, 0.727, and 0.910 M(-1) in CCl4, CHCl3, CH2Cl2, acetone, and CH3CN, respectively. The femtosecond Raman-induced Kerr effect spectroscopy and NMR results are in good agreement. PMID:24191715

Shirota, Hideaki; Fukuda, Takao; Kato, Tatsuya

2013-12-19

196

Logarithmic conformal field theory  

NASA Astrophysics Data System (ADS)

Conformal field theory (CFT) has proven to be one of the richest and deepest subjects of modern theoretical and mathematical physics research, especially as regards statistical mechanics and string theory. It has also stimulated an enormous amount of activity in mathematics, shaping and building bridges between seemingly disparate fields through the study of vertex operator algebras, a (partial) axiomatisation of a chiral CFT. One can add to this that the successes of CFT, particularly when applied to statistical lattice models, have also served as an inspiration for mathematicians to develop entirely new fields: the Schramm-Loewner evolution and Smirnov's discrete complex analysis being notable examples. When the energy operator fails to be diagonalisable on the quantum state space, the CFT is said to be logarithmic. Consequently, a logarithmic CFT is one whose quantum space of states is constructed from a collection of representations which includes reducible but indecomposable ones. This qualifier arises because of the consequence that certain correlation functions will possess logarithmic singularities, something that contrasts with the familiar case of power law singularities. While such logarithmic singularities and reducible representations were noted by Rozansky and Saleur in their study of the U (1|1) Wess-Zumino-Witten model in 1992, the link between the non-diagonalisability of the energy operator and logarithmic singularities in correlators is usually ascribed to Gurarie's 1993 article (his paper also contains the first usage of the term 'logarithmic conformal field theory'). The class of CFTs that were under control at this time was quite small. In particular, an enormous amount of work from the statistical mechanics and string theory communities had produced a fairly detailed understanding of the (so-called) rational CFTs. However, physicists from both camps were well aware that applications from many diverse fields required significantly more complicated non-rational theories. Examples include critical percolation, supersymmetric string backgrounds, disordered electronic systems, sandpile models describing avalanche processes, and so on. In each case, the non-rationality and non-unitarity of the CFT suggested that a more general theoretical framework was needed. Driven by the desire to better understand these applications, the mid-1990s saw significant theoretical advances aiming to generalise the constructs of rational CFT to a more general class. In 1994, Nahm introduced an algorithm for computing the fusion product of representations which was significantly generalised two years later by Gaberdiel and Kausch who applied it to explicitly construct (chiral) representations upon which the energy operator acts non-diagonalisably. Their work made it clear that underlying the physically relevant correlation functions are classes of reducible but indecomposable representations that can be investigated mathematically to the benefit of applications. In another direction, Flohr had meanwhile initiated the study of modular properties of the characters of logarithmic CFTs, a topic which had already evoked much mathematical interest in the rational case. Since these seminal theoretical papers appeared, the field has undergone rapid development, both theoretically and with regard to applications. Logarithmic CFTs are now known to describe non-local observables in the scaling limit of critical lattice models, for example percolation and polymers, and are an integral part of our understanding of quantum strings propagating on supermanifolds. They are also believed to arise as duals of three-dimensional chiral gravity models, fill out hidden sectors in non-rational theories with non-compact target spaces, and describe certain transitions in various incarnations of the quantum Hall effect. Other physical applications range from two-dimensional turbulence and non-equilibrium systems to aspects of the AdS/CFT correspondence and describing supersymmetric sigma models beyond the topological sector. We refer the reader to the

Gainutdinov, Azat; Ridout, David; Runkel, Ingo

2013-12-01

197

CONFORM/SPECIFOR.  

National Technical Information Service (NTIS)

This paper has a twofold purpose: first, it describes the recently developed constrained forced model, CONFORM, currently operational and in use at the United States Army Management System Support Agency for structuring theater forces for the outyears. Th...

R. H. Gramann

1973-01-01

198

Conformational Characteristics of Polystyrene.  

National Technical Information Service (NTIS)

Conformational energies of meso and racemic dyads of polystyrene have been computed as functions of skeletal bond rotations. Confinement of rotations of the phenyl groups to a small range within which they are nearly perpendicular to the plane defined by ...

D. Y. Yoon P. R. Sundararajan P. J. Flory

1975-01-01

199

Representations of conformal supersymmetry  

NASA Astrophysics Data System (ADS)

The superalgebras of (generalized) conformal supersymmetry have some very interesting unitarizable representations that contain only massless representations of the conformal subalgebra, in spite of contrary claims that have recently been made Castell, L., and Heidenreich, W., Phys. Rev. D25, 1745 (1982). , Castell, L. and Kunemund, Th., Phys. Rev. D26, 1485 (1982). .

Flato, Moshé; Fronsdal, Christian

1984-03-01

200

Assemblies of Conformal Tanks  

NASA Technical Reports Server (NTRS)

Assemblies of tanks having shapes that conform to each other and/or conform to other proximate objects have been investigated for use in storing fuels and oxidizers in small available spaces in upper stages of spacecraft. Such assemblies might also prove useful in aircraft, automobiles, boats, and other terrestrial vehicles in which space available for tanks is limited. The basic concept of using conformal tanks to maximize the utilization of limited space is not new in itself: for example, conformal tanks are used in some automobiles to store windshield -washer liquid and coolant that overflows from radiators. The novelty of the present development lies in the concept of an assembly of smaller conformal tanks, as distinguished from a single larger conformal tank. In an assembly of smaller tanks, it would be possible to store different liquids in different tanks. Even if the same liquid were stored in all the tanks, the assembly would offer an advantage by reducing the mechanical disturbance caused by sloshing of fuel in a single larger tank: indeed, the requirement to reduce sloshing is critical in some applications. The figure shows a prototype assembly of conformal tanks. Each tank was fabricated by (1) copper plating a wax tank mandrel to form a liner and (2) wrapping and curing layers of graphite/epoxy composite to form a shell supporting the liner. In this case, the conformal tank surfaces are flat ones where they come in contact with the adjacent tanks. A band of fibers around the outside binds the tanks together tightly in the assembly, which has a quasi-toroidal shape. For proper functioning, it would be necessary to maintain equal pressure in all the tanks.

DeLay, Tom

2009-01-01

201

Enhanced conformational sampling using enveloping distribution sampling.  

PubMed

To lessen the problem of insufficient conformational sampling in biomolecular simulations is still a major challenge in computational biochemistry. In this article, an application of the method of enveloping distribution sampling (EDS) is proposed that addresses this challenge and its sampling efficiency is demonstrated in simulations of a hexa-?-peptide whose conformational equilibrium encompasses two different helical folds, i.e., a right-handed 2.7(10?12)-helix and a left-handed 3(14)-helix, separated by a high energy barrier. Standard MD simulations of this peptide using the GROMOS 53A6 force field did not reach convergence of the free enthalpy difference between the two helices even after 500 ns of simulation time. The use of soft-core non-bonded interactions in the centre of the peptide did enhance the number of transitions between the helices, but at the same time led to neglect of relevant helical configurations. In the simulations of a two-state EDS reference Hamiltonian that envelops both the physical peptide and the soft-core peptide, sampling of the conformational space of the physical peptide ensures that physically relevant conformations can be visited, and sampling of the conformational space of the soft-core peptide helps to enhance the transitions between the two helices. The EDS simulations sampled many more transitions between the two helices and showed much faster convergence of the relative free enthalpy of the two helices compared with the standard MD simulations with only a slightly larger computational effort to determine optimized EDS parameters. Combined with various methods to smoothen the potential energy surface, the proposed EDS application will be a powerful technique to enhance the sampling efficiency in biomolecular simulations. PMID:24116601

Lin, Zhixiong; van Gunsteren, Wilfred F

2013-10-14

202

Conformal theories with an infrared cutoff  

NASA Astrophysics Data System (ADS)

We give a new perspective on the dynamics of conformal theories realized in the SU(N) gauge theory, when the number of flavors Nf is within the conformal window. Motivated by the renormalization group argument on conformal theories with a finite IR cutoff ?IR, we conjecture that the propagator of a meson GH(t) on a lattice behaves at large t as a power-law corrected Yukawa-type decaying form GH(t)=c˜Hexp?(-m˜Ht)/t?H instead of the exponentially decaying form cHexp?(-mHt), in the small quark mass region where mH?c?IR: mH is the mass of the ground state hadron in the channel H and c is a constant of order 1. The transition between the “conformal region” and the “confining region” is a first order transition. Our numerical results verify the predictions for the Nf=7 case and the Nf=16 case in the SU(3) gauge theory with the fundamental representation.

Ishikawa, K.-I.; Iwasaki, Y.; Nakayama, Yu; Yoshie, T.

2013-04-01

203

The open pore conformation of potassium channels  

Microsoft Academic Search

Living cells regulate the activity of their ion channels through a process known as gating. To open the pore, protein conformational changes must occur within a channel's membrane-spanning ion pathway. KcsA and MthK, closed and opened K+ channels, respectively, reveal how such gating transitions occur. Pore-lining `inner' helices contain a `gating hinge' that bends by approximately 30°. In a straight

Youxing Jiang; Alice Lee; Jiayun Chen; Martine Cadene; Brian T. Chait; Roderick MacKinnon

2002-01-01

204

Conformational flexibility of mephenesin.  

PubMed

The mephenesin molecule (3-(2-methylphenoxy)propane-1,2-diol) serves as a test bank to explore several structural and dynamical issues, such as conformational flexibility, the orientation of the carbon linear chain relative to the benzene plane, or the effect of substituent position on the rotational barrier of a methyl group. The molecule has been studied by rotational spectroscopy in the 4-18 GHz frequency range by Fourier-transform methods in a supersonic expansion. The experiment has been backed by a previous conformational search plus optimization of the lowest energy structures by ab initio and density functional quantum calculations. The three lowest-lying conformers that can interconvert to each other by simple bond rotations have been detected in the jet. Rotational parameters for all structures have been obtained, and methyl torsional barriers have been determined for the two lowest-lying rotamers. The lowest-lying structure of mephenesin is highly planar, with all carbon atoms lying nearly in the benzene ring plane, and is stabilized by the formation of cooperative intramolecular hydrogen bonding. An estimation of the relative abundance of the detected conformers indicates that the energetically most stable conformer will have an abundance near 80% at temperatures relevant for biological activity. PMID:24754523

Ecija, Patricia; Evangelisti, Luca; Vallejo, Montserrat; Basterretxea, Francisco J; Lesarri, Alberto; Castaño, Fernando; Caminati, Walther; Cocinero, Emilio J

2014-05-22

205

[Conformational fluctuations in chloroplasts].  

PubMed

Characteristic features of conformational changes in chloroplasts have been studied by microfilm technique at BMI-13 installation. The oscillatory character of changes in chloroplast cross-section area in time, determined earlier by the tele-lazer microscopy technique, has been confirmed by our data. When chloroplasts are simultaneously seen in the microscope it is possible to observe their synchronous oscillation. The stationarity check of conformational changes shows that is a non-stationary process in the general case. So it is concluded that the standard technique of analysing accidental non-stationary processes can be used for study of conformational changes in chloroplasts provided that the corresponding parts of their kinetics are selected or trends are eliminated depending on the type of non-stationarity. PMID:623830

Rudenko, T I; Makarov, A D; Budnitski?, A A

1978-01-01

206

Molecular dynamics studies of the conformation of sorbitol  

PubMed Central

Molecular dynamics simulations of a 3 m aqueous solution of D-sorbitol (also called D-glucitol) have been performed at 300 K, as well as at two elevated temperatures to promote conformational transitions. In principle, sorbitol is more flexible than glucose since it does not contain a constraining ring. However, a conformational analysis revealed that the sorbitol chain remains extended in solution, in contrast to the bent conformation found experimentally in the crystalline form. While there are 243 staggered conformations of the backbone possible for this open-chain polyol, only a very limited number were found to be stable in the simulations. Although many conformers were briefly sampled, only eight were significantly populated in the simulation. The carbon backbones of all but two of these eight conformers were completely extended, unlike the bent crystal conformation. These extended conformers were stabilized by a quite persistent intramolecular hydrogen bond between the hydroxyl groups of carbon C-2 and C-4. The conformational populations were found to be in good agreement with the limited available NMR data except for the C-2–C-3 torsion (spanned by the O-2–O-4 hydrogen bond), where the NMR data supports a more bent structure.

Lerbret, A.; Mason, P.E.; Venable, R.M.; Cesaro, A.; Saboungi, M.-L.; Pastor, R.W.; Brady, J.W.

2009-01-01

207

Two conformational states of Candida rugosa lipase.  

PubMed Central

The structure of Candida rugosa lipase in a new crystal form has been determined and refined at 2.1 A resolution. The lipase molecule was found in an inactive conformation, with the active site shielded from the solvent by a part of the polypeptide chain-the flap. Comparison of this structure with the previously determined "open" form of this lipase, in which the active site is accessible to the solvent and presumably the substrate, shows that the transition between these 2 states requires only movement of the flap. The backbone NH groups forming the putative oxyanion hole do not change position during this rearrangement, indicating that this feature is preformed in the inactive state. The 2 lipase conformations probably correspond to states at opposite ends of the pathway of interfacial activation. Quantitative analysis indicates a large increase of the hydrophobic surface in the vicinity of the active site. The flap undergoes a flexible rearrangement during which some of its secondary structure refolds. The interactions of the flap with the rest of the protein change from mostly hydrophobic in the inactive form to largely hydrophilic in the "open" conformation. Although the flap movement cannot be described as a rigid body motion, it has very definite hinge points at Glu 66 and at Pro 92. The rearrangement is accompanied by a cis-trans isomerization of this proline, which likely increases the energy required for the transition between the 2 states, and may play a role in the stabilization of the active conformation at the water/lipid interface. Carbohydrate attached at Asn 351 also provides stabilization for the open conformation of the flap.

Grochulski, P.; Li, Y.; Schrag, J. D.; Cygler, M.

1994-01-01

208

Taming the conformal zoo  

Microsoft Academic Search

All known rational conformal field theories may be obtained from (2+1) dimensional Chern-Simons gauge theories by appropriate choice of gauge group. We conjecture that all rational field theories are classified by groups via (2+1)-dimensional Chern-Simons gauge theories. On leave of absence from the Department of Physics, Weizmann Institute of Science, Rehovot 76100, Israel.

Gregory Moore; Nathan Seiberg

1989-01-01

209

Conformally Flat FRW Metrics  

Microsoft Academic Search

We find a new family of non-separable coordinate transformations bringing the FRW metrics into the manifestly conformally flat form. Our results are simple and complete, while our derivation is quite explicit. We also calculate all the FRW curvatures, including the Weyl tensor.

Masao Iihoshi; Sergei V. Ketov; Atsushi Morishita

2007-01-01

210

Conformal cloak for waves  

NASA Astrophysics Data System (ADS)

Conformal invisibility devices are only supposed to work within the valid range of geometrical optics. Here, we show by numerical simulations and analytical arguments that for certain quantized frequencies, they are nearly perfect even in a regime that clearly violates geometrical optics. The quantization condition follows from the analogy between the Helmholtz equation and the stationary Schrödinger equation.

Chen, Huanyang; Leonhardt, Ulf; Tyc, Tomáš

2011-05-01

211

Conformal cloak for waves  

SciTech Connect

Conformal invisibility devices are only supposed to work within the valid range of geometrical optics. Here, we show by numerical simulations and analytical arguments that for certain quantized frequencies, they are nearly perfect even in a regime that clearly violates geometrical optics. The quantization condition follows from the analogy between the Helmholtz equation and the stationary Schroedinger equation.

Chen Huanyang [School of Physical Science and Technology, Soochow University, Suzhou, 215006 Jiangsu (China); Leonhardt, Ulf [School of Physics and Astronomy, University of St. Andrews, North Haugh, St. Andrews KY16 9SS (United Kingdom); Tyc, Tomas [Faculty of Science, Kotlarska 2, and Faculty of Informatics, Botanicka 68a, Masaryk University, CZ-61137 Brno (Czech Republic)

2011-05-15

212

Galilean conformal and superconformal symmetries  

SciTech Connect

Firstly we discuss briefly three different algebras named as nonrelativistic (NR) conformal: Schroedinger, Galilean conformal, and infinite algebra of local NR conformal isometries. Further we shall consider in some detail Galilean conformal algebra (GCA) obtained in the limit c{yields}{infinity} from relativistic conformal algebraO(d+1, 2) (d-number of space dimensions). Two different contraction limits providing GCA and some recently considered realizations will be briefly discussed. Finally by considering NR contraction of D = 4 superconformal algebra the Galilei conformal superalgebra (GCSA) is obtained, in the formulation using complexWeyl supercharges.

Lukierski, J., E-mail: lukier@ift.uni.wroc.pl [University of Wroclaw, Institute for Theoretical Physics (Poland)

2012-10-15

213

Studies of (-)-Pironetin Binding to ?-Tubulin: Conformation, Docking, and Molecular Dynamics.  

PubMed

A comprehensive conformational analysis for the anticancer agent pironetin (1) was achieved by molecular modeling using density functional theory calculations at the B3PW91/DGTZVP level in combination with calculated and experimental (1)H-(1)H coupling constants comparison. Two solvent-dependent conformational families (L and M) were revealed for the optimum conformations. Docking studies of the pironetin-tubulin complex determined a quantitative model for the hydrogen-bond interactions of pironetin through the ?Asn249, ?Asn258, and ?Lys352 amino groups in ?-tubulin, which supported the formation of a covalent adduct between the ?Lys352 and the ? carbon atom of the ?,?-unsaturated lactone. Saturation-transfer difference NMR spectroscopy confirmed that pironetin binds to tubulin, while molecular dynamics exposed a distortion of the tubulin secondary structure at the H8 and H10 ?-helices as well as at the S9 ?-sheet, where ?Lys352 is located. A large structural perturbation in the M-loop geometry between the ?Ile274 and ?Leu285 residues, an essential region for molecular recognition between ?-? and ?-? units of protofilaments, was also identified and provided a rationale for the pironetin inhibitory activity. PMID:24761989

Bañuelos-Hernández, Angel E; Mendoza-Espinoza, José Alberto; Pereda-Miranda, Rogelio; Cerda-García-Rojas, Carlos M

2014-05-01

214

Vibrational Spectroscopic Investigation and Conformational Analysis of 1-HEPTYLAMINE: a Comparative Density Functional Study  

NASA Astrophysics Data System (ADS)

FT-IR and Raman spectra of 1-heptylamine (1-ha) were experimentally reported in the region of 4000-10 cm-1 and 4000-100 cm-1, respectively. The conformational analysis, optimized geometric parameters, normal mode frequencies and corresponding vibrational assignments of 1-ha (C7H17N) were theoretically examined by means of Becke-3-Lee-Yang-Parr (B3-LYP) density functional theory (DFT) method together with 6-31++G(d,p) basis set. Furthermore, reliable vibrational assignments were made on the basis of potential energy distribution (PED) calculated and the thermodynamics functions, highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) of 1-ha were predicted. Calculations were carried out with the possible ten conformational isomers (TT, TG, GT, GT1, GG1, GG2, GG3, GG4, GG5, GG6; T and G denote trans and gauge) of 1-ha, both in gas phase and in solution. Solvent effects were investigated using benzene and methanol. All results indicates that B3-LYP method provides satisfactory results for the prediction vibrational wavenumbers, TT isomer is the most stable form of 1-ha and the conformational energy barrier is independent of the solvent whereas the vibrational frequencies and assignments, IR and Raman intensities of 1-ha are solvent dependent.

Tursun, Mahir; Kesan, Gurkan; Parlak, Cemal; Senyel, Mustafa

2013-06-01

215

User's Manual for Program CONFORM (CONFORMal Contact Stress Problems).  

National Technical Information Service (NTIS)

CONFORM (Conformal Contact of Two Elastic Bodies) is an all Fortran Computer program for the solution of contact stress between two elastic bodies in conformal contact. It is used to find the pressure distribution between the two bodies, the boundary of c...

B. Paul J. Hashemi

1978-01-01

216

Conformal scalar field wormholes  

NASA Technical Reports Server (NTRS)

The Euclidian Einstein equations with a cosmological constant and a conformally coupled scalar field are solved, taking the metric to be of the Robertson-Walker type. In the case Lambda = 0, solutions are found which represent a wormhole connecting two asymptotically flat Euclidian regions. In the case Lambda greater than 0, the solutions represent tunneling from a small Tolman-like universe to a large Robertson-Walker universe.

Halliwell, Jonathan J.; Laflamme, Raymond

1989-01-01

217

Atomic cranks and levers control sugar ring conformations  

NASA Astrophysics Data System (ADS)

In this paper we review the conformational analysis of sugar rings placed under tension during mechanical manipulations of single polysaccharide molecules with the atomic force microscope and during steered molecular dynamics simulations. We examine the role of various chemical bonds and linkages between sugar rings in inhibiting or promoting their conformational transitions by means of external forces. Small differences in the orientation of one chemical bond on the sugar ring can produce significantly different mechanical properties at the polymer level as exemplified by two polysaccharides: cellulose, composed of ?-1\\to 4 -linked D-glucose, and amylose, composed of ?-1\\to 4 -linked D-glucose. In contrast to ?-glucose rings, which are mechanically stable and produce simple entropic elasticity of the chain, ?-glucose rings flip under tension from their chair to a boat-like structure and these transitions produce deviations of amylose elasticity from the freely jointed chain model. We also examine the deformation of two mechanically complementary 1 \\to 6 -linked polysaccharides: pustulan, a ?-1\\to 6 -linked glucan, and dextran, a ?-1\\to 6 -linked glucan. Forced rotations about the C5-C6 bonds govern the elasticity of pustulan, and complex conformational transitions that involve simultaneous C5-C6 rotations and chair-boat transitions govern the elasticity of dextran. Finally, we discuss the likelihood of various conformational transitions in sugar rings in biological settings and speculate on their significance.

Zhang, Qingmin; Lee, Gwangrog; Marszalek, Piotr E.

2005-05-01

218

Conformational analysis and stereoelectronic effects in trans-1,2-dihalocyclohexanes: 1H NMR and theoretical investigation  

NASA Astrophysics Data System (ADS)

The conformational equilibrium of trans-1,2-difluoro- ( 1), trans-1,2-dichloro- ( 2) and trans-1,2-dibromo-cyclohexane ( 3) was studied through a combined method of NMR, theoretical calculations and solvation theory. The solvent dependence of the JH,H3 NMR coupling constants together with theoretical calculations allow the direct determination of the conformational equilibria without recourse to model compounds. The coupling constants were obtained with the aid of spectrum simulation, since these symmetric molecules present complex coupling systems. The observed couplings, when analysed by solvation theory and utilising DFT geometries (B3LYP/6-311+G**), gave energy values of Eee - Eaa of 0.10, 0.95 and 1.40 kcal mol -1 in the vapour phase for 1, 2 and 3, respectively, decreasing to -0.63, 0.36 and 0.93 kcal mol -1 in CCl 4 and to -1.91, -0.80 and -0.05 kcal mol -1 in DMSO solution. The diaxial preference for all compounds is explained by natural bond orbital (NBO) analysis, which shows important hyperconjugative effects in this conformation. The " gauche effect" for compounds with more electronegative substituents, which are in gauche arrangement in the ee conformation, also plays a relevant role in more polar solvents.

Freitas, Matheus P.; Rittner, Roberto; Tormena, Cláudio F.; Abraham, Raymond J.

2005-06-01

219

Mapping L1 Ligase ribozyme conformational switch  

PubMed Central

L1 Ligase (L1L)molecular switch is an in vitro optimized synthetic allosteric ribozyme that catalyzes the regioselective formation of a 5’-to-3’ phosphodiester bond, a reaction for which there is no known naturally occurring RNA catalyst. L1L serves as a proof of principle that RNA can catalyze a critical reaction for prebiotic RNA self-replication according to the RNA World hypothesis. L1L crystal structure captures two distinct conformations that differ by a re-orientation of one of the stems by around 80 Å and are presumed to correspond to the active and inactive state, respectively. It is of great interest to understand the nature of these two states in solution, and the pathway for their interconversion. In this study, we use explicit solvent molecular simulation together with a novel enhanced sampling method that utilizes concepts from network theory to map out the conformational transition between active and inactive states of L1L. We find that the overall switching mechanism can be described as a 3-state/2-step process. The first step involves a large-amplitude swing that re-orients stem C. The second step involves the allosteric activation of the catalytic site through distant contacts with stem C. Using a conformational space network representation of the L1L switch transition, it is shown that the connection between the three states follows different topographical patterns: the stem C swing step passes through a narrow region of the conformational space network, whereas the allosteric activation step covers a much wider region and a more diverse set of pathways through the network.

