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Sample records for calcium-induced conformational transition

  1. Calcium binding domains and calcium-induced conformational transition of SPARC/BM-40/osteonectin, an extracellular glycoprotein expressed in mineralized and nonmineralized tissues

    SciTech Connect

    Engel, J.; Taylor, W.; Paulsson, M.; Sage, H.; Hogan, B.

    1987-11-03

    PSARC, BM-40, and osteonectin are identical or very closely related extracellular proteins of apparent M/sub r/ 43,000 (M/sub r/ 33,000 predicted from sequence). They were originally isolated from parietal endoderm cells, basement membrane producing tumors, and bone, respectively, but are rather widely distributed in various tissues. In view of the calcium binding activity reported for osteonectin, the authors analyzed the SPARC sequence and found two putative calcium binding domains. One is an N-terminal acid region with clusters of glutamic acid residues. This region, although neither ..gamma..-carboxylated nor homologous, resembles the ..gamma..-carboxyglutamic acid (Gla) domain of vitamin K dependent proteins of the blood clotting system in charge density, size of negatively charged clusters, and linkage to the rest of the molecule by a cysteine-rich domain. The other region is an EF-hand calcium binding domain located near the C-terminus. A disulfide bond between the E and F helix is predicted from modeling the EF-hand structure with the known coordinates of intestinal calcium binding protein. The disulfide bridge apparently serves to stabilize the isolated calcium loop in the extracellular protein. As observed for cytoplasmic EF-hand-containing proteins and for Gla domain containing proteins, a major conformational transition is induced in BM-40 upon binding of several Ca/sup 2 +/ ions. This is accompanied by a 35% increase in ..cap alpha..-helicity. A pronounced sigmoidicity of the dependence of the circular dichroism signal at 220 nm on calcium concentration indicates that the process is cooperative. In view of its properties, abundance, and wide distribution, it is proposed that SPARC/BM-40/osteonectin has a rather general regulatory function in calcium-dependent processes of the extra-cellular matrix.

  2. Molecular mechanism of the calcium-induced conformational change in the spectrin EF-hands.

    PubMed Central

    Travé, G; Lacombe, P J; Pfuhl, M; Saraste, M; Pastore, A

    1995-01-01

    Calcium is a universally employed cytosolic messenger in eukaryotic cells. Most of the proteins that bind signalling calcium are members of the calmodulin superfamily and share two or more helix-loop-helix motifs known as EF-hands. A model, based on structure comparison of different domains and supported by preliminary NMR data, has suggested that EF-hands involved in signal transduction undergo a major conformational change upon calcium binding from a 'closed' to an 'open' state allowing protein-protein interaction. We have determined the solution structures of the EF-hand pair from alpha-spectrin in the absence and in the presence of calcium. The structures are in the closed and open conformation respectively, providing a definite experimental proof for the closed-to-open model. Our results allow formulation of the rules which govern the movement induced by calcium. These rules may be generalized to other EF-hands since the key residues involved are conserved within the calmodulin family. Images PMID:7588621

  3. Quantifying macromolecular conformational transition pathways

    NASA Astrophysics Data System (ADS)

    Seyler, Sean; Kumar, Avishek; Thorpe, Michael; Beckstein, Oliver

    2015-03-01

    Diverse classes of proteins function through large-scale conformational changes that are challenging for computer simulations. A range of fast path-sampling techniques have been used to generate transitions, but it has been difficult to compare paths from (and assess the relative strengths of) different methods. We introduce a comprehensive method (pathway similarity analysis, PSA) for quantitatively characterizing and comparing macromolecular pathways. The Hausdorff and Fréchet metrics (known from computational geometry) are used to quantify the degree of similarity between polygonal curves in configuration space. A strength of PSA is its use of the full information available from the 3 N-dimensional configuration space trajectory without requiring additional specific knowledge about the system. We compare a sample of eleven different methods for the closed-to-open transitions of the apo enzyme adenylate kinase (AdK) and also apply PSA to an ensemble of 400 AdK trajectories produced by dynamic importance sampling MD and the Geometrical Pathways algorithm. We discuss the method's potential to enhance our understanding of transition path sampling methods, validate them, and help guide future research toward deeper physical insights into conformational transitions.

  4. Conformational Transitions in Molecular Systems

    NASA Astrophysics Data System (ADS)

    Bachmann, M.; Janke, W.

    2008-11-01

    Proteins are the "work horses" in biological systems. In almost all functions specific proteins are involved. They control molecular transport processes, stabilize the cell structure, enzymatically catalyze chemical reactions; others act as molecular motors in the complex machinery of molecular synthetization processes. Due to their significance, misfolds and malfunctions of proteins typically entail disastrous diseases, such as Alzheimer's disease and bovine spongiform encephalopathy (BSE). Therefore, the understanding of the trinity of amino acid composition, geometric structure, and biological function is one of the most essential challenges for the natural sciences. Here, we glance at conformational transitions accompanying the structure formation in protein folding processes.

  5. Theory of conformational transitions of viral shells

    NASA Astrophysics Data System (ADS)

    Guérin, Thomas; Bruinsma, Robijn

    2007-12-01

    We propose a continuum theory for the conformational transitions of viral shells. Conformational transitions of viral shells, as encountered during viral maturation, are associated with a soft mode instability of the capsid proteins [F. Tama and C. L. Brooks, J. Mol. Biol. 345(2), 299 (2005)]. The continuum theory presented here is an adaptation of the Ginzburg-Landau theory of soft-mode structural phase transitions of solids to viral shells. The theory predicts that the conformational transitions are characterized by a pronounced softening of the shell elasticity in the critical region. We demonstrate that the thermodynamics of the conformational transition can be probed quantitatively by a micromechanical atomic force microscope study. The external force can drive a capsid into a state of phase coexistence characterized by a highly nonlinear force deformation curve.

  6. Conformational transitions of a weak polyampholyte

    NASA Astrophysics Data System (ADS)

    Narayanan Nair, Arun Kumar; Uyaver, Sahin; Sun, Shuyu

    2014-10-01

    Using grand canonical Monte Carlo simulations of a flexible polyelectrolyte where the charges are in contact with a reservoir of constant chemical potential given by the solution pH, we study the behavior of weak polyelectrolytes in poor and good solvent conditions for polymer backbone. We address the titration behavior and conformational properties of a flexible diblock polyampholyte chain formed of two oppositely charged weak polyelectrolyte blocks, each containing equal number of identical monomers. The change of solution pH induces charge asymmetry in a diblock polyampholyte. For diblock polyampholyte chains in poor solvents, we demonstrate that a discontinuous transition between extended (tadpole) and collapsed (globular) conformational states is attainable by varying the solution pH. The double-minima structure in the probability distribution of the free energy provides direct evidence for the first-order like nature of this transition. At the isoelectric point electrostatically driven coil-globule transition of diblock polyampholytes in good solvents is found to consist of different regimes identified with increasing electrostatic interaction strength. At pH values above or below the isoelectric point diblock chains are found to have polyelectrolyte-like behavior due to repulsion between uncompensated charges along the chain.

  7. Conformations and structural transitions in polydeoxynucleotides.

    PubMed

    Pilet, J; Blicharski, J; Brahms, J

    1975-05-01

    Polydeoxynucleotides of different base sequence, the alternating poly[d(A-T)]-poly[d(A-T)], crab satellite DNA, on the one hand, and double-stranded homopolymer complexes poly[d(A)]-poly[d(T)], poly[d(I)]-poly[d(C)], on the other, display significant differences in their conformation and conformational transitions. Infrared linear dichroism investigations indicate that the alternating poly[d(A-T)]-poly[d(A-T)], enzymatically synthesized, adopts a lower humidity a well-expressed A* form in which stability is relatively small,i.e., restricted to limited relative humidity. This A form is characterized by the orientation of the bisector of the phosphate OPO group at 34 degrees with respect to the helical axis, which is slightly lower than that of DNA. In contrast, for the homopolynucleotide double-stranded complex poly(dA)-poly(dT) and also for poly(dI)-poly(dC), the B yields A conformational change is not observed. Instead poly(dA)-poly(dT) exists at lower humidity in a stable modified B form. Thus the present results indicate that homo(dA)-homo(dT) double-stranded sequences prevent the B yields A structural transition. All AT-containing polydeoxynucleotides and crab satellite DNA adopt a high humidity a modified B form characterized by the orientation of the bisector of the phosphate group OPO at 64 degrees with respect to the helical axis which is significantly lower than 68-74 degrees observed in DNAs. The base pairing geometry in poly(dA)-poly(dT), poly[d(A-T)]-poly[d(A-T)], and also in poly(dI)-poly(dC) is apparently a Watson and Crick type. Thus the observed differences in conformation are not due to different base pairing scheme. It is suggested that in DNAs of high AT content the presence of homo(dT)-homo(dA) sequences and the relatively low stability of the A form of d(A-T) alternating sequences may inhibit the change to the A form. A possible role of these sequences in DNA recognition by protein is suggested.

  8. The calcium-induced conformation and glycosylation of scavenger-rich cysteine repeat (SRCR) domains of glycoprotein 340 influence the high affinity interaction with antigen I/II homologs.

    PubMed

    Purushotham, Sangeetha; Deivanayagam, Champion

    2014-08-01

    Oral streptococci adhere to tooth-immobilized glycoprotein 340 (GP340) via the surface protein antigen I/II (AgI/II) and its homologs as the first step in pathogenesis. Studying this interaction using recombinant proteins, we observed that calcium increases the conformational stability of the scavenger-rich cysteine repeat (SRCRs) domains of GP340. Our results also show that AgI/II adheres specifically with nanomolar affinity to the calcium-induced SRCR conformation in an immobilized state and not in solution. This interaction is significantly dependent on the O-linked carbohydrates present on the SRCRs. This study also establishes that a single SRCR domain of GP340 contains the two surfaces to which the apical and C-terminal regions of AgI/II noncompetitively adhere. Compared with the single SRCR domain, the three tandem SRCR domains displayed a collective/cooperative increase in their bacterial adherence and aggregation. The previously described SRCRP2 peptide that was shown to aggregate several oral streptococci displayed limited aggregation and also nonspecific adherence compared to SRCR domains. Finally, we show distinct species-specific adherence/aggregation between Streptococcus mutans AgI/II and Streptococcus gordonii SspB in their interaction with the SRCRs. This study concludes that identification of the metal ion and carbohydrate adherence motifs on both SRCRs and AgI/II homologs could lead to the development of anti-adhesive inhibitors that could deter the adherence of pathogenic oral streptococci and thereby prevent the onset of infections.

  9. Predicting order of conformational changes during protein conformational transitions using an interpolated elastic network model.

    PubMed

    Tekpinar, Mustafa; Zheng, Wenjun

    2010-08-15

    The decryption of sequence of structural events during protein conformational transitions is essential to a detailed understanding of molecular functions of various biological nanomachines. Coarse-grained models have proven useful by allowing highly efficient simulations of protein conformational dynamics. By combining two coarse-grained elastic network models constructed based on the beginning and end conformations of a transition, we have developed an interpolated elastic network model to generate a transition pathway between the two protein conformations. For validation, we have predicted the order of local and global conformational changes during key ATP-driven transitions in three important biological nanomachines (myosin, F(1) ATPase and chaperonin GroEL). We have found that the local conformational change associated with the closing of active site precedes the global conformational change leading to mechanical motions. Our finding is in good agreement with the distribution of intermediate experimental structures, and it supports the importance of local motions at active site to drive or gate various conformational transitions underlying the workings of a diverse range of biological nanomachines.

  10. Fluctuation Flooding Method (FFM) for accelerating conformational transitions of proteins

    NASA Astrophysics Data System (ADS)

    Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru

    2014-03-01

    A powerful conformational sampling method for accelerating structural transitions of proteins, "Fluctuation Flooding Method (FFM)," is proposed. In FFM, cycles of the following steps enhance the transitions: (i) extractions of largely fluctuating snapshots along anisotropic modes obtained from trajectories of multiple independent molecular dynamics (MD) simulations and (ii) conformational re-sampling of the snapshots via re-generations of initial velocities when re-starting MD simulations. In an application to bacteriophage T4 lysozyme, FFM successfully accelerated the open-closed transition with the 6 ns simulation starting solely from the open state, although the 1-μs canonical MD simulation failed to sample such a rare event.

  11. Hierarchical Biomolecular Dynamics: Picosecond Hydrogen Bonding Regulates Microsecond Conformational Transitions.

    PubMed

    Buchenberg, Sebastian; Schaudinnus, Norbert; Stock, Gerhard

    2015-03-10

    Biomolecules exhibit structural dynamics on a number of time scales, including picosecond (ps) motions of a few atoms, nanosecond (ns) local conformational transitions, and microsecond (μs) global conformational rearrangements. Despite this substantial separation of time scales, fast and slow degrees of freedom appear to be coupled in a nonlinear manner; for example, there is theoretical and experimental evidence that fast structural fluctuations are required for slow functional motion to happen. To elucidate a microscopic mechanism of this multiscale behavior, Aib peptide is adopted as a simple model system. Combining extensive molecular dynamics simulations with principal component analysis techniques, a hierarchy of (at least) three tiers of the molecule's free energy landscape is discovered. They correspond to chiral left- to right-handed transitions of the entire peptide that happen on a μs time scale, conformational transitions of individual residues that take about 1 ns, and the opening and closing of structure-stabilizing hydrogen bonds that occur within tens of ps and are triggered by sub-ps structural fluctuations. Providing a simple mechanism of hierarchical dynamics, fast hydrogen bond dynamics is found to be a prerequisite for the ns local conformational transitions, which in turn are a prerequisite for the slow global conformational rearrangement of the peptide. As a consequence of the hierarchical coupling, the various processes exhibit a similar temperature behavior which may be interpreted as a dynamic transition. PMID:26579778

  12. Conformational transitions in random heteropolymer models

    NASA Astrophysics Data System (ADS)

    Blavatska, Viktoria; Janke, Wolfhard

    2014-01-01

    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.

  13. General trends of dihedral conformational transitions in a globular protein

    DOE PAGESBeta

    Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C.; McCammon, J. Andrew

    2016-02-15

    In this paper, dihedral conformational transitions are analyzed systematically in a model globular protein, cytochrome P450cam, to examine their structural and chemical dependences through combined conventional molecular dynamics (cMD), accelerated molecular dynamics (aMD) and adaptive biasing force (ABF) simulations. The aMD simulations are performed at two acceleration levels, using dihedral and dual boost, respectively. In comparison with cMD, aMD samples protein dihedral transitions approximately two times faster on average using dihedral boost, and ~3.5 times faster using dual boost. In the protein backbone, significantly higher dihedral transition rates are observed in the bend, coil, and turn flexible regions, followed bymore » the β bridge and β sheet, and then the helices. Moreover, protein side chains of greater length exhibit higher transition rates on average in the aMD-enhanced sampling. Side chains of the same length (particularly Nχ = 2) exhibit decreasing transition rates with residues when going from hydrophobic to polar, then charged and aromatic chemical types. The reduction of dihedral transition rates is found to be correlated with increasing energy barriers as identified through ABF free energy calculations. In conclusion, these general trends of dihedral conformational transitions provide important insights into the hierarchical dynamics and complex free energy landscapes of functional proteins.« less

  14. General trends of dihedral conformational transitions in a globular protein.

    PubMed

    Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C; McCammon, J Andrew

    2016-04-01

    Dihedral conformational transitions are analyzed systematically in a model globular protein, cytochrome P450cam, to examine their structural and chemical dependences through combined conventional molecular dynamics (cMD), accelerated molecular dynamics (aMD) and adaptive biasing force (ABF) simulations. The aMD simulations are performed at two acceleration levels, using dihedral and dual boost, respectively. In comparison with cMD, aMD samples protein dihedral transitions approximately two times faster on average using dihedral boost, and ∼ 3.5 times faster using dual boost. In the protein backbone, significantly higher dihedral transition rates are observed in the bend, coil, and turn flexible regions, followed by the β bridge and β sheet, and then the helices. Moreover, protein side chains of greater length exhibit higher transition rates on average in the aMD-enhanced sampling. Side chains of the same length (particularly Nχ = 2) exhibit decreasing transition rates with residues when going from hydrophobic to polar, then charged and aromatic chemical types. The reduction of dihedral transition rates is found to be correlated with increasing energy barriers as identified through ABF free energy calculations. These general trends of dihedral conformational transitions provide important insights into the hierarchical dynamics and complex free energy landscapes of functional proteins. PMID:26799251

  15. Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA

    PubMed Central

    Zhabinskaya, Dina; Benham, Craig J.