Giambasu, George M.; Lee, Tai-Sung; Scott, William G.; York, Darrin M.

2012-01-01

220

Glass Transition Temperature and Conformational Changes of Poly(methyl methacrylate) Thin Films Determined by a Two-Dimensional Map Representation of Temperature-Dependent Reflection?Absorption FTIR Spectra  

Microsoft Academic Search

Temperature-dependent reflection-absorption Fourier transform infrared spectra of poly(methyl methacrylate) (PMMA) thin films were measured. From these spectra, two-dimensional (2D) maps of the first derivative of the absorbance with respect to temperature over the space of wavenumber and temperature were constructed. These maps were used to determine the glass transition temperature and to investigate the subtle temperature dependence of the population

Hyeon Suk Shin; Young Mee Jung; Tae Young Oh; Taihyun Chang; Seung Bin Kim; Do Hyung Lee; Isao Noda

2002-01-01

221

OSI Conformance Testing for Bibliographic Applications.  

ERIC Educational Resources Information Center

Describes the development of Open Systems Interconnection (OSI) conformance testing sites, conformance testing tools, and conformance testing services. Discusses related topics such as interoperability testing, arbitration testing, and international harmonization of conformance testing. A glossary is included. (24 references) (SD)

Arbez, Gilbert; Swain, Leigh

1990-01-01

222

Antibody-probed conformational transitions in the protease domain of human factor IX upon calcium binding and zymogen activation: putative high-affinity Ca(2+)-binding site in the protease domain.  

PubMed Central

The Fab fragment of a monoclonal antibody (mAb) reactive to the N-terminal half (residues 180-310) of the protease domain of human factor IX has been previously shown to inhibit the binding of factor IXa to its cofactor, factor VIIIa. These data suggested that this segment of factor IXa may participate in binding to factor VIIIa. We now report that the binding rate (kon) of the mAb is 3-fold higher in the presence of Ca2+ than in its absence for both factors IX and IXa; the half-maximal effect was observed at approximately 300 microM Ca2+. Furthermore, the off rate (koff) of the mAb is 10-fold higher for factor IXa than for factor IX with or without Ca2+. Moreover, like the kon for mAb binding, the incorporation of dansyl-Glu-Gly-Arg chloromethyl ketone (dEGR-CK) into factor IXa was approximately 3 times faster in the presence of Ca2+ than in its absence. Since steric factors govern the kon and the strength of noncovalent interactions governs the koff, the data indicate that the region of factor IX at residues 180-310 undergoes two separate conformational changes before expression of its biologic activity: one upon Ca2+ binding and the other upon zymogen activation. Furthermore, the dEGF-CK incorporation data suggest that both conformational changes also affect the active site residues. Analyses of the known three-dimensional structures of serine proteases indicate that in human factor IX a high-affinity Ca(2+)-binding site may be formed by the carboxyl groups of glutamates 235 and 245 and by the main chain carbonyl oxygens of residues 237 and 240. In support of this conclusion, a synthetic peptide including residues 231-265 was shown to bind Ca2+ with a Kd of approximately 500 microM. This peptide also bound to the mAb, although with approximately 500-fold reduced affinity. Moreover, like factor IX, the peptide bound to the mAb more strongly (approximately 3-fold) in the presence of Ca2+ than in its absence. Thus, it appears that a part of the epitope for the mAb described above is contained in the proposed Ca(2+)-binding site in the protease domain of human factor IX. This proposed site is analogous to the Ca(2+)-binding site in trypsin and elastase, and it may be involved in binding factor IXa to factor VIIIa. Images

Bajaj, S P; Sabharwal, A K; Gorka, J; Birktoft, J J

1992-01-01

223

A study of local crankshaft-type mobility in vitreous polyvinyl chloride and polyacrylonitrile by the method of conformational probes  

NASA Astrophysics Data System (ADS)

Secondary relaxation transitions and local conformational dynamics in polyacrylonitrile and polyvinyl chloride were studied by the method of conformational probes. Relaxation transitions at 210 and 260 K (polyvinyl chloride) and 165 K (polyacrylonitrile) were explained by freezing of “crankshaft-type” motions.

Kamalova, D. I.; Kolyadko, I. M.; Remizov, A. B.

2009-12-01

224

Determination of conformational free energies of peptides by multidimensional adaptive umbrella sampling  

NASA Astrophysics Data System (ADS)

We improve the multidimensional adaptive umbrella sampling method for the computation of conformational free energies of biomolecules. The conformational transition between the ?-helical and ?-hairpin conformational states of an alanine decapeptide is used as an example. Convergence properties of the weighted-histogram-analysis-based adaptive umbrella sampling can be improved by using multiple replicas in each adaptive iteration and by using adaptive updating of the bounds of the umbrella potential. Using positional root-mean-square deviations from structures of the ?-helical and ?-hairpin reference states as reaction coordinates, we obtained well-converged free energy surfaces of both the in-vacuum and in-solution decapeptide systems. From the free energy surfaces well-converged relative free energies between the two conformational states can be derived. Advantages and disadvantages of different methods for obtaining conformational free energies as well as implications of our results in studying conformational transitions of proteins and in improving force field are discussed.

Wang, Jun; Gu, Yan; Liu, Haiyan

2006-09-01

225

Theory for the conformational changes of double-stranded chain molecules  

NASA Astrophysics Data System (ADS)

We develop statistical mechanical theory to predict the thermodynamic properties of chain molecules having noncovalent double-stranded conformations, as in RNA molecules and ?-sheets in proteins. Sequence dependence and excluded volume interactions are explicitly taken into account. We classify conformations by their polymer graphs and enumerate all the conformations corresponding to each graph by a recently developed matrix method [S-J. Chen and K. A. Dill, J. Chem. Phys. 103, 5802 (1995)]. All such graphs are summed by a recursive method. Tests against exact computer enumeration for short chains on a 2D lattice show that the density of states and partition function are given quite accurately. So far, we have explored two classes of conformations; hairpins, which model small ?-sheets, and RNA secondary structures. The main folding transition is predicted to be quite different for these two conformational classes: the hairpin transition is two-state while the RNA secondary structure transition is one-state for homopolymeric chains.

Chen, Shi-Jie; Dill, Ken A.

1998-09-01

226

An Expression of Periodic Phenomena of Fashion on Sexual Selection Model with Conformity Genes and Memes  

NASA Astrophysics Data System (ADS)

It is generally thought that living things have trends in their preferences. The mechanism of occurrence of another trends in successive periods is concerned in their conformity. According to social impact theory, the minority is always exists in the group. There is a possibility that the minority make the transition to the majority by conforming agents. Because of agent's promotion of their conform actions, the majority can make the transition. We proposed an evolutionary model with both genes and memes, and elucidated the interaction between genes and memes on sexual selection. In this paper, we propose an agent model for sexual selection imported the concept of conformity. Using this model we try an environment where male agents and female agents are existed, we find that periodic phenomena of fashion are expressed. And we report the influence of conformity and differentiation on the transition of their preferences.

Mutoh, Atsuko; Tokuhara, Shinya; Kanoh, Masayoshi; Oboshi, Tamon; Kato, Shohei; Itoh, Hidenori

227

Targeting Inactive Enzyme Conformation  

PubMed Central

There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.

Liu, Sijiu; Zeng, Li-Fan; Wu, Li; Yu, Xiao; Xue, Ting; Gunawan, Andrea M.; Ya-Qiu, Long; Zhang, Zhong-Yin

2009-01-01

228

Conformally symmetric traversable wormholes  

SciTech Connect

Exact solutions of traversable wormholes are found under the assumption of spherical symmetry and the existence of a nonstatic conformal symmetry, which presents a more systematic approach in searching for exact wormhole solutions. In this work, a wide variety of solutions are deduced by considering choices for the form function, a specific linear equation of state relating the energy density and the pressure anisotropy, and various phantom wormhole geometries are explored. A large class of solutions impose that the spatial distribution of the exotic matter is restricted to the throat neighborhood, with a cutoff of the stress-energy tensor at a finite junction interface, although asymptotically flat exact solutions are also found. Using the 'volume integral quantifier', it is found that the conformally symmetric phantom wormhole geometries may, in principle, be constructed by infinitesimally small amounts of averaged null energy condition violating matter. Considering the tidal acceleration traversability conditions for the phantom wormhole geometry, specific wormhole dimensions and the traversal velocity are also deduced.

Boehmer, Christian G.; Harko, Tiberiu; Lobo, Francisco S. N. [Institute of Cosmology and Gravitation, University of Portsmouth, Portsmouth PO1 2EG (United Kingdom); Department of Physics and Center for Theoretical and Computational Physics, University of Hong Kong, Pok Fu Lam Road, Hong Kong (China); Institute of Cosmology and Gravitation, University of Portsmouth, Portsmouth PO1 2EG, United Kingdom and Centro de Astronomia e Astrofisica da Universidade de Lisboa, Campo Grande, Ed. C8 1749-016 Lisbon (Portugal)

2007-10-15

229

Intramolecular conformational changes optimize protein kinase C signaling.  

PubMed

Optimal tuning of enzyme signaling is critical for cellular homeostasis. We use fluorescence resonance energy transfer reporters in live cells to follow conformational transitions that tune the affinity of a multidomain signal transducer, protein kinase C (PKC), for optimal response to second messengers. This enzyme comprises two diacylglycerol sensors, the C1A and C1B domains, that have a sufficiently high intrinsic affinity for ligand so that the enzyme would be in a ligand-engaged, active state if not for mechanisms that mask its domains. We show that both diacylglycerol sensors are exposed in newly synthesized PKC and that conformational transitions following priming phosphorylations mask the domains so that the lower affinity sensor, the C1B domain, is the primary diacylglycerol binder. The conformational rearrangements of PKC serve as a paradigm for how multimodule transducers optimize their dynamic range of signaling. PMID:24631122

Antal, Corina E; Violin, Jonathan D; Kunkel, Maya T; Skovsø, Søs; Newton, Alexandra C

2014-04-24

230

Conformer Selective and Vibrationally Mediated Photodissociation Study of Propanal Cation  

NASA Astrophysics Data System (ADS)

We report the conformationally and vibrationally selected imaging study of propanal obtained by resonance-enhanced multiphoton ionization (REMPI). The photoelectron spectra, employing the (2+1) ionization via the (n, 3s) Rydberg transitions in the range from 365 to 371 nm, confirm that there are two stable conformer origins in the lowest ionic state, the cis conformer with a co-planar CCCO geometry and a gauche conformer with a 119° CCCO dihedral angle. We also study the photodissociation dynamics of propanal cation initially prepared in some certain vibrational modes or conformation. The product kinetic energy distributions for the H elimination channels are bimodal, and the two peaks are readily assigned to propanal cation + H and hydroxyallyl cation + H. The ratio of the fast product with respect to the whole product is varied according to different vibrational mode preparation. However, cis form appears the lowest and gauche form yield the highest ratio. Full multiple spawning dynamical calculations show that distinct ultrafast dynamics in the excited state leads to internal conversion to the ground state in isolated regions of the potential surface for the two conformers, and from these distinct regions, conformer interconversion does not effectively compete with dissociation.

Shen, Lei; Kim, Myung Hwa; Zhang, Bailin; Suits, Arthur G.

2009-06-01

231

Conformational distributions of unfolded polypeptides from novel NMR techniques.  

PubMed

How the information content of an unfolded polypeptide sequence directs a protein towards a well-formed three-dimensional structure during protein folding remains one of the fundamental questions in structural biology. Unfolded proteins have recently attracted further interest due to their surprising prevalence in the cellular milieu, where they fulfill not only central regulatory functions, but also are implicated in diseases involving protein aggregation. The understanding of both the protein folding transition and these often natively unfolded proteins hinges on a more detailed experimental characterization of the conformations and conformational transitions in the unfolded state. This description is intrinsically very difficult due to the very large size of the conformational space. In principle, solution NMR can monitor unfolded polypeptide conformations and their transitions at atomic resolution. However, traditional NMR parameters such as chemical shifts, J couplings, and nuclear Overhauser enhancements yield only rather limited and often qualitative descriptions. This situation has changed in recent years by the introduction of residual dipolar couplings and paramagnetic relaxation enhancements, which yield a high number of well-defined, quantitative parameters reporting on the averages of local conformations and long-range interactions even under strongly denaturing conditions. This information has been used to obtain plausible all-atom models of the unfolded state at increasing accuracy. Currently, the best working model is the coil model, which derives amino acid specific local conformations from the distribution of amino acid torsion angles in the nonsecondary structure conformations of the protein data bank. Deviations from the predictions of such models can often be interpreted as increased order resulting from long-range contacts within the unfolded ensemble. PMID:18266409

Meier, Sebastian; Blackledge, Martin; Grzesiek, Stephan

2008-02-01

232

The Conformational Analysis of 14-Membered Macrocyclic Ethers  

Microsoft Academic Search

The conformational analysis of a series of 14-membered macrocyclic ethers possessing a variety of methyl substitution patterns was performed using both NMR spectroscopy and molecular mechanics calculations. Low temperature DNMR spectra of the macrocyclic ethers were interpreted using van der Waals steric compression and anisotropic shielding effects. The macrocyclic ether transition state energies were determined from the DNMR spectra to

Dean S. Clyne; Larry Weiler

2000-01-01

233

Electronically Rich N-Substituted Tetrahydroisoquinoline 3-Carboxylic Acid Esters: Concise Synthesis and Conformational Studies  

PubMed Central

Recent work in our laboratory has shown that the highly substituted, electronically rich 1,2,3,4–tetrahydroisoquinoline–3–carboxylic acid (THIQ3CA) scaffold is a key building block for a novel class of promising anticoagulants (Al-Horani et al. J. Med. Chem. 2011, 54, 6125–6138). The synthesis of THIQ3CA analogs, especially containing specific, electronically rich substituents, has been a challenge and essentially no efficient methods have been reported in the literature. We describe three complementary, glycine donor-based strategies for high yielding synthesis of highly substituted, electronically rich THIQ3CA esters. Three glycine donors studied herein include hydantoin 1, (±)-Boc-?-phosphonoglycine trimethyl ester 2 and (±)-Z-?-phosphonoglycine trimethyl ester 3. Although the synthesis of THIQ3CA analogs could be achieved using either of the three, an optimal, high yielding approach for the desired THIQ3CA esters was best achieved using 3 in three mild, efficient steps. Using this approach, a focused library of advanced N-arylacyl, N-arylalkyl, and bis-THIQ3CA analogs was synthesized. Variable temperature and solvent-dependent NMR chemical shift studies indicated the presence of two major conformational rotamers in 3:1 proportion for N–arylacyl–THIQ3CA analogs, which were separated by a high kinetic barrier of ~17 kcal/mol. In contrast, N–arylalkyl and bis–THIQ3CA variants displayed no rotamerism, which implicates restricted rotation around the amide bond as the origin for high-barrier conformational interconversion. This phenomenon is of major significance because structure-based drug design typically utilizes only one conformation. Overall, the work presents fundamental studies on the synthesis and conformational properties of highly substituted, electronically rich THIQ3CA analogs.

Al-Horani, Rami A.; Desai, Umesh R.

2012-01-01

234

40 CFR 93.106 - Content of transportation plans and timeframe of conformity determinations.  

Code of Federal Regulations, 2010 CFR

...2009-07-01 false Content of transportation plans and timeframe of conformity...or Federal Implementation Plans of Transportation Plans, Programs, and Projects Developed...Transit Laws § 93.106 Content of transportation plans and timeframe of...

2009-07-01

235

40 CFR 93.106 - Content of transportation plans and timeframe of conformity determinations.  

Code of Federal Regulations, 2010 CFR

...2010-07-01 false Content of transportation plans and timeframe of conformity...or Federal Implementation Plans of Transportation Plans, Programs, and Projects Developed...Transit Laws § 93.106 Content of transportation plans and timeframe of...

2010-07-01

236

Quantum conformal cosmology.  

NASA Astrophysics Data System (ADS)

This article discusses an approach to quantum gravity via path integrals. The more conventional approaches look upon general relativity as a field theory. It is argued here that relativity in fact seeks to replace the standard notion of force fields by the concept of non-Euclidean geometry. Any quantization program should take due note of this fundamental aspect. Here it is shown that considerable insight can be gained into the complexities of quantum gravity by a more limited but exact approach that quantizes the conformal degree of freedom only. It is shown, for example, that the likelihood of the universe having originated from a spacetime singularity is vanishingly small. Other interesting consequences of the approach are briefly described.

Narlikar, J. V.

237

Conformal Faraday Effect Antenna  

US Patent & Trademark Office Database

The device, a conformal antenna, includes an antenna element directly coupled to a layer of gyrotropic material and means for creating a magnetic field, the magnetic field having a component substantially perpendicular to, and passing through, the layer of gyrotropic material and the antenna element. The gyrotropic material may be at least partially disposed on a ground plane and may comprise a material such as yttrium iron garnet. The means for creating a magnetic field can be located within the layer of gyrotropic material and may comprise at least one external magnet. The reflective metal ground plane can be the outer surface of a vehicle. The antenna element could have a dipole antenna configuration, and can produce a wave that is linearly polarized. The operation of the device may be at or above the resonant frequency of the gyrotropic material.

2013-02-05

238

Computing chromosome conformation.  

PubMed

The "Chromosome Conformation Capture" (3C) and 3C-related technologies are used to measure physical contacts between DNA segments at high resolution in vivo. 3C studies indicate that genomes are likely organized into dynamic networks of physical contacts between genes and regulatory DNA elements. These interactions are mediated by proteins and are important for the regulation of genes. For these reasons, mapping physical connectivity networks with 3C-related approaches will be essential to fully understand how genes are regulated. The 3C-Carbon Copy (5C) technology can be used to measure chromatin contacts genome-scale within (cis) or between (trans) chromosomes. Although unquestionably powerful, this approach can be challenging to implement without proper understanding and application of publicly available bioinformatics tools. This chapter explains how 5C studies are performed and describes stepwise how to use currently available bioinformatics tools for experimental design, data analysis, and interpretation. PMID:20827597

Fraser, James; Rousseau, Mathieu; Blanchette, Mathieu; Dostie, Josée

2010-01-01

239

Synthesis, molecular conformation, vibrational and electronic transition, isometric chemical shift, polarizability and hyperpolarizability analysis of 3-(4-methoxy-phenyl)-2-(4-nitro-phenyl)-acrylonitrile: a combined experimental and theoretical analysis.  

PubMed

This work presents the synthesis and characterization of a novel compound, 3-(4-methoxy-phenyl)-2-(4-nitro-phenyl)-acrylonitrile (abbreviated as 3-(4MP)-2-(4-NP)-AN, C(16)H(12)N(2)O(3)). The spectroscopic properties of the compound were examined by FT-IR, UV-vis and NMR ((1)H and (13)C) techniques. FT-IR spectrum in solid state was observed in the region 4000-400 cm(-1). The UV-vis absorption spectrum of the compound which dissolved in chloroform was recorded in the range of 200-800 nm. The (1)H and (13)C NMR spectra were recorded in CDCl(3) solution. To determine lowest-energy molecular conformation of the title molecule, the selected torsion angle is varied every 10° and molecular energy profile is calculated from 0° to 360°. The structural and spectroscopic data of the molecule in the ground state were calculated using density functional theory (DFT) employing B3LYP/6-31G(d,p) basis set. The dipole moment, linear polarizability and first hyperpolarizability values were also computed using the same basis set. A study on the electronic properties, such as HOMO and LUMO energies, were performed by time-dependent DFT (TD-DFT) approach. The HOMO and LUMO analysis were used to elucidate information regarding charge transfer within the molecule. The vibrational wavenumbers were calculated and scaled values were compared with experimental FT-IR spectrum. The complete assignments were performed on the basis of the experimental results and total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. Isotropic chemical shifts were calculated using the gauge-invariant atomic orbital (GIAO) method. Comparison of the calculated frequencies, NMR chemical shifts, absorption wavelengths with the experimental values revealed that DFT and TD-DFT method produce good results. The linear polarizabilities and first hyperpolarizabilities of the studied molecule indicate that the title compound can be used as a good nonlinear optical material. The thermodynamic properties of the studied compound at different temperatures were calculated, revealing the correlations between standard heat capacity, standard entropy, standard enthalpy changes and temperatures. PMID:21856218

Asiri, Abdullah Mohamed; Karabacak, Mehmet; Kurt, Mustafa; Alamry, Khalid A

2011-11-01

240

Fe-heme conformations in ferric myoglobin.  

PubMed Central

X-ray absorption near-edge structure (XANES) spectra of ferric myoglobin from horse heart have been acquired as a function of pH (between 5.3 and 11.3). At pH = 11.3 temperature-dependent spectra (between 20 and 293 K) have been collected as well. Experimental data solve three main conformations of the Fe-heme: the first, at low pH, is related to high-spin aquomet-myoglobin (Mb+OH2). The other two, at pH 11.3, are related to hydroxymet-myoglobin (Mb+OH-), and are in thermal equilibrium, corresponding to high- and low-spin Mb+OH-. The structure of the three Fe-heme conformations has been assigned according to spin-resolved multiple scattering simulations and fitting of the XANES data. The chemical transition between Mb+OH2 and high-spin Mb+OH-, and the spin transition of Mb+OH-, are accompanied by changes of the Fe coordination sphere due to its movement toward the heme plane, coupled to an increase of the axial asymmetry.

Longa, S D; Pin, S; Cortes, R; Soldatov, A V; Alpert, B

1998-01-01

241

Replacement between conformity and counter-conformity in consumption decisions.  

PubMed

This study assessed, in a Chinese context, how self-esteem interacts with perceived similarity and uniqueness to yield cognitive dissonance, and whether the dissonance leads to self-reported conformity or counter-conformity behavior. Participants were 408 respondents from 4 major Chinese cities (M age = 33.0 yr., SD = 4.3; 48% men). Self-perceptions of uniqueness, similarity, cognitive dissonance, self-esteem and need to behave in conformity or counter-conformity were measured. A theoretical model was assessed in four situations, relating the ratings of self-esteem and perceived similarity/uniqueness to the way other people at a wedding were dressed, and the resultant cognitive dissonance and conformity/ counter-conformity behavior. Regardless of high or low self-esteem, all participants reported cognitive dissonance when they were told that they were dressed extremely similarly to or extremely differently from the other people attending the wedding. However, the conforming/counter-conforming strategies used by participants to resolve the cognitive dissonance differed. When encountering dissonance induced by the perceived extreme uniqueness of dress, participants with low self-esteem tended to say they would dress next time so as to conform with the way others were dressed, while those with high self-esteem indicated they would continue their counter-conformity in attire. When encountering dissonance induced by the perceived extreme similarity to others, both those with high and low self-esteem tended to say they would dress in an unorthodox manner to surprise other people in the future. PMID:23654033

Chou, Ting-Jui; Chang, En-Chung; Dai, Qi; Wong, Veronica

2013-02-01

242

Changes in MM-CK conformational mobility upon formation of the ADP-Mg(2+)-NO(3)(-)-creatine transition state analogue complex as detected by hydrogen/deuterium exchange.  

PubMed

In the presence of ADP, Mg(2+), creatine, and the planar nitrate ion, creatine kinase isoenzymes undergo significant structural changes accompanying the formation of a very stable transition state analogue complex (TSAC). We have compared, by using hydrogen/deuterium exchange followed by proteolysis of the labeled enzyme and mass spectrometric analysis of the peptic peptides, the backbone dynamics fluctuations of the free enzyme and those of the TSAC. In most peptides, exchange is not affected by ligand binding, except that observed in seven areas located in or at the entrance to the active site, where some protection is detected. On the basis of a comparison with the three-dimensional structures of free or liganded guanidino kinases, four of these peptides (residues 54-72, 226-234, 287-311, and 315-333) can be considered part of the substrate binding site. The other three (residues 162-186, 193-201, and 202-224) are not directly involved in the binding of substrates and are located in a dynamic domain, which allows the enzyme to properly align the substrates for optimal catalysis. PMID:14622006

Mazon, Hortense; Marcillat, Olivier; Forest, Eric; Vial, Christian

2003-11-25

243

Algebraic orbifold conformal field theories  

Microsoft Academic Search

The unitary rational orbifold conformal field theories in the algebraic quantum field theory and subfactor theory framework are formulated. Under general conditions, it is shown that the orbifold of a given unitary rational conformal field theory generates a unitary modular category. Many new unitary modular categories are obtained. It is also shown that the irreducible representations of orbifolds of rank

Feng Xu

2000-01-01

244

Conformations of immunoglobulin hypervariable regions  

Microsoft Academic Search

On the basis of comparative studies of known antibody structures and sequences it has been argued that there is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies, and that the particular conformation adopted is determined by a few key conserved residues. These hypotheses are now supported by reasonably successful predictions of

Cyrus Chothia; Arthur M. Lesk; Anna Tramontano; Michael Levitt; Sandra J. Smith-Gill; Gillian Air; Steven Sheriff; Eduardo A. Padlan; David Davies; William R. Tulip; Peter M. Colman; Silvia Spinelli; Pedro M. Alzari; Roberto J. Poljak

1989-01-01

245

Counselor Identity: Conformity or Distinction?  