    2012-01-01

    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. PMID:22570598

  16. Accurate Determination of Conformational Transitions in Oligomeric Membrane Proteins

    PubMed Central

    Sanz-Hernández, Máximo; Vostrikov, Vitaly V.; Veglia, Gianluigi; De Simone, Alfonso

    2016-01-01

    The structural dynamics governing collective motions in oligomeric membrane proteins play key roles in vital biomolecular processes at cellular membranes. In this study, we present a structural refinement approach that combines solid-state NMR experiments and molecular simulations to accurately describe concerted conformational transitions identifying the overall structural, dynamical, and topological states of oligomeric membrane proteins. The accuracy of the structural ensembles generated with this method is shown to reach the statistical error limit, and is further demonstrated by correctly reproducing orthogonal NMR data. We demonstrate the accuracy of this approach by characterising the pentameric state of phospholamban, a key player in the regulation of calcium uptake in the sarcoplasmic reticulum, and by probing its dynamical activation upon phosphorylation. Our results underline the importance of using an ensemble approach to characterise the conformational transitions that are often responsible for the biological function of oligomeric membrane protein states. PMID:26975211

  17. Laser induced popcornlike conformational transition of nanodiamond as a nanoknife

    NASA Astrophysics Data System (ADS)

    Chang, Chia-Ching; Chen, Pei-Hsin; Chu, Hsueh-Liang; Lee, Tzu-Cheng; Chou, Ching-Chung; Chao, Jui-I.; Su, Chien-Ying; Chen, Jyh Shin; Tsai, Jin-Sheng; Tsai, Chuan-Mei; Ho, Yen-Peng; Sun, Kien Wen; Cheng, Chia-Liang; Chen, Fu-Rong

    2008-07-01

    Nanodiamond (ND) is surrounded by layers of graphite on its surface. This unique structure feature creates unusual fluorescence spectra, which can be used as an indicator to monitor its surface modification. Meanwhile, the impurity, nitroso (CNO) inside the ND can be photolyzed by two-photon absorption, releasing NO to facilitate the formation of a sp3 diamond structure in the core of ND and transforming it into a sp2 graphite structure. Such a conformational transition enlarges the size of ND from 8to90nm, resulting in a popcornlike structure. This transition reaction may be useful as nanoknives in biomedical application.

  18. Quantum Hall transitions: An exact theory based on conformal restriction

    NASA Astrophysics Data System (ADS)

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

    2012-10-01

    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

  19. Surface immobilization of antibody on silk fibroin through conformational transition.

    PubMed

    Lu, Qiang; Wang, Xiaoqin; Zhu, Hesun; Kaplan, David L

    2011-07-01

    In recent studies silk fibroin has been explored as a new material platform for biosensors. Based on these developments, a procedure for the immobilization of antibodies on silk fibroin substrates was developed as a route to functionalizing these biosensor systems. By controlling the conformational transition of the silk fibroin, a primary antibody was immobilized and enriched at the surface of silk fibroin substrates under mild reaction conditions to maintain antibody function. Compared to chemical crosslinking, the immobilization efficiency in the present approach was increased significantly. This method, achieving high loading of antibody while retaining function, improves the feasibility of silk fibroin as a platform material for biosensor applications.

  20. Disorder transitions and conformational diversity cooperatively modulate biological function in proteins.

    PubMed

    Zea, Diego Javier; Monzon, Alexander Miguel; Gonzalez, Claudia; Fornasari, María Silvina; Tosatto, Silvio C E; Parisi, Gustavo

    2016-06-01

    Structural differences between conformers sustain protein biological function. Here, we studied in a large dataset of 745 intrinsically disordered proteins, how ordered-disordered transitions modulate structural differences between conformers as derived from crystallographic data. We found that almost 50% of the proteins studied show no transitions and have low conformational diversity while the rest show transitions and a higher conformational diversity. In this last subset, 60% of the proteins become more ordered after ligand binding, while 40% more disordered. As protein conformational diversity is inherently connected with protein function our analysis suggests differences in structure-function relationships related to order-disorder transitions.

  1. Broadband transition between microstrip line and conformal surface plasmon waveguide

    NASA Astrophysics Data System (ADS)

    Liao, Zhen; Zhao, Jie; Cao Pan, Bai; Shen, Xiao Peng; Cui, Tie Jun

    2014-08-01

    We propose a broadband and high-efficiency transition from a microstrip line to a conformal surface plasmon (CSP) waveguide that is made of an ultrathin corrugated metallic strip, to transform the guide wave into a spoof surface plasmon polariton (SPP) in the microwave region. The transition consists of three parts: a convertor which converts the direction of the electric field from perpendicular to parallel to the strip, a matching area with gradient corrugations and a flaring metallic line to match both the momentum and impedance, and a CSP waveguide to support the SPP waves. A back-to-back transition sample is fabricated using the proposed method. Experimental results of S parameters and near-field distributions verify the excellent performance of the sample to transform guided waves to SPPs and transmit SPP waves in a wide band. The sample exhibits low energy loss when the CSP waveguide is bent or even twisted. The proposed transition may have potential applications in integrating conventional microwave devices with the SPP devices.

  2. Conformation transitions of eukaryotic polyribosomes during multi-round translation.

    PubMed

    Afonina, Zhanna A; Myasnikov, Alexander G; Shirokov, Vladimir A; Klaholz, Bruno P; Spirin, Alexander S

    2015-01-01

    Using sedimentation and cryo electron tomography techniques, the conformations of eukaryotic polyribosomes formed in a long-term cell-free translation system were analyzed over all the active system lifetime (20-30 translation rounds during 6-8 h in wheat germ extract at 25°C). Three distinct types of the conformations were observed: (i) circular polyribosomes, varying from ring-shaped forms to circles collapsed into double rows, (ii) linear polyribosomes, tending to acquire planar zigzag-like forms and (iii) densely packed 3D helices. At the start, during the first two rounds of translation mostly the circular (ring-shaped and double-row) polyribosomes and the linear (free-shaped and zigzag-like) polyribosomes were formed ('juvenile phase'). The progressive loading of the polyribosomes with translating ribosomes induced the opening of the circular polyribosomes and the transformation of a major part of the linear polyribosomes into the dense 3D helices ('transitional phase'). After 2 h from the beginning (about 8-10 rounds of translation) this compact form of polyribosomes became predominant, whereas the circular and linear polyribosome fractions together contained less than half of polysomal ribosomes ('steady-state phase'). The latter proportions did not change for several hours. Functional tests showed a reduced translational activity in the fraction of the 3D helical polyribosomes.

  3. Sequence Recognition of DNA by Protein-Induced Conformational Transitions

    SciTech Connect

    Watkins, Derrick; Mohan, Srividya; Koudelka, Gerald B.; Williams, Loren Dean

    2010-11-09

    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.

  4. Generating conformational transitions using the euclidean distance matrix.

    PubMed

    Li, Xiao-Bo; Burkowski, Forbes

    2015-03-01

    Elastic network interpolation (ENI) is an efficient method for generating intermediate conformations between two end protein conformations. Its current formulation uses interatomic distance. We show how this can be generalized to interatomic distances-squared. This generalization is part of an effort to study protein dynamics on the set of positive semidefinite (PSD) matrices, which has a rich mathematical structure. We use lattice structures to test this interpolation scheme, and discuss some limitations observed. We conclude with some suggestions for future research.

  5. Modeling of solvent-dependent conformational transitions in Burkholderia cepacia lipase

    PubMed Central

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

    2009-01-01

    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 β-hairpin was moving away from the lid in all simulations in water, which was not observed in simulations in

  6. Mapping the Dynamics Landscape of Conformational Transitions in Enzyme: The Adenylate Kinase Case

    PubMed Central

    Li, Dechang; Liu, Ming S.; Ji, Baohua

    2015-01-01

    Conformational transition describes the essential dynamics and mechanism of enzymes in pursuing their various functions. The fundamental and practical challenge to researchers is to quantitatively describe the roles of large-scale dynamic transitions for regulating the catalytic processes. In this study, we tackled this challenge by exploring the pathways and free energy landscape of conformational changes in adenylate kinase (AdK), a key ubiquitous enzyme for cellular energy homeostasis. Using explicit long-timescale (up to microseconds) molecular dynamics and bias-exchange metadynamics simulations, we determined at the atomistic level the intermediate conformational states and mapped the transition pathways of AdK in the presence and absence of ligands. There is clearly chronological operation of the functional domains of AdK. Specifically in the ligand-free AdK, there is no significant energy barrier in the free energy landscape separating the open and closed states. Instead there are multiple intermediate conformational states, which facilitate the rapid transitions of AdK. In the ligand-bound AdK, the closed conformation is energetically most favored with a large energy barrier to open it up, and the conformational population prefers to shift to the closed form coupled with transitions. The results suggest a perspective for a hybrid of conformational selection and induced fit operations of ligand binding to AdK. These observations, depicted in the most comprehensive and quantitative way to date, to our knowledge, emphasize the underlying intrinsic dynamics of AdK and reveal the sophisticated conformational transitions of AdK in fulfilling its enzymatic functions. The developed methodology can also apply to other proteins and biomolecular systems. PMID:26244746

  7. CALCIUM-INDUCED SUPRAMOLECULAR STRUCTURES IN THE CALCIUM CASEINATE SYSTEM

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The molecular details deciphering the spontaneous calcium-induced protein aggregation process in the calcium caseinate system remain obscure. Understanding this complex process could lead to potential new applications of this important food ingredient. In this work, we studied calcium-induced supra...

  8. Conformational transitions of weak polyacids grafted to nanoparticles

    NASA Astrophysics Data System (ADS)

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

    2012-10-01

    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.

  9. A new method to calculate reaction paths for conformation transitions of large molecules

    NASA Astrophysics Data System (ADS)

    Smart, Oliver S.

    1994-05-01

    Path energy minimization (PEM), a novel method for the generation of a reaction path linking two known conformers of a molecule, is presented. The technique is based on optimizing a function which closely approximates the peak potential energy of a quasi-continuous path between the fixed end points. A transition involving the change in the pucker angle of α-D-xylulofuranose is used as a test case. The method is shown to, be capable of identifying transition state structures and energy barries. The utility of the method is demonstrated by an application to substantial conformational transition of the ion-channel forming polypeptide gramicidin A.

  10. Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories

    PubMed Central

    Yang, Sichun; Banavali, Nilesh K.; Roux, Benoît

    2009-01-01

    The Src-family kinases are allosteric enzymes that play a key role in the regulation of cell growth and proliferation. In response to cellular signals, they undergo large conformational changes to switch between distinct inactive and active states. A computational strategy for characterizing the conformational transition pathway is presented to bridge the inactive and active states of the catalytic domain of Hck. The information from a large number (78) of independent all-atom molecular dynamics trajectories with explicit solvent is combined together to assemble a connectivity map of the conformational transition. Two intermediate states along the activation pathways are identified, and their structural features are characterized. A coarse free-energy landscape is built in terms of the collective motions corresponding to the opening of the activation loop (A-loop) and the rotation of the αC helix. This landscape shows that the protein can adopt a multitude of conformations in which the A-loop is partially open, while the αC helix remains in the orientation characteristic of the inactive conformation. The complete transition leading to the active conformation requires a concerted movement involving further opening of the A-loop, the relative alignment of N-lobe and C-lobe, and the rotation of the αC helix needed to recruit the residues necessary for catalysis in the active site. The analysis leads to a dynamic view of the full-length kinase activation, whereby transitions of the catalytic domain to intermediate configurations with a partially open A-loop are permitted, even while the SH2-SH3 clamp remains fully engaged. These transitions would render Y416 available for the transphosphorylation event that ultimately locks down the active state. The results provide a broad framework for picturing the conformational transitions leading to kinase activation. PMID:19225111

  11. Conformational transitions in human translin enable nucleic acid binding

    PubMed Central

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

    2013-01-01

    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

  12. Pressure-induced conformation transition of o-phenylene solvated in bulk hydrocarbons.

    PubMed

    Riello, Massimo; Doni, Giovanni; Filip, Sorin V; Gold, Martin; De Vita, Alessandro

    2014-11-26

    The conformational behavior of o-phenylene 8-mers and 10-mers solvated in a series of linear alkane solvents by means of classical molecular dynamics and first-principles calculations was studied. Irrespective of the solvent used, we find that at ambient pressure the molecule sits in the well-defined close-helical arrangement previously observed in light polar solvents. However, for pressures greater than 50 atm, and for tetradecane or larger solvent molecules, our simulations predict that o-phenylene undergoes a conformational transition to an uncoiled, extended geometry with a 35% longer head-to-tail distance and a much larger overlap between its lateral aromatic ring groups. The free energy barrier for the transition was studied as a function of pressure and temperature for both solute molecules in butane and hexadecane. Gas-phase density functional theory-based nudged elastic band calculations on 8-mer and 10-mer o-phenylene were used to estimate how the pressure-induced transition energy barrier changes with solute length. Our results indicate that a sufficiently large solvent molecule size is the key factor enabling a configuration transition upon pressure changes and that longer solute molecules associate with higher conformation transition energy barriers. This suggests the possibility of designing systems in which a solute molecule can be selectively "activated" by a controlled conformation transition achieved at a predefined set of pressure and temperature conditions.

  13. Pressure-induced conformation transition of o-phenylene solvated in bulk hydrocarbons.

    PubMed

    Riello, Massimo; Doni, Giovanni; Filip, Sorin V; Gold, Martin; De Vita, Alessandro

    2014-11-26

    The conformational behavior of o-phenylene 8-mers and 10-mers solvated in a series of linear alkane solvents by means of classical molecular dynamics and first-principles calculations was studied. Irrespective of the solvent used, we find that at ambient pressure the molecule sits in the well-defined close-helical arrangement previously observed in light polar solvents. However, for pressures greater than 50 atm, and for tetradecane or larger solvent molecules, our simulations predict that o-phenylene undergoes a conformational transition to an uncoiled, extended geometry with a 35% longer head-to-tail distance and a much larger overlap between its lateral aromatic ring groups. The free energy barrier for the transition was studied as a function of pressure and temperature for both solute molecules in butane and hexadecane. Gas-phase density functional theory-based nudged elastic band calculations on 8-mer and 10-mer o-phenylene were used to estimate how the pressure-induced transition energy barrier changes with solute length. Our results indicate that a sufficiently large solvent molecule size is the key factor enabling a configuration transition upon pressure changes and that longer solute molecules associate with higher conformation transition energy barriers. This suggests the possibility of designing systems in which a solute molecule can be selectively "activated" by a controlled conformation transition achieved at a predefined set of pressure and temperature conditions. PMID:25380225

  14. Conformational transitions of single polymer adsorption in poor solvent: Wetting transition due to molecular confinement induced line tension

    NASA Astrophysics Data System (ADS)

    Wei, Hsien-Hung; Li, Yen-Ching

    2016-07-01

    We report a theory capable of describing conformational transitions for single polymer adsorption in a poor solvent. We show that an additional molecular confinement effect near the contact line can act exactly like line tension, playing a critical role in the behavior of an absorbed polymer chain. Using this theory, distinct conformational states: desorbed globule (DG), surface attached cap (SAC), and adsorbed lens (AL), can be vividly revealed, resembling the drying-wetting transition of a nanodroplet. But the transitions between these states can behave rather differently from those in the usual wetting transitions. The DG-SAC transition is discrete, occurring at the adsorption threshold when the globule size at the desorbed state is equal to the adsorption blob. The SAC-AL transition is smooth for finite chain lengths, but can change to discontinuous in the infinite chain limit, characterized by the different end-to-end exponent 3/8 and the unique crossover exponent 1/4. Distinctive critical exponents near this transition are also determined, indicating that it is an additional universality class of phase transitions. This work also sheds light on nanodrop spreading, wherein the important role played by line tension might simply be a manifestation of the local molecular confinement near the contact line.

  15. Conformational transitions of single polymer adsorption in poor solvent: Wetting transition due to molecular confinement induced line tension.

    PubMed

    Wei, Hsien-Hung; Li, Yen-Ching

    2016-07-01

    We report a theory capable of describing conformational transitions for single polymer adsorption in a poor solvent. We show that an additional molecular confinement effect near the contact line can act exactly like line tension, playing a critical role in the behavior of an absorbed polymer chain. Using this theory, distinct conformational states: desorbed globule (DG), surface attached cap (SAC), and adsorbed lens (AL), can be vividly revealed, resembling the drying-wetting transition of a nanodroplet. But the transitions between these states can behave rather differently from those in the usual wetting transitions. The DG-SAC transition is discrete, occurring at the adsorption threshold when the globule size at the desorbed state is equal to the adsorption blob. The SAC-AL transition is smooth for finite chain lengths, but can change to discontinuous in the infinite chain limit, characterized by the different end-to-end exponent 3/8 and the unique crossover exponent 1/4. Distinctive critical exponents near this transition are also determined, indicating that it is an additional universality class of phase transitions. This work also sheds light on nanodrop spreading, wherein the important role played by line tension might simply be a manifestation of the local molecular confinement near the contact line. PMID:27575170

  16. Conformation transitions of a polyelectrolyte chain: a replica-exchange Monte-Carlo study.

    PubMed

    Chi, Peng; Li, Baohui; Shi, An-Chang

    2011-08-01

    The thermodynamic behavior of a strongly charged polyelectrolyte chain immersed in a salt-free solution is studied using replica-exchange Monte-Carlo simulations. The results reveal that the chain can assume a variety of conformations, and it undergoes two phase transitions upon cooling. The first transition is identified as a continuous counterion condensation transition while the second one as a first-order coil-globule transition. In the globular state, the counterions and the charged chain segments are densely packed forming a three-dimensional Wigner crystal.

  17. Constrained proper sampling of conformations of transition state ensemble of protein folding.

    PubMed

    Lin, Ming; Zhang, Jian; Lu, Hsiao-Mei; Chen, Rong; Liang, Jie

    2011-02-21

    Characterizing the conformations of protein in the transition state ensemble (TSE) is important for studying protein folding. A promising approach pioneered by Vendruscolo et al. [Nature (London) 409, 641 (2001)] to study TSE is to generate conformations that satisfy all constraints imposed by the experimentally measured φ values that provide information about the native likeness of the transition states. Faísca et al. [J. Chem. Phys. 129, 095108 (2008)] generated conformations of TSE based on the criterion that, starting from a TS conformation, the probabilities of folding and unfolding are about equal through Markov Chain Monte Carlo (MCMC) simulations. In this study, we use the technique of constrained sequential Monte Carlo method [Lin et al., J. Chem. Phys. 129, 094101 (2008); Zhang et al. Proteins 66, 61 (2007)] to generate TSE conformations of acylphosphatase of 98 residues that satisfy the φ-value constraints, as well as the criterion that each conformation has a folding probability of 0.5 by Monte Carlo simulations. We adopt a two stage process and first generate 5000 contact maps satisfying the φ-value constraints. Each contact map is then used to generate 1000 properly weighted conformations. After clustering similar conformations, we obtain a set of properly weighted samples of 4185 candidate clusters. Representative conformation of each of these cluster is then selected and 50 runs of Markov chain Monte Carlo (MCMC) simulation are carried using a regrowth move set. We then select a subset of 1501 conformations that have equal probabilities to fold and to unfold as the set of TSE. These 1501 samples characterize well the distribution of transition state ensemble conformations of acylphosphatase. Compared with previous studies, our approach can access much wider conformational space and can objectively generate conformations that satisfy the φ-value constraints and the criterion of 0.5 folding probability without bias. In contrast to previous

  18. Molecular Dynamics Simulations of Factor Xa: Insight into Conformational Transition of its Binding Subsites

    PubMed Central

    Singh, Narender; Briggs, James M.

    2016-01-01

    Protein flexibility and conformational diversity is well known to be a key characteristic of the function of many proteins. Human blood coagulation proteins have multiple substrates, and various protein-protein interactions are required for the smooth functioning of the coagulation cascade to maintain blood hemostasis. To address how a protein may cope with multiple interactions with its structurally diverse substrates and the accompanied structural changes that may drive these changes, we studied human Factor X. We employed 20 ns of molecular dynamics (MD) and steered molecular dynamics (SMD) simulations on two different conformational forms of Factor X, open and closed, and observed an interchangeable conformational transition from one to another. This work also demonstrates the roles of various aromatic residues involved in aromatic-aromatic interactions which make this dynamic transition possible. PMID:18680100

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

    PubMed Central

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

    2010-01-01

    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 β1,4-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. PMID:18712827

  20. Parallel Cascade Selection Molecular Dynamics (PaCS-MD) to generate conformational transition pathway.

    PubMed

    Harada, Ryuhei; Kitao, Akio

    2013-07-21

    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.

  1. Statistical Mechanical Theory of Protein Conformation and Its Transition

    NASA Astrophysics Data System (ADS)

    Kobayashi, Yukio; Wako, Hiroshi; Saitô, Nobuhiko

    2007-07-01

    The statistical mechanical theory of the structural transitions of proteins is developed in accordance with the island model by considering the hydrophobic interactions and the entropy factors while connecting the two hydrophobic residues. The proteins treated here are apo-α-lactalbumin (1B9O), lysozyme (1LZ1), ferrocytochrome c (1CYC), cytochrome c (isozyme 1) (1YCC), chymotrypsin inhibitor 2 (2CI2), and ubiquitin (1UBQ). Among them, according to the experiments, 2CI2 and 1UBQ do not exhibit intermediate structures (two-state model), but others do exhibit intermediate structures that are sometimes termed molten globules (three-state model). The theory related to these facts is given in terms of the island model, specifically 1B9O and 1LZ1. The stability or instability of the intermediate structures is explained by the effects of entropy during folding and the amino acid sequence. The intermediate structure is composed of several stable islands, which become unstable during unfolding.

  2. Substrate binding accelerates the conformational transitions and substrate dissociation in multidrug efflux transporter AcrB

    PubMed Central

    Wang, Beibei; Weng, Jingwei; Wang, Wenning

    2015-01-01

    The tripartite efflux pump assembly AcrAB-TolC is the major multidrug resistance transporter in E. coli. The inner membrane transporter AcrB is a homotrimer, energized by the proton movement down the transmembrane electrochemical gradient. The asymmetric crystal structures of AcrB with three monomers in distinct conformational states [access (A), binding (B) and extrusion (E)] support a functional rotating mechanism, in which each monomer of AcrB cycles among the three states in a concerted way. However, the relationship between the conformational changes during functional rotation and drug translocation has not been totally understood. Here, we explored the conformational changes of the AcrB homotrimer during the ABE to BEA transition in different substrate-binding states using targeted MD simulations. It was found that the dissociation of substrate from the distal binding pocket of B monomer is closely related to the concerted conformational changes in the translocation pathway, especially the side chain reorientation of Phe628 and Tyr327. A second substrate binding at the proximal binding pocket of A monomer evidently accelerates the conformational transitions as well as substrate dissociation in B monomer. The acceleration effect of the multi-substrate binding mode provides a molecular explanation for the positive cooperativity observed in the kinetic studies of substrate efflux and deepens our understanding of the functional rotating mechanism of AcrB. PMID:25918513

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

    NASA Astrophysics Data System (ADS)

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

    2014-06-01

    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.

  4. Conformational States of Human Purine Nucleoside Phosphorylase at Rest, at Work and with Transition State Analogues†

    PubMed Central

    Edwards, Achelle A.; Tipton, Jeremiah D.; Brenowitz, Michael D.; Emmett, Mark R.; Marshall, Alan G.; Evans, Gary B.; Tyler, Peter C.; Schramm, Vern L.

    2010-01-01

    Human purine nucleoside phosphorylase (PNP) is a homotrimer binding tightly to the transition state analogues Immucillin-H (ImmH, Kd = 56 pM) and DATMe-ImmH-Immucillin-H (DATMe-ImmH, Kd = 8.6 pM). ImmH binds with a larger entropic penalty than DATMe-ImmH, a chemically more flexible inhibitor. The testable hypothesis is that PNP conformational states are more relaxed (dynamic) with DATMe-ImmH, despite tighter binding than with ImmH. PNP conformations are probed by peptide amide deuterium exchange (HDX) using liquid chromatography high-resolution Fourier transform ion cyclotron resonance mass spectrometry and by sedimentation rates. Catalytically equilibrating Michaelis complexes (PNP•PO4•Inosine ↔ PNP•Hx•R-1-P) and inhibited complexes (PNP•PO4•DATMe-ImmH and PNP•PO4•ImmH) show protection from HDX at 9, 13 and 15 sites per subunit relative to resting PNP (PNP•PO4) in extended incubations. The PNP•PO4•ImmH complex is more compact (by sedimentation rate) than the other complexes. HDX kinetic analysis of ligand-protected sites corresponds to peptides near the catalytic sites. HDX and sedimentation results establish that PNP protein conformation (dynamic motion) correlates more closely to entropy of binding than to affinity. Catalytically active turnover with saturated substrate sites causes less change in HDX and sedimentation rates than binding of transition state analogues. DATMe-ImmH more closely mimics the transition of human PNP than does ImmH, and achieves strong binding interactions at the catalytic site while causing relatively modest alterations of the protein dynamic motion. Transition state analogues causing the most rigid, closed protein conformation are therefore not necessarily the most tightly bound. Close mimics of the transition state are hypothesized to retain enzymatic dynamic motions related to transition state formation. PMID:20108972

  5. Multicanonical simulation of biomolecules and microcanonical statistical analysis of conformational transitions

    NASA Astrophysics Data System (ADS)

    Bachmann, Michael

    2013-05-01

    The simulation of biomolecular structural transitions such as folding and aggregation does not only require adequate models that reflect the key aspects of the cooperative transition behaviour. It is likewise important to employ thermodynamically correct simulation methods and to perform an accurate subsequent statistical analysis of the data obtained in the simulation. The efficient combination of methodology and analysis can be quite sophisticated, but also very instructive in their feedback to a better understanding of the physics of the underlying cooperative processes that drive the conformational transition. We here show that the density of states, which is the central result of multicanonical sampling and any other generalized-ensemble simulation, serves as the optimal basis for the microcanonical statistical analysis of transitions. The microcanonical inflection-point analysis method, which has been introduced for this purpose recently, is a perfect tool for a precise, unique identification and classification of all structural transitions.

  6. Conformational Transition Pathways in Signaling and Enzyme Catalysis Explored by Computational Methods

    NASA Astrophysics Data System (ADS)

    Pachov, Dimitar V.

    Biomolecules are dynamic in nature and visit a number of states while performing their biological function. However, understanding how they interconvert between functional substates is a challenging task. In this thesis, we employ enhanced computational strategies to reveal in atomistic resolution transition states and molecular mechanism along conformational pathways of the signaling protein Nitrogen Regulatory Protein C (NtrC) and the enzyme Adenylate Kinase (Adk). Targeted Molecular Dynamics (TMD) simulations and NMR experiments have previously found the active/inactive interconversion of NtrC is stabilized by non-native transient contacts. To find where along the conformational pathway they lie and probe the existence of multiple intermediates, a beyond 8mus-extensive mapping of the conformational landscape was performed by a multitude of straightforward MD simulations relaxed from the biased TMD pathway. A number of metastable states stabilized by local interactions was found to underline the conformational pathway of NtrC. Two spontaneous transitions of the last stage of the active-to-inactive conversion were identified and used in path sampling procedures to generate an ensemble of truly dynamic reactive pathways. The transition state ensemble (TSE) and mechanistic descriptors of this transition were revealed in atomic detail and verified by committor analysis. By analyzing how pressure affects the dynamics and function of two homologous Adk proteins - the P.Profundum Adk surviving at 700atm pressure in the deep sea, and the E. coli Adk that lives at ambient pressures - we indirectly obtained atomic information about the TSE of the large-amplitude rate-limiting conformational opening of the Adk lids. Guided by NMR experiments showing significantly decreased activation volumes of the piezophile compared to its mesophilic counterpart, TMD simulations revealed the formation of an extended hydrogen-bonded water network in the transition state of the piezophile

  7. Finite-Size Conformational Transitions: A Unifying Concept Underlying Chromosome Dynamics

    NASA Astrophysics Data System (ADS)

    Bertrand, R. Caré; Pascal, Carrivain; Thierry, Forné; Jean-Marc, Victor; Annick, Lesne

    2014-10-01

    Investigating average thermodynamic quantities is not sufficient to understand conformational transitions of a finite-size polymer. We propose that such transitions are better described in terms of the probability distribution of some finite-size order parameter, and the evolution of this distribution as a control parameter varies. We demonstrate this claim for the coil-globule transition of a linear polymer and its mapping onto a two-state model. In a biological context, polymer models delineate the physical constraints experienced by the genome at different levels of organization, from DNA to chromatin to chromosome. We apply our finite-size approach to the formation of plectonemes in a DNA segment submitted to an applied torque and the ensuing helix-coil transition that can be numerically observed, with a coexistence of the helix and coil states in a range of parameters. Polymer models are also essential to analyze recent in vivo experiments providing the frequency of pairwise contacts between genomic loci. The probability distribution of these contacts yields quantitative information on the conformational fluctuations of chromosome regions. The changes observed in the shape of the distribution when the cell type or the physiological conditions vary may reveal an epigenetic modulation of the conformational constraints experienced by the chromosomes.