ERIC Educational Resources Information Center

The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

McLaughlin, Jerry E.; Boettcher, Kathryn

2009-01-01

246

Dynamics of flexible cycloalkanes. Ab initio and DFT study of the conformational energy hypersurface of cyclononane.  

PubMed

The multidimensional Potential Energy Hypersurface (PEHS) for the cyclononane molecule was comprehensively investigated at the Hartree-Fock (HF), and Density Functional Theory (DFT) levels of theory. Second-order Møller-Plesset perturbation theory (MP2) optimizations were also carried out to confirm the low-energy conformations. The previously reported Geometrical Algorithm to Search Conformational Space (GASCOS) has been used to generate the starting geometries for the conformational analysis. The GASCOS algorithm combined with ab initio and DFT optimization permits searching of the potential energy hypersurface for all minimum-energy conformations as well as transition structures connecting the low-energy forms. The search located all previously reported structures together with 11 transition states, some of which were not found by earlier searching techniques. Altogether, 16 geometries (five low-energy conformations and 11 transition states) were found to be important for a description of the conformational features of cyclononane. RB3LYP/aug-cc-pVTZ//RB3LYP/6-31G(d) calculations suggest a conformational mixture between the twist boat-chair and twist chair-boat conformations as the preferred forms. In addition only the twist chair-chair conformation with 1.52 kcal/mol above the global minimum should contribute somewhat to the equilibrium mixture of conformations. Our results allow us to form a concise idea about the internal intricacies of the 9D vector space describing the conformation of cyclononane as well as the associated conformational potential energy hypersurface of nine independent variables. PMID:16323160

Suvire, Fernando D; Santagata, Luis N; Bombasaro, José A; Enriz, Ricardo D

2006-01-30

247

Conformational Dynamics of Thermus aquaticus DNA Polymerase I during Catalysis.  

PubMed

Despite the fact that DNA polymerases have been investigated for many years and are commonly used as tools in a number of molecular biology assays, many details of the kinetic mechanism they use to catalyze DNA synthesis remain unclear. Structural and kinetic studies have characterized a rapid, pre-catalytic open-to-close conformational change of the Finger domain during nucleotide binding for many DNA polymerases including Thermus aquaticus DNA polymerase I (Taq Pol), a thermostable enzyme commonly used for DNA amplification in PCR. However, little has been performed to characterize the motions of other structural domains of Taq Pol or any other DNA polymerase during catalysis. Here, we used stopped-flow Förster resonance energy transfer to investigate the conformational dynamics of all five structural domains of the full-length Taq Pol relative to the DNA substrate during nucleotide binding and incorporation. Our study provides evidence for a rapid conformational change step induced by dNTP binding and a subsequent global conformational transition involving all domains of Taq Pol during catalysis. Additionally, our study shows that the rate of the global transition was greatly increased with the truncated form of Taq Pol lacking the N-terminal domain. Finally, we utilized a mutant of Taq Pol containing a de novo disulfide bond to demonstrate that limiting protein conformational flexibility greatly reduced the polymerization activity of Taq Pol. PMID:24931550

Xu, Cuiling; Maxwell, Brian A; Suo, Zucai

2014-08-12

248

Projectors, shadows, and conformal blocks  

NASA Astrophysics Data System (ADS)

We introduce a method for computing conformal blocks of operators in arbitrary Lorentz representations in any spacetime dimension, making it possible to apply bootstrap techniques to operators with spin. The key idea is to implement the "shadow formalism" of Ferrara, Gatto, Grillo, and Parisi in a setting where conformal invariance is manifest. Conformal blocks in d-dimensions can be expressed as integrals over the projective null-cone in the "embedding space" d+1,1. Taking care with their analytic structure, these integrals can be evaluated in great generality, reducing the computation of conformal blocks to a bookkeeping exercise. To facilitate calculations in four-dimensional CFTs, we introduce techniques for writing down conformally-invariant correlators using auxiliary twistor variables, and demonstrate their use in some simple examples.

Simmons-Duffin, David

2014-04-01

249

Theoretical studies of DNA-RNA hybrid conformations.  

PubMed Central

Molecular modelling has been used to probe the conformational preferences of double stranded DNA-RNA hybrids. As might be expected, the sugars of the DNA strand have higher conformational flexibility, but, for the majority of the repetitive sequences studied, these sugars prefer a C2-endo pucker, while ribose sugars uniformly adopt a C3-endo pucker. This gives rise to a strongly heteronomous duplex conformation. One exception to this rule involves the thymidine strand of poly(dT).poly(rA), which marginally prefers a C3-endo pucker. Our study further indicates that the DNA strands of the hybrids favour backbone torsions in the canonical B domain, rather than the modified values proposed on the basis of fibre diffraction studies. Backbone conformational transitions can nevertheless be induced leading to an alpha gamma-flip (alpha:gamma, g-/g(+)-->t/t) or to the alpha beta gamma-flip form proposed from fibre studies (alpha:beta:gamma, g-/t/g(+)-->t/g+/t). The latter transition is also found to be linked to BI-->BII transitions (epsilon:zeta, t/g(-)-->g-/t). Images

Sanghani, S R; Lavery, R

1994-01-01

250

Theoretical studies of DNA-RNA hybrid conformations.  

PubMed

Molecular modelling has been used to probe the conformational preferences of double stranded DNA-RNA hybrids. As might be expected, the sugars of the DNA strand have higher conformational flexibility, but, for the majority of the repetitive sequences studied, these sugars prefer a C2-endo pucker, while ribose sugars uniformly adopt a C3-endo pucker. This gives rise to a strongly heteronomous duplex conformation. One exception to this rule involves the thymidine strand of poly(dT).poly(rA), which marginally prefers a C3-endo pucker. Our study further indicates that the DNA strands of the hybrids favour backbone torsions in the canonical B domain, rather than the modified values proposed on the basis of fibre diffraction studies. Backbone conformational transitions can nevertheless be induced leading to an alpha gamma-flip (alpha:gamma, g-/g(+)-->t/t) or to the alpha beta gamma-flip form proposed from fibre studies (alpha:beta:gamma, g-/t/g(+)-->t/g+/t). The latter transition is also found to be linked to BI-->BII transitions (epsilon:zeta, t/g(-)-->g-/t). PMID:7514787

Sanghani, S R; Lavery, R

1994-04-25

251

Conformations and laser-induced fluorescence spectroscopy of jet-cooled 2-( p-fluorophenyl)ethanol  

NASA Astrophysics Data System (ADS)

Vibronically-resolved S 1-S 0 electronic spectra of 2-( p-fluorophenyl)ethanol have been studied by use of laser-induced fluorescence excitation and dispersed fluorescence spectroscopic methods in a supersonic free jet expansion. Two conformational isomers of the molecule are identified, and with the aid of the predictions of quantum chemistry calculations these are assigned to gauche and anti conformers. The assignments are corroborated by analyzing the vibronic features in the dispersed fluorescence spectra of the two conformers and their TDDFT predicted electronic transition energies. Energetic and spectral features of the conformers are compared with those of the parent molecule 2-phenylethanol.

Panja, Sujit S.; Biswas, Partha; Chakraborty, Tapas

2005-08-01

252

Dynamics of protein conformations  

NASA Astrophysics Data System (ADS)

A novel theoretical methodology is introduced to identify dynamic structural domains and analyze local flexibility in proteins. The methodology employs a multiscale approach combining identification of essential collective coordinates based on the covariance analysis of molecular dynamics trajectories, construction of the Mori projection operator with these essential coordinates, and analysis of the corresponding generalized Langevin equations [M.Stepanova, Phys.Rev.E 76(2007)051918]. Because the approach employs a rigorous theory, the outcomes are physically transparent: the dynamic domains are associated with regions of relative rigidity in the protein, whereas off-domain regions are relatively soft. This also allows scoring the flexibility in the macromolecule with atomic-level resolution [N.Blinov, M.Berjanskii, D.S.Wishart, and M.Stepanova, Biochemistry, 48(2009)1488]. The applications include the domain coarse-graining and characterization of conformational stability in protein G and prion proteins. The results are compared with published NMR experiments. Potential applications for structural biology, bioinformatics, and drug design are discussed.

Stepanova, Maria

2010-10-01

253

DoD Biometric Conformity Assessment Initiative.  

National Technical Information Service (NTIS)

The comprehensive discipline of conformity assessment involves conformance testing activities and the certification of information systems to ensure that adopted standards are met. This article provides an overview of conformity assessment, and details th...

J. Woodward S. Cava

2005-01-01

254

Does conformational free energy distinguish loop conformations in proteins?  

PubMed Central

Limitations in protein homology modeling often arise from the inability to adequately model loops. In this paper we focus on the selection of loop conformations. We present a complete computational treatment that allows the screening of loop conformations to identify those that best fit a molecular model. The stability of a loop in a protein is evaluated via computations of conformational free energies in solution, i.e., the free energy difference between the reference structure and the modeled one. A thermodynamic cycle is used for calculation of the conformational free energy, in which the total free energy of the reference state (i.e., gas phase) is the CHARMm potential energy. The electrostatic contribution of the solvation free energy is obtained from solving the finite-difference Poisson-Boltzmann equation. The nonpolar contribution is based on a surface area-based expression. We applied this computational scheme to a simple but well-characterized system, the antibody hypervariable loop (complementarity-determining region, CDR). Instead of creating loop conformations, we generated a database of loops extracted from high-resolution crystal structures of proteins, which display geometrical similarities with antibody CDRs. We inserted loops from our database into a framework of an antibody; then we calculated the conformational free energies of each loop. Results show that we successfully identified loops with a "reference-like" CDR geometry, with the lowest conformational free energy in gas phase only. Surprisingly, the solvation energy term plays a confusing role, sometimes discriminating "reference-like" CDR geometry and many times allowing "non-reference-like" conformations to have the lowest conformational free energies (for short loops). Most "reference-like" loop conformations are separated from others by a gap in the gas phase conformational free energy scale. Naturally, loops from antibody molecules are found to be the best models for long CDRs (> or = 6 residues), mainly because of a better packing of backbone atoms into the framework of the antibody model. Images FIGURE 1 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6

Pellequer, J L; Chen, S W

1997-01-01

255

Dark matter from conformal sectors  

NASA Astrophysics Data System (ADS)

We show that a conformal-invariant dark sector, interacting conformally with the Standard Model (SM) fields through the Higgs portal, provides a viable framework where cold dark matter (CDM) and invisible Higgs decays can be addressed concurrently. Conformal symmetry naturally subsumes the Z2 symmetry needed for stability of the CDM. It also guarantees that the weaker the couplings of the dark sector fields to the SM Higgs field, the smaller the masses they acquire through electroweak breaking. The model comfortably satisfies the bounds from Large Hadron Collider (LHC) and Planck Space Telescope (PLANCK 2013).

Demir, Durmu? Ali; Frank, Mariana; Korutlu, Beste

2014-01-01

256

Conformational variations amongst scorpion toxins.  

PubMed

Circular dichroism spectra were obtained for ten scorpion neurotoxins (representing five species of scorpion) in order to provide an understanding of their relative conformations in solution. Despite a high degree of amino acid sequence homology, the toxins clearly differ from each other in terms of CD-detectable structure. When superimposed, the CD spectra suggest that the toxins form a series of related conformational variants. Since the resemblances amongst the individual CD spectra can be correlated to degrees of sequence resemblance and pharmacological specificity, conformational balance could be an important factor in both toxin evolution and target recognition. PMID:3942749

Dufton, M J; Drake, A F; Rochat, H

1986-01-17

257

CONFORMANCE IMPROVEMENT USING GELS  

SciTech Connect

This technical progress report describes work performed from June 20 through December 19, 2001, for the project, ''Conformance Improvement Using Gels''. Interest has increased in some new polymeric products that purport to substantially reduce permeability to water while causing minimum permeability reduction to oil. In view of this interest, we are currently studying BJ's Aqua Con. Results from six corefloods revealed that the Aqua Con gelant consistently reduced permeability to water more than that to oil. However, the magnitude of the disproportionate permeability reduction varied significantly for the various experiments. Thus, as with most materials tested to date, the issue of reproducibility and control of the disproportionate permeability remains to be resolved. Concern exists about the ability of gels to resist washout after placement in fractures. We examined whether a width constriction in the middle of a fracture would cause different gel washout behavior upstream versus downstream of the constriction. Tests were performed using a formed Cr(III)-acetate-HPAM gel in a 48-in.-long fracture with three sections of equal length, but with widths of 0.08-, 0.02-, and 0.08-in., respectively. The pressure gradients during gel extrusion (i.e., placement) were similar in the two 0.08-in.-wide fracture sections, even though they were separated by a 0.02-in.-wide fracture section. The constriction associated with the middle fracture section may have inhibited gel washout during the first pulse of brine injection after gel placement. However, during subsequent phases of brine injection, the constriction did not inhibit washout in the upstream fracture section any more than in the downstream section.

Randall S. Seright

2002-02-28

258

Conformal mapping of rectangular heptagons  

SciTech Connect

A new effective approach to calculating the direct and inverse conformal mapping of rectangular polygons onto a half-plane is put forward; it is based on the use of Riemann theta functions. Bibliography: 14 titles.

Bogatyrev, Andrei B

2012-12-31

259

Nonexponential protein relaxation: dynamics of conformational change in myoglobin.  

PubMed Central

The picosecond evolution of the tertiary conformation of myoglobin (Mb) after photodissociation of MbCO was investigated at room temperature by probing band III, a weak iron-porphyrin charge-transfer transition near 13,110 cm-1 (763 nm) that is sensitive to the out-of-plane displacement of the iron. Upon photolysis, the iron moves out of the plane of the porphyrin, causing a blue-shift of band III and a concomitant change in the protein conformation. The dynamics for this functionally important motion are highly nonexponential, in agreement with recent molecular dynamics simulations [Kuczera, K., Lambry, J.-C., Martin, J.-L. & Karplus, M. (1993) Proc. Natl. Acad. Sci. USA 90, 5805-5807]. The conformational change likely affects the height of the barrier to ligand rebinding and may explain nonexponential NO rebinding.

Lim, M; Jackson, T A; Anfinrud, P A

1993-01-01

260

Xanthan-galactomannan interactions as related to xanthan conformations.  

PubMed

The influence of xanthan conformation on the physicochemical behaviour of their mixtures with galactomannan from Schizolobium parahybae mannose:galactose ratio (M/G=3), was studied by viscoelastic measurements, differential scanning calorimetry (DSC) and chiroptical (circular dichroism) methods. The results suggested a more effective interaction of the galactomannan with disordered xanthan segments, which are more abundant in low salt concentrations but are still present in lower proportion at temperatures lower than the temperature of xanthan conformational transition (Tm). The dependence of ellipticity with temperature in a circular dichroism (CD) spectra suggested an ordering of the xanthan chains induced by galactomannan at the temperature of gel formation (Tg approximately 25 degrees C), under conditions where xanthan alone exhibits a disordered conformation. The lower Tg value found (approximately 25 degrees C) compared with that (60 degrees C) usually described in the literature is certainly related to the M/G ratio and the galactosyl unit distribution along the mannan main chain. PMID:9849624

Bresolin, T M; Milas, M; Rinaudo, M; Ganter, J L

1998-11-01

261

Conformal representations of Leibniz algebras  

Microsoft Academic Search

We study the embedding construction of Lie dialgebras (Leibniz algebras) into conformal algebras. This construction leads\\u000a to the concept of a conformal representation of Leibniz algebras. We prove that each (finite-dimensional) Leibniz algebra\\u000a possesses a faithful linear representation (of finite type). As a corollary we give a new proof of the Poincaré-Birkhoff-Witt\\u000a theorem for Leibniz algebras.

Pavel Kolesnikov

2008-01-01

262

Extensive Conformational Heterogeneity within Protein Cores.  

PubMed

Basic principles of statistical mechanics require that proteins sample an ensemble of conformations at any nonzero temperature. However, it is still common to treat the crystallographic structure of a protein as the structure of its native state, largely because high-resolution structural characterization of protein flexibility remains a profound challenge. To assess the typical degree of conformational heterogeneity within folded proteins, we construct Markov state models describing the thermodynamics and kinetics of proteins ranging from 72 to 263 residues in length. Each of these models is built from hundreds of microseconds of atomically detailed molecular dynamics simulations. Examination of the side-chain degrees of freedom reveals that almost every residue visits at least two rotameric states over this time frame, with rotamer transition rates spanning a wide range of time scales (from nanoseconds to tens of microseconds). We also report substantial backbone dynamics on time scales longer than are typically addressed by experimental measures of protein flexibility, such as NMR order parameters. Finally, we demonstrate that these extensive rearrangements are consistent with NMR and crystallographic data, which supports the validity of our models. Altogether, these results depict the interior of proteins not as well-ordered solids, as is often imagined, but instead as dense fluids, which undergo substantial structural fluctuations despite their high packing fraction. PMID:24564338

Bowman, Gregory R; Geissler, Phillip L

2014-06-19

263

Extensive Conformational Heterogeneity within Protein Cores  

PubMed Central

Basic principles of statistical mechanics require that proteins sample an ensemble of conformations at any nonzero temperature. However, it is still common to treat the crystallographic structure of a protein as the structure of its native state, largely because high-resolution structural characterization of protein flexibility remains a profound challenge. To assess the typical degree of conformational heterogeneity within folded proteins, we construct Markov state models describing the thermodynamics and kinetics of proteins ranging from 72 to 263 residues in length. Each of these models is built from hundreds of microseconds of atomically detailed molecular dynamics simulations. Examination of the side-chain degrees of freedom reveals that almost every residue visits at least two rotameric states over this time frame, with rotamer transition rates spanning a wide range of time scales (from nanoseconds to tens of microseconds). We also report substantial backbone dynamics on time scales longer than are typically addressed by experimental measures of protein flexibility, such as NMR order parameters. Finally, we demonstrate that these extensive rearrangements are consistent with NMR and crystallographic data, which supports the validity of our models. Altogether, these results depict the interior of proteins not as well-ordered solids, as is often imagined, but instead as dense fluids, which undergo substantial structural fluctuations despite their high packing fraction.

Geissler, Phillip L.

2014-01-01

264

Analysis of the stability of looped-out and stacked-in conformations of an adenine bulge in DNA using a continuum model for solvent and ions.  

PubMed Central

A combination of conformational search, energy minimization, and energetic evaluation using a continuum solvent treatment has been employed to study the stability of various conformations of the DNA fragment d(CGCAGAA)/d(TTCGCG) containing a single adenine bulge. The extra-helical (looped-out) bulge conformation derived from a published x-ray structure and intra-helical (stacked bulge base) model structures partially based on nuclear magnetic resonance (NMR) data were used as start structures for the conformational search. Solvent-dependent contributions to the stability of the conformations were calculated from the solvent exposed molecular surface area and by using the finite difference Poisson-Boltzmann approach. Three classes (I-III) of bulge conformations with calculated low energies can be distinguished. The lowest-energy conformations were found in class I, corresponding to structures with the bulge base stacked between flanking helices, and class II, composed of structures forming a triplet of the bulge base and a flanking base pair. All extra-helical bulge structures, forming class III, were found to be less stable compared with the lowest energy structures of class I and II. The results are consistent with NMR data on an adenine bulge in the same sequence context indicating an intra-helical or triplet bulge conformation in solution. Although the total energies and total electrostatic energies of the low-energy conformations show only relatively modest variations, the energetic contributions to the stability were found to vary significantly among the classes of bulge structures. All intra-helical bulge structures are stabilized by a more favorable Coulomb charge-charge interaction but destabilized by a larger electrostatic reaction field contribution compared with all extra-helical and most triplet bulge structures. Van der Waals packing interactions and nonpolar surface-area-dependent contributions appear to favor triplet class II structures and to a lesser degree also the intra-helical stacked bulge conformations. The large conformational variation found for class III conformers might add a favorable entropic contribution to the stability of the extra-helical bulge form.

Zacharias, M; Sklenar, H

1997-01-01

265

Solution conformations of a trimannoside from nuclear magnetic resonance and molecular dynamics simulations.  

PubMed Central

N-linked oligosaccharides often act as ligands for receptor proteins in a variety of cell recognition processes. Knowledge of the solution conformations, as well as protein-bound conformations, of these oligosaccharides is required to understand these important interactions. In this paper we present a model for the solution conformations sampled by a simple trimannoside, methyl 3, 6-di-O-(alpha-D-mannopyranosyl)-alpha-D-mannopyranoside, which contains two of the most commonly found glycosidic linkages in N-linked oligosaccharides. This model was derived from simulated annealing protocols incorporating distance restraints extracted from NOESY spectra along with torsional restraints computed from three-bond (1)H-(13)C coupling constants measured across the glycosidic bonds. The model was refined in light of unrestrained molecular dynamics simulations conducted in the presence of solvent water. The resulting model depicts a molecule undergoing conformational averaging in solution, adopting four major and two minor conformations. The four major conformations arise from a pair of two-state transitions, one each at the alpha(1-->3) and alpha(1-->6) linkages, whereas the minor conformations result from an additional transition of the alpha(1-->6) linkage. Our data also suggest that the alpha(1-->3) transition is fast and changes the molecular shape slightly, whereas the alpha(1-->6) is much slower and alters the molecular shape dramatically.

Sayers, E W; Prestegard, J H

2000-01-01

266

To Conform or Not to Conform: Spontaneous Conformity Diminishes the Sensitivity to Monetary Outcomes  

PubMed Central

When people have different opinions in a group, they often adjust their own attitudes and behaviors to match the group opinion, known as social conformity. The affiliation account of normative conformity states that people conform to norms in order to ‘fit in’, whereas the accuracy account of informative conformity posits that the motive to learn from others produces herding. Here, we test another possibility that following the crowd reduces the experienced negative emotion when the group decision turns out to be a bad one. Using event related potential (ERP) combined with a novel group gambling task, we found that participants were more likely to choose the option that was predominately chosen by other players in previous trials, although there was little explicit normative pressure at the decision stage and group choices were not informative. When individuals' choices were different from others, the feedback related negativity (FRN), an ERP component sensitive to losses and errors, was enhanced, suggesting that being independent is aversive. At the outcome stage, the losses minus wins FRN effect was significantly reduced following conformity choices than following independent choices. Analyses of the P300 revealed similar patterns both in the response and outcome period. Our study suggests that social conformity serves as an emotional buffer that protects individuals from experiencing strong negative emotion when the outcomes are bad.

2013-01-01

267

Solvation and conformational dynamics of dicarboxylic suberic acid  

NASA Astrophysics Data System (ADS)

Solvation structure and conformational preferences of the dicarboxylic suberic acid, HOOC(CH2)6COOH, both neutral and protolyzed in water and neutral in methanol have been studied using molecular-dynamics (MO) computer simulations. According to results from MD simulations in water solution, the backbone hydrocarbon chain shows a very clear tendency to curl up into a helical structure, forming either a tgggt or a tg'g'g't conformation. The carboxylic head groups are strongly hydrated in the water solution, while the hydrophobic hydrocarbon skeleton is surrounded by water molecules in a packed structure. In the helical conformation, the surface area of the nonpolar part of the fatty acid is minimized against water phase. Transitions between the right and the left-handed helices are observed in neutral and mono-anionic forms of suberic acid in water solution. Suberic acid dissolved in methanol does not show any conformational preferences. Along the hydrocarbon chain, g, g', and t conformers are equally populated. The head group torsional angles, however, strongly prefer trans conformation due to dipolar interactions between the carboxyl groups and the solvent hydroxyl groups. In addition to MD simulations, corresponding water and methanol solutions are prepared and 13C NMR (nuclear magnetic resonance) chemical shifts are measured in both solutions. Using a time-averaged geometry for suberic acid from MD simulations in water, chemical shielding constants are calculated quantum chemically. Agreement between the theoretical and the experimental chemical shifts is good, and gives indirect support to the simulated conformations of suberic acid in the investigated solutions. The simulation results are also consistent with recent Raman investigations of suberic acid in both water and methanol solutions.

Nilsson, J. Arvid; Laaksonen, A.; Eriksson, Leif A.