  8. Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases.

    PubMed

    Wong, Chung F

    2016-01-01

    This short article examines the usefulness of fast simulations of conformational transition paths in elucidating enzymatic mechanisms and guiding drug discovery for protein kinases. It applies the transition path method in the MOIL software package to simulate the paths of conformational transitions between six pairs of structures from the Protein Data Bank. The structures along the transition paths were found to resemble experimental structures that mimic transient structures believed to form during enzymatic catalysis or conformational transitions, or structures that have drug candidates bound. These findings suggest that such simulations could provide quick initial insights into the enzymatic mechanisms or pathways of conformational transitions of proteins kinases, or could provide structures useful for aiding structure-based drug design.

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

    PubMed

    Moradi, Mahmoud; Tajkhorshid, Emad

    2013-11-19

    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. PMID:24191018

  10. Multivariate curve resolution: a powerful tool for the analysis of conformational transitions in nucleic acids

    PubMed Central

    Jaumot, Joaquim; Escaja, Núria; Gargallo, Raimundo; González, Carlos; Pedroso, Enrique; Tauler, Romà

    2002-01-01

    A successful application is reported of the multivariate curve resolution alternating least-squares method (MCR-ALS) for the analysis of nucleic acid melting and salt-induced transitions. Under conditions where several structures co-exist in a conformational equilibrium, MCR-ALS analysis of the UV and circular dichroism (CD) spectra at different temperatures, ionic strength and oligonucleotide concentration allows for the resolution of concentration profiles and pure spectra of the different species. The methodology is illustrated by the case of the cyclic oligonucleotide d. The melting transition of this molecule at different oligonucleotide concentrations was studied at 0, 2 and 10 mM MgCl2 by UV and CD spectroscopy. In addition, salt titration experiments were carried out at 21.0 and 54.0°C. The MCR-ALS analysis indicates that three different conformations of this molecule co-exist in solution. In agreement with previous NMR studies, these conformations were assigned to a monomeric dumbbell-like structure, a dimeric four-stranded conformation and a disordered (random coil) structure. The MCR-ALS methodology allows for a detailed analysis of how this equilibrium is affected by temperature, salt and oligonucleotide concentration. PMID:12202780

  11. Conformational and phase transitions in DNA--photosensitive surfactant solutions: Experiment and modeling.

    PubMed

    Kasyanenko, N; Lysyakova, L; Ramazanov, R; Nesterenko, A; Yaroshevich, I; Titov, E; Alexeev, G; Lezov, A; Unksov, I

    2015-02-01

    DNA binding to trans- and cis-isomers of azobenzene containing cationic surfactant in 5 mM NaCl solution was investigated by the methods of dynamic light scattering (DLS), low-gradient viscometry (LGV), atomic force microscopy (AFM), circular dichroism (CD), gel electrophoresis (GE), flow birefringence (FB), UV-Vis spectrophotometry. Light-responsive conformational transitions of DNA in complex with photosensitive surfactant, changes in DNA optical anisotropy and persistent length, phase transition of DNA into nanoparticles induced by high surfactant concentration, as well as transformation of surfactant conformation under its binding to macromolecule were studied. Computer simulations of micelles formation for cis- and trans-isomers of azobenzene containing surfactant, as well as DNA-surfactant interaction, were carried out. Phase diagram for DNA-surfactant solutions was designed. The possibility to reverse the DNA packaging induced by surfactant binding with the dilution and light irradiation was shown.

  12. Binding to the lipid monolayer induces conformational transition in Aβ monomer.

    PubMed

    Kim, Seongwon; Klimov, Dmitri K

    2013-02-01

    Using implicit solvent atomistic model and replica exchange molecular dynamics, we study binding of Aβ monomer to zwitterionic dimyristoylphosphatidylcholine (DMPC) lipid monolayer. Our results suggest that Aβ binding to the monolayer is governed primarily by positively charged and aromatic amino acids. Lysine residues tend to interact with surface choline and phosphorous lipid groups, whereas aromatic amino acids penetrate deeper into the monolayer, reaching its hydrophobic core. We show that binding to the DMPC monolayer causes a dramatic conformational transition in Aβ monomer, resulting in chain extension, loss of intrapeptide interactions, and formation of β-structure. This conformational transition is far more significant than that occurring during the initial stages of aggregation in water. We also found that Aβ binding perturbs surface ordering of lipids interacting with Aβ. PMID:23053007

  13. A transferable coarse-grained model for diphenylalanine: How to represent an environment driven conformational transition

    SciTech Connect

    Dalgicdir, Cahit; Sensoy, Ozge; Sayar, Mehmet; Peter, Christine

    2013-12-21

    One of the major challenges in the development of coarse grained (CG) simulation models that aim at biomolecular structure formation processes is the correct representation of an environment-driven conformational change, for example, a folding/unfolding event upon interaction with an interface or upon aggregation. In the present study, we investigate this transferability challenge for a CG model using the example of diphenylalanine. This dipeptide displays a transition from a trans-like to a cis-like conformation upon aggregation as well as upon transfer from bulk water to the cyclohexane/water interface. Here, we show that one can construct a single CG model that can reproduce both the bulk and interface conformational behavior and the segregation between hydrophobic/hydrophilic medium. While the general strategy to obtain nonbonded interactions in the present CG model is to reproduce solvation free energies of small molecules representing the CG beads in the respective solvents, the success of the model strongly depends on nontrivial decisions one has to make to capture the delicate balance between the bonded and nonbonded interactions. In particular, we found that the peptide's conformational behavior is qualitatively affected by the cyclohexane/water interaction potential, an interaction that does not directly involve the peptide at all but merely influences the properties of the hydrophobic/hydrophilic interface. Furthermore, we show that a small modification to improve the structural/conformational properties of the CG model could dramatically alter the thermodynamic properties.

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

    SciTech Connect

    Solberg, Jerome Michael

    2012-12-04

    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.

  15. Deconfined quantum criticality and conformal phase transition in two-dimensional antiferromagnets

    NASA Astrophysics Data System (ADS)

    Nogueira, Flavio S.; Sudbø, Asle

    2013-12-01

    Deconfined quantum criticality of two-dimensional SU(2) quantum antiferromagnets featuring a transition from an antiferromagnetically ordered ground state to a so-called valence-bond solid state, is governed by a non-compact CP1 model with a Maxwell term in 2+1 spacetime dimensions. We introduce a new perspective on deconfined quantum criticality within a field-theoretic framework based on an expansion in powers of \\epsilon=4-d for fixed number N of complex matter fields. We show that in the allegedly weak first-order transition regime, a so-called conformal phase transition leads to a genuine deconfined quantum critical point. In such a transition, the gap vanishes when the critical point is approached from above and diverges when it is approached from below. We also find that the spin stiffness has a universal jump at the critical point.

  16. The conformational transition pathway of ATP binding cassette transporter MsbA revealed by atomistic simulations.

    PubMed

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

    2010-01-29

    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.

  17. Conformational Transitions in β-Lactoglobulin Induced by Cationic Amphiphiles: Equilibrium Studies

    PubMed Central

    Viseu, Maria Isabel; Carvalho, Teresa Isabel; Costa, Sílvia M. B.

    2004-01-01

    The conformational transition from the native state in water (“β-state”) to a state containing a considerable amount of α-helices (“α-state”) was studied for the protein β-lactoglobulin (BLG), from bovine milk, in several colloidal solutions containing mixed micelles or spontaneous vesicles. These aggregates were formed in the bicationic system containing the surfactant dodecyltrimethylammonium chloride (DTAC) and the lipid didodecyldimethylammonium bromide (DDAB). The β→α transition in BLG, investigated by far-ultraviolet circular dichroism spectroscopy, is induced to the same protein α-state by pure and mixed DDAB/DTAC micelles or vesicles. This implies a similar interaction mechanism of BLG with DDAB or DTAC, once the colloidal aggregates are formed. In premicelle DTAC solutions, the fraction of α-helix is lower and increases with the DTAC concentration. DDAB and DTAC also promote conformational changes in the protein tertiary structure that expose the tryptophans to a less constrained environment. These unfolding transitions were investigated by near-ultraviolet circular dichroism and steady-state fluorescence spectroscopies. In equilibrium conditions, it was found that higher DTAC (and, probably, DDAB) concentrations are needed to induce the β→α transition than to unfold the protein. β-Lactoglobulin may therefore be considered as a model for protein–surfactant and protein–lipid interactions. PMID:15041677

  18. Modulation of plasminogen activator inhibitor 1 by Triton X-100--identification of two consecutive conformational transitions.

    PubMed

    Gils, A; Declerck, P J

    1998-08-01

    Plasminogen activator inhibitor-1 (PAI-1) is a unique member of the serpin superfamily because of its conformational and functional flexibility. In the present study, we have evaluated the influence of the non-ionic detergent Triton X-100 (TX-100) on the functional stability and conformational transitions of PAI-1. At 37 degrees C, TX-100 induced a concentration-dependent decrease of the functional half-life of PAI-1 resulting in half-lives of 177 +/- 54 min (mean +/- SD, n = 3), 19 +/- 2 min, 1.7 +/- 0.3 min and 0.53 +/- 0.03 min in the presence of 0.005, 0.010, 0.020 and 0.2% TX-100, respectively, compared to a half-life of 270 +/- 146 min in the absence of TX-100. Conformational analysis at various time points and at different temperatures (0 degrees C, 25 degrees C, 37 degrees C) revealed that this inactivation proceeds through the formation of a substrate-like intermediate followed by the formation of the latent form. Kinetic evaluation demonstrated that this conversion fits to two consecutive first-order transitions, i.e. active k1--> substrate k2--> latent. The k1 value was strongly dependent on the concentration of TX-100 (e.g. 0.002 +/- 0.0006 s(-1) and 0.029 +/- 0.003 s(-1) for 0.01% and 0.2% TX-100 at 37 degrees C) whereas the conversion of substrate to latent (k2) was virtually independent of the TX-100 concentration (i.e. 0.012 +/- 0.002 s(-1) and 0.011 +/- 0.001 s(-1) for 0.01 and 0.2% TX-100 at 37 degrees C). Experiments with a variety of other non-ionic amphiphilic compounds revealed that the amphiphilic character of the compound is, at least in part, responsible for the observed effects and strongly indicate that the currently reported mechanism of inactivation is of general importance for the conformational transitions in PAI-1. In conclusion, TX- 100 changes the initial conformation of PAI-1 resulting in altered functional properties. This observation allows us to develop a new model for the mechanism involved in the conformational flexibility of

  19. Conformational Transitions and Glycation of Serum Albumin in Patients with Minimal-Change Glomerulopathy

    PubMed Central

    Hong, Sae Yong; Lee, Eun Young; Yang, Jong Oh; Kim, Tae Yeong; Kim, Eun Hee; Cheong, Mi Young; Kim, Soo Hyun; Cheong, Chae Joon

    2004-01-01

    Background There has been a lack of study on the structural changes of serum albumin in patients with minimal change disease (MCD). To determine whether glycation and/or conformational transitions of albumin are involved in the pathogenesis of albuminuria, nine patients with MCD were enrolled in a prospective follow-up study for comparison of these parameters in serum albumin during the remission and relapse of nephrotic syndrome. Methods Circular dichroism measurements were made with purified albumin. Ellipticities at each wavelength were transformed to mean residue ellipticity. Monosaccharide composition was analyzed by high-pH anion-exchange chromatography with pulsed amperometric detection. Results There was no difference in the proportions of α-helix, β-conformation, and β-turn of albumin between the sera of control patients and those with nephrotic syndrome. However, the proportion of the random configuration was slightly higher in the plasma albumin of patients in relapse than in those in remission. The proportion of the random configuration was lower in the albumin of the serum than in the urine of patients with nephrotic syndrome, but there was no difference in the proportions of α-helix, β-conformation, and β-turn of albumin between their plasma and urine. Conclusion Our results suggest that conformational changes in albumin are involved in albuminuria in patients with MCD. PMID:15481604

  20. Mapping the Structure and Conformational Movements of Proteins with Transition Metal Ion FRET

    SciTech Connect

    Taraska, J.; Puljung, M; Olivier, N; Olivier, G; Zagotta, W

    2009-01-01

    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 fluorescence resonance energy transfer (FRET) between a small fluorescent dye and a nickel ion bound to a dihistidine 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. Our results suggest a general model for the conformational switch in the cyclic nucleotide-binding site of cyclic nucleotide-regulated ion channels.

  1. Conformational transitions of plasmid ds-DNA on ultrathin films of alkylamines on graphite

    NASA Astrophysics Data System (ADS)

    Falk, Caroline; Liang, Hua; Severin, Nikolai; Zhuang, Wei; Zauscher, Stefan; Rabe, Jürgen P.

    2015-03-01

    DNA replication is an important process in the human body. Replication of double-stranded (ds)-DNA requires its local melting into two single strands. DNA, when stretched in solution, overwinds and melts. This was argued to give insight onto the replication mechanism. It is difficult, however, to access the direct conformational changes during stretching in solution. Recent work demonstrated that this transition can be imaged with scanning force microscopy on a graphite surface that is coated with an alkylamine layer. ds-DNA can be controlled by an amphiphilic layer, since the DNA conformation depends on the amphiphile concentration. In particular we analyzed different DNA lengths on the same surface, and we found that at a specific concentration of octadecylamine the ds-DNA pUC19 plasmid ring splits into two single strands at one position. We will discuss methods to mark the DNA to determine the exact location at which the plasmid ring splits.

  2. Electronic detection of dsDNA transition from helical to zipper conformation using graphene nanopores

    PubMed Central

    Sathe, Chaitanya; Girdhar, Anuj; Leburton, Jean-Pierre; Schulten, Klaus

    2014-01-01

    Mechanical manipulation of DNA, by forced extension, can lead to a structural transformation of double-stranded DNA (dsDNA) from a helical form to a linear zipper-like form. By employing classical molecular dynamics and quantum mechanical non-equilibrium Greens function-based transport simulations, we show the ability of graphene nanopores to discern different dsDNA conformations, in a helical to zipper transition, using transverse electronic conductance. In particular, conductance oscillations due to helical dsDNA vanish as dsDNA extends from helical to zipper form as it is transported through the nanopore. The predicted ability to detect conformational changes in dsDNA, via transverse electronic conductance, can widen the potential of graphene-based nanosensors for DNA detection. PMID:25325530

  3. Conformational Transitions in Human AP Endonuclease 1 and Its Active Site Mutant during Abasic Site Repair†

    PubMed Central

    Kanazhevskaya, Lyubov Yu.; Koval, Vladimir V.; Zharkov, Dmitry O.; Strauss, Phyllis R.; Fedorova, Olga S.

    2010-01-01

    AP endonuclease 1 (APE 1) is a crucial enzyme of the base excision repair pathway (BER) in human cells. APE1 recognizes apurinic/apyrimidinic (AP) sites and makes a nick in the phosphodiester backbone 5′ to them. The conformational dynamics and presteady-state kinetics of wild-type APE1 and its active site mutant, Y171F-P173L-N174K, have been studied. To observe conformational transitions occurring in the APE1 molecule during the catalytic cycle, we detected intrinsic tryptophan fluorescence of the enzyme under single turnover conditions. DNA duplexes containing a natural AP site, its tetrahydrofuran analogue, or a 2′-deoxyguanosine residue in the same position were used as specific substrates or ligands. The stopped-flow experiments have revealed high flexibility of the APE1 molecule and the complexity of the catalytic process. The fluorescent traces indicate that wild-type APE1 undergoes at least four conformational transitions during the processing of abasic sites in DNA. In contrast, nonspecific interactions of APE1 with undamaged DNA can be described by a two-step kinetic scheme. Rate and equilibrium constants were extracted from the stopped-flow and fluorescence titration data for all substrates, ligands, and products. A replacement of three residues at the enzymatic active site including the replacement of tyrosine 171 with phenylalanine in the enzyme active site resulted in a 2 × 104-fold decrease in the reaction rate and reduced binding affinity. Our data indicate the important role of conformational changes in APE1 for substrate recognition and catalysis. PMID:20575528

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

    PubMed

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

    2011-09-01

    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

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

    PubMed Central

    2013-01-01

    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. PMID:24564964

  6. Allosteric modulation of the human P-glycoprotein involves conformational changes mimicking catalytic transition intermediates.

    PubMed

    Ghosh, Pratiti; Moitra, Karobi; Maki, Nazli; Dey, Saibal

    2006-06-01

    The drug transport function of human P-glycoprotein (Pgp, ABCB1) can be inhibited by a number of pharmacological agents collectively referred to as modulators or reversing agents. In this study, we demonstrate that certain thioxanthene-based Pgp modulators with an allosteric mode of action induce a distinct conformational change in the cytosolic domain of Pgp, which alters susceptibility to proteolytic digestion. Both cis and trans-isomers of the Pgp modulator flupentixol confer considerable protection of an 80 kDa Pgp fragment against trypsin digestion, that is recognized by a polyclonal antibody specific for the NH(2)-terminal half to Pgp. The protection by flupentixol is abolished in the Pgp F983A mutant that is impaired in modulation by flupentixols, indicating involvement of the allosteric site in generating the conformational change. A similar protection to an 80 kDa fragment is conferred by ATP, its nonhydrolyzable analog ATPgammaS, and by trapping of ADP-vanadate at the catalytic domain, but not by transport substrate vinblastine or by the competitive modulator cyclosporin A, suggesting different outcomes from modulator interaction at the allosteric site and at the substrate site. In summary, we demonstrate that allosteric interaction of flupentixols with Pgp generates conformational changes that mimic catalytic transition intermediates induced by nucleotide binding and hydrolysis, which may play a crucial role in allosteric inhibition of Pgp-mediated drug transport.

  7. Conformational flexibility of RecA protein filament: transitions between compressed and stretched states.

    PubMed

    Petukhov, Michael; Lebedev, Dmitry; Shalguev, Valery; Islamov, Akhmed; Kuklin, Aleksandr; Lanzov, Vladislav; Isaev-Ivanov, Vladimir

    2006-11-01

    RecA protein is a central enzyme in homologous DNA recombination, repair and other forms of DNA metabolism in bacteria. It functions as a flexible helix-shaped filament bound on stretched single-stranded or double-stranded DNA in the presence of ATP. In this work, we present an atomic level model for conformational transitions of the RecA filament. The model describes small movements of the RecA N-terminal domain due to coordinated rotation of main chain dihedral angles of two amino acid residues (Psi/Lys23 and Phi/Gly24), while maintaining unchanged the RecA intersubunit interface. The model is able to reproduce a wide range of observed helix pitches in transitions between compressed and stretched conformations of the RecA filament. Predictions of the model are in agreement with Small Angle Neutron Scattering (SANS) measurements of the filament helix pitch in RecA::ADP-AlF(4) complex at various salt concentrations. PMID:16909421

  8. Conformational transitions of cytochrome c in sub-micron-sized capsules at air/buffer interface.

    PubMed

    Jaganathan, Maheshkumar; Dhathathreyan, Aruna

    2014-09-30

    This work presents the design of sub-micron-sized capsules of Cytochrome c (cyt c) in the range 300-350 nm and the conformational transitions of the protein that occur when the films of these capsules spread at the air/buffer interface are subjected to repeated compression-expansion cycles. Steady state fluorescence, time-resolved fluorescence, and circular dichroic (CD) spectra have been used to study the highly compact native conformation (70% helicity) of the protein in the capsules and its stability has been analyzed using cyclic voltammetry. The capsules have been characterized using zeta sizer and high resolution transmission electron microscopy (HRTEM). Surface concentration-surface pressure (Γ-π) isotherms of the films of the capsules spread at air/buffer interface following compression-expansion show destabilizing effect on cyt c. FTIR and CD spectra of these films skimmed from the surface show that the protein transitions gradually from its native helical to an anomalous beta sheet aggregated state. This results from a competition between stabilizing hydrated polar segments of the protein in the capsule and destabilizing nonspecific hydrophobic interactions arising at the air/buffer interface. This 2D model could further our understanding of the spatial and temporal roles of proteins in confined spaces and also in the design of new drug delivery vehicles using proteins.

  9. Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway.

    PubMed

    U, Kin Pong; Subramanian, Venkataraman; Nicholas, Antony P; Thompson, Paul R; Ferretti, Patrizia

    2014-06-01

    PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.

  10. Distinguishing Unfolding and Functional Conformational Transitions of Calmodulin Using Ultraviolet Resonance Raman Spectroscopy

    SciTech Connect

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

    2014-06-14

    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 paper, 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 Ca2+ binding. This spectral difference is entirely due to differences in teritary contacts at the inter-domain 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.

  11. Conformational transitions of cinnamoyl CoA reductase 1 from Leucaena leucocephala.

    PubMed

    Sonawane, Prashant D; Khan, Bashir M; Gaikwad, Sushama M

    2014-03-01

    Conformational transitions of cinnamoyl CoA reductase, a key regulatory enzyme in lignin biosynthesis, from Leucaena leucocephala (Ll-CCRH1) were studied using fluorescence and circular dichroism spectroscopy. The native protein possesses four trp residues exposed on the surface and 66% of helical structure, undergoes rapid structural transitions at and above 45 °C and starts forming aggregates at 55 °C. Ll-CCRH1 was transformed into acid induced (pH 2.0) molten globule like structure, exhibiting altered secondary structure, diminished tertiary structure and exposed hydrophobic residues. The molten globule like structure was examined for the thermal and chemical stability. The altered secondary structure of L1-CCRH1 at pH 2.0 was stable up to 90 °C. Also, in presence of 0.25 M guanidine hydrochloride (GdnHCl), it got transformed into different structure which was stable in the vicinity of 2M GdnHCl (as compared to drastic loss of native structure in 2M GdnHCl) as seen in far UV-CD spectra. The structural transition of Ll-CCRH1 at pH 2.0 followed another transition after readjusting the pH to 8.0, forming a structure with hardly any similarity to that of native protein. PMID:24309513

  12. Mutation in the SH1 helix reduces the activation energy of the ATP-induced conformational transition of myosin.

    PubMed

    Iwai, Sosuke; Chaen, Shigeru

    2007-05-25

    The SH1 helix is a joint that links the converter subdomain to the rest of the myosin motor domain. Recently, we showed that a mutation within the SH1 helix in Dictyostelium myosin II (R689H) reduced the elasticity and thermal stability of the protein. To reveal the involvement of the SH1 helix in ATP-dependent conformational changes of the motor domain, we have investigated the effects of the R689H mutation on the conformational changes of the converter, using a GFP-based fluorescence resonance energy transfer method. Although the mutation does not seem to strongly affect conformations, we found that it significantly reduced the activation energy required for the ATP-induced conformational transition corresponding to the recovery stroke. Given the effects of the mutation on the mechanical properties of myosin, we propose that the SH1 helix plays an important role in the mechanochemical energy conversion underlying the conformational change of the myosin motor domain.

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

    PubMed Central

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

    2011-01-01

    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. PMID:21423709

  14. Interaction between cyclodextrin and neuronal membrane results in modulation of GABAA receptor conformational transitions

    PubMed Central

    Pytel, Maria; Mercik, Katarzyna; Mozrzymas, Jerzy W

    2006-01-01

    Cyclodextrins (CDs) are nanostructures widely applied in biotechnology and chemistry. Owing to partially hydrophobic character, CDs interact with biological membranes. While the mechanisms of CDs interactions with lipids were widely studied, their effects on proteins are less understood. In the present study we investigated the effects of beta cyclodextrin (βCD) on GABAA receptor (GABAAR) gating. To reliably resolve the kinetics of conformational transitions, currents were elicited by ultrafast gamma-aminobutyric acid (GABA) applications to outside-out patches from rat cultured hippocampal neurons. βCD increased the amplitude of responses to saturating GABA concentration ([GABA]) in a dose-dependent manner and this effect was accompanied by profound alterations in the current kinetics. Current deactivation was slowed down by βCD but this effect was biphasic with a maximum at around 0.5 mM βCD. While the fast deactivation time constant was monotonically slowed down within considered βCD concentration range, the slow component first increased and then, at millimolar βCD concentration, decreased. The rate and extent of desensitization was decreased by βCD in a dose-dependent manner. The analysis of current responses to nonsaturating [GABA] indicated that βCD affected the GABAAR agonist binding site by slowing down the unbinding rate. Modulation of GABAAR desensitization and binding showed different concentration-dependence suggesting different modualtory sites with higher affinity of the latter one. All the βCD effects were fully reversible indicating that cholesterol uptake into βCD was not the primary mechanism. We conclude that βCD is a strong modulator of GABAAR conformational transitions. PMID:16702996

  15. Interaction between cyclodextrin and neuronal membrane results in modulation of GABA(A) receptor conformational transitions.

    PubMed

    Pytel, Maria; Mercik, Katarzyna; Mozrzymas, Jerzy W

    2006-06-01

    Cyclodextrins (CDs) are nanostructures widely applied in biotechnology and chemistry. Owing to partially hydrophobic character, CDs interact with biological membranes. While the mechanisms of CDs interactions with lipids were widely studied, their effects on proteins are less understood. In the present study we investigated the effects of beta cyclodextrin (betaCD) on GABA(A) receptor (GABA(A)R) gating. To reliably resolve the kinetics of conformational transitions, currents were elicited by ultrafast gamma-aminobutyric acid (GABA) applications to outside-out patches from rat cultured hippocampal neurons. betaCD increased the amplitude of responses to saturating GABA concentration ([GABA]) in a dose-dependent manner and this effect was accompanied by profound alterations in the current kinetics. Current deactivation was slowed down by betaCD but this effect was biphasic with a maximum at around 0.5 mM betaCD. While the fast deactivation time constant was monotonically slowed down within considered betaCD concentration range, the slow component first increased and then, at millimolar betaCD concentration, decreased. The rate and extent of desensitization was decreased by betaCD in a dose-dependent manner. The analysis of current responses to nonsaturating [GABA] indicated that betaCD affected the GABA(A)R agonist binding site by slowing down the unbinding rate. Modulation of GABA(A)R desensitization and binding showed different concentration-dependence suggesting different modualtory sites with higher affinity of the latter one. All the betaCD effects were fully reversible indicating that cholesterol uptake into betaCD was not the primary mechanism. We conclude that betaCD is a strong modulator of GABA(A)R conformational transitions.

  16. Functional and conformational transitions of mevalonate diphosphate decarboxylase from Bacopa monniera.

    PubMed

    Abbassi, Shakeel; Patel, Krunal; Khan, Bashir; Bhosale, Siddharth; Gaikwad, Sushama

    2016-02-01

    Functional and conformational transitions of mevalonate diphosphate decarboxylase (MDD), a key enzyme of mevalonate pathway in isoprenoid biosynthesis, from Bacopa monniera (BmMDD), cloned and overexpressed in Escherichia coli were studied under thermal, chemical and pH-mediated denaturation conditions using fluorescence and Circular dichroism spectroscopy. Native BmMDD is a helix dominant structure with 45% helix and 11% sheets and possesses seven tryptophan residues with two residues exposed on surface, three residues partially exposed and two situated in the interior of the protein. Thermal denaturation of BmMDD causes rapid structural transitions at and above 40°C and transient exposure of hydrophobic residues at 50°C, leading to aggregation of the protein. An acid induced molten globule like structure was observed at pH 4, exhibiting altered but compact secondary structure, distorted tertiary structure and exposed hydrophobic residues. The molten globule displayed different response at higher temperature and similar response to chemical denaturation as compared to the native protein. The surface tryptophans have predominantly positively charged amino acids around them, as indicated by higher KSV for KI as compared to that for CsCl. The native enzyme displayed two different lifetimes, τ1 (1.203±0.036 ns) and τ2 (3.473±0.12 ns) indicating two populations of tryptophan.

  17. Distinct Conformational Transition Patterns of Noncoding 7SK snRNA and HIV TAR RNAs upon Tat Binding

    PubMed Central

    2015-01-01

    Noncoding 7SK snRNA is believed to play an important role in the recruitment of P-TEFb by viral protein Tat to stimulate HIV processive transcription. Because HIV-2 TAR RNA and 7SK both evolved to feature a dinucleotide bulge region, compared to the trinucleotide bulge for HIV-1 TAR, ultrafast time-resolved fluorescence spectroscopy has been used to probe the conformational landscape of HIV-2 TAR and 7SK-SL4 RNA to monitor the conformational changes upon Tat binding. Our studies demonstrate that both HIV-1/2 TAR and 7SK-SL4 sample heterogeneous ensembles in the free state and undergo distinct conformational transitions upon Tat binding. These findings provide exquisite knowledge on the conformational complexity and intricate mechanism of molecular recognition and pave the way for drug design and discovery that incorporate dynamics information. PMID:24422492

  18. Conformational transitions in the calcium adenosinetriphosphatase studied by time-resolved fluorescence resonance energy transfer.

    PubMed

    Birmachu, W; Nisswandt, F L; Thomas, D D

    1989-05-01

    We have used time-resolved fluorescence to study proposed conformational transitions in the Ca-ATPase in skeletal sarcoplasmic reticulum (SR). Resonance energy transfer was used to measure distances between the binding sites of 5-[[2-[(iodoacetyl)amino]ethyl]amino]naphthalene-1-sulfonic acid (IAEDANS) and fluorescein 5-isothiocyanate (FITC) as a function of conditions proposed to affect the enzyme's conformation. When 1.0 +/- 0.15 IAEDANS is bound per Ca-ATPase, most (76 +/- 4%) of the probes have an excited-state lifetime (tau) of 18.6 +/- 0.5 ns, and the remainder have a lifetime of 2.5 +/- 0.9 ns. When FITC is bound to a specific site on each IAEDANS-labeled enzyme, most of the long-lifetime component is quenched into two short-lifetime components, indicating energy transfer that corresponds to two donor-acceptor distances. About one-third of the quenched population has a lifetime tau = 11.1 +/- 2.5 ns, corresponding to a transfer efficiency E = 0.40 +/- 0.07 and a donor-acceptor distance R1 = 52 +/- 3 A. The remaining two-thirds exhibit lifetimes in the range of 1.2-4.2 ns, corresponding to a second distance 31 A less than or equal to R2 less than or equal to 40 A. Addition of Ca2+ (in the micromolar to millimolar range), or vanadate (to produce a phosphoenzyme analogue), had no effect on the donor-acceptor distances. Addition of decavanadate results in the quenching of IAEDANS fluorescence but has no effect on the energy-transfer distance.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Proposed temperature-dependent conformational transition in D-amino acid oxidase: a differential scanning microcalorimetric study.