1998-08-01

268

Metadynamics in the conformational space nonlinearly dimensionally reduced by Isomap  

NASA Astrophysics Data System (ADS)

Atomic motions in molecules are not linear. This infers that nonlinear dimensionality reduction methods can outperform linear ones in analysis of collective atomic motions. In addition, nonlinear collective motions can be used as potentially efficient guides for biased simulation techniques. Here we present a simulation with a bias potential acting in the directions of collective motions determined by a nonlinear dimensionality reduction method. Ad hoc generated conformations of trans,trans-1,2,4-trifluorocyclooctane were analyzed by Isomap method to map these 72-dimensional coordinates to three dimensions, as described by Brown and co-workers [J. Chem. Phys. 129, 064118 (2008)]. Metadynamics employing the three-dimensional embeddings as collective variables was applied to explore all relevant conformations of the studied system and to calculate its conformational free energy surface. The method sampled all relevant conformations (boat, boat-chair, and crown) and corresponding transition structures inaccessible by an unbiased simulation. This scheme allows to use essentially any parameter of the system as a collective variable in biased simulations. Moreover, the scheme we used for mapping out-of-sample conformations from the 72D to 3D space can be used as a general purpose mapping for dimensionality reduction, beyond the context of molecular modeling.

Spiwok, Vojt?ch; Králová, Blanka

2011-12-01

269

HAMP domain conformers that propagate opposite signals in bacterial chemoreceptors.  

PubMed

HAMP domains are signal relay modules in >26,000 receptors of bacteria, eukaryotes, and archaea that mediate processes involved in chemotaxis, pathogenesis, and biofilm formation. We identify two HAMP conformations distinguished by a four- to two-helix packing transition at the C-termini that send opposing signals in bacterial chemoreceptors. Crystal structures of signal-locked mutants establish the observed structure-to-function relationships. Pulsed dipolar electron spin resonance spectroscopy of spin-labeled soluble receptors active in cells verify that the crystallographically defined HAMP conformers are maintained in the receptors and influence the structure and activity of downstream domains accordingly. Mutation of HR2, a key residue for setting the HAMP conformation and generating an inhibitory signal, shifts HAMP structure and receptor output to an activating state. Another HR2 variant displays an inverted response with respect to ligand and demonstrates the fine energetic balance between "on" and "off" conformers. A DExG motif found in membrane proximal HAMP domains is shown to be critical for responses to extracellular ligand. Our findings directly correlate in vivo signaling with HAMP structure, stability, and dynamics to establish a comprehensive model for HAMP-mediated signal relay that consolidates existing views on how conformational signals propagate in receptors. Moreover, we have developed a rational means to manipulate HAMP structure and function that may prove useful in the engineering of bacterial taxis responses. PMID:23424282

Airola, Michael V; Sukomon, Nattakan; Samanta, Dipanjan; Borbat, Peter P; Freed, Jack H; Watts, Kylie J; Crane, Brian R

2013-01-01

270

HAMP Domain Conformers That Propagate Opposite Signals in Bacterial Chemoreceptors  

PubMed Central

HAMP domains are signal relay modules in >26,000 receptors of bacteria, eukaryotes, and archaea that mediate processes involved in chemotaxis, pathogenesis, and biofilm formation. We identify two HAMP conformations distinguished by a four- to two-helix packing transition at the C-termini that send opposing signals in bacterial chemoreceptors. Crystal structures of signal-locked mutants establish the observed structure-to-function relationships. Pulsed dipolar electron spin resonance spectroscopy of spin-labeled soluble receptors active in cells verify that the crystallographically defined HAMP conformers are maintained in the receptors and influence the structure and activity of downstream domains accordingly. Mutation of HR2, a key residue for setting the HAMP conformation and generating an inhibitory signal, shifts HAMP structure and receptor output to an activating state. Another HR2 variant displays an inverted response with respect to ligand and demonstrates the fine energetic balance between “on” and “off” conformers. A DExG motif found in membrane proximal HAMP domains is shown to be critical for responses to extracellular ligand. Our findings directly correlate in vivo signaling with HAMP structure, stability, and dynamics to establish a comprehensive model for HAMP-mediated signal relay that consolidates existing views on how conformational signals propagate in receptors. Moreover, we have developed a rational means to manipulate HAMP structure and function that may prove useful in the engineering of bacterial taxis responses.

Airola, Michael V.; Sukomon, Nattakan; Samanta, Dipanjan; Borbat, Peter P.; Freed, Jack H.; Watts, Kylie J.; Crane, Brian R.

2013-01-01

271

Conformational sampling, catalysis, and evolution of the bacterial phosphotriesterase  

PubMed Central

To efficiently catalyze a chemical reaction, enzymes are required to maintain fast rates for formation of the Michaelis complex, the chemical reaction and product release. These distinct demands could be satisfied via fluctuation between different conformational substates (CSs) with unique configurations and catalytic properties. However, there is debate as to how these rapid conformational changes, or dynamics, exactly affect catalysis. As a model system, we have studied bacterial phosphotriesterase (PTE), which catalyzes the hydrolysis of the pesticide paraoxon at rates limited by a physical barrier—either substrate diffusion or conformational change. The mechanism of paraoxon hydrolysis is understood in detail and is based on a single, dominant, enzyme conformation. However, the other aspects of substrate turnover (substrate binding and product release), although possibly rate-limiting, have received relatively little attention. This work identifies “open” and “closed” CSs in PTE and dominant structural transition in the enzyme that links them. The closed state is optimally preorganized for paraoxon hydrolysis, but seems to block access to/from the active site. In contrast, the open CS enables access to the active site but is poorly organized for hydrolysis. Analysis of the structural and kinetic effects of mutations distant from the active site suggests that remote mutations affect the turnover rate by altering the conformational landscape.

Jackson, C. J.; Foo, J.-L.; Tokuriki, N.; Afriat, L.; Carr, P. D.; Kim, H.-K.; Schenk, G.; Tawfik, D. S.; Ollis, D. L.

2009-01-01

272

Conformational Elasticity can Facilitate TALE-DNA Recognition.  

PubMed

Sequence-programmable transcription activator-like effector (TALE) proteins have emerged as a highly efficient tool for genome engineering. Recent crystal structures depict a transition between an open unbound solenoid and more compact DNA-bound solenoid formed by the 34 amino acid repeats. How TALEs switch conformation between these two forms without substantial energetic compensation, and how the repeat-variable di-residues (RVDs) discriminate between the cognate base and other bases still remain unclear. Computational analysis on these two aspects of TALE-DNA interaction mechanism has been conducted in order to achieve a better understanding of the energetics. High elasticity was observed in the molecular dynamics simulations of DNA-free TALE structure that started from the bound conformation where it sampled a wide range of conformations including the experimentally determined apo and bound conformations. This elastic feature was also observed in the simulations starting from the apo form which suggests low free energy barrier between the two conformations and small compensation required upon binding. To analyze binding specificity, we performed free energy calculations of various combinations of RVDs and bases using Poisson-Boltzmann surface area (PBSA) and other approaches. The PBSA calculations indicated that the native RVD-base structures had lower binding free energy than mismatched structures for most of the RVDs examined. Our theoretical analyses provided new insight on the dynamics and energetics of TALE-DNA binding mechanism. PMID:24629191

Lei, Hongxing; Sun, Jiya; Baldwin, Enoch P; Segal, David J; Duan, Yong

2014-01-01

273

Conformational analyses of the reaction coordinate of glycosidases.  

PubMed

The enzymatic hydrolysis of the glycosidic bond is catalyzed by diverse enzymes generically termed glycoside hydrolases (hereafter GHs) or glycosidases. The many sequence-based families of glycosidases have served as a rich hunting ground for enzymologists for years. Not only are these enzymes of fundamental interest, providing paradigms for enzymatic catalysis that extend beyond the bounds of carbohydrate chemistry, but the enzymes themselves play myriad essential roles in diverse biological processes. The wide utility of glycosidases, from their industrial harnessing in the hydrolysis of plant biomass to their roles in human physiology and disease, has engendered a large scientific constituency with an interest in glycosidase chemistry. A fascinating thread of this research, and one with major impact on the design of enzyme inhibitors, is the conformational analysis of reaction pathways within the diverse families. These GH families provide a large pallet of enzymes with which chemists have attempted to depict the conformational landscape of glycosidase action. In this Account, we review three-dimensional insight into the conformational changes directed by glycosidases, primarily from structural observations of the stable enzyme-ligand species adjacent to the transition state (or states) and of enzyme-inhibitor complexes. We further show how recent computational advances dovetail with structural insight to provide a quantum mechanical basis for glycosidase action. The glycosidase-mediated hydrolysis of the acetal or ketal bond in a glycoside may occur with either inversion or retention of the configuration of the anomeric carbon. Inversion involves a single step and transition state, whereas retention, often referred to as the double displacement, is a two-step process with two transition states. The single transition state for the inverting enzymes and the two transition states (those flanking the covalent intermediate) in the double displacement have been shown to have substantial oxocarbenium ion character. The dissociative nature of these transition states results in significant relative positive charge accumulation on the pyranose ring. The delocalization of lone-pair electrons from the ring oxygen that stabilizes the cationic transition state implies that at, or close to, the transition states the pyranose will be distorted away from its lowest energy conformation to one that favors orbital overlap. Over the preceding decade, research has highlighted the harnessing of noncovalent interactions to aid this distortion of the sugar substrates from their lowest energy chair conformation to a variety of different boat, skew boat, and half-chair forms, each of which favors catalysis with a given enzyme and substrate. Crystallographic observation of stable species that flank the transition state (or states), of both retaining and inverting glycosidases, has allowed a description of their conformational itineraries, illustrating how enzymes facilitate the "electrophilic migration" of the anomeric center along the reaction coordinate. The blossoming of computational approaches, such as ab initio metadynamics, has underscored the quantum mechanical basis for glycoside hydrolysis. Conformational analyses highlight not only the itineraries used by enzymes, enabling their inhibition, but are also reflected in the nonenzymatic synthesis of glycosides, wherein chemists mimic strategies found in nature. PMID:21923088

Davies, Gideon J; Planas, Antoni; Rovira, Carme

2012-02-21

274

Self-Dual Conformal Gravity  

NASA Astrophysics Data System (ADS)

We find necessary and sufficient conditions for a Riemannian four-dimensional manifold (M, g) with anti-self-dual Weyl tensor to be locally conformal to a Ricci-flat manifold. These conditions are expressed as the vanishing of scalar and tensor conformal invariants. The invariants obstruct the existence of parallel sections of a certain connection on a complex rank-four vector bundle over M. They provide a natural generalisation of the Bach tensor which vanishes identically for anti-self-dual conformal structures. We use the obstructions to demonstrate that LeBrun's anti-self-dual metrics on connected sums of {{CP}^2} s are not conformally Ricci-flat on any open set. We analyze both Riemannian and neutral signature metrics. In the latter case we find all anti-self-dual metrics with a parallel real spinor which are locally conformal to Einstein metrics with non-zero cosmological constant. These metrics admit a hyper-surface orthogonal null Killing vector and thus give rise to projective structures on the space of ?-surfaces.

Dunajski, Maciej; Tod, Paul

2014-04-01

275

Conformational disorder of conjugated polymers.  

PubMed

Conformational disorder of conjugated polymers is an important issue to be understood and quantified. In this paper we present a new method to assess the chain conformation of conjugated polymers based on measurements of intrachain energy transfer. The chain conformation is modeled on the basis of monomer-monomer interactions, such as torsion, bending, and stretching of the connecting bond. The latter two potentials are assumed to be harmonic, while the torsional potential was calculated by density functional theory using B3-LYP functional with the SVP basis set. The energy transfer dynamics of excitons on these chains are quantitatively simulated using Forster-type line-dipole energy transfer. This allows us to compare the simulated ground state conformation of single polymer chains to ultrafast depolarization experiments of poly [3-(2,5-dioctylphenyl)thiophene] in solution. We identify torsional rotation as the main contributor to conformational disorder and find that this disorder is mainly controlled by the energy difference between syn and anti bonds. PMID:17059289

Westenhoff, Sebastian; Beenken, Wichard J D; Yartsev, Arkady; Greenham, Neil C

2006-10-21

276

Conformational disorder of conjugated polymers  

NASA Astrophysics Data System (ADS)

Conformational disorder of conjugated polymers is an important issue to be understood and quantified. In this paper we present a new method to assess the chain conformation of conjugated polymers based on measurements of intrachain energy transfer. The chain conformation is modeled on the basis of monomer-monomer interactions, such as torsion, bending, and stretching of the connecting bond. The latter two potentials are assumed to be harmonic, while the torsional potential was calculated by density functional theory using B3-LYP functional with the SVP basis set. The energy transfer dynamics of excitons on these chains are quantitatively simulated using Förster-type line-dipole energy transfer. This allows us to compare the simulated ground state conformation of single polymer chains to ultrafast depolarization experiments of poly [3-(2,5-dioctylphenyl)thiophene] in solution. We identify torsional rotation as the main contributor to conformational disorder and find that this disorder is mainly controlled by the energy difference between syn and anti bonds.

Westenhoff, Sebastian; Beenken, Wichard J. D.; Yartsev, Arkady; Greenham, Neil C.

2006-10-01

277

Interacting electrons in ballistic conformal billiard quantum dots  

NASA Astrophysics Data System (ADS)

Interacting electrons in a ballistic quantum dot present a novel regime of disorder + interactions. An instability of the ground state towards a spontaneous deformation of the Fermi surface (the Pomeranchuk transition) has been found by the present authors[1], by assuming that Random Matrix Theory describes the states in the Thouless shell near the Fermi energy. However, the question of whether the mesoscopic transition occurs before the bulk transition remains open[2]. Here we describe calculations on the conformal billiard[3] and attempt to see how well RMT assumptions hold, and to what extent the physics of the transition is described by our previous work. 1. G. Murthy, R. Shankar, D. Herman, and H. Mathur, cond-mat/0306529. 2. S. Adam, P. W. Brouwer, and P. Sharma, cond-mat/0309074. 3. M. V. Berry and M. Robnik, J. Phys. A19, 669 (1986).

Murthy, Ganpathy; Mathur, Harsh; Shankar, Ramamurti

2004-03-01

278

Cation-mediated conformational variants of surfactant protein A.  

PubMed

Surfactant protein A (SP-A) is the major protein of pulmonary surfactant. This protein is implicated in regulating surfactant secretion, alveolar processing, recycling, and in non-serum-induced immune response. An increasing body of work indicates the importance of cations, particularly calcium, on SP-A function. However, little information exists on the effects of cations on SP-A quaternary structure. Here, the quaternary organisation of bovine surfactant protein A in the presence of cations has been quantitatively and systematically studied by transmission electron microscopy. The conformation of SP-A is altered by the presence of cations, especially calcium, then sodium, and to a small extent, magnesium. There is a transition concentration, unique for each cation, at which a conformational switch occurs. These transition concentrations are: 5 mM for CaCl2, 100 mM for NaCl and 1 mM for MgCl2. Below these concentrations, SP-A exists primarily in an opened form with a large head diameter of 20 nm; above it, SP-A is mostly in a closed form due to a compaction of the headgroups resulting in a head diameter of 11 nm. There is a corresponding increase in particle length from 17 nm for opened SP-A to 20 nm for closed SP-A. The fact that the transition concentrations are within physiological range suggests that cation-mediated conformational changes of SP-A could be operative in vivo. PMID:9989242

Ridsdale, R A; Palaniyar, N; Holterman, C E; Inchley, K; Possmayer, F; Harauz, G

1999-01-01

279

A Threaded Loop Conformation Adopted by a Family of Peptoid Nonamers  

PubMed Central

Non-natural polymers with well-defined three-dimensional folds offer considerable potential for engineering novel functions that are outside the scope of biological polymers. Here we describe a family of N-substituted glycine or ‘peptoid’ nonamers that folds into an unusual ‘threaded loop’ structure of exceptional thermal stability and conformational homogeneity in acetonitrile. The structure is chain length-specific and relies on bulky, chiral side chains and chain-terminating functional groups for stability. Notable elements of the structure include the engagement of the positively charged amino-terminus by carbonyl groups of the backbone through hydrogen bonding interactions, and shielding of polar groups from and near-complete exposure of hydrophobic groups to solvent, in a manner resembling a folded polypeptide globular domain turned ‘inside-out’. The structure is stable in a variety of organic solvents but is readily denatured in any solvent/cosolvent milieu with hydrogen bonding potential. The structure could serve as a scaffold for the elaboration of novel functions and could be used to test methodologies for predicting solvent-dependent polymer folding.

Huang, Kai; Wu, Cindy W.; Sanborn, Tracy J.; Patch, James A.; Kirshenbaum, Kent; Zuckermann, Ronald N.; Barron, Annelise E.; Radhakrishnan, Ishwar

2008-01-01

280

Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations  

Microsoft Academic Search

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein\\/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein\\/ligand complexes if

Daniel Seeliger; Bert L. de Groot

2010-01-01

281

Conformational Transitions Upon Ligand Binding: Holo Structure Prediction from Apo Conformations  

Microsoft Academic Search

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein\\/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein\\/ligand complexes if

Daniel Seeliger; Bert L. de Groot; Thomas Lengauer

2010-01-01

282

Conformal curvature flows: from phase transitions to active contours  

Microsoft Academic Search

Abstract: In this paper, we analyze geometric active contour models from a curve evolutionpoint of view and propose some modifications based on gradient flows relative to certainnew feature-based Riemannian metrics. This leads to a novel edge-detection paradigmin which the feature of interest may be considered to lie at the bottom of a potentialwell. Thus an edge-seeking curve is attracted very

S. Kichenasamy; P. Olver; A. Tannenbaum; A. Yezzi

1996-01-01

283

Conformal Curvature Flows: From Phase Transitions to Active Vision  

Microsoft Academic Search

In this paper, we analyze geometric active contour models from a curve evolutionpoint of view and propose some modifications based on gradient flows relative to certainnew feature-based Riemannian metrics. This leads to a novel edge-detection paradigmin which the feature of interest may be considered to lie at the bottom of a potentialwell. Thus an edge-seeking curve is attracted very naturally

Satyanad Kichenassamy; Arun Kumar

1995-01-01

284

Conformal curvature flows: From phase transitions to active vision  

Microsoft Academic Search

In this paper, we analyze geometric active contour models from a curve evolution point of view and propose some modifications based on gradient flows relative to certain new feature-based Riemannian metrics. This leads to a novel edge-detection paradigm in which the feature of interest may be considered to lie at the bottom of a potential well. Thus an edge-seeking curve

Satyanad Kichenassamy; Arun Kumar; Peter Olver; Allen Tannenbaum; Anthony Yezzi

1996-01-01

285

Universality class in conformal inflation  

NASA Astrophysics Data System (ADS)

We develop a new class of chaotic inflation models with spontaneously broken conformal invariance. Observational consequences of a broad class of such models are stable with respect to strong deformations of the scalar potential. This universality is a critical phenomenon near the point of enhanced symmetry, SO(1,1), in case of conformal inflation. It appears because of the exponential stretching of the moduli space and the resulting exponential flattening of scalar potentials upon switching from the Jordan frame to the Einstein frame in this class of models. This result resembles stretching and flattening of inhomogeneities during inflationary expansion. It has a simple interpretation in terms of velocity versus rapidity near the Kähler cone in the moduli space, similar to the light cone of special theory of relativity. This effect makes inflation possible even in the models with very steep potentials. We describe conformal and superconformal versions of this cosmological attractor mechanism.

Kallosh, Renata; Linde, Andrei

2013-07-01

286

Patterns and conformations in molecularly thin films  

NASA Astrophysics Data System (ADS)

Molecularly thin films have been a subject of great interest for the last several years because of their large variety of industrial applications ranging from micro-electronics to bio-medicine. Additionally, molecularly thin films can be used as good models for biomembrane and other systems where surfaces are critical. Many different kinds of molecules can make stable films. My research has considered three such molecules: a polymerizable phospholipid, a bent-core molecules, and a polymer. One common theme of these three molecules is chirality. The phospolipid molecules studied here are strongly chiral, which can be due to intrinsically chiral centers on the molecules and also due to chiral conformations. We find that these molecules give rise to chiral patterns. Bent-core molecules are not intrinsically chiral, but individual molecules and groups of molecules can show chiral structures, which can be changed by surface interactions. One major, unconfirmed hypothesis for the polymer conformation at surface is that it forms helices, which would be chiral. Most experiments were carried out at the air/water interface, in what are called Langmuir films. Our major tools for studying these films are Brewster Angle Microscopy (BAM) coupled with the thermodynamic information that can be deduced from surface pressure isotherms. Phospholipids are one of the important constituents of liposomes -- a spherical vesicle com-posed of a bilayer membrane, typically composed of a phospholipid and cholesterol bilayer. The application of liposomes in drug delivery is well-known. Crumpling of vesicles of polymerizable phospholipids has been observed. With BAM, on Langmuir films of such phospholipids, we see novel spiral/target patterns during compression. We have found that both the patterns and the critical pressure at which they formed depend on temperature (below the transition to a i¬‘uid layer). Bent-core liquid crystals, sometimes knows as banana liquid crystals, have drawn increasing attention because of the richness in phases that they exhibit. Due to the unique coupling between dipole properties and the packing constraints placed by the bent shape, these molecules are emerging as strong candidates in electromechanical devices. However, most applications require that the molecules be aligned, which has proved difficult. Our group has tested such molecules both as Langmuir layers and, when transferred to a solid, as alignment layers with some limited success. However, these molecules do not behave well with the surfaces and the domains at the air/water interface tend to form ill-controlled multilayer structures since attraction with the surfaces is relatively weak. New bent-core molecules obtained from Prof. Dr. C. Tsehiemke from Department of Chemistry Institute of Organic Chemistry, Martin-Luther-University, Germany, have a hydrophilic group at one end. We expect this molecule to behave better on the surface because of the stronger attraction of the hydrophilic group towards the surface than for the bent-core molecules without the hydrophilic group. Polydimethylsiloxane (PDMS) is a polymer which finds many applications in modifying surface properties. It is used in manufacturing lubricants, protective coatings, hair conditioner and glass-coating. However its properties are not well understood. This polymer has been proposed to follow either helical or caterpillar conformations on a surface. The orientational order of CH3 side groups can test for these conformations (they would be predominantly up/down for the caterpillar conformation, but rotating through the entire 360 degree for the helical one). Thus previous work on the Langmuir polymer films at the air/water interface were complemented by deuterium NMR studies to probe their conformations at a surface. These experiments were performed using humid porous solids, in order to provide sufficient surface area for the technique. Previous tests in this group at room temperature were suggestive but inconclusive because of the rapid averaging motion of the molecules. Here, we attempt t

Basnet, Prem B.

287

Epigenetic Dominance of Prion Conformers  

PubMed Central

Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP) primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg) mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A) at (OvPrP-A136) infected with SSBP/1 scrapie prions propagated a relatively stable (S) prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V) at 136 (OvPrP-V136) infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U), diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb) PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to the otherwise unfavorable U conformer. This epigenetic mechanism thus expands the range of selectable conformations that can be adopted by PrP, and therefore the variety of options for strain propagation.

Saijo, Eri; Kang, Hae-Eun; Bian, Jifeng; Bowling, Kristi G.; Browning, Shawn; Kim, Sehun; Hunter, Nora; Telling, Glenn C.

2013-01-01

288

Conformational dynamics and thermodynamics of protein-ligand binding studied by NMR relaxation.  

PubMed

Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein-ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions. PMID:22435823

Akke, Mikael

2012-04-01

289

Structural characterization and spectroelectrochemical, anion sensing and solvent dependence photophysical studies of a bimetallic Ru(II) complex derived from 1,3-di(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)benzene.  

PubMed

The X-ray crystal structure of a mixed-ligand bimetallic ruthenium(II) complex of composition [(bipy)(2)Ru(H(2)Impib)Ru(bipy)(2)](ClO(4))(4) (1), where H(2)Impib = 1,3-di(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)benzene and bipy = 2,2'-bipyridine, has been determined and showed that the compound crystallized in monoclinic form with the space group P2(1)/c. The absorption, steady state and time-resolved luminescence spectral properties of the complex were thoroughly investigated in different solvents. The compound displays strong luminescence at room temperature with lifetimes in the range of 140-470 ns, depending upon the nature of the solvent. Solvent-induced lifetime tuning makes the complex a suitable solvatochromic probe. The complex is found to undergo one simultaneous two-electron reversible oxidation in the positive potential window (0 to +1.6 V) and four quasi-reversible reductions in the negative potential window (0 to -2.2 V). Spectroelectrochemical studies have also been carried out for the bimetallic compound in the range of 300-1600 nm. With stepwise oxidation of the Ru(ii) centers replacement of MLCT bands by LMCT bands occur with the development of a broad band at ?(max) = 1260 nm, which is ascribed to inter-valence charge-transfer (IVCT) transition for the mixed-valence Ru(II)Ru(III) species. The anion sensing properties of the receptor were thoroughly investigated in acetonitrile solution using absorption, steady state and time-resolved emission spectroscopic studies. The anion sensing studies revealed that the receptor acts as sensor for F(-), AcO(-) and H(2)PO(4)(-). It is evident that in the presence of excess F(-) and AcO(-) ions, deprotonation of the imidazole N-H fragments of the receptor occurs, an event which is signaled by the change of color from yellow to orange visible to the naked eye. From the absorption and emission titration studies the binding/equilibrium constants of the receptor with the anions have also been determined. Anion-induced lifetime quenching by F(-) and AcO(-) and enhancement by H(2)PO(4)(-) makes the receptor a suitable lifetime-based sensor for selective anions. Cyclic voltammetry (CV) measurements of the compound carried out in acetonitrile have provided evidence in favor of anion-dependent electrochemical responses with F(-) and AcO(-) ions. PMID:22706379

Saha, Debasish; Das, Shyamal; Mardanya, Sourav; Baitalik, Sujoy

2012-08-01

290

Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate.  

PubMed

Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence-based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X-ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole-type inhibitors are energetically poised to report faithfully on mannosidase transition-state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including ?-mannanases from families GH26 and GH113. Isofagomine-type inhibitors are poor mimics of transition-state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar-shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active-site residues involved in substrate recognition. PMID:24339341

Williams, Rohan J; Iglesias-Fernández, Javier; Stepper, Judith; Jackson, Adam; Thompson, Andrew J; Lowe, Elisabeth C; White, Jonathan M; Gilbert, Harry J; Rovira, Carme; Davies, Gideon J; Williams, Spencer J

2014-01-20

291

Role of Electrostatic Repulsion in Controlling pH-dependent Conformational Changes of Viral Fusion Proteins  

PubMed Central

Viral fusion proteins undergo dramatic conformational transitions during membrane fusion. For viruses that enter through the endosome, these conformational rearrangements are typically pH sensitive. Here we provide a comprehensive review of the molecular interactions that govern pH-dependent rearrangements and introduce a novel paradigm for electrostatic residue pairings that regulate progress through the viral fusion coordinate. Analysis of structural data demonstrates a significant role for side chain protonation in triggering conformational change. To characterize this behavior we identify two distinct residue pairings, which we define as Histidine-Cation (HisCat) and Anion-Anion (AniAni) interactions. These side chain pairings destabilize a particular conformation via electrostatic repulsion through side chain protonation. Furthermore, two energetic control mechanisms, thermodynamic and kinetic, regulate these structural transitions. This review expands on the current literature by identification of these residue clusters, discussion of data demonstrating their function, and speculation of how these residue pairings contribute to the energetic controls.

Harrison, Joseph S.; Higgins, Chelsea D.; O'Meara, Matthew J.; Koellhoffer, Jayne F.; Kuhlman, Brian A.; Lai, Jonathan R.

2013-01-01

292

Transition Planning  

ERIC Educational Resources Information Center

Post-school transition is the movement of a child with disabilities from school to activities that occur after the completion of school. This paper provides information about: (1) post-school transition; (2) transition plan; (3) transition services; (4) transition planning; (5) vocational rehabilitation services; (6) services that are available…

Statfeld, Jenna L.

2011-01-01

293

Precision conformal optics technology program  

NASA Astrophysics Data System (ADS)

Conformal optics are defined as optics that deviate from conventional form to best satisfy the contour and shape needs of system platforms. Precision Conformal Optics Technology (PCOT), a comprehensive 48 month program funded by the Defense Advanced Research Program Agency (DARPA) and the U. S. Army Missile Research, Development, and Engineering Center (MRDEC), assessed the potential benefits achieved by use of conformal optics on a variety of U.S. weapon systems. Also addressed were all barriers impeding conformal optics use. The PCOT program was executed by a consortium of organizations ranging from major U.S. defense prime contractors, to small businesses, and academia. The diversity of organizations encouraged synergy across a broad array of skills and perspectives. Smooth team interaction was made possible by the 845 contractual structure of the program. Benefits identified by the PCOT consortium included major reductions in aerodynamic drag (by as much as 50%), reduced time-to-targets (by as much as 60%), and reduced weapon signatures. Impediments addressed included inadequacies in optical design tools, optical manufacturing methods and equipment, optical testing, and system integration. The PCOT program was successfully completed with a demonstration of a highly contoured missile dome, which reduced overall missile drag by 25%, and led to a predicted twofold increase in missile range.

Trotta, Patrick A.

2001-09-01

294

Temperature: Human Regulating, Ants Conforming  

ERIC Educational Resources Information Center

Biological processes speed up as temperature rises. Procedures for demonstrating this with ants traveling on trails, and data gathered by students on the Argentine ant ("Linepithema humile") are presented. The concepts of temperature regulation and conformity are detailed with a focus on the processes rather than on terms that label the organisms.

Clopton, Joe R.

2007-01-01

295

Conformational Changes in Acetylcholine Binding Protein Investigated by Temperature Accelerated Molecular Dynamics  

PubMed Central

Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniques, we study the ligand-induced conformational changes of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) simulations we investigate the AChBP transition between the apo and the agonist-bound state. In long standard MD simulations, both conformations of the native protein are stable, while the agonist-bound structure evolves toward the apo one if the orientation of few key sidechains in the orthosteric cavity is modified. Conversely, TAMD simulations initiated from the native conformations are able to produce the spontaneous transition. With respect to the modified conformations, TAMD accelerates the transition by at least a factor 10. The analysis of some specific residue-residue interactions points out that the transition mechanism is based on the disruption/formation of few key hydrogen bonds. Finally, while early events of ligand dissociation are observed already in standard MD, TAMD accelerates the ligand detachment and, at the highest TAMD effective temperature, it is able to produce a complete dissociation path in one AChBP subunit.

Mohammad Hosseini Naveh, Zeynab; Malliavin, Therese E.; Maragliano, Luca; Cottone, Grazia; Ciccotti, Giovanni

2014-01-01

296

Enzymatic Detoxication, Conformational Selection, and the Role of Molten Globule Active Sites*  

PubMed Central

The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning “induced fit” versus “conformational selection” has, however, ignored detoxication enzymes, which exhibit catalytic promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1–1 (GSTA1–1), exploits a molten globule-like active site to achieve remarkable catalytic promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic promiscuity is used to compare engineered variants of GSTA1–1 and the catalytic promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that “local” molten globule behavior optimizes detoxication enzymes.

Honaker, Matthew T.; Acchione, Mauro; Zhang, Wei; Mannervik, Bengt; Atkins, William M.

2013-01-01

297

Double resonance spectroscopy of different conformers of the neurotransmitter amphetamine and its clusters with water  

NASA Astrophysics Data System (ADS)

In this paper the conformational landscape of amphetamine in the neutral ground state is examined by both spectroscopy and theory. Several spectroscopic methods are used: laser-induced fluorescence (LIF), resonance-enhanced two-photon ionization (R2PI), dispersed fluorescence and IR/R2PI hole burning spectroscopy. The latter two methods provide for the first time vibrationally resolved spectra of the neutral ground state of dl-amphetamine and the amphetamine-(H 2O) 1,2 complexes. Nine stable conformers of the monomer were found by DFT (B3LYP/6-311++G(d,p)) and ab initio (MP2/6-311++G(d,p)) calculations. For conformer analysis the vibrations observed in the IR/R2PI hole burning and dispersed fluorescence spectra obtained from single vibronic levels (SVLF) of a selected conformer were compared with the results of an ab initio normal mode analysis. By this procedure three S 0 ? S 1 transitions in the R2PI spectrum were assigned to three different conformer structures. Another weak transition earlier attributed to another conformer could be assigned to a vibronic band of one of the three conformers. Furthermore spectra of amphetamine-(H 2O) 1,2 are tentatively assigned.

Brause, R.; Fricke, H.; Gerhards, M.; Weinkauf, R.; Kleinermanns, K.

2006-08-01

298

Laser spectroscopy of a chiral drug in a supersonic beam: conformation and complexation of S-(+)- Naproxen  

NASA Astrophysics Data System (ADS)

The S 0-S 1 electronic transition of jet-cooled Naproxen has been investigated by laser-induced fluorescence excitation and emission spectroscopy. Two electronic transitions separated by 102 cm -1 have been evidenced and attributed to the presence of two conformers. With the help of DFT calculations, the structure of these conformers has been shown to correspond to a rotation by 180° of the chiral substituent with respect to the aromatic plane. When associated with alcohols, both conformers of the chromophore form complexes which give rise to different microscopic solvent shifts of the S 0-S 1 transition. In the case of complexation with R- or S-2-butanol, the hetero- and homo-chiral pairs are characterised by different spectroscopic patterns, which allow a clear discrimination between them.

Lahmani, Françoise; Le Barbu-Debus, Katia; Seurre, Nathalie; Zehnacker-Rentien, Anne

2003-07-01

299

Coordinated conformational and compositional dynamics drive ribosome translocation  

PubMed Central

During translation elongation, the compositional factors, elongation factor G (EF-G; encoded by fusA) and transfer RNA (tRNA), alternately bind to the ribosome to direct protein synthesis, in turn regulating the conformation of the ribosome. Here, we use single-molecule fluorescence with zero-mode waveguides to correlate directly ribosome conformations and compositions during multiple rounds of elongation at high factor concentrations in Escherichia coli. Our results show that EF-G-GTP continuously samples both rotational sates of the ribosome, binding with higher affinity to the rotated state. Upon successful accommodation into the rotated ribosome, the EF-G-ribosome complex evolves through several rate-limiting conformational changes and the hydrolysis of GTP, which results in a transition back to the non-rotated state, in turn driving translocation and facilitating both EF-G-GDP and E-site tRNA release. These experiments highlight the power of tracking single-molecule conformation and composition simultaneously in real-time.

Chen, Jin; Petrov, Alexey; Tsai, Albert; O'Leary, Sean E.; Puglisi, Joseph D.

2013-01-01

300

Nucleosome Geometry and Internucleosomal Interactions Control the Chromatin Fiber Conformation  

PubMed Central

Based on model structures with atomic resolution, a coarse-grained model for the nucleosome geometry was implemented. The dependence of the chromatin fiber conformation on the spatial orientation of nucleosomes and the path and length of the linker DNA was systematically explored by Monte Carlo simulations. Two fiber types were analyzed in detail that represent nucleosome chains without and with linker histones, respectively: two-start helices with crossed-linker DNA (CL conformation) and interdigitated one-start helices (ID conformation) with different nucleosome tilt angles. The CL conformation was derived from a tetranucleosome crystal structure that was extended into a fiber. At thermal equilibrium, the fiber shape persisted but relaxed into a structure with a somewhat lower linear mass density of 3.1 ± 0.1 nucleosomes/11 nm fiber. Stable ID fibers required local nucleosome tilt angles between 40° and 60°. For these configurations, much higher mass densities of up to 7.9 ± 0.2 nucleosomes/11 nm fiber were obtained. A model is proposed, in which the transition between a CL and ID fiber is mediated by relatively small changes of the local nucleosome geometry. These were found to be in very good agreement with changes induced by linker histone H1 binding as predicted from the high resolution model structures.

Kepper, Nick; Foethke, Dietrich; Stehr, Rene; Wedemann, Gero; Rippe, Karsten

2008-01-01

301

Rydberg electrons spy conformational dynamics of hot molecules  

NASA Astrophysics Data System (ADS)

The observation of structural dynamics of flexible molecules at high temperatures is arguably one of the most challenging problems of molecular dynamics. We succeeded in observing conformational dynamics by using electrons in Rydberg orbits as spies of the molecular structure. The time-resolved photoionization from the Rydberg states, providing a purely electronic spectrum that serves to characterize the molecular structure, allows us to follow the molecular motions in real time. The internal rotation about carbon-carbon bonds affords the unsaturated hydrocarbon chain molecules N,N-dimethyl-2-butanamine (DM2BA) and N,N-dimethyl-3-hexanamine (DM3HA) an opportunity to assume multiple conformeric structures. We explore the equilibrium compositions and the dynamics of transitions between such structures. An ultrashort laser pulse rapidly increases the molecule's internal energy and changes the potential energy landscape. The molecules respond by adjusting their shape, i.e. by converting between conformeric molecular structures. For DM2BA at a total internal energy of 1.79 eV, the time constants for interconversion between conformers are 19 ps and 66 ps, respectively. In DM3HA, the respective time constants are 23 and 41 ps. Comparison with a calculated conformational energy landscape reveals the conformeric forms of DM2BA involved in the molecular shape transformation. Thus, for the first time a time-resolved and quantitative view of the conformational dynamics of a flexible hydrocarbon chain at high temperature is revealed.

Weber, Peter M.

2007-03-01

302

40 CFR 51.854 - Conformity analysis.  

Code of Federal Regulations, 2010 CFR

...2010-07-01 false Conformity analysis. 51.854 Section 51.854...Plans § 51.854 Conformity analysis. Link to an amendment published at 75...agency may choose to adopt the analysis of another Federal agency or...

2010-07-01

303

Modeling the conformational changes underlying channel opening in CFTR.  

PubMed

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Changes in side-chain interactions are observed in all major domains of the protein, and experimental confirmation was obtained for a novel intra-protein salt bridge that breaks near the end of the transition. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel. PMID:24086355

Rahman, Kazi S; Cui, Guiying; Harvey, Stephen C; McCarty, Nael A

2013-01-01

304

Regeneration of native ovalbumin conformation disrupted by citraconylation.  

PubMed

Ovalbumin was reacted with a 960-fold molar excess of citraconic anhydride, and 91% of the epsilon-amino groups, representing 18 of the 20 lysine residues, were citraconylated. As detected by fluorescence and far-ultraviolet circular dichroic (CD) measurements, the modified protein displayed significant disruption of the native conformation. Treatment at pH 2.2 for 5 h resulted in the hydrolysis of 10 of the 18 citraconyl groups, but when subjected to the acid conditions for 12 h, all 18 modifying groups were removed. Electrophoretically, the 5-h and the 12-h acid-treated proteins were homogeneous and showed decreasing anodic mobility at pH 8.3; indeed, the anodic mobility of the 12-h acid-treated protein was identical to that of the native protein. Similarly, the 12-h acid-treated protein possessed conformational properties almost indistinguishable from the native protein. These properties included similar emission fluorescence spectra and far-ultraviolet CD spectra, similar resistance to undergoing helix-to-coil transition at pH 12.2, and identical urea unfolding curves, and thus identical urea transition mid-point of about 8.0 M. These observations indicate that the protein with all the epsilon-amino groups regenerated by acid treatment has the same conformational stability as the native ovalbumin. PMID:1799633

Batra, P P

1991-11-01

305

Modeling the Conformational Changes Underlying Channel Opening in CFTR  

PubMed Central

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Changes in side-chain interactions are observed in all major domains of the protein, and experimental confirmation was obtained for a novel intra-protein salt bridge that breaks near the end of the transition. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.

Rahman, Kazi S.; Cui, Guiying; Harvey, Stephen C.; McCarty, Nael A.

2013-01-01

306

Conformation of local denaturation in double-stranded DNA.  

PubMed

Double-stranded DNA (dsDNA) undergoes a denaturing transition above which the strands unbind completely. At temperatures (including the physiological temperature) below the transition the base pairs tend to unbind locally, giving way to loops, i.e., locally denatured states. In the flexible-chain model, the imaginary time Schrödinger equation describes the interstrand distance distribution of dsDNA with the time variable replaced by the sequence number. We transform the equation to the Fokker-Planck equation (FPE), which provides a convenient and powerful analytical method and, via the equivalent Langevin equation, a simulation scheme. The temperature-dependent potential that emerges in the FPE manifests how the DNA conformation changes dramatically near the transition temperature. We present several simulation plots along with analytical results illustrating the order parameter (concentration of bound base pairs), base pair distance correlation function, and loop size distribution at different temperatures. PMID:15089317

Sung, Wokyung; Jeon, Jae-Hyung

2004-03-01

307

Conformal Window and Correlation Functions in Lattice Conformal QCD  

NASA Astrophysics Data System (ADS)

We discuss various aspects of Conformal Field Theories on the Lattice. We mainly investigate the SU(3) gauge theory with Nf degenerate fermions in the fundamental representation, employing the one-plaquette gauge action and the Wilson fermion action. First we make a brief review of our previous works on the phase structure of lattice gauge theories in terms of the gauge coupling constant and the quark mass. We thereby clarify the reason why we conjecture that the conformal window is 7 ? Nf ? 16. Secondly, we introduce a new concept, "conformal theories with IR cutof" and point out that any numerical simulation on a lattice is bounded by an IR cutoff ?IR. Then we make predictions that when Nf is within the conformal window, the propagator of a meson G(t) behaves at large t, as G(t) = c exp (-mHt)/t?, that is, a modified Yukawa-type decay form, instead of the usual exponential decay form exp (-mHt), in the small quark mass region. This holds on an any lattice for any coupling constant g, as far as g is between 0 and g*, where g* is the IR fixed point. We verify that numerical results really satisfy the predictions for the Nf = 7 case and the Nf = 16 case. Thirdly, we discuss small number of flavors (Nf = 2 ˜ 6) QCD at finite temperatures. We point out theoretically and verify numerically that the correlation functions at T/Tc > 1 exhibit the characteristics of the conformal function with IR cutoff, an exponential decay with power correction. Investigating our numerical data by a new method which we call the "local-analysis" of propagators, we observe that the Nf = 7 case and the Nf = 2 at T ˜ 2Tc case are similar to each other, while the Nf = 16 case and the Nf = 2 at T = 102 ˜ 105Tc cases are similar to each other. Further, we observe our data are consistent with the picture that the Nf = 7 case and the Nf = 2 at T ˜ 2Tc case are close to the meson unparticle model. On the other hand, the Nf = 16 case and the Nf = 2 at T = 102 ˜ 105Tc cases are close to a free state in the Z(3) twisted vacuum. All results are consistent with naive physical intuition and give clues for long standing issues at high temperatures such as why the free energy at high temperatures does not reach the Stefan-Boltzmann ideal gas limit even at T = 100Tc.

Iwasaki, Y.

308

Transition Planning.  

ERIC Educational Resources Information Center

Four exemplary programs that effectively plan and coordinate transitions between early intervention programs and preschool/elementary programs are described. They include Project BEST (Building Effective School Transitions), Projects STEPS (Sequenced Transition to Education in the Public School), Project TEEM (Transitioning into the Elementary…

Fowler, Susan A.

1988-01-01

309

Probing Conformational Changes of Gramicidin Ion Channels by Single-Molecule Patch-Clamp Fluorescence Microscopy  

PubMed Central

Complex conformational changes influence and regulate the dynamics of ion channels. Such conformational changes are stochastic and often inhomogeneous, which makes it extremely difficult, if not impossible, to characterize them by ensemble-averaged experiments or by single-channel recordings of the electric current that report the open-closed events but do not specifically probe the associated conformational changes. Here, we report our studies on ion channel conformational changes using a new approach, patch-clamp fluorescence microscopy, which simultaneously combines single-molecule fluorescence spectroscopy and single-channel current recordings to probe the open-closed transitions and the conformational dynamics of individual ion channels. We demonstrate patch-clamp fluorescence microscopy by measuring gramicidin ion channel conformational changes in a lipid bilayer formed at a patch-clamp micropipette tip under a buffer solution. By measuring single-pair fluorescence resonance energy transfer and fluorescence self-quenching from dye-labeled gramicidin channels, we observed that the efficiency of single-pair fluorescence resonance energy transfer and self-quenching is widely distributed, which reflects a broad distribution of conformations. Our results strongly suggest a hitherto undetectable correlation between the multiple conformational states of the gramicidin channel and its closed and open states in a lipid bilayer.

Harms, Greg S.; Orr, Galya; Montal, Mauricio; Thrall, Brian D.; Colson, Steve D.; Lu, H. Peter

2003-01-01

310

Conformal compactifications from spinor geometry  

SciTech Connect

Compactified Minkowski spacetime is suggested by conformal covariance of Maxwell equations, while E. Cartan's definition of simple spinors leads to the idea of compactified momentum space. Assuming both diffeomorphic to (S[sub 3] [times] S[sub 1])/Z[sub 2], one may obtain in the conformally flat stereographic projection field theories both infrared and ultraviolet regularized. On the compact manifold themselves instead, Fourier integrals of wave-field oscillations would have to be replaced by Fourier series summed over indices of spherical eigenfunctions: n, l, m, m[prime]. Tentatively identifying those wave structures with spacetime itself (in the frame of Big-Bang) and/or with matter and radiation distribution, some large-scale (hydrogenic) and small-scale (lattice) space structures are conjectured. 14 refs.

Budinich, P. (International Centre for Theoretical Physics, Trieste (Italy))

1993-06-01

311

Conformal FDTD modeling wake fields  

SciTech Connect

Many computer codes have been written to model wake fields. Here we describe the use of the Conformal Finite Difference Time Domain (CFDTD) method to model the wake fields generated by a rigid beam traveling through various accelerating structures. The non- cylindrical symmetry of some of the problems considered here requires the use of a three dimensional code. In traditional FDTD codes, curved surfaces are approximated by rectangular steps. The errors introduced in wake field calculations by such an approximation can be reduced by increasing the mesh size, therefore increasing the cost of computing. Another approach, validated here, deforms Ampere and Faraday contours near a media interface so as to conform to the interface. These improvements of the FDTD method result in better accuracy of the fields at asymptotically no computational cost. This method is also capable of modeling thin wires as found in beam profile monitors, and slots and cracks as found in resistive wall motions. 4 refs., 5 figs.

Jurgens, T.; Harfoush, F.

1991-05-01

312

Cell toxicity and conformational disease.  

PubMed

Numerous disorders, including Alzheimer's, Parkinson's and other late-onset neurodegenerative diseases, arise from the conformationally driven aggregation of individual proteins. Previous focus on just one end-product of such aggregation - extracellular deposits of amyloid - has diverted attention from what is now recognized as being primarily intracellular disease processes. Recent structural findings show how cytotoxicity can result from even minor changes in conformation that do not lead to amyloid formation, as with the accumulation within the endoplasmic reticulum of intact mutant alpha-1-antitrypsin in hepatocytes and of neuroserpin in neurons. Studies in Alzheimer's and other dementias also indicate that the damage occurs at the stage of the initial intermolecular linkages that precede amyloid formation. The challenge now is to determine the detailed mechanisms of this cytotoxicity. PMID:16202603

Carrell, Robin W

2005-11-01

313

New criterion for conformational polymorphism  

SciTech Connect

An analysis of nonvalent interactions in 29 crystal structures of compounds that have the C{sub a}H{sub b}N{sub c}O{sub d} composition (salicylaldoxime, glycine, and 2,4,6,8,10,12-hexaazaisowurzitane) and form polymorphic modifications is performed using molecular Voronoi-Dirichlet polyhedra. It is found that each conformational polymorph is characterized by a unique combination of the types of intramolecular and intermolecular nonvalent interactions. It is shown that a criterion which takes into account the total number of intramolecular nonvalent contacts and their distribution depending on the nature of neighboring atoms and the rank of faces of molecular Voronoi-Dirichlet polyhedra can be used to reveal conformational polymorphs.

Serezhkin, V. N., E-mail: serezhkin@ssu.samara.ru; Serezhkina, L. B. [Samara State University (Russian Federation)

2012-01-15

314

Generative models of conformational dynamics.  

PubMed

Atomistic simulations of the conformational dynamics of proteins can be performed using either Molecular Dynamics or Monte Carlo procedures. The ensembles of three-dimensional structures produced during simulation can be analyzed in a number of ways to elucidate the thermodynamic and kinetic properties of the system. The goal of this chapter is to review both traditional and emerging methods for learning generative models from atomistic simulation data. Here, the term 'generative' refers to a model of the joint probability distribution over the behaviors of the constituent atoms. In the context of molecular modeling, generative models reveal the correlation structure between the atoms, and may be used to predict how the system will respond to structural perturbations. We begin by discussing traditional methods, which produce multivariate Gaussian models. We then discuss GAMELAN (GRAPHICAL MODELS OF ENERGY LANDSCAPES), which produces generative models of complex, non-Gaussian conformational dynamics (e.g., allostery, binding, folding, etc.) from long timescale simulation data. PMID:24446358

Langmead, Christopher James

2014-01-01

315

Conformal invariance from nonconformal gravity  

SciTech Connect

We discuss the conditions under which classically conformally invariant models in four dimensions can arise out of nonconformal (Einstein) gravity. As an 'existence proof' that this is indeed possible we show how to derive N=4 super Yang-Mills theory with any compact gauge group G from nonconformal gauged N=4 supergravity as a special flat space limit. We stress the role that the anticipated UV finiteness of the (so far unknown) underlying theory of quantum gravity would have to play in such a scheme, as well as the fact that the masses of elementary particles would have to arise via quantum gravitational effects which mimic the conformal anomalies of standard (flat space) UV divergent quantum field theory.