    PubMed Central

    Sturtevant, J M; Mateo, P L

    1978-01-01

    A number of authors have reported observations on D-amino acid oxidase [D-amino acid: O2 oxidoreductase (deaminating), EC 1.4.3.3.] that they have interpreted in terms of a temperature-dependent conformational transition having a van't Hoff enthalpy amounting to more than 1 cal per g of protein (1 cal = 4.184J). No indication of this transition is obtained by using a differential scanning calorimeter having a sensitivity considerably in excess of that required to detect such a transition. The implications of this discrepancy are discussed. PMID:26913

  20. Computational Study of the “DFG-Flip” Conformational Transition in c-Abl and c-Src Tyrosine Kinases

    PubMed Central

    2015-01-01

    Protein tyrosine kinases are crucial to cellular signaling pathways regulating cell growth, proliferation, metabolism, differentiation, and migration. To maintain normal regulation of cellular signal transductions, the activities of tyrosine kinases are also highly regulated. The conformation of a three-residue motif Asp-Phe-Gly (DFG) near the N-terminus of the long “activation” loop covering the catalytic site is known to have a critical impact on the activity of c-Abl and c-Src tyrosine kinases. A conformational transition of the DFG motif can switch the enzyme from an active (DFG-in) to an inactive (DFG-out) state. In the present study, the string method with swarms-of-trajectories was used to computationally determine the reaction pathway connecting the two end-states, and umbrella sampling calculations were carried out to characterize the thermodynamic factors affecting the conformations of the DFG motif in c-Abl and c-Src kinases. According to the calculated free energy landscapes, the DFG-out conformation is clearly more favorable in the case of c-Abl than that of c-Src. The calculations also show that the protonation state of the aspartate residue in the DFG motif strongly affects the in/out conformational transition in c-Abl, although it has a much smaller impact in the case of c-Src due to local structural differences. PMID:25548962

  1. [Dynamics of electron-conformational transitions in proteins and physical mechanisms of biomacromolecule function].

    PubMed

    Shaĭtan, K V

    1992-01-01

    The proteins can be considered as a microheterogeneous structured media possessing memory and feedback properties. The conformational energy surface depends on the chemical states of protein groups. Conformational motions are local diffusion with relaxation times much longer than vibrational relaxation times in condensed media. Owing to the hierarchy of relaxation times chemical reaction rates depend on conformation parametrically. Regulation of functional activity by conformational mobility is accomplished via transmission of information in the form of changes in the distribution functions of separate groups along the conformational substates. The interpretation of drastic effects on conformational mobility needs super-stochastic approaches. A possible mechanism of sharp conformational change are discussed in terms of the catastrophe theory.

  2. Enhancing pairwise state-transition weights: A new weighting scheme in simulated tempering that can minimize transition time between a pair of conformational states

    NASA Astrophysics Data System (ADS)

    Qiao, Qin; Zhang, Hou-Dao; Huang, Xuhui

    2016-04-01

    Simulated tempering (ST) is a widely used enhancing sampling method for Molecular Dynamics simulations. As one expanded ensemble method, ST is a combination of canonical ensembles at different temperatures and the acceptance probability of cross-temperature transitions is determined by both the temperature difference and the weights of each temperature. One popular way to obtain the weights is to adopt the free energy of each canonical ensemble, which achieves uniform sampling among temperature space. However, this uniform distribution in temperature space may not be optimal since high temperatures do not always speed up the conformational transitions of interest, as anti-Arrhenius kinetics are prevalent in protein and RNA folding. Here, we propose a new method: Enhancing Pairwise State-transition Weights (EPSW), to obtain the optimal weights by minimizing the round-trip time for transitions among different metastable states at the temperature of interest in ST. The novelty of the EPSW algorithm lies in explicitly considering the kinetics of conformation transitions when optimizing the weights of different temperatures. We further demonstrate the power of EPSW in three different systems: a simple two-temperature model, a two-dimensional model for protein folding with anti-Arrhenius kinetics, and the alanine dipeptide. The results from these three systems showed that the new algorithm can substantially accelerate the transitions between conformational states of interest in the ST expanded ensemble and further facilitate the convergence of thermodynamics compared to the widely used free energy weights. We anticipate that this algorithm is particularly useful for studying functional conformational changes of biological systems where the initial and final states are often known from structural biology experiments.

  3. Teaching Calcium-Induced Calcium Release in Cardiomyocytes Using a Classic Paper by Fabiato

    ERIC Educational Resources Information Center

    Liang, Willmann

    2008-01-01

    This teaching paper utilizes the materials presented by Dr. Fabiato in his review article entitled "Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum." In the review, supporting evidence of calcium-induced calcium release (CICR) is presented. Data concerning potential objections to the CICR theory are discussed as well. In…

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

    NASA Astrophysics Data System (ADS)

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

    2007-10-01

    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.

  5. An allolactose trapped at the lacZ β-galactosidase active site with its galactosyl moiety in a (4)H3 conformation provides insights into the formation, conformation, and stabilization of the transition state.

    PubMed

    Wheatley, Robert W; Huber, Reuben E

    2015-12-01

    When lactose was incubated with G794A-β-galactosidase (a variant with a "closed" active site loop that binds transition state analogs well) an allolactose was trapped with its Gal moiety in a (4)H3 conformation, similar to the oxocarbenium ion-like conformation expected of the transition state. The numerous interactions formed between the (4)H3 structure and β-galactosidase indicate that this structure is representative of the transition state. This conformation is also very similar to that of d-galactono-1,5-lactone, a good transition state analog. Evidence indicates that substrates take up the (4)H3 conformation during migration from the shallow to the deep mode. Steric forces utilizing His418 and other residues are important for positioning the O1 leaving group into a quasi-axial position. An electrostatic interaction between the O5 of the distorted Gal and Tyr503 as well as C-H-π bonds with Trp568 are also significant. Computational studies of the energy of sugar ring distortion show that the β-galactosidase reaction itinerary is driven by energetic considerations in utilization of a (4)H3 transition state with a novel (4)C1-(4)H3-(4)C1 conformation itinerary. To our knowledge, this is the first X-ray crystallographic structural demonstration that the transition state of a natural substrate of a glycosidase has a (4)H3 conformation.

  6. An allolactose trapped at the lacZ β-galactosidase active site with its galactosyl moiety in a (4)H3 conformation provides insights into the formation, conformation, and stabilization of the transition state.

    PubMed

    Wheatley, Robert W; Huber, Reuben E

    2015-12-01

    When lactose was incubated with G794A-β-galactosidase (a variant with a "closed" active site loop that binds transition state analogs well) an allolactose was trapped with its Gal moiety in a (4)H3 conformation, similar to the oxocarbenium ion-like conformation expected of the transition state. The numerous interactions formed between the (4)H3 structure and β-galactosidase indicate that this structure is representative of the transition state. This conformation is also very similar to that of d-galactono-1,5-lactone, a good transition state analog. Evidence indicates that substrates take up the (4)H3 conformation during migration from the shallow to the deep mode. Steric forces utilizing His418 and other residues are important for positioning the O1 leaving group into a quasi-axial position. An electrostatic interaction between the O5 of the distorted Gal and Tyr503 as well as C-H-π bonds with Trp568 are also significant. Computational studies of the energy of sugar ring distortion show that the β-galactosidase reaction itinerary is driven by energetic considerations in utilization of a (4)H3 transition state with a novel (4)C1-(4)H3-(4)C1 conformation itinerary. To our knowledge, this is the first X-ray crystallographic structural demonstration that the transition state of a natural substrate of a glycosidase has a (4)H3 conformation. PMID:26291713

  7. Hofmeister series and ionic effects of alkali metal ions on DNA conformation transition in normal and less polarised water solvent

    NASA Astrophysics Data System (ADS)

    Wen, Jing; Shen, Xin; Shen, Hao; Zhang, Feng-Shou

    2014-10-01

    Normal and less polarised water models are used as the solvent to investigate Hofmeister effects and alkali metal ionic effects on dodecamer d(CGCGAATTCGCG) B-DNA with atomic dynamics simulations. As normal water solvent is replaced by less polarised water, the Hofmeister series of alkali metal ions is changed from Li+ > Na+ ≃ K+ ≃ Cs+ ≃ Rb+ to Li+ > Na+ > K+ > Rb+ > Cs+. In less polarised water, DNA experiences the B→A conformational transition for the lighter alkali metal counterions (Li+, Na+ and K+). However, it keeps B form for the heavier ions (Rb+ and Cs+). We find that the underlying cause of the conformation transition for these alkali metal ions except K+ is the competition between water molecules and counterions coupling to the free oxygen atoms of the phosphate groups. For K+ ions, the 'economics' of phosphate hydration and 'spine of hydration' are both concerned with the DNA helixes changing.

  8. Increasing the sampling efficiency of protein conformational transition using velocity-scaling optimized hybrid explicit/implicit solvent REMD simulation

    SciTech Connect

    Yu, Yuqi; Wang, Jinan; Shao, Qiang E-mail: Jiye.Shi@ucb.com Zhu, Weiliang E-mail: Jiye.Shi@ucb.com; Shi, Jiye E-mail: Jiye.Shi@ucb.com

    2015-03-28

    The application of temperature replica exchange molecular dynamics (REMD) simulation on protein motion is limited by its huge requirement of computational resource, particularly when explicit solvent model is implemented. In the previous study, we developed a velocity-scaling optimized hybrid explicit/implicit solvent REMD method with the hope to reduce the temperature (replica) number on the premise of maintaining high sampling efficiency. In this study, we utilized this method to characterize and energetically identify the conformational transition pathway of a protein model, the N-terminal domain of calmodulin. In comparison to the standard explicit solvent REMD simulation, the hybrid REMD is much less computationally expensive but, meanwhile, gives accurate evaluation of the structural and thermodynamic properties of the conformational transition which are in well agreement with the standard REMD simulation. Therefore, the hybrid REMD could highly increase the computational efficiency and thus expand the application of REMD simulation to larger-size protein systems.

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

    PubMed Central

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

    2011-01-01

    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

  10. Study on the Application of the Combination of TMD Simulation and Umbrella Sampling in PMF Calculation for Molecular Conformational Transitions

    PubMed Central

    Wang, Qing; Xue, Tuo; Song, Chunnian; Wang, Yan; Chen, Guangju

    2016-01-01

    Free energy calculations of the potential of mean force (PMF) based on the combination of targeted molecular dynamics (TMD) simulations and umbrella samplings as a function of physical coordinates have been applied to explore the detailed pathways and the corresponding free energy profiles for the conformational transition processes of the butane molecule and the 35-residue villin headpiece subdomain (HP35). The accurate PMF profiles for describing the dihedral rotation of butane under both coordinates of dihedral rotation and root mean square deviation (RMSD) variation were obtained based on the different umbrella samplings from the same TMD simulations. The initial structures for the umbrella samplings can be conveniently selected from the TMD trajectories. For the application of this computational method in the unfolding process of the HP35 protein, the PMF calculation along with the coordinate of the radius of gyration (Rg) presents the gradual increase of free energies by about 1 kcal/mol with the energy fluctuations. The feature of conformational transition for the unfolding process of the HP35 protein shows that the spherical structure extends and the middle α-helix unfolds firstly, followed by the unfolding of other α-helices. The computational method for the PMF calculations based on the combination of TMD simulations and umbrella samplings provided a valuable strategy in investigating detailed conformational transition pathways for other allosteric processes. PMID:27171075

  11. Classical trajectory simulations of photoionization dynamics of tryptophan: intramolecular energy flow, hydrogen-transfer processes and conformational transitions.

    PubMed

    Shemesh, Dorit; Gerber, R Benny

    2006-07-13

    One-photon and two-photon ionization dynamics of tryptophan is studied by classical trajectory simulations using the semiempirical parametric method number 3 (PM3) potential surface in "on the fly" calculations. The tryptophan conformer is assumed to be in the vibrational ground state prior to ionization. Initial conditions for the trajectories are weighted according to the Wigner distribution function computed for that state. Vertical ionization in the spirit of the classical Franck-Condon principle is assumed. For the two-photon ionization process the ionization is assumed to go resonantively through the first excited state. Most trajectories are computed, and the analysis is carried out for the first 10 ps. A range of interesting effects are observed. The main findings are as follows: (1) Multiple conformational transitions are observed in most of the trajectories within the ultrafast duration of 10 ps. (2) Hydrogen transfer from the carboxyl group to the amino group and back has been observed. A zwitterion is formed as a transient state. (3) Two new isomers are formed during the dynamics, which have apparently not been previously observed. (4) Fast energy flow between the ring modes and the amino acid backbone is observed for both one- and two-photon ionization. However, the effective vibrational temperatures only approach the same value after 90 ps. The conformation transition dynamics, the proton-transfer processes and the vibrational energy flow are discussed and analyzed.

  12. Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study.

    PubMed

    Baweja, Lokesh; Balamurugan, Kanagasabai; Subramanian, Venkatesan; Dhawan, Alok

    2015-09-01

    The interactions between nanomaterials (NMs) and amyloid proteins are central to the nanotechnology-based diagnostics and therapy in neurodegenerative disorders such as Alzheimer's and Parkinson's. Graphene oxide (GO) and its derivatives have shown to modulate the aggregation pattern of disease causing amyloid beta (Aβ) peptide. However, the mechanism is still not well understood. Using molecular dynamics simulations, the effect of graphene oxide (GO) and reduced graphene oxide (rGO) having carbon:oxygen ratio of 4:1 and 10:1, respectively, on the conformational transitions (alpha-helix to beta-sheet) and the dynamics of the peptide was investigated. GO and rGO decreased the beta-strand propensity of amino acid residues in Aβ. The peptide displayed different modes of adsorption on GO and rGO. The adsorption on GO was dominated by electrostatic interactions, whereas on rGO, both van der Waals and electrostatic interactions contributed in the adsorption of the peptide. Our study revealed that the slight increase in the hydrophobic patches on rGO made it more effective inhibitor of conformational transitions in the peptide. Alpha helix-beta sheet transition in Aβ peptide could be one of the plausible mechanism by which graphene oxide may inhibit amyloid fibrillation. PMID:26275931

  13. Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study.

    PubMed

    Baweja, Lokesh; Balamurugan, Kanagasabai; Subramanian, Venkatesan; Dhawan, Alok

    2015-09-01

    The interactions between nanomaterials (NMs) and amyloid proteins are central to the nanotechnology-based diagnostics and therapy in neurodegenerative disorders such as Alzheimer's and Parkinson's. Graphene oxide (GO) and its derivatives have shown to modulate the aggregation pattern of disease causing amyloid beta (Aβ) peptide. However, the mechanism is still not well understood. Using molecular dynamics simulations, the effect of graphene oxide (GO) and reduced graphene oxide (rGO) having carbon:oxygen ratio of 4:1 and 10:1, respectively, on the conformational transitions (alpha-helix to beta-sheet) and the dynamics of the peptide was investigated. GO and rGO decreased the beta-strand propensity of amino acid residues in Aβ. The peptide displayed different modes of adsorption on GO and rGO. The adsorption on GO was dominated by electrostatic interactions, whereas on rGO, both van der Waals and electrostatic interactions contributed in the adsorption of the peptide. Our study revealed that the slight increase in the hydrophobic patches on rGO made it more effective inhibitor of conformational transitions in the peptide. Alpha helix-beta sheet transition in Aβ peptide could be one of the plausible mechanism by which graphene oxide may inhibit amyloid fibrillation.