Meissner, Krzysztof A. [Institute of Theoretical Physics, Faculty of Physics University of Warsaw, Hoza 69, 00-681 Warsaw (Poland); Nicolai, Hermann [Max-Planck-Institut fuer Gravitationsphysik (Albert-Einstein-Institut), Muehlenberg 1, D-14476 Potsdam (Germany)

2009-10-15

316

Transit Tracks  

NSDL National Science Digital Library

In this space science activity, learners explore transits and the conditions when a transit may be seen. Learners use models to investigate how a planet's size and distance from its star affects the behavior of transits. Learners also use mathematics to interpret graphs of brightness vs. time to deduce information about planet-star systems. This lesson includes educator instructions, photocopy masters for Transit Light Curves, Option Math for Transit Tracks, Keplerâs 3rd Law graphs, cube root tables, an account of Jeremiah Horrocks' 1639 observation of the transit of Venus, and an answer key for the Transit Tracks Light Curves.

Science, Lawrence H.

2008-01-01

317

Detection of negative fullerene conformers  

Microsoft Academic Search

Negative fullerene metastable negative conformers have been detected using electron transfer neutral atom scattering. The anions have been produced through alkali–fullerene collision process, in an energy range well above the ion-pair formation threshold, but still low enough where only the negative parent ion is formed. The interpretation of the parent ion band structure, in time-of-flight spectra, points to the formation

R. F. M. Lobo; B. N. Vicente; F. V. Berardo; I. V. Gouveia; J. H. Ribeiro; P. Pereira

2006-01-01

318

An extension theorem for conformal gauge singularities  

SciTech Connect

We analyze conformal gauge, or isotropic, singularities in cosmological models in general relativity. Using the calculus of tractors, we find conditions in terms of tractor curvature for a local extension of the conformal structure through a cosmological singularity and prove a local extension theorem along a congruence of timelike conformal geodesics.

Luebbe, Christian [Mathematical Institute, Oxford OX1 3LB (United Kingdom); Queen Mary University of London, London E1 4NS (United Kingdom); Tod, Paul [Mathematical Institute, Oxford OX1 3LB (United Kingdom); St. John's College, Oxford OX1 3JP (United Kingdom)

2009-11-15

319

Limit cycles and conformal invariance  

NASA Astrophysics Data System (ADS)

There is a widely held belief that conformal field theories (CFTs) require zero beta functions. Nevertheless, the work of Jack and Osborn implies that the beta functions are not actually the quantites that decide conformality, but until recently no such behavior had been exhibited. Our recent work has led to the discovery of CFTs with nonzero beta functions, more precisely CFTs that live on recurrent trajectories, e.g., limit cycles, of the beta-function vector field. To demonstrate this we study the S function of Jack and Osborn. We use Weyl consistency conditions to show that it vanishes at fixed points and agrees with the generator Q of limit cycles on them. Moreover, we compute S to third order in perturbation theory, and explicitly verify that it agrees with our previous determinations of Q. A byproduct of our analysis is that, in perturbation theory, unitarity and scale invariance imply conformal invariance in four-dimensional quantum field theories. Finally, we study some properties of these new, "cyclic" CFTs, and point out that the a-theorem still governs the asymptotic behavior of renormalization-group flows.

Fortin, Jean-François; Grinstein, Benjamín; Stergiou, Andreas

2013-01-01

320

Phase transitions in M-theory and F-theory  

Microsoft Academic Search

Phase transitions are studied in M-theory and F-theory. In M-theory compactification to five dimensions on a Calabi-Yau, one can find topology-changing transitions similar to those seen in conformal field theory, but the non-geometrical phases known in conformal field theory are absent. At boundaries of moduli space where such phases might have been expected, the moduli space ends, by a conventional

Edward Witten

1996-01-01

321

Conformational Variety of Polyanionic Peptides At Low Salt Concentrations  

NASA Astrophysics Data System (ADS)

Cordially dedicated to Dr. Leslie Orgel on the occasion of his 70th birthday. Sequential oligo- and polypeptides based on glutamic acid and leucine residues have been synthesized. In pure water, they exhibit a random coil conformation. Addition of very small amounts of divalent metallic cations induces the formation of ordered structure in the peptides which remain in solution. Higher salt concentrations precipitate the peptides. Polypeptides with alternating glutamic acid and leucine residues undergo a coil to ?-sheet transition in the presence of Ca^2+, Ba^2+, Mn^2+, Co^2+, Zn^2+ and Hg^2+. Addition of Cu^2+ or Fe^3+ induces the formation of an ?-helix. Solid amorphous CdS generates water soluble ?-sheets, as well. Sequential poly(Leu-Glu-Glu-Leu) adopts an ?-helix in the presence of divalent cations. The sequence-dependent conformational diversity was extended to poly(Asp-Leu) and poly(Leu-Asp-Asp-Leu).

Bertrand, Marylène; Brack, André

1997-12-01

322

Adsorption and Conformation Change of Helical Peptides on Colloidal Silica  

NASA Astrophysics Data System (ADS)

Helical conformations of short peptides in solution are partly stabilized by the pattern of electrostatic charge formed by the amino acid sequence. We have studied the role of electrostatics in the adsorption and helix-coil transition of peptides on oxide surfaces. Adsorption isotherms, along with a combination of spectroscopic techniques, show that this is a reversible equilibrium process. Strong electrostatic forces between ionic side chains and charged surface sites increase the adsorbed amount, and promote a loss of helicity in the adsorbed state qualitatively different from that observed upon thermal or chemical perturbation. The electrical dipole of the peptide, arising from the amino acid side chains, serves to orient the molecules on the surface. Effects of adsorption, orientation, and conformation change on the activity of peptides in model biological reactions, as well as the relevance of this simplified system to protein adsorption, are considered.

Read, Michael; Zhang, Shuguang; Mayes, Anne; Burkett, Sandra

2001-03-01

323

Theoretical Study of Phosphonamidates, Phosphonamides and Sulfonamides as Transition State Isosteres of Hiv Protease  

Microsoft Academic Search

Ab-initio calculations at the RHF\\/6-31+G* level are performed on the N-methyl(methyl) conformers of phosphonamidates, phosphonamides, and sulfonamides. Sulfonamides and phosphonamidates are found to have very similar conformers and energies as potential transition state isosteres. Local minima in both are separated by a 2.0 kcal\\/mol barrier. The anti conformation and molecular dipole moments of phosphonamides play a role in the transition

Elisheva Goldstein; M. McAllister; J. Radkiewicz; K. N. Houk

1996-01-01

324

Myosin and tropomyosin stabilize the conformation of formin-nucleated actin filaments.  

PubMed

The conformational elasticity of the actin cytoskeleton is essential for its versatile biological functions. Increasing evidence supports that the interplay between the structural and functional properties of actin filaments is finely regulated by actin-binding proteins; however, the underlying mechanisms and biological consequences are not completely understood. Previous studies showed that the binding of formins to the barbed end induces conformational transitions in actin filaments by making them more flexible through long range allosteric interactions. These conformational changes are accompanied by altered functional properties of the filaments. To get insight into the conformational regulation of formin-nucleated actin structures, in the present work we investigated in detail how binding partners of formin-generated actin structures, myosin and tropomyosin, affect the conformation of the formin-nucleated actin filaments using fluorescence spectroscopic approaches. Time-dependent fluorescence anisotropy and temperature-dependent Förster-type resonance energy transfer measurements revealed that heavy meromyosin, similarly to tropomyosin, restores the formin-induced effects and stabilizes the conformation of actin filaments. The stabilizing effect of heavy meromyosin is cooperative. The kinetic analysis revealed that despite the qualitatively similar effects of heavy meromyosin and tropomyosin on the conformational dynamics of actin filaments the mechanisms of the conformational transition are different for the two proteins. Heavy meromyosin stabilizes the formin-nucleated actin filaments in an apparently single step reaction upon binding, whereas the stabilization by tropomyosin occurs after complex formation. These observations support the idea that actin-binding proteins are key elements of the molecular mechanisms that regulate the conformational and functional diversity of actin filaments in living cells. PMID:22753415

Ujfalusi, Zoltán; Kovács, Mihály; Nagy, Nikolett T; Barkó, Szilvia; Hild, Gábor; Lukács, András; Nyitrai, Miklós; Bugyi, Beáta

2012-09-14

325

Solvent-dependent cation exchange in metal-organic frameworks.  

PubMed

We investigated which factors govern the critical steps of cation exchange in metal-organic frameworks by studying the effect of various solvents on the insertion of Ni(2+) into MOF-5 and Co(2+) into MFU-4l. After plotting the extent of cation insertion versus different solvent parameters, trends emerge that offer insight into the exchange processes for both systems. This approach establishes a method for understanding critical aspects of cation exchange in different MOFs and other materials. PMID:24782420

Brozek, Carl K; Bellarosa, Luca; Soejima, Tomohiro; Clark, Talia V; López, Núria; Dinc?, Mircea

2014-06-01

326

Synthesis and conformation of fluorinated ?-peptidic compounds.  

PubMed

Experimental and theoretical data indicate that, for ?-fluoroamides, the F-C-C(O)-N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C-F and C-N(CO) bonds in N-?-fluoroethylamides. This study details the synthesis of a series of fluorinated ?-peptides (1-8) designed to use these stereoelectronic effects to control the conformation of ?-peptide bonds. X-ray crystal structures of these compounds revealed the expected conformations: with fluorine ? to a nitrogen adopting a gauche conformation, and fluorine ? to a C=O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a ?-peptide bond, with the possibility of directing the secondary structures of ?-peptides. PMID:22517667

Peddie, Victoria; Butcher, Raymond J; Robinson, Ward T; Wilce, Matthew C J; Traore, Daouda A K; Abell, Andrew D

2012-05-21

327

Conformation and intramolecular relaxation dynamics of semiflexible randomly hyperbranched polymers  

NASA Astrophysics Data System (ADS)

The conformational and dynamic properties of semiflexible randomly hyperbranched polymers are investigated in dilute solutions within the framework of optimized Rouse-Zimm formalism. Semiflexibility is incorporated by restricting the directions and orientations of the respective bond vectors, while hydrodynamic interactions are modeled through the preaveraged Oseen tensor. The effect of semiflexibility is typically reflected in the intermediate frequency regime of the viscoelastic relaxation moduli where the bond orientation angle restores the characteristic power-law scaling in fractal structures, as in randomly hyperbranched polymers. Despite the absence of this power-law scaling regime in flexible randomly hyperbranched polymers and in earlier models of semiflexible randomly branched polymers due to weak disorder [C. von Ferber and A. Blumen, J. Chem. Phys. 116, 8616 (2002)], this power-law behavior may be reinstated by explicitly modeling hyperbranched polymers as a Vicsek fractals. The length of this power-law zone in the intermediate frequency region is a combined function of the number of monomers and the degree of semiflexibility. A clear conformational transition from compact to open structures is facilitated by changing the bond orientation angle, where the compressed conformations are compact, while the expanded ones are relatively non-compact. The extent of compactness in the compressed conformations are much less compared to the semiflexible dendrimers, which resemble hard spheres. The fractal dimensions of the compressed and expanded conformations calculated from the Porod's scaling law vary as a function of the bond orientation angle, spanning the entire range of three distinct scaling regimes of linear polymers in three-dimensions. The results confirm that semiflexibility exactly accounts for the excluded volume interactions which are expected to be significant for such polymers with complex topologies.

Kumar, Amit; Rai, Gobind Ji; Biswas, Parbati

2013-03-01

328

Logarithmic conformal field theory: a lattice approach  

NASA Astrophysics Data System (ADS)

Logarithmic conformal field theories (LCFT) play a key role, for instance, in the description of critical geometrical problems (percolation, self-avoiding walks, etc), or of critical points in several classes of disordered systems (transition between plateaux in the integer and spin quantum Hall effects). Much progress in their understanding has been obtained by studying algebraic features of their lattice regularizations. For reasons which are not entirely understood, the non-semi-simple associative algebras underlying these lattice models—such as the Temperley-Lieb algebra or the blob algebra—indeed exhibit, in finite size, properties that are in full correspondence with those of their continuum limits. This applies not only to the structure of indecomposable modules, but also to fusion rules, and provides an ‘experimental’ way of measuring couplings, such as the ‘number b’ quantifying the logarithmic coupling of the stress-energy tensor with its partner. Most results obtained so far have concerned boundary LCFTs and the associated indecomposability in the chiral sector. While the bulk case is considerably more involved (mixing in general left and right moving sectors), progress has also recently been made in this direction, uncovering fascinating structures. This study provides a short general review of our work in this area.

Gainutdinov, A. M.; Jacobsen, J. L.; Read, N.; Saleur, H.; Vasseur, R.

2013-12-01

329

Conformation and aggregation of melittin: dependence on pH and concentration.  

PubMed

Melittin, a 26-residue peptide from bee venom, is transformed from a largely random to a largely alpha-helical conformation at elevated pH. At 3 x 10(-5) M melittin, circular dichroism spectra show a transition with a pK near 9.6. At 8 x 10(-5) M, two approximately equal transitions occur with pKs at 7.2 and 9.6. At 6 x 10(-4) M, a single transition is seen with a pK of 6.8, followed by a more gradual increase to at least pH 11. The transitions near pH 7 presumably arise from deprotonation of the alpha-amino group. When the amino groups are acetylated or succinylated, a 60% alpha-helical conformation is adopted at neutral or low pH. The acylated melittins form more stable oligomers than does native melittin. PMID:7066299

Bello, J; Bello, H R; Granados, E

1982-02-01

330

Conformational mobility of small molecules in glass-forming solutions studied by FTIR spectroscopy  

NASA Astrophysics Data System (ADS)

Small molecules with two or more stable conformations when embedded in a glass-forming liquid (matrix) serve the role of "conformational probes", i.e., their conformational transitions are used to follow local mobility in the matrix. In the present study, conformational probes were embedded in low-molecular-weight glass-forming liquids, and the molecular mobility was studied in a broad temperature range including the glass transition temperature (Tg). Paraffin oil, dibutylphthalate, bis(2-ethylhexyl)phthalate and isopropylbenzene were used as glass-forming liquids while 1,2-dichloroethane, 1,2-diphenylethane, chlorocyclohexane and bromocyclohexane were used as conformational probes. For some of the matrix/probe systems, the conformational mobility was found to freeze-in at Tg, while for the others it froze-in at certain temperatures Tf < Tg. In the latter case, it was possible to evaluate the activation energies related to mobility of free volume entities in the glassy matrices. In addition, it was possible to estimate the volumes of sub-molecular groups of the matrix that freeze-in at Tf.

Fishman, A. I.; Noskov, A. I.; Stolov, A. A.

2012-06-01

331

The Biological Bases of Conformity  

PubMed Central

Humans are characterized by an extreme dependence on culturally transmitted information and recent formal theory predicts that natural selection should favor adaptive learning strategies that facilitate effective copying and decision making. One strategy that has attracted particular attention is conformist transmission, defined as the disproportionately likely adoption of the most common variant. Conformity has historically been emphasized as significant in the social psychology literature, and recently there have also been reports of conformist behavior in non-human animals. However, mathematical analyses differ in how important and widespread they expect conformity to be, and relevant experimental work is scarce, and generates findings that are both mutually contradictory and inconsistent with the predictions of the models. We review the relevant literature considering the causation, function, history, and ontogeny of conformity, and describe a computer-based experiment on human subjects that we carried out in order to resolve ambiguities. We found that only when many demonstrators were available and subjects were uncertain was subject behavior conformist. A further analysis found that the underlying response to social information alone was generally conformist. Thus, our data are consistent with a conformist use of social information, but as subjects’ behavior is the result of both social and asocial influences, the resultant behavior may not be conformist. We end by relating these findings to an embryonic cognitive neuroscience literature that has recently begun to explore the neural bases of social learning. Here conformist transmission may be a particularly useful case study, not only because there are well-defined and tractable opportunities to characterize the biological underpinnings of this form of social learning, but also because early findings imply that humans may possess specific cognitive adaptations for effective social learning.

Morgan, T. J. H.; Laland, K. N.

2012-01-01

332

Conformance Testing: Measurement Decision Rules  

NASA Technical Reports Server (NTRS)

The goal of a Quality Management System (QMS) as specified in ISO 9001 and AS9100 is to provide assurance to the customer that end products meet specifications. Measuring devices, often called measuring and test equipment (MTE), are used to provide the evidence of product conformity to specified requirements. Unfortunately, processes that employ MTE can become a weak link to the overall QMS if proper attention is not given to the measurement process design, capability, and implementation. Documented "decision rules" establish the requirements to ensure measurement processes provide the measurement data that supports the needs of the QMS. Measurement data are used to make the decisions that impact all areas of technology. Whether measurements support research, design, production, or maintenance, ensuring the data supports the decision is crucial. Measurement data quality can be critical to the resulting consequences of measurement-based decisions. Historically, most industries required simplistic, one-size-fits-all decision rules for measurements. One-size-fits-all rules in some cases are not rigorous enough to provide adequate measurement results, while in other cases are overly conservative and too costly to implement. Ideally, decision rules should be rigorous enough to match the criticality of the parameter being measured, while being flexible enough to be cost effective. The goal of a decision rule is to ensure that measurement processes provide data with a sufficient level of quality to support the decisions being made - no more, no less. This paper discusses the basic concepts of providing measurement-based evidence that end products meet specifications. Although relevant to all measurement-based conformance tests, the target audience is the MTE end-user, which is anyone using MTE other than calibration service providers. Topics include measurement fundamentals, the associated decision risks, verifying conformance to specifications, and basic measurement decisions rules.

Mimbs, Scott M.

2010-01-01

333

Phase transition in the Sznajd model with independence  

NASA Astrophysics Data System (ADS)

We propose a model of opinion dynamics which describes two major types of social influence —conformity and independence. Conformity in our model is described by the so-called outflow dynamics (known as Sznajd model). According to sociologists' suggestions, we introduce also a second type of social influence, known in social psychology as independence. Various social experiments have shown that the level of conformity depends on the society. We introduce this level as a parameter of the model and show that there is a continuous phase transition between conformity and independence.

Sznajd-Weron, K.; Tabiszewski, M.; Timpanaro, A. M.

2011-11-01

334

Conformance Verification of Privacy Policies  

NASA Astrophysics Data System (ADS)

Web applications are both the consumers and providers of information. To increase customer confidence, many websites choose to publish their privacy protection policies. However, policy conformance is often neglected. We propose a logic based framework for formally specifying and reasoning about the implementation of privacy protection by a web application. A first order extension of computation tree logic is used to specify a policy. A verification paradigm, built upon a static control/data flow analysis, is presented to verify if a policy is satisfied.

Fu, Xiang

335

Mg(2+)-induced conformational changes in the btuB riboswitch from E. coli.  

PubMed

Mg(2+) has been shown to modulate the function of riboswitches by facilitating the ligand-riboswitch interactions. The btuB riboswitch from Escherichia coli undergoes a conformational change upon binding to its ligand, coenzyme B12 (adenosyl-cobalamine, AdoCbl), and down-regulates the expression of the B12 transporter protein BtuB in order to control the cellular levels of AdoCbl. Here, we discuss the structural folding attained by the btuB riboswitch from E. coli in response to Mg(2+) and how it affects the ligand binding competent conformation of the RNA. The btuB riboswitch notably adopts different conformational states depending upon the concentration of Mg(2+). With the help of in-line probing, we show the existence of at least two specific conformations, one being achieved in the complete absence of Mg(2+) (or low Mg(2+) concentration) and the other appearing above ?0.5 mM Mg(2+). Distinct regions of the riboswitch exhibit different dissociation constants toward Mg(2+), indicating a stepwise folding of the btuB RNA. Increasing the Mg(2+) concentration drives the transition from one conformation toward the other. The conformational state existing above 0.5 mM Mg(2+) defines the binding competent conformation of the btuB riboswitch which can productively interact with the ligand, coenzyme B12, and switch the RNA conformation. Moreover, raising the Mg(2+) concentration enhances the ratio of switched RNA in the presence of AdoCbl. The lack of a AdoCbl-induced conformational switch experienced by the btuB riboswitch in the absence of Mg(2+) indicates a crucial role played by Mg(2+) for defining an active conformation of the riboswitch. PMID:24243114

Choudhary, Pallavi K; Sigel, Roland K O

2014-01-01

336

Conformational behavior of pheromones and analogues Part I. 3-methyl-2-buten-1-ol, 3,3,6-trimethyl-1, 5- heptadien-4-ol and 2-methyl-6-methylene-2,7-octadien-4- on  

NASA Astrophysics Data System (ADS)

Conformational potential energy hypersurface paths of three molecules, 3-methyl-2-buten-1-ol, 3,3,6-trimethyl-1,5-heptadien-4-ol and 2-methyl-6-methylene-2,7-octadien-4-on, and conformational softness have been computed using the program system DAISY. The molecular mechanics method has been used for energy calculations in conjunction with DAISY. Low energy conformations as well as an approximation of "transition states" for conformational changes are presented.

Ko?a, Jaroslav; Carlsen, Per H. J.

1991-06-01

337

Equilibrium and shear-induced conformations of a side-chain liquid crystal polymer  

Microsoft Academic Search

These studies delineate the conformations adopted by a side-chain liquid-crystalline polymer subjected to a steady-state shear flow as well as the corresponding me so pha se director orientations. Two distinct director orientations are identified in the nematic phase, giving evidence of a shear-induced transition from a flow-aligning to a non flow-aligning behavior. This transition coincides, at rest, with a subtle

V. Castelletto; L. Noirez; P. Vigoureux

2000-01-01

338

China's urban transition.  

PubMed

This article describes recent changes in urban patterns in Shanghai-Nanjing, Beijing-Tianjin-Tangshan, Canton-Hong Kong, and Dalian-Shenyang. The urban patterns in these metropolitan areas are viewed as part of an urban transition that is responding to population growth, a structural shift in employment, relaxed rules on migration and household registration, and foreign investment and trade. It is argued that these metropolitan coastal areas will form the key growth centers and will lead China's economic development. Urban transition is defined as the shift from rural to urban and from agricultural employment to industrial, commercial, or service employment. China's large cities always dominated as important centers of politics and trade. The recent shift is from interior to coastal cities due to a new world view and a movement away from the isolationism of prior centuries. It is assumed that cities are formed to take advantage of economies of scale in production, consumption, and distribution and to conform to regional specialization. Governments can intervene in growth processes. China's development of cities reflects state controls and market forces. The size and scale of China's population influenced the development process, which resulted in differences in the shape and process of the urban transition. It was under Chinese communism that cities became more than a set of discrete regional urban systems. Reference is made to Oshima's model of change that is specific to monsoon countries. Oshima argues that monsoon agricultural conditions require a distinct strategy based on full employment in order to achieve industrial transition. Rice cultivation requires a large and disciplined labor force. The discussion focuses on other models as well, such as the McGee's model of the extended metropolis and its extension by Zhou Yixing to China. China's changes may not follow Skeldon's models of urbanization in developing countries, because of state control of migration. However, the longer migrants remain in cities the more likely Skeldon's models of early European transitions apply to China's urban transition. PMID:12178548

Pannell, C

1995-01-01

339

Coexisting stable conformations of gaseous protein ions.  

PubMed Central

For further insight into the role of solvent in protein conformer stabilization, the structural and dynamic properties of protein ions in vacuo have been probed by hydrogen-deuterium exchange in a Fourier-transform mass spectrometer. Multiply charged ions generated by electrospray ionization of five proteins show exchange reactions with 2H2O at 10(-7) torr (1 torr = 133.3 Pa) exhibiting pseudo-first-order kinetics. Gas-phase compactness of the S-S cross-linked RNase A relative to denatured S-derivatized RNase A is indicated by exchange of 35 and 135 hydrogen atoms, respectively. For pure cytochrome c ions, the existence of at least three distinct gaseous conformers is indicated by the substantially different values--52, 113, and 74--of reactive H atoms; the observation of these same values for ions of a number--2, 7, and 5, respectively--of different charge states indicates conformational insensitivity to coulombic forces. For each of these conformers, the compactness in vacuo indicated by these values corresponds directly to that of a known conformer structure in the solution from which the conformer ions are produced by electrospray. S-derivatized RNase A ions also exist as at least two gaseous conformers exchanging 50-140 H atoms. Gaseous conformer ions are isometrically stable for hours; removal of solvent greatly increases conformational rigidity. More specific ion-molecule reactions could provide further details of conformer structures. Images

Suckau, D; Shi, Y; Beu, S C; Senko, M W; Quinn, J P; Wampler, F M; McLafferty, F W

1993-01-01

340

?-Helical to ?-Helical Conformation Change in the C-Terminal of the Mammalian Prion Protein  

NASA Astrophysics Data System (ADS)

We employ all-atom structure-based models with mixed basis contact maps to explore whether there are any significant geometric or energetic constraints limiting conjectured conformational transitions between the alpha-helical (?H) and the left handed beta helical (LHBH) conformations for the C-terminal (residues 166-226) of the mammalian prion protein. The LHBH structure has been proposed to describe infectious oligomers and one class of in vitro grown fibrils, as well as possibly self- templating the conversion of normal cellular prion protein to the infectious form. Our results confirm that the kinetics of the conformation change are not strongely limited by large scale geometry modification and there exists an overall preference for the LHBH conformation.

Singh, Jesse; Whitford, Paul; Hayre, Natha; Cox, Daniel; Onuchic, José.

2011-03-01

341

Manipulating and probing enzymatic conformational fluctuations and enzyme-substrate interactions by single-molecule FRET-magnetic tweezers microscopy.  

PubMed

Enzyme-substrate interaction plays a critical role in enzymatic reactions, forming the active enzyme-substrate complex, the transition state ready to react. Studying the enzyme-substrate interaction will help in the ultimate molecular-level characterization of the enzymatic transition state that defines the reaction pathway, energetics, and the dynamics. In our initial effort to experimentally investigate the enzyme-substrate interactions and the related conformational fluctuations, we have developed a new approach to manipulate the enzymatic conformation and enzyme-substrate interaction at a single-molecule level by using a combined magnetic tweezers and simultaneous fluorescence resonance energy transfer (FRET) spectroscopic microscopy. By a repetitive pulling-releasing manipulation of a Cy3-Cy5 dye labeled 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) molecule under the conditions with and without enzymatic substrates, we have probed and analyzed the enzymatic conformational dynamics. Our results indicate that the enzyme conformational flexibility can be regulated by enzyme-substrate interactions: (1) enzyme at its conformation-perturbed state has less flexibility when binding substrates, and (2) substrate binding to enzyme significantly changes the enzyme conformational flexibility, an experimental evidence of so called entropy trapping in the enzyme-substrate reactive transition state. Furthermore, our results provide a significant experimental analysis of the folding-binding enzyme-substrate interactions, a dynamic nature of the enzymatic active transition state formation process. PMID:24853252

Guo, Qing; He, Yufan; Lu, H Peter

2014-06-11

342

Charged gravastars admitting conformal motion  

NASA Astrophysics Data System (ADS)

We propose a new model of a gravastar admitting conformal motion. While retaining the framework of the Mazur-Mottola model, the gravastar is assumed to be internally charged, with an exterior defined by a Reissner-Nordström instead of a Schwarzschild line element. The solutions, obtained by exploiting an assumed conformal Killing vector, involve (i) the interior region, (ii) the shell, and (iii) the exterior region of the sphere. Of these three cases the first one is of primary interest since the total gravitational mass here turns out to be an electromagnetic mass under some specific conditions. This suggests that the interior de Sitter vacuum of a charged gravastar is essentially an electromagnetic mass model that must generate gravitational mass which provides a stable configuration by balancing the repulsive pressure arising from charge with its attractive gravity to avert a singularity. Therefore the present model, like the Mazur-Mottola model, results in the construction of a compact astrophysical object, as an alternative to a black hole. We have also analyzed various other aspects such as the stress energy tensor in the thin shell and the entropy of the system.

Usmani, A. A.; Rahaman, F.; Ray, Saibal; Nandi, K. K.; Kuhfittig, Peter K. F.; Rakib, Sk. A.; Hasan, Z.

2011-07-01

343

Conformal Lifshitz gravity from holography  

NASA Astrophysics Data System (ADS)

We show that holographic renormalization of relativistic gravity in asymptotically Lifshitz spacetimes naturally reproduces the structure of gravity with anisotropic scaling: the holographic counterterms induced near anisotropic infinity take the form of the action for gravity at a Lifshitz point, with the appropriate value of the dynamical critical exponent z. In the particular case of 3 + 1 bulk dimensions and z = 2 asymptotic scaling near infinity, we find a logarithmic counterterm, related to anisotropic Weyl anomaly of the dual CFT, and show that this counterterm reproduces precisely the action of conformal gravity at a z = 2 Lifshitz point in 2 + 1 dimensions, which enjoys anisotropic local Weyl invariance and satisfies the detailed balance condition. We explain how the detailed balance is a consequence of relations among holographic counterterms, and point out that a similar relation holds in the relativistic case of holography in AdS 5. Upon analytic continuation, analogous to the relativistic case studied recently by Maldacena, the action of conformal gravity at the z = 2 Lifshitz point features in the ground-state wavefunction of a gravitational system with an interesting type of spatial anisotropy.

Griffin, Tom; Ho?ava, Petr; Melby-Thompson, Charles M.

2012-05-01

344

Conformal inflation coupled to matter  

NASA Astrophysics Data System (ADS)

We formulate new conformal models of inflation and dark energy which generalise the Higgs-Dilaton scenario. We embed these models in unimodular gravity whose effect is to break scale invariance in the late time Universe. In the early Universe, inflation occurs close to a maximum of both the scalar potential and the scalar coupling to the Ricci scalar in the Jordan frame. At late times, the dilaton, which decouples from the dynamics during inflation, receives a potential term from unimodular gravity and leads to the acceleration of the Universe. We address two central issues in this scenario. First we show that the Damour-Polyalov mechanism, when non-relativistic matter is present prior to the start of inflation, sets the initial conditions for inflation at the maximum of the scalar potential. We then show that conformal invariance implies that matter particles are not coupled to the dilaton in the late Universe at the classical level. When fermions acquire masses at low energy, scale invariance is broken and quantum corrections induce a coupling between the dilaton and matter which is still small enough to evade the gravitational constraints in the solar system.

Brax, Philippe; Davis, Anne-Christine

2014-05-01

345

Metrics with Galilean conformal isometry  

SciTech Connect

The Galilean conformal algebra (GCA) arises in taking the nonrelativistic limit of the symmetries of a relativistic conformal field theory in any dimensions. It is known to be infinite dimensional in all spacetime dimensions. In particular, the 2d GCA emerges out of a scaling limit of linear combinations of two copies of the Virasoro algebra. In this paper, we find metrics in dimensions greater than 2 which realize the finite 2d GCA (the global part of the infinite algebra) as their isometry by systematically looking at a construction in terms of cosets of this finite algebra. We list all possible subalgebras consistent with some physical considerations motivated by earlier work in this direction and construct all possible higher-dimensional nondegenerate metrics. We briefly study the properties of the metrics obtained. In the standard one higher-dimensional ''holographic'' setting, we find that the only nondegenerate metric is Minkowskian. In four and five dimensions, we find families of nontrivial metrics with a rather exotic signature. A curious feature of these metrics is that all but one of them are Ricci-scalar flat.

Bagchi, Arjun [School of Mathematics, University of Edinburgh, Edinburgh, EH9 3JZ (United Kingdom); Kundu, Arnab [Theory Group, Department of Physics, University of Texas at Austin, Austin, Texas 78712 (United States)

2011-03-15

346

Conformational Substates of Myoglobin Intermediate Resolved by Picosecond X-ray Solution Scattering  

PubMed Central

Conformational substates of proteins are generally considered to play important roles in regulating protein functions, but an understanding of how they influence the structural dynamics and functions of the proteins has been elusive. Here, we investigate the structural dynamics of sperm whale myoglobin associated with the conformational substates using picosecond X-ray solution scattering. By applying kinetic analysis considering all of the plausible candidate models, we establish a kinetic model for the entire cycle of the protein transition in a wide time range from 100 ps to 10 ms. Four structurally distinct intermediates are formed during the cycle, and most importantly, the transition from the first intermediate to the second one (B ? C) occurs biphasically. We attribute the biphasic kinetics to the involvement of two conformational substates of the first intermediate, which are generated by the interplay between the distal histidine and the photodissociated CO. SECTION Biophysical Chemistry and Biomolecules

Yang, Cheolhee; Kim, Tae Wu; Kim, Youngmin; Kim, Kyung Hwan; Kim, Jeongho; Ihee, Hyotcherl

2014-01-01

347

Straight and Curved Conformations of FtsZ Are Regulated by GTP Hydrolysis  

PubMed Central

FtsZ assembles in vitro into protofilaments that can adopt two conformations—the straight conformation, which can assemble further into two-dimensional protofilament sheets, and the curved conformation, which forms minirings about 23 nm in diameter. Here, we describe the structure of FtsZ tubes, which are a variation of the curved conformation. In the tube the curved protofilament forms a shallow helix with a diameter of 23 nm and a pitch of 18 or 24°. We suggest that this shallow helix is the relaxed structure of the curved protofilament in solution. We provide evidence that GTP favors the straight conformation while GDP favors the curved conformation. In particular, exclusively straight protofilaments and protofilament sheets are assembled in GMPCPP, a nonhydrolyzable GTP analog, or in GTP following chelation of Mg, which blocks GTP hydrolysis. Assembly in GDP produces exclusively tubes. The transition from straight protofilaments to the curved conformation may provide a mechanism whereby the energy of GTP hydrolysis is used to generate force for the constriction of the FtsZ ring in cell division.

Lu, Chunlin; Reedy, Mary; Erickson, Harold P.

2000-01-01

348

Conformational stability of Met20 loop of DHFR: A molecular dynamics study  

NASA Astrophysics Data System (ADS)

In the catalytic cycle of dihydrofolate reductase (DHFR), the conformational change of the Met20 loop plays an important role. There are known to be two stable conformations (closed and open states) in the conformational change of the Met20 loop before binding the substrate. However, the conformational stability of these states is still not clear. In this study, we carried out two molecular dynamics simulations corresponding to the closed and open states of DHFR and estimated the free energy of each state of DHFR by using the molecular mechanics-Poisson Bolzmann surface area (MM-PBSA) method. Although the free energy calculations showed the closed state of DHFR was more stable in the solution condition, the difference of free energies between the closed and open state showed the large deviation. This finding shows that the conformational transition between the closed and open state of the Met20 loop could occur frequently under the solution condition. The frequency distributions along the reaction coordinate was calculated to find the possible metastable conformations, indicating that six metastable conformations exist between the closed and open states.

Nishimura, Megumi; Saito, Hiroaki; Kawaguchi, Kazutomo; Nagao, Hidemi

2013-02-01

349

STUDY OF LIQUID CRYSTAL CONFORMATION BY MULTIPLE QUANTUM NMR: n-PENTYL CYANOBIPHENYL  

SciTech Connect

The multiple quantum NMR spectrum of 4-cyano-4'-n-pentyl-d{sub 11}-biphenyl in the nematic phase is presented. The sub-spectra of the higher quantum transitions are easier to interpret than the single quantum spectrum. A preliminary analysis of the biphenyl conformation indicates that the dihedral angle is 32° ± 1°.

Sinton, S.; Pines, A.

1980-09-01

350

TRAVEL DEMAND MODELING AND CONFORMITY DETERMINATION: ATLANTA REGIONAL COMMISSION CASE STUDY  

Microsoft Academic Search

The Atlanta Regional Commission (ARC) regional travel demand model is described as it relates to its link-based emissions postprocessor. In addition to conformity determination, an overview of other elements is given. The transit networks include the walk and highway access links. Trip generation addresses trip production, trip attraction, reconciliation of productions and attractions, and special adjustments made for Hartsfield Atlanta

Guy Rousseau; Tracy Clymer

2002-01-01

351

Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer  

Microsoft Academic Search

Purpose: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment

Vijay K. Sangar; Catherine A. McBain; Jeanette Lyons; Vijay A. C. Ramani; John P. Logue; James P. Wylie; Noel W. Clarke; Richard A.. Cowan

2005-01-01

352

Conformational analysis of a model synthetic prodiginine.  

PubMed

A conformational analysis of a synthetic model prodiginine was carried out. In solution this compound showed a strong preference for the ? conformation, in which all the heterocycles are mutually cis. This conformation provided an ideal alignment of the three N-H groups for interacting with anions when the molecule is protonated. A different conformation was also detected in d(6)-DMSO for the mesylate salt, assigned to the ? conformation, in which the C ring is engaged in an intramolecular hydrogen bond with the OMe group. The formation of a homodimer was observed in concentrated CDCl(3) solutions of the neutral free base form of this prodiginine derivative. DFT calculations and the solid state structures of the hydrochloric and methanesulfonic acid salts were in good agreement with the results observed in solution. A complete study of the relative energies of different tautomers, isomers, and supramolecular complexes supported the preference for the ? conformation both in water and in the gas phase. PMID:22812509

García-Valverde, María; Alfonso, Ignacio; Quiñonero, David; Quesada, Roberto

2012-08-01

353

Conformal symmetries of FRW accelerating cosmologies  

NASA Astrophysics Data System (ADS)

We show that any accelerating Friedmann-Robertson-Walker (FRW) cosmology with equation of state w<-1/3 (and therefore not only a de Sitter stage with w=-1) exhibits three-dimensional conformal symmetry on future constant-time hypersurfaces if the bulk theory is invariant under bulk conformal Killing vectors. We also offer an alternative derivation of this result in terms of conformal Killing vectors and show that long wavelength comoving curvature perturbations of the perturbed FRW metric are just conformal Killing motions of the FRW background. We then extend the boundary conformal symmetry to the bulk for accelerating cosmologies. Our findings indicate that one can easily generate perturbations of scalar fields which are not only scale invariant, but also fully conformally invariant on super-Hubble scales. Measuring a scale-invariant power spectrum for the cosmological perturbation does not automatically imply that the universe went through a de Sitter stage.

Kehagias, A.; Riotto, A.

2014-07-01

354

Collagen I matrix contributes to determination of adult human stem cell lineage via differential, structural conformation-specific elicitation of cellular stress response  

Microsoft Academic Search

Previously, we reported that the conformational transition of collagen I matrix plays, along with differentiation stimuli, a regulatory role in determination of differentiation lineage of bone marrow stromal sells via distinct signaling pathways specific for the structural state of the matrix. The present study addresses mechanisms underlying differential structural conformation-specific effects of collagen matrices on differentiation into diverse lineages. The

Josh Mauney; Vladimir Volloch

2009-01-01

355

Biharmonic maps and morphisms from conformal mappings  

Microsoft Academic Search

Inspired by the all-important conformal invariance of harmonic maps on\\u000atwo-dimensional domains, this article studies the relationship between biharmonicity\\u000aand conformality. We first give a characterization of biharmonic morphisms,\\u000aanalogues of harmonic morphisms investigated by Fuglede and Ishihara, which, in\\u000aparticular, explicits the conditions required for a conformal map in dimension four\\u000ato preserve biharmonicity and helps producing the first

Eric Loubeau; Ye-Lin Ou

2010-01-01

356

Conformational analysis of 1-acetyl-2-methylhydrazine  

Microsoft Academic Search

The conformational analysis of 1-acetyl-2-methylhydrazine was performed using DNMR spectroscopy and quantum chemical calculations (B3LYP\\/6-31+G*, AM1 and PM3). Activation barrier for interconversion of Z and E conformers was measured to be 16.1kcal\\/mol by DNMR. DFT calculations indicate that there are four minima on the 1-acetyl-2-methylhydrazine potential energy surface and the most stabile is Z conformer with the hydrogen bond between

O Tšubrik; P Burk; T Pehk; U Mäeorg

2001-01-01

357

Terbium luminescence-lifetime heterogeneity and protein equilibrium conformational dynamics.  

PubMed Central

The fluorescence decay of the rare earth terbium when bound to the protein calmodulin changes from a simple exponential decay to a complex nonexponential decay as the temperature is lowered below 200 K. We have fit the observed decay curves by assuming that the terbium emission is a forced electric dipole transition and proteins have a distribution of continuous conformational states. Quantitative fits to the data indicate that the root-mean-square configurational deviation of the atoms surrounding the terbium ion is 0.2 A, in good agreement with other measurements. We further point out that because the protein seems to undergo a glass transition yet retains configurational order at room temperature, the proper name for the physical state of a protein at room temperature is the rubber-like state.

Austin, R H; Stein, D L; Wang, J

1987-01-01

358

Conformational stability and vibrations of aminopropylsilanol molecule.  

PubMed

Density functional theory (DFT), using the B3-LYP/6-31G(d,p) method have been used to investigate the conformation and vibrational spectra of aminopropylsilanetriol (APST) NH2CH2CH2CH2Si(OH)3. The potential function for CCCSi torsion gives rise to two distinct conformers trans and gauche. The predicted energy of the more stable trans conformer is 337 cm-1 less than the energy of gauche conformer. The calculated barriers to the conformation interchange are: 1095, 2845 and 438 cm-1 for the trans to gauche, gauche to gauche and gauche to trans conformers, respectively. For the trans conformer the potential energy curve for the Si(OH)3 groups torsion in APST has been calculated changing the HOSiC dihedral angle. The barrier for the internal rotation of 3065 cm-1 has been obtained. The optimized molecular structure of APST dimer calculated for trans conformer has a SiOSi angle of 143.2 degrees, and a SiOSi bond length of 0.164 nm. A complete vibrational assignment for both conformers as well as for trans-dimer is supported by the normal coordinate analysis, calculated IR intensities as well as Raman activities. On the basis of the results, the vibrational spectra of APST aqueous solution and APST polymer have been analyzed. The average error between the observed and calculated frequencies is 14 cm-1. PMID:16386453

Bistrici?, Lahorija; Volovsek, Vesna; Danani?, Vladimir; Sapi?, Iva Movre

2006-05-15

359

Conformational dynamics in nitrogen-fused azabicycles.  

PubMed

Using molecular mechanics (MM3 force field)-based methodology, conformational dynamics have been studied for 1-azabicyclo[2.2.0]hexane, 1-azabicylo[3.3.0]octane, and 1-azabicylo[4.4.0]decane. Obtained conformational schemes describe the flexibity of these parent azabicyles as well as permit us to estimate conformational mobility in related N-fused systems. Quantum mechanics ab initio calculations have been used in order to check the reliability of molecular mechanics-provided estimates of relative energy of conformers. The previous dynamic NMR (DNMR) data have been reinterpreted for some polycyclic alkaloids. PMID:12688772

Belostotskii, Anatoly M; Markevich, Elena

2003-04-18

360

Noncommutative geometry and twisted conformal symmetry  

SciTech Connect

The twist-deformed conformal algebra is constructed as a Hopf algebra with twisted coproduct. This allows for the definition of conformal symmetry in a noncommutative background geometry. The twisted coproduct is reviewed for the Poincare algebra and the construction is then extended to the full conformal algebra. The case of Moyal-type noncommutativity of the coordinates is considered. It is demonstrated that conformal invariance need not be viewed as incompatible with noncommutative geometry; the noncommutativity of the coordinates appears as a consequence of the twisting, as has been shown in the literature in the case of the twisted Poincare algebra.

Matlock, Peter [Institute of Mathematical Sciences, Chennai (India)

2005-06-15

361

Conformation of liquid N-alkanes.  

PubMed Central

The conformations of liquid n-alkanes have been studied using neutron scattering techniques to better understand the conformational forces present in membrane lipid interiors. We have studied hydrocarbon chains having lengths comparable to those found for esterified membrane lipid fatty acids, and find that the steric constraints of packing in the liquid state do not change the conformational distributions of hydrocarbon chains from those imposed by the intrachain forces present in the gas phase. It follows that the central region of membranes containing lipids in the disordered state should contain hydrocarbon chain conformations determined primarily by intrachain forces.

Goodsaid-Zalduondo, F; Engelman, D M

1981-01-01

362

Test of conformal gravity with astrophysical observations  

NASA Astrophysics Data System (ADS)

Since it can describe the rotation curves of galaxies without dark matter and can give rise to accelerated expansion, conformal gravity attracts much attention recently. As a theory of modified gravity, it is important to test conformal gravity with astrophysical observations. Here we constrain conformal gravity with SNIa and Hubble parameter data and investigate whether it suffers from an age problem with the age of APM 08279+5255. We find conformal gravity can accommodate the age of APM 08279+5255 at 3? deviation, unlike most of dark energy models which suffer from an age problem.

Yang, Rongjia; Chen, Bohai; Zhao, Haijun; Li, Jun; Liu, Yuan

2013-11-01

363

Explorations in conformal symmetry for quantum relativity  

NASA Astrophysics Data System (ADS)

The conformal group is a supergroup of the Poincare group that leaves Maxwell's equations invariant. Conformal symmetry has many applications in physics. Can conformal symmetry be applied to bring together special relativity, which treats space and time on the same level, and quantum theory, which does not? Quantum relativity, as developed by Jaekel and Reynaud [1], introduces operators X^? for space-time localization from the generators of the conformal group in an Einsteinian operational way. We explore how this approach can help describe elementary space-time processes like pair creation and pair annihilation. [1] M.T. Jaekel and S. Reynaud, Found.Phys.28, 439-456 (1998).

Earl, Lucas; van Huele, Jean-Francois

2007-10-01

364

Conformational stability and vibrations of aminopropylsilanol molecule  

NASA Astrophysics Data System (ADS)

Density functional theory (DFT), using the B3-LYP/6-31G(d,p) method have been used to investigate the conformation and vibrational spectra of aminopropylsilanetriol (APST) NH 2CH 2CH 2CH 2Si(OH) 3. The potential function for CCCSi torsion gives rise to two distinct conformers trans and gauche. The predicted energy of the more stable trans conformer is 337 cm -1 less than the energy of gauche conformer. The calculated barriers to the conformation interchange are: 1095, 2845 and 438 cm -1 for the trans to gauche, gauche to gauche and gauche to trans conformers, respectively. For the trans conformer the potential energy curve for the Si(OH) 3 groups torsion in APST has been calculated changing the HOSiC dihedral angle. The barrier for the internal rotation of 3065 cm -1 has been obtained. The optimized molecular structure of APST dimer calculated for trans conformer has a Si sbnd O sbnd Si angle of 143.2°, and a Si sbnd OSi bond length of 0.164 nm. A complete vibrational assignment for both conformers as well as for trans-dimer is supported by the normal coordinate analysis, calculated IR intensities as well as Raman activities. On the basis of the results, the vibrational spectra of APST aqueous solution and APST polymer have been analyzed. The average error between the observed and calculated frequencies is 14 cm -1.

Bistri?i?, Lahorija; Volovšek, Vesna; Danani?, Vladimir; Šapi?, Iva Movre

2006-05-01

365

Simple Model Study of Phase Transition Properties of Isolated and Aggregated Protein  

NASA Astrophysics Data System (ADS)

We investigate the phase transition properties of isolated and aggregated protein by exhaustive numerical study in the confined conformation space with maximally compact lattice model. The study within the confined conformation space shows some general folding properties. Various sequences show different folding properties: two-state folding, three-state folding and prion-like folding behavior. We find that the aggregated protein holds a more evident transition than isolated one and the transition temperature is generally lower than that in isolated case.

Ji, Yong-Yun; Yi, Wei-Qi; Zhang, Lin-Xi

2011-03-01

366

Gravitomagnetic effects in conformal gravity  

NASA Astrophysics Data System (ADS)

Gravitomagnetic effects are characterized by two phenomena: first, the geodetic effect which describes the precession of the spin of a gyroscope in a free orbit around a massive object, and second the Lense-Thirring effect which describes the precession of the orbital plane about a rotating source mass. We calculate both these effects in the fourth-order theory of conformal Weyl gravity for the test case of circular orbits. We show that for the geodetic effect a linear term arises which may be interesting for high radial orbits, whereas for the Lense-Thirring effect the additional term has a diminishing effect for most orbits. Circular orbits are also considered in general leading up to a generalization of Kepler’s third law.

Said, Jackson Levi; Sultana, Joseph; Adami, Kristian Zarb

2013-10-01

367

Conformational Sampling of Maltose-transporter Components in Cartesian Collective Variables is Governed by the Low-frequency Normal Modes.  

PubMed

We have studied large-scale conformational transitions in the maltose-binding protein, and the nucleotide binding domains of a maltose-transporter using enhanced conformational sampling in Cartesian collective variables (CVs) with temperature-accelerated molecular dynamics (TAMD), and C(?)-based elastic network normal mode analysis. Significantly, every functional displacement in the TAMD-generated pathways of each protein could be rationalized via a single low-frequency soft mode, while a combination of 2 to 3 low-frequency modes were found to describe the entire conformational change suggesting that collective functional movement in TAMD trajectories is facilitated by the intrinsically accessible low-frequency normal modes. By applying a harmonic potential to facilitate functional motion in TAMD simulations, we also provide a recipe to reproducibly generate structural transitions in both proteins, which can be used to characterize large-scale conformational changes in other biomolecules. PMID:23185650

Vashisth, H; Brooks, C L

2012-11-15

368

Kinetics and conformational stability studies of recombinant leucine aminopeptidase.  