  14. Escherichia coli purine repressor: key residues for the allosteric transition between active and inactive conformations and for interdomain signaling.

    PubMed

    Lu, F; Brennan, R G; Zalkin, H

    1998-11-10

    The Escherichia coli purine repressor, PurR, exists in an equilibrium between open and closed conformations. Binding of a corepressor, hypoxanthine or guanine, shifts the allosteric equilibrium in favor of the closed conformation and increases the operator DNA binding affinity by 40-fold compared to aporepressor. Glu70 and Trp147 PurR mutations were isolated which perturb the allosteric equilibrium. Three lines of evidence indicate that the allosteric equilibrium of E70A and W147A aporepressors was shifted toward the closed conformation. First, compared to wild-type PurR, these mutant repressors had a 10-30-fold higher corepressor binding affinity. Second, the mutant aporepressors bound to operator DNA with an affinity that is characteristic of the wild-type PurR holorepressor. Third, binding of guanine to wild-type PurR resulted in a near-UV circular dichroism spectral change at 297-305 nm that is attributed to the closed conformation. The circular dichroism spectrum of the E70A aporepressor at 297-305 nm was that expected for the closed conformation, and it was not appreciably altered by corepressor binding. Mutational analysis was used to identify an Arg115-Ser46' interdomain intersubunit hydrogen bond that is necessary for transmitting the allosteric transition in the corepressor binding domain to the DNA binding domain. R115A and S46G PurR mutants were defective in DNA binding in vitro and repressor function in vivo although corepressor binding was identical to the wild type. These results establish that the hydrogen bond between the side chain NH2 of Arg115 and the main chain CO of Ser46' plays a critical role in interdomain signaling.

  15. Calcium-induced contraction of sarcomeres changes the regulation of mitochondrial respiration in permeabilized cardiac cells.

    PubMed

    Anmann, Tiia; Eimre, Margus; Kuznetsov, Andrey V; Andrienko, Tatiana; Kaambre, Tuuli; Sikk, Peeter; Seppet, Evelin; Tiivel, Toomas; Vendelin, Marko; Seppet, Enn; Saks, Valdur A

    2005-06-01

    The relationships between cardiac cell structure and the regulation of mitochondrial respiration were studied by applying fluorescent confocal microscopy and analysing the kinetics of mitochondrial ADP-stimulated respiration, during calcium-induced contraction in permeabilized cardiomyocytes and myocardial fibers, and in their 'ghost' preparations (after selective myosin extraction). Up to 3 microm free calcium, in the presence of ATP, induced strong contraction of permeabilized cardiomyocytes with intact sarcomeres, accompanied by alterations in mitochondrial arrangement and a significant decrease in the apparent K(m) for exogenous ADP and ATP in the kinetics of mitochondrial respiration. The V(max) of respiration showed a moderate (50%) increase, with an optimum at 0.4 microm free calcium and a decrease at higher calcium concentrations. At high free-calcium concentrations, the direct flux of ADP from ATPases to mitochondria was diminished compared to that at low calcium levels. All of these effects were unrelated either to mitochondrial calcium overload or to mitochondrial permeability transition and were not observed in 'ghost' preparations after the selective extraction of myosin. Our results suggest that the structural changes transmitted from contractile apparatus to mitochondria modify localized restrictions of the diffusion of adenine nucleotides and thus may actively participate in the regulation of mitochondrial function, in addition to the metabolic signalling via the creatine kinase system. PMID:15955072

  16. Thermodynamic and spectroscopic analysis of the conformational transition of poly(vinyl alcohol) by temperature-dependent FTIR

    NASA Astrophysics Data System (ADS)

    Han, Shan; Luan, Ye-Mei; Pang, Shu-Feng; Zhang, Yun-Hong

    2015-03-01

    The conformational change of poly(vinyl alcohol) has been studied by Fourier transform infrared spectroscopy at various temperatures in the 4000-400 cm-1 region. The molecular motion and the trans/gauche content are sensitive to the Csbnd H, Csbnd C stretching modes. FTIR spectra show that the I2920/I2849 decreases from 1.84 to 1.0 with increasing temperature, companying the decrease in I1047/I1095 from 0.78 to 0.58, implying the conformational transition from trans to gauche in alkyl chain. Based on the van't Hoff relation, the enthalpies and entropies have been calculated in different temperatures, which are 4.61 kJ mol-1 and 15.23 J mol-1 K-1, respectively, in the region of 80-140 °C. From the Cdbnd O stretching mode and Osbnd H band, it can be concluded that the intermolecular hydrogen bonds decrease owing to elevating temperature, which leads to more gauche conformers.

  17. Conformational transitions of flexible hydrophobic polyelectrolytes in solutions of monovalent and multivalent salts and their mixtures.

    PubMed

    Trotsenko, Oleksandr; Roiter, Yuri; Minko, Sergiy

    2012-04-10

    Conformations of cationic polyelectrolytes (PEs), a weak poly(2-vinylpyridine) (P2VP) and a strong poly(N-methyl-2-vinylpyridinium iodide) (qP2VP), adsorbed on mica from saline solutions in the presence of counterions of different valences are studied using in situ atomic force microscopy (AFM). Quantitative characteristics of chain conformations are analyzed using AFM images of the adsorbed molecules. The results of the statistical analysis of the chain contour reveal collapse of the PE coils when ionic strength is in a range from tens to hundreds of millimoles per kilogram and re-expansion of the coils with a further increase of ionic strength up to a region of the saturated saline solutions. The competition between monovalent and multivalent counterions simultaneously present in solutions strongly affects conformations of PE chains even at a very small fraction of multivalent counterions. Shrinkage of PE coils is steeper for multivalent counterions than for monovalent counterions. However, the re-expansion is only incremental in the presence of multivalent counterions. Extended adsorbed coils at low salt concentrations and at very high concentrations of monovalent salt exhibit conformation corresponding to a 2D coil with 0.95 fraction of bound segments (segments in "trains") in the regime of diluted surface concentration of the PE. Shrunken coils in the intermediate range of ionic strength resemble 3D-globules with 0.8 fraction of trains. The incrementally re-expanded PE coils at a high ionic strength remain unchanged at higher multivalent salt concentrations up to the solubility limit of the salt. The formation of a strong PE complex with multivalent counterions at high ionic strength is not well understood yet. A speculative explanation of the observed experimental result is based on possible stabilization of the complex due to hydrophobic interactions of the backbone.

  18. Modulation of Calmodulin Lobes by Different Targets: An Allosteric Model with Hemiconcerted Conformational Transitions

    PubMed Central

    Lai, Massimo; Brun, Denis; Edelstein, Stuart J.; Le Novère, Nicolas

    2015-01-01

    Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe) joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins. Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines) several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulin’s saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be explained as modulation

  19. Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions

    PubMed Central

    Finzi, Andrés; Xiang, Shi-Hua; Pacheco, Beatriz; Wang, Liping; Haight, Jessica; Kassa, Aemro; Danek, Brenda; Pancera, Marie; Kwong, Peter D.; Sodroski, Joseph

    2010-01-01

    SUMMARY The entry of human immunodeficiency virus (HIV-1) into cells is initiated by binding of the gp120 exterior envelope glycoprotein to the receptor, CD4. How does CD4 binding trigger conformational changes in gp120 that allow the gp41 transmembrane envelope glycoprotein to mediate viral-cell membrane fusion? The transition from the unliganded to the CD4-bound state is regulated by two potentially flexible topological layers (“Layers 1 and 2”) in the gp120 inner domain. Both layers apparently contribute to the non-covalent association of unliganded gp120 with gp41. After CD4 makes initial contact with the gp120 outer domain, Layer 1-Layer 2 interactions strengthen gp120-CD4 binding by reducing the off-rate. Layer 1-Layer 2 interactions also destabilize the activated state induced on HIV-1 by treatment with soluble CD4. Thus, despite lack of contact with CD4, the gp120 inner domain layers govern CD4 triggering by participating in conformational transitions within gp120 and regulating the interaction with gp41. PMID:20227370

  20. Steered Molecular Dynamics Simulations of a Type IV Pilus Probe Initial Stages of a Force-Induced Conformational Transition

    PubMed Central

    Baker, Joseph L.; Biais, Nicolas; Tama, Florence

    2013-01-01

    Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the gonococcal type IV pilus (GC-T4P) from Neisseria gonorrhoeae, the causative agent of gonorrhea. Cryo-electron microscopy has been used to construct a model of this filament, offering insights into the structure of type IV pili. In addition, experiments have demonstrated that GC-T4P can withstand very large tension forces, and transition to a force-induced conformation. However, the details of force-generation, and the atomic-level characteristics of the force-induced conformation, are unknown. Here, steered molecular dynamics (SMD) simulation was used to exert a force in silico on an 18 subunit segment of GC-T4P to address questions regarding the nature of the interactions that lead to the extraordinary strength of bacterial pili. SMD simulations revealed that the buried pilin α1 domains maintain hydrophobic contacts with one another within the core of the filament, leading to GC-T4P's structural stability. At the filament surface, gaps between pilin globular head domains in both the native and pulled states provide water accessible routes between the external environment and the interior of the filament, allowing water to access the pilin α1 domains as reported for VC-T4P in deuterium exchange experiments. Results were also compared to the experimentally observed force-induced conformation. In particular, an exposed amino acid sequence in the experimentally stretched filament was also found to become exposed during the SMD simulations, suggesting that initial stages of the force induced transition are well captured. Furthermore, a second sequence was shown to be initially hidden in the native filament and became exposed upon stretching. PMID

  1. α-Fluorophosphonates reveal how a phosphomutase conserves transition state conformation over hexose recognition in its two-step reaction

    PubMed Central

    Jin, Yi; Bhattasali, Debabrata; Pellegrini, Erika; Forget, Stephanie M.; Baxter, Nicola J.; Cliff, Matthew J.; Bowler, Matthew W.; Jakeman, David L.; Blackburn, G. Michael; Waltho, Jonathan P.

    2014-01-01

    β-Phosphoglucomutase (βPGM) catalyzes isomerization of β-d-glucose 1-phosphate (βG1P) into d-glucose 6-phosphate (G6P) via sequential phosphoryl transfer steps using a β-d-glucose 1,6-bisphosphate (βG16BP) intermediate. Synthetic fluoromethylenephosphonate and methylenephosphonate analogs of βG1P deliver novel step 1 transition state analog (TSA) complexes for βPGM, incorporating trifluoromagnesate and tetrafluoroaluminate surrogates of the phosphoryl group. Within an invariant protein conformation, the β-d-glucopyranose ring in the βG1P TSA complexes (step 1) is flipped over and shifted relative to the G6P TSA complexes (step 2). Its equatorial hydroxyl groups are hydrogen-bonded directly to the enzyme rather than indirectly via water molecules as in step 2. The (C)O–P bond orientation for binding the phosphate in the inert phosphate site differs by ∼30° between steps 1 and 2. By contrast, the orientations for the axial O–Mg–O alignment for the TSA of the phosphoryl group in the catalytic site differ by only ∼5°, and the atoms representing the five phosphorus-bonded oxygens in the two transition states (TSs) are virtually superimposable. The conformation of βG16BP in step 1 does not fit into the same invariant active site for step 2 by simple positional interchange of the phosphates: the TS alignment is achieved by conformational change of the hexose rather than the protein. PMID:25104750

  2. Molecular Mechanism for Conformational Dynamics of Ras·GTP Elucidated from In-Situ Structural Transition in Crystal

    PubMed Central

    Matsumoto, Shigeyuki; Miyano, Nao; Baba, Seiki; Liao, Jingling; Kawamura, Takashi; Tsuda, Chiemi; Takeda, Azusa; Yamamoto, Masaki; Kumasaka, Takashi; Kataoka, Tohru; Shima, Fumi

    2016-01-01

    Ras•GTP adopts two interconverting conformational states, state 1 and state 2, corresponding to inactive and active forms, respectively. However, analysis of the mechanism for state transition was hampered by the lack of the structural information on wild-type Ras state 1 despite its fundamental nature conserved in the Ras superfamily. Here we solve two new crystal structures of wild-type H-Ras, corresponding to state 1 and state 2. The state 2 structure seems to represent an intermediate of state transition and, intriguingly, the state 1 crystal is successfully derived from this state 2 crystal by regulating the surrounding humidity. Structural comparison enables us to infer the molecular mechanism for state transition, during which a wide range of hydrogen-bonding networks across Switch I, Switch II and the α3-helix interdependently undergo gross rearrangements, where fluctuation of Tyr32, translocation of Gln61, loss of the functional water molecules and positional shift of GTP play major roles. The NMR-based hydrogen/deuterium exchange experiments also support this transition mechanism. Moreover, the unveiled structural features together with the results of the biochemical study provide a new insight into the physiological role of state 1 as a stable pool of Ras•GTP in the GDP/GTP cycle of Ras. PMID:27180801

  3. The 32 kDa Enamelin Undergoes Conformational Transitions upon Calcium Binding

    PubMed Central

    Fan, Daming; Lakshminarayanan, Rajamani; Moradian-Oldak, Janet

    2008-01-01

    The 32 kDa hydrophilic and acidic enamelin, the most stable cleavage fragment of the enamel specific glycoprotein, is believed to play vital roles in controlling crystal nucleation or growth during enamel biomineralization. Circular dichroism and Fourier transform infrared spectra demonstrate that the secondary structure of the 32 kDa enamelin has a high content of α-helix (81.5%). Quantitative analysis on the circular dichroism data revealed that the 32 kDa enamelin undergoes conformational changes with a structural preference to β-sheet as a function of calcium ions. We suggest that the increase of β-sheet conformation upon presence of Ca2+ may allow preferable interaction of the 32 kDa enamelin with apatite crystal surfaces during enamel biomineralization. The calcium association constant of the 32 kDa enamelin calculated from the fitting curve of ellipticity at 222 nm is Ka = 1.55 (±0.13) × 103 M−1, indicating a relatively low affinity. Our current biophysical studies on the 32 kDa enamelin structure provide novel insights towards understanding the enamelin-mineral interaction and subsequently the functions of enamelin during enamel formation. PMID:18508280

  4. Specificity rendering 'hot-spots' for aurora kinase inhibitor design: the role of non-covalent interactions and conformational transitions.

    PubMed

    Badrinarayan, Preethi; Sastry, G Narahari

    2014-01-01

    The present study examines the conformational transitions occurring among the major structural motifs of Aurora kinase (AK) concomitant with the DFG-flip and deciphers the role of non-covalent interactions in rendering specificity. Multiple sequence alignment, docking and structural analysis of a repertoire of 56 crystal structures of AK from Protein Data Bank (PDB) has been carried out. The crystal structures were systematically categorized based on the conformational disposition of the DFG-loop [in (DI) 42, out (DO) 5 and out-up (DOU) 9], G-loop [extended (GE) 53 and folded (GF) 3] and αC-helix [in (CI) 42 and out (CO) 14]. The overlapping subsets on categorization show the inter-dependency among structural motifs. Therefore, the four distinct possibilities a) 2W1C (DI, CI, GE) b) 3E5A (DI, CI, GF) c) 3DJ6 (DI, CO, GF) d) 3UNZ (DOU, CO, GF) along with their co-crystals and apo-forms were subjected to molecular dynamics simulations of 40 ns each to evaluate the variations of individual residues and their impact on forming interactions. The non-covalent interactions formed by the 157 AK co-crystals with different regions of the binding site were initially studied with the docked complexes and structure interaction fingerprints. The frequency of the most prominent interactions was gauged in the AK inhibitors from PDB and the four representative conformations during 40 ns. Based on this study, seven major non-covalent interactions and their complementary sites in AK capable of rendering specificity have been prioritized for the design of different classes of inhibitors. PMID:25485544

  5. Molecular dynamics simulation of phosphorylation-induced conformational transitions in the mycobacterium tuberculosis response regulator PrrA

    SciTech Connect

    Chen, Guo; Mcmahon, Benjamin H; Tung, Chang - Shung

    2008-01-01

    Phosphorylation-activated modulation of response regulators (RR) is predominantly used by bacteria as a strategy in regulating their two-component signaling (TCS) systems, the underlying molecular mechanisms are however far from fully understood. In this work we have conducted a molecular dynamics (MD) simulation of the phosphorylation-induced conformational transitions of RRs with the Mycobacterium Tuberculosis PrrA as a particular example. Starting from the full-length inactive structure of PrrA we introduced a local disturbance by phosphorylating the conserved aspartic acid residue, Asp-58, in the regulatory domain. A Go-model-type algorithm packaged with AMBER force fields was then applied to simulate the dynamics upon phosphorylation. The MD simulation shows that the phosphorylation of Asp-58 facilitates PrrA, whose inactive state has a compact conformation with a closed interdomain interface, to open up with its interdomain separation being increased by an average of about 1.5 {angstrom} for a simulation of 20 ns. The trans-activation loop, which is completely buried within the interdomain interface in the inactive PrrA, is found to become more exposed with the phosphorylated structure as well. These results provide more structural details of how the phosphorylation of a local aspartate activates PrrA to undergo a global conformational rearrangement toward its extended active state. This work also indicates that MD simulations can serve as a fast tool to unravel the regulation mechanisms of all RRs, which is especially valuable when the structures of full-length active RRs are currently unavailable.

  6. Anthrax Edema Factor: An Ion-Adaptive Mechanism of Catalysis with Increased Transition-State Conformational Flexibility.

    PubMed

    Jara, Gabriel E; Martínez, Leandro

    2016-07-14

    Edema Factor (EF) is one of three major toxins of anthrax. EF is an adenylyl cyclase that disrupts cell signaling by accelerating the conversion of ATP into cyclic-AMP. EF has a much higher catalytic rate than that of mammalian adenylyl cyclases (mACs). Crystal structures were obtained for mACs and EF, but the molecular basis for different catalytic activities remained poorly understood. In particular, the arrangement of the active site in EF is unclear in what concerns the number of ions present and the conformation of the substrate. Here, we use quantum mechanics-molecular mechanics simulations to estimate the free-energy profiles for the reaction catalyzed by EF and a mAC. We found that EF catalysis is possible, and faster than that of mACs, in both one and two Mg(2+)-ion-binding modes, providing adaptive plasticity to host-cell environments. In both enzymes, the reaction mechanisms are highly associative. However, mechanistic differences exist. In the mAC, the nucleophile oxygen (ATP-O3') is consistently coordinated to one of the Mg(2+) ions, increasing its acidity. In EF, on the other hand, this coordination is eventual and not essential for the reaction to proceed. The persistent coordination of O3' to the ion is favored in mACs by a greater ion partial charge. In EF, the reduced acidity of the O3' oxygen is compensated by the presence of the His351 residue for proton abstraction. As proton transfer in EF does not require persistent attachment of the substrate to an ion, the substrate (ATP) and transition state display greater conformational flexibilities. These greater flexibilities allow the sampling of lower-energy conformations and might represent an entropic advantage for catalytic efficiency. PMID:27260163

  7. Immobilization of the distal hinge in the labile serpin plasminogen activator inhibitor 1: identification of a transition state with distinct conformational and functional properties.

    PubMed

    De Taeye, Bart; Compernolle, Griet; Dewilde, Maarten; Biesemans, Wouter; Declerck, Paul J

    2003-06-27

    The serpin plasminogen activator inhibitor-1 (PAI-1) plays an important role in the regulation of the fibrinolytic activity in blood. In plasma, PAI-1 circulates mainly in the active conformation. However, PAI-1 spontaneously converts to a latent conformation. This conversion comprises drastic conformational changes in both the distal and the proximal hinge region of the reactive center loop. To study the functional and conformational rearrangements associated solely with the mobility of the proximal hinge, disulfide bonds were introduced to immobilize the distal hinge region. These mutants exhibited specific activities comparable with that of PAI-1-wt. However, the engineered disulfide bond had a major effect on the conformational and associated functional transitions. Strikingly, in contrast to PAI-1-wt, inactivation of these mutants yielded a virtually complete conversion to a substrate-like conformation. Comparison of the digestion pattern (with trypsin and elastase) of the mutants and PAI-1-wt revealed that the inactivated mutants have a conformation differing from that of latent and active PAI-1-wt. Unique trypsin-susceptible cleavage sites arose upon inactivation of these mutants. The localization of these exposed residues provides evidence that a displacement of alphahF has occurred, indicating that the proximal hinge is partly inserted between s3A and s5A. In conclusion, immobilization of the distal hinge region in PAI-1 allowed the identification of an "intermediate" conformation characterized by a partial insertion of the proximal hinge region. We hypothesize that locking PAI-1 in this transition state between active and latent conformations is associated with a displacement of alphahF, subsequently resulting in substrate behavior.

  8. The influence of sodium perfluorooctanoate on the conformational transitions of human immunoglobulin.

    PubMed

    Messina, Paula V; Prieto, Gerardo; Salgado, Francisco; Varela, Carla; Nogueira, Montserrat; Dodero, Verónica; Ruso, Juan M; Sarmiento, Félix

    2007-07-19

    In the field of bioscience, the study of the interactions between blood proteins and fluorinated materials is very important from both theoretical and applied points of view. Fluorinated materials have potential use in drug delivery, as blood substitutes, and in biotechnology. Using a combination of ultraviolet-visible (UV-vis) and ultraviolet-circular dichroism (UV-CD) spectroscopies and ion-selective electrodes, the complete interaction of sodium perfluorooctanoate (SPFO) and the most important immunoglobulin (on a quantitative basis) in human serum, immunoglobulin G (IgG), has been evaluated. The study has been focused on bulk solution. By the application of an SPFO selective electrode, it was determined that there were true specific unions between surfactant molecules and IgG structure. The experimental data were presented as Koltz and Scatchard plots and analyzed on the basis of an empirical Hill equation. The conformational changes at the bulk solution were well characterized by UV-vis and UV-CD spectroscopies. As a consequence of these changes, the protein structure was affected.

  9. Conformational Transition Between Four and Five-Stranded Phenylalanine Zippers Determined by a Local Packing Interaction

    SciTech Connect

    Liu,J.; Zheng, Q.; Deng, Y.; Kallenbach, N.; Lu, M.

    2006-01-01

    Alpha-helical coiled coils play a crucial role in mediating specific protein-protein interactions. However, the rules and mechanisms that govern helix-helix association in coiled coils remain incompletely understood. Here we have engineered a seven heptad 'Phe-zipper' protein (Phe-14) with phenylalanine residues at all 14 hydrophobic a and d positions, and generated a further variant (Phe-14{sub M}) in which a single core Phe residue is substituted with Met. Phe-14 forms a discrete {alpha}-helical pentamer in aqueous solution, while Phe-14M folds into a tetrameric helical structure. X-ray crystal structures reveal that in both the tetramer and the pentamer the a and d side-chains interlock in a classical knobs-into-holes packing to produce parallel coiled-coil structures enclosing large tubular cavities. However, the presence of the Met residue in the apolar interface of the tetramer markedly alters its local coiled-coil conformation and superhelical geometry. Thus, short-range interactions involving the Met side-chain serve to preferentially select for tetramer formation, either by inhibiting a nucleation step essential for pentamer folding or by abrogating an intermediate required to form the pentamer. Although specific trigger sequences have not been clearly identified in dimeric coiled coils, higher-order coiled coils, as well as other oligomeric multi-protein complexes, may require such sequences to nucleate and direct their assembly.

  10. Single-Molecule Analysis of Protein Large-Amplitude Conformational Transitions

    NASA Astrophysics Data System (ADS)

    Yang, Haw

    2011-03-01

    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 Förster 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.

  11. The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation.

    PubMed

    Cecchini, Marco; Changeux, Jean-Pierre

    2015-09-01

    Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communications in the nervous system by converting the binding of a chemical messenger - a neurotransmitter - into an ion flux through the postsynaptic membrane. Here, we present an overview of the most recent advances on the signal transduction mechanism boosted by X-ray crystallography of both prokaryotic and eukaryotic homologues of the nicotinic acetylcholine receptor (nAChR) in conjunction with time-resolved analyses based on single-channel electrophysiology and Molecular Dynamics simulations. The available data consistently point to a global mechanism of gating that involves a large reorganization of the receptor mediated by two distinct quaternary transitions: a global twisting and a radial expansion/contraction of the extracellular domain. These transitions profoundly modify the organization of the interface between subunits, which host several sites for orthosteric and allosteric modulatory ligands. The same mechanism may thus mediate both positive and negative allosteric modulations of pLGICs ligand binding at topographically distinct sites. The emerging picture of signal transduction is expected to pave the way to new pharmacological strategies for the development of allosteric modulators of nAChR and pLGICs in general. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

  12. Network representation of conformational transitions between hidden intermediates of Rd-apocytochrome b562

    PubMed Central

    Duan, Mojie; Liu, Hanzhong; Li, Minghai; Huo, Shuanghong

    2015-01-01

    The folding kinetics of Rd-apocytochrome b562 is two-state, but native-state hydrogen exchange experiments show that there are discrete partially unfolded (PUF) structures in equilibrium with the native state. These PUF structures are called hidden intermediates because they are not detected in kinetic experiments and they exist after the rate-limiting step. Structures of the mimics of hidden intermediates of Rd-apocytochrome b562 are resolved by NMR. Based upon their relative stability and structural features, the folding mechanism was proposed to follow a specific pathway (unfolded → rate-limiting transition state → PUF1 → PUF2 → native). Investigating the roles of equilibrium PUF structures in folding kinetics and their interrelationship not only deepens our understanding of the details of folding mechanism but also provides guides in protein design and prevention of misfolding. We performed molecular dynamics simulations starting from a hidden intermediate and the native state of Rd-apocytochrome b562 in explicit solvent, for a total of 37.18 μs mainly with Anton. We validated our simulations by detailed comparison with experimental data and other computations. We have verified that we sampled the post rate-limiting transition state region only. Markov state model was used to analyze the simulation results. We replace the specific pathway model with a network model. Transition-path theory was employed to calculate the net effective flux from the most unfolded state towards the most folded state in the network. The proposed sequential folding pathway via PUF1 then more stable, more native-like PUF2 is one of the routes in our network, but it is not dominant. The dominant path visits PUF2 without going through PUF1. There is also a route from PUF1 directly to the most folded state in the network without visiting PUF2. Our results indicate that the PUF states are not necessarily sequential in the folding. The major routes predicted in our network are

  13. Conformational Transitions Underlying Pore Opening and Desensitization in Membrane-embedded Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

    PubMed Central

    Velisetty, Phanindra; Chalamalasetti, Sreevatsa V.; Chakrapani, Sudha

    2012-01-01

    Direct structural insight into the mechanisms underlying activation and desensitization remain unavailable for the pentameric ligand-gated channel family. Here, we report the structural rearrangements underlying gating transitions in membrane-embedded GLIC, a prokaryotic homologue, using site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy. We particularly probed the conformation of pore-lining second transmembrane segment (M2) under conditions that favor the closed and the ligand-bound desensitized states. The spin label mobility, intersubunit spin-spin proximity, and the solvent-accessibility parameters in the two states clearly delineate the underlying protein motions within M2. Our results show that during activation the extracellular hydrophobic region undergoes major changes involving an outward translational movement, away from the pore axis, leading to an increase in the pore diameter, whereas the lower end of M2 remains relatively immobile. Most notably, during desensitization, the intervening polar residues in the middle of M2 move closer to form a solvent-occluded barrier and thereby reveal the location of a distinct desensitization gate. In comparison with the crystal structure of GLIC, the structural dynamics of the channel in a membrane environment suggest a more loosely packed conformation with water-accessible intrasubunit vestibules penetrating from the extracellular end all the way to the middle of M2 in the closed state. These regions have been implicated to play a major role in alcohol and drug modulation. Overall, these findings represent a key step toward understanding the fundamentals of gating mechanisms in this class of channels. PMID:22977232

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

    PubMed

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

    2002-01-01

    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

  15. Conformational transitions in peptides containing two putative alpha-helices of the prion protein.

    PubMed

    Zhang, H; Kaneko, K; Nguyen, J T; Livshits, T L; Baldwin, M A; Cohen, F E; James, T L; Prusiner, S B

    1995-07-21

    Prions are composed largely, if not entirely, of the scrapie isoform of the prion protein (PrPSc). Conversion of the cellular isoform (PrPC) to PrPSc is accompanied by a diminution in the alpha-helical content and an increase in the beta-sheet structure. To investigate the structural basis of this transition, peptide fragments corresponding to Syrian hamster PrP residues 90 to 145 and 109 to 141, which contain the most conserved residues of the prion protein and the first two putative alpha-helical regions in a PrPC model, were studied using infrared spectroscopy and circular dichroism. The peptides could be induced to form alpha-helical structures in aqueous solutions in the presence of organic solvents, such as trifluoroethanol and hexafluoroisopropanol, or detergents, such as sodium dodecyl sulfate and dodecyl phosphocholine. NaCl at physiological concentration or acetonitrile induced the peptides to acquire substantial beta-sheet. The intermolecular nature of the beta-sheet was evident in the formation of rod-shaped polymers as detected by electron microscopy. Resistance to hydrolysis by proteinase K and epitope mapping argue that the beta-sheet structures were formed by the interaction of residues lying between 109 and 141. A similar range of residues was shown by nuclear magnetic resonance spectroscopy to be capable of forming alpha-helices. The alpha-helical structures seem to require a hydrophobic support from either intermolecular interactions or the hydrophobic environment provided by micelles, in agreement with the predicted hydrophobic nature of the packing surface among the four putative helices of PrPC and the outer surfaces of the first two helices. Our results suggest that perturbation of the packing environment of the highly conserved residues is a possible mechanism for triggering the conversion of PrPC to PrPSc where alpha-helices appear to be converted into beta-sheets.

  16. Coarse-grained simulations of transitions in the E2-to-E1 conformations for Ca ATPase (SERCA) show entropy-enthalpy compensation.

    PubMed

    Nagarajan, Anu; Andersen, Jens Peter; Woolf, Thomas B

    2012-09-28

    SERCA is a membrane transport protein that has been extensively studied. There are a large number of highly resolved X-ray structures and several hundred mutations that have been characterized functionally