PubMed

Leucine aminopeptidase from Vibrio proteolyticus is a broad specificity N-terminal aminopeptidase that is widely used in pharmaceutical processes where the removal of N-terminal residues in recombinant proteins is required. We previously reported the expression of a heterologous construction of the mature protein fused to a 6-histidine tag that presents a reasonable refolding rate for its use at industrial level. Here, we investigate this recombinant leucine aminopeptidase (rLAP) to explain the gain of activity observed when incubated at 37 °C after its production. Unfolding transitions of rLAP as a function of urea concentration were monitored by circular dichroism (CD) and fluorescence (FL) spectroscopy exhibiting single transitions by both techniques. Free energy change for unfolding measured by CD and FL spectroscopy are 2.8 ± 0.4 and 3.7 ± 0.4 kcal mol(-1), respectively. Thermal stability conformation of rLAP is 2.6 ± 0.1 and 6.1 kcal mol(-1) for CD and Nano-Differential Scanning Calorimetry (Nano-DSC), respectively. Enzyme activity was assessed with L-leucine-p-nitroanilide (L-pNA) as substrate. The catalytic efficiency was 3.87 ± 0.10 min(-1) ?M(-1) at 37 °C and pH 8.0. Kinetic and conformation studies show differences between the enzyme native and rLAP; however rLAP is selective and specific to remove N-terminal groups from amino acids. PMID:24368112

Hernández-Moreno, Ana V; Villaseñor, Francisco; Medina-Rivero, Emilio; Pérez, Néstor O; Flores-Ortiz, Luis F; Saab-Rincón, Gloria; Luna-Bárcenas, Gabriel

2014-03-01

369

Travelling through conformational space: an approach for analyzing the conformational behaviour of flexible molecules  

Microsoft Academic Search

The applications of the single-co-ordinate-driving (SCD) method in conformational analysis of flexible molecules have been discussed. SCD can best be characterised as travelling through low energy areas of the conformational space. It has been shown that SCD provides detailed information about the conformational behaviour of small and middle sized flexible molecules. It has been demonstrated that SCD may fail for

Jaroslav Ko?a

1998-01-01

370

Coarse-Grained Free Energy Functions for Studying Protein Conformational Changes: A Double-Well Network Model  

Microsoft Academic Search

In this work, a double-well network model (DWNM) is presented for generating a coarse-grained free energy function that can be used to study the transition between reference conformational states of a protein molecule. Compared to earlier work that uses a single, multidimensional double-well potential to connect two conformational states, the DWNM uses a set of interconnected double-well potentials for this

Jhih-Wei Chu; Gregory A. Voth

2007-01-01

371

Mg2+-dependent conformational change of RNA studied by fluorescence correlation and FRET on immobilized single molecules  

Microsoft Academic Search

Fluorescence correlation spectroscopy (FCS) of fluorescence resonant energy transfer (FRET) on immobilized individual fluorophores was used to study the Mg2+-facilitated conformational change of an RNA three-helix junction, a structural element that initiates the folding of the 30S ribosomal subunit. Transitions of the RNA junction between open and folded conformations resulted in fluctuations in fluorescence by FRET. Fluorescence fluctuations occurring between

Harold D. Kim; G. Ulrich Nienhaus; Taekjip Ha; Jeffrey W. Orr; James R. Williamson; Steven Chu

2002-01-01

372

Magnetically-conformed, Variable Area Discharge Chamber for Hall Thruster, and Method  

NASA Technical Reports Server (NTRS)

The invention is a Hall thruster that incorporates a discharge chamber having a variable area channel including an ionization zone, a transition region, and an acceleration zone. The variable area channel is wider through the acceleration zone than through the ionization zone. An anode is located in a vicinity of the ionization zone and a cathode is located in a vicinity of the acceleration zone. The Hall thruster includes a magnetic circuit which is capable of forming a local magnetic field having a curvature within the transition region of the variable area channel whereby the transition region conforms to the curvature of the local magnetic field. The Hall thruster optimizes the ionization and acceleration efficiencies by the combined effects of the variable area channel and magnetic conformity.

Hofer, Richard R. (Inventor)

2013-01-01

373

Munc13 mediates the transition from the closed syntaxin–Munc18 complex to the SNARE complex  

Microsoft Academic Search

During the priming step that leaves synaptic vesicles ready for neurotransmitter release, the SNARE syntaxin-1 transitions from a closed conformation that binds Munc18-1 tightly to an open conformation within the highly stable SNARE complex. Control of this conformational transition is important for brain function, but the underlying mechanism is unknown. NMR and fluorescence experiments now show that the Munc13-1 MUN

Cong Ma; Wei Li; Yibin Xu; Josep Rizo

2011-01-01

374

Reflection and transmission for conformal defects  

Microsoft Academic Search

We consider conformal defects joining two conformal field theories along a line. We define two new quantities associated to such defects in terms of expectation values of the stress tensors and we propose them as measures of the reflectivity and transmissivity of the defect. Their properties are investigated and they are computed in a number of examples. We obtain a

Thomas Quella; Ingo Runkel; Gérard M. T. Watts

2007-01-01

375

Conformally related null Einstein-Maxwell fields  

NASA Astrophysics Data System (ADS)

We present a class of pairs of non-trivially conformally related solutions of Einstein-Maxwell equations that are not pp-waves. To our knowledge, this is the first such case and thus an extension of theorems by Brinkmann, Daftardar-Gejji and Van den Bergh concerning conformal transformations of solutions with null electromagnetic fields.

Hruška, J.; Žofka, M.

2013-01-01

376

Regulatory Conformance Checking: Logic and Logical Form  

ERIC Educational Resources Information Center

We consider the problem of checking whether an organization conforms to a body of regulation. Conformance is studied in a runtime verification setting. The regulation is translated to a logic, from which we synthesize monitors. The monitors are evaluated as the state of an organization evolves over time, raising an alarm if a violation is…

Dinesh, Nikhil

2010-01-01

377

Conformal invariance, supersymmetry and string theory  

Microsoft Academic Search

Covariant quantization of string theories is developed in the context of conformal field theory and the BRST quantization procedure. The BRST method is used to covariantly quantize superstrings, and in particular to construct the vertex operators for string emission as well as the supersymmetry charge. The calculation of string loop diagrams is sketched. We discuss how conformal methods can be

Daniel Friedan; Emil Martinec; Stephen Shenker

1986-01-01

378

MicroRT---Small animal conformal irradiator  

Microsoft Academic Search

A novel small animal conformal radiation therapy system has been designed and prototyped: MicroRT. The microRT system integrates multimodality imaging, radiation treatment planning, and conformal radiation therapy that utilizes a clinical ¹²Ir isotope high dose rate source as the radiation source (teletherapy). A multiparameter dose calculation algorithm based on Monte Carlo dose distribution simulations is used to efficiently and accurately

S. Stojadinovic; D. A. Low; A. J. Hope; M. Vicic; J. O. Deasy; J. Cui; D. Khullar; P. J. Parikh; K. T. Malinowski; E. W. Izaguirre; S. Mutic; P. W. Grigsby

2007-01-01

379

Distinguishing induced fit from conformational selection.  

PubMed

The interactions between proteins and ligands often involve a conformational change in the protein. This conformational change can occur before (conformational selection) or after (induced fit) the association with ligand. It is often very difficult to distinguish induced fit from conformational selection when hyperbolic binding kinetics are observed. In light of a recent paper in this journal (Vogt et al., Biophys. Chem., 186, 2014, 13-21) and the current interest in binding mechanisms emerging from observed sampling of distinct conformations in protein domains, as well as from the field of intrinsically disordered proteins, we here describe a kinetic method that, at least in some cases, unequivocally distinguishes induced fit from conformational selection. The method relies on measuring the observed rate constant ? for binding and varying both the protein and the ligand in separate experiments. Whereas induced fit always yields a hyperbolic dependence of increasing ? values, the conformational selection mechanism gives rise to distinct kinetics when the ligand and protein (displaying the conformational change) concentration is varied in separate experiments. We provide examples from the literature and discuss the limitations of the approach. PMID:24747333

Gianni, Stefano; Dogan, Jakob; Jemth, Per

2014-05-01

380

Conformity to Peer Pressure in Preschool Children  

ERIC Educational Resources Information Center

Both adults and adolescents often conform their behavior and opinions to peer groups, even when they themselves know better. The current study investigated this phenomenon in 24 groups of 4 children between 4;2 and 4;9 years of age. Children often made their judgments conform to those of 3 peers, who had made obviously erroneous but unanimous…

Haun, Daniel B. M.; Tomasello, Michael

2011-01-01

381

Reconciling mediating and slaving roles of water in protein conformational dynamics.  

PubMed

Proteins accomplish their physiological functions with remarkably organized dynamic transitions among a hierarchical network of conformational substates. Despite the essential contribution of water molecules in shaping functionally important protein dynamics, their exact role is still controversial. Water molecules were reported either as mediators that facilitate or as masters that slave protein dynamics. Since dynamic behaviour of a given protein is ultimately determined by the underlying energy landscape, we systematically analysed protein self energies and protein-water interaction energies obtained from extensive molecular dynamics simulation trajectories of barstar. We found that protein-water interaction energy plays the dominant role when compared with protein self energy, and these two energy terms on average have negative correlation that increases with increasingly longer time scales ranging from 10 femtoseconds to 100 nanoseconds. Water molecules effectively roughen potential energy surface of proteins in the majority part of observed conformational space and smooth in the remaining part. These findings support a scenario wherein water on average slave protein conformational dynamics but facilitate a fraction of transitions among different conformational substates, and reconcile the controversy on the facilitating and slaving roles of water molecules in protein conformational dynamics. PMID:23593243

Zhao, Li; Li, Wenzhao; Tian, Pu

2013-01-01

382

Reconciling Mediating and Slaving Roles of Water in Protein Conformational Dynamics  

PubMed Central

Proteins accomplish their physiological functions with remarkably organized dynamic transitions among a hierarchical network of conformational substates. Despite the essential contribution of water molecules in shaping functionally important protein dynamics, their exact role is still controversial. Water molecules were reported either as mediators that facilitate or as masters that slave protein dynamics. Since dynamic behaviour of a given protein is ultimately determined by the underlying energy landscape, we systematically analysed protein self energies and protein-water interaction energies obtained from extensive molecular dynamics simulation trajectories of barstar. We found that protein-water interaction energy plays the dominant role when compared with protein self energy, and these two energy terms on average have negative correlation that increases with increasingly longer time scales ranging from 10 femtoseconds to 100 nanoseconds. Water molecules effectively roughen potential energy surface of proteins in the majority part of observed conformational space and smooth in the remaining part. These findings support a scenario wherein water on average slave protein conformational dynamics but facilitate a fraction of transitions among different conformational substates, and reconcile the controversy on the facilitating and slaving roles of water molecules in protein conformational dynamics.

Tian, Pu

2013-01-01

383

PH-dependent Conformational Changes in Tear Lipocalin by Site Directed Tryptophan Fluorescence  

PubMed Central

Tear lipocalin (TL), a major protein of human tears, binds a broad array of endogenous ligands. PH-dependent ligand binding in TL may have functional implications in tears. Previously, conformational selections of the loops AB and GH have been implicated in ligand binding by site-directed tryptophan fluorescence (SDTF). In this study, SDTF was applied on the loops AB and GH to investigate pH-driven conformational changes relevant to ligand binding. Both loops demonstrate significant but distinct conformational rearrangements over a wide pH range. In the low pH transition, from 7.3 to 3.0, residues of the loop GH show the decreased solvent accessibilities. In acrylamide quenching experiments, the average quenching rate constant (kq, accessibility parameter) of the residues in the loop GH is decreased about 38%, from 2.1×109 M?1s?1 to 1.3×109 M?1s?1. However, despite the significant changes in accessibilities for some residues in the loop AB, the average accessibility per residue remained unchanged (average kq= 1.2 M?1s?1). Accordingly, low pH transition induces conformational changes that reshuffle accessibility profiles of the residues in the loop AB. A significant difference in the titration curves between holo- and apo-forms of W28 mutant suggests that the protonation states of the residues around the position 28 modulate conformational switches of the loop AB relevant to ligand binding.

Gasymov, Oktay K.; Abduragimov, Adil R.; Glasgow, Ben J.

2010-01-01

384

Vibrational and vibronic spectra of tryptamine conformers  

NASA Astrophysics Data System (ADS)

Conformation-specific ionization-detected stimulated Raman spectra, including both Raman loss and Raman gain lines, along with visible-visible-ultraviolet hole-burning spectra of tryptamine (TRA) conformers have been measured simultaneously, with the aim of obtaining new data for identifying them. The slightly different orientations of the ethylamine side chain relative to the indole lead to unique spectral signatures, pointing to the presence of seven TRA conformers in the molecular beam. Comparison of ionization-loss stimulated Raman spectra to computationally scaled harmonic Raman spectra, especially in the alkyl C-H and amine N-H stretch regions together with the retrieved information on the stabilities of the TRA conformers assisted their characterization and structural identification. The prospects and limitations of using these spectroscopic methods as potential conformational probes of flexible molecules are discussed.

Mayorkas, Nitzan; Bernat, Amir; Izbitski, Shay; Bar, Ilana

2013-03-01

385

Performance of Conformable Ablators in Aerothermal Environments  

NASA Technical Reports Server (NTRS)

Conformable Phenolic Impregnated Carbon Ablator, a cousin of Phenolic Impregnated Carbon Ablator (PICA), was developed at NASA Ames Research Center as a lightweight thermal protection system under the Fundamental Aeronautics Program. PICA is made using a brittle carbon substrate, which has a very low strain to failure. Conformable PICA is made using a flexible carbon substrate, a felt in this case. The flexible felt significantly increases the strain to failure of the ablator. PICA is limited by its thermal mechanical properties. Future NASA missions will require heatshields that are more fracture resistant than PICA and, as a result, NASA Ames is working to improve PICAs performance by developing conformable PICA to meet these needs. Research efforts include tailoring the chemistry of conformable PICA with varying amounts of additives to enhance mechanical properties and testing them in aerothermal environments. This poster shows the performance of conformable PICA variants in arc jets tests. Some mechanical and thermal properties will also be presented.

Thornton, J.; Fan, W.; Skokova, K.; Stackpoole, M.; Beck, R.; Chavez-Garcia, J.

2012-01-01

386

Classifying leukemia types with chromatin conformation data  

PubMed Central

Background Although genetic or epigenetic alterations have been shown to affect the three-dimensional organization of genomes, the utility of chromatin conformation in the classification of human disease has never been addressed. Results Here, we explore whether chromatin conformation can be used to classify human leukemia. We map the conformation of the HOXA gene cluster in a panel of cell lines with 5C chromosome conformation capture technology, and use the data to train and test a support vector machine classifier named 3D-SP. We show that 3D-SP is able to accurately distinguish leukemias expressing MLL-fusion proteins from those expressing only wild-type MLL, and that it can also classify leukemia subtypes according to MLL fusion partner, based solely on 5C data. Conclusions Our study provides the first proof-of-principle demonstration that chromatin conformation contains the information value necessary for classification of leukemia subtypes.

2014-01-01

387

Tryptophol cation conformations studied with ZEKE spectroscopy.  

PubMed

The relative energies of several conformations of the tryptophol cation are determined by zero kinetic energy (ZEKE) photoelectron spectroscopy and photoionization efficiency measurements. Recently published high-resolution electronic spectroscopy on the neutral species determined the absolute configuration of the different conformers in the S1 spectrum. These assignments are utilized in the photoelectron experiments by pumping through conformer specific S1 resonances yielding ZEKE spectra of the specific, assigned conformations. The adiabatic ionization of one specific conformation is definitively determined, and two others are estimated. The photoelectron spectra, coupled with calculations, reveal that structural changes upon ionization are dominated by interactions of the hydroxyl group with the changes of electronic structure in the aromatic system. PMID:17305323

Gu, Quanli; Basu, Swarna; Knee, J L

2007-03-15

388

Technidilaton at the conformal edge  

SciTech Connect

Technidilaton (TD) was proposed long ago in the technicolor near criticality/conformality. To reveal the critical behavior of TD, we explicitly compute the nonperturbative contributions to the scale anomaly <{theta}{sub {mu}}{sup {mu}>} and to the technigluon condensate <{alpha}G{sub {mu}{nu}}{sup 2}>, which are generated by the dynamical mass m of the technifermions. Our computation is based on the (improved) ladder Schwinger-Dyson equation, with the gauge coupling {alpha} replaced by the two-loop running coupling {alpha}({mu}) having the Caswell-Banks-Zaks infrared fixed point {alpha}{sub *}: {alpha}({mu}){approx_equal}{alpha}={alpha}{sub *} for the infrared region m<{mu}<{Lambda}{sub TC}, where {Lambda}{sub TC} is the intrinsic scale (analogue of {Lambda}{sub QCD} of QCD) relevant to the perturbative scale anomaly. We find that -<{theta}{sub {mu}}{sup {mu}}>/m{sup 4}{yields}const{ne}0 and <{alpha}G{sub {mu}}{nu}{sup 2}>/m{sup 4}{yields}({alpha}/{alpha}{sub cr}-1){sup -3/2}{yields}{infinity} in the criticality limit m/{Lambda}{sub TC}{approx}exp(-{pi}/({alpha}/{alpha}{sub cr}-1){sup 1/2}){yields}0 ({alpha}={alpha}{sub *}=>{alpha}{sub cr}, or N{sub f} approaches N{sub f}{sup cr}) ('conformal edge'). Our result precisely reproduces the formal identity <{theta}{sub {mu}}{sup {mu}>}=({beta}({alpha})/4{alpha}{sup 2})<{alpha}G{sub {mu}{nu}}{sup 2}>, where {beta}({alpha})={Lambda}{sub TC}({partial_derivative}{alpha}/{partial_derivative}{Lambda}{sub TC})=-(2{alpha}{sub cr}/{pi}){center_dot}({alpha}/{alpha}{sub cr}-1){sup 3/2} is the nonperturbative beta function corresponding to the above essential singularity scaling of m/{Lambda}{sub TC}. Accordingly, the partially conserved dilatation current implies (M{sub TD}/m){sup 2}(F{sub TD}/m){sup 2}=-4<{theta}{sub {mu}}{sup {mu}}>/m{sup 4}{yields}const{ne}0 at criticality limit, where M{sub TD} is the mass of TD and F{sub TD} the decay constant of TD. We thus conclude that at criticality limit the TD could become a ''true (massless) Nambu-Goldstone boson'' M{sub TD}/m{yields}0, only when m/F{sub TD}{yields}0, namely, getting decoupled, as was the case of ''holographic technidilaton'' of Haba-Matsuzaki-Yamawaki. The decoupled TD can be a candidate of dark matter.

Hashimoto, Michio; Yamawaki, Koichi [Maskawa Institute for Science and Culture, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-Ku, Kyoto 603-8555 (Japan); Kobayashi-Maskawa Institute for the Origin of Particles and the Universe (KMI), Nagoya University, Nagoya 464-8602 (Japan)

2011-01-01

389

Perceived Symbols of Authority and Their Influence on Conformity.  

ERIC Educational Resources Information Center

Although there are many variables that influence conformity, Bickman (1974) found that the apparel of the person making a request had a significant influence on conformity. To evaluate other factorswhicn may influence conformity (gender, age, status of the conforming subject, and altruism in conforming), 150 adult pedestrians (45% female, 71%…

Bushman, Brad J.

390

Comparing and analysing three kinds of conformal predictor  

Microsoft Academic Search

This paper studies the conformal predictor based on k-nearest neighbour, the conformal predictor based on support vector machine, the conformal predictor based on logistic regression model. We use the three conformal predictors to predict the irises standard data sets and cigarette strength index data sets, then by comparing the results we find that in irises standard data sets, the conformal

Jian-Xin Zeng; Hui-Li Gong; Ting Liu; Yue Men; Ning Yang

2012-01-01

391

Transitional Care  

ERIC Educational Resources Information Center

Transitional care encompasses a broad range of services and environments designed to promote the safe and timely passage of patients between levels of health care and across care settings. High-quality transitional care is especially important for older adults with multiple chronic conditions and complex therapeutic regimens, as well as for their…

Naylor, Mary; Keating, Stacen A.

2008-01-01

392

Newborn transition.  

PubMed

The transition from intrauterine to extrauterine life is a complex adaptation. Although, in a sense, the entire time in utero is in preparation for this transition, there are many specific anatomic and physiologic changes that take place in the weeks and days leading up to labor that facilitate a healthy transition. Some, including increasing pulmonary vasculature and blood flow, are part of an ongoing process of maturation. Others, such as a reversal in the lung from secreting fluid to absorbing fluid and the secretion of pulmonary surfactant, are associated with the hormonal milieu that occurs when spontaneous labor is impending. Interventions such as elective cesarean birth or induction of labor may interfere with this preparation for birth. Postnatal interventions such as immediate clamping of the umbilical cord and oropharyngeal suction may also compromise the normal process of newborn transition. This article reviews the physiology of the fetal to newborn transition and explores interventions that may facilitate or hinder the optimal process. PMID:24103003

Graves, Barbara W; Haley, Mary Mumford

2013-01-01

393

Molecular dynamics simulations reveal that apo-HisJ can sample a closed conformation.  

PubMed

The Escherichia coli histidine binding protein HisJ is a type II periplasmic binding protein (PBP) that preferentially binds histidine and interacts with its cytoplasmic membrane ABC transporter, HisQMP2 , to initiate histidine transport. HisJ is a bilobal protein where the larger Domain 1 is connected to the smaller Domain 2 via two linking strands. Type II PBPs are thought to undergo "Venus flytrap" movements where the protein is able to reversibly transition from an open to a closed conformation. To explore the accessibility of the closed conformation to the apo state of the protein, we performed a set of all-atom molecular dynamics simulations of HisJ starting from four different conformations: apo-open, apo-closed, apo-semiopen, and holo-closed. The simulations reveal that the closed conformation is less dynamic than the open one. HisJ experienced closing motions and explored semiopen conformations that reverted to closed forms resembling those found in the holo-closed state. Essential dynamics analysis of the simulations identified domain closing/opening and twisting as main motions. The formation of specific inter-hinge strand and interdomain polar interactions contributed to the adoption of the closed apo-conformations although they are up to 2.5-fold less prevalent compared with the holo-closed simulations. The overall sampling of the closed form by apo-HisJ provides a rationale for the binding of unliganded PBPs with their cytoplasmic membrane ABC transporters. PMID:23966221

Chu, B C H; Chan, D I; DeWolf, T; Periole, X; Vogel, H J

2014-03-01

394

Rotational spectra of methyl ethyl and methyl propyl nitrosamines. Conformational assignment, internal rotation and quadrupole coupling  

NASA Astrophysics Data System (ADS)

A structural determination of two carcinogenic nitrosamines, methyl ethyl and methyl propyl nitrosamine, was performed. Microwave spectra were gathered from both a Stark cell spectrometer and a pulsed jet Fabry-Perot Fourier transform microwave spectrometer. Each rotational transition is split into quadrupole hyperfine components by two nitrogen nuclei. This quadrupole pattern is doubled by a low barrier methyl rotor which produces resolvable A and E states. Rotational spectra were assigned for one conformer of methyl ethyl nitrosamine and two conformers of methyl propyl nitrosamine. The lowest energy conformers of each compound, according to empirical force field calculations, were assigned. The structure found for methyl ethyl nitrosamine has the nitrosyl oxygen on the methyl side with the terminal methyl group of the ethyl chain in the gauche position (OMG). Both conformers of methyl propyl nitrosamine have the same skeletal structure as the methyl ethyl compound; one conformer has the terminal methyl of the propyl group in the anti position (OMGA) while the other conformer has this methyl in the gauche position (OMGG -). Rotational constants and quadrupole coupling constants are reported for each assigned species. A barrier to internal rotation of the N-methyl group in each compound is also reported.

Walker, A. R. Hight; Lou, Qi; Bohn, Robert K.; Novick, Stewart E.

1995-02-01

395

Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling  

PubMed Central

MutS protein recognizes mispaired bases in DNA and targets them for mismatch repair. Little is known about the transient conformations of MutS as it signals initiation of repair. We have used single-molecule fluorescence resonance energy transfer (FRET) measurements to report the conformational dynamics of MutS during this process. We find that the DNA-binding domains of MutS dynamically interconvert among multiple conformations when the protein is free and while it scans homoduplex DNA. Mismatch recognition restricts MutS conformation to a single state. Steady-state measurements in the presence of nucleotides suggest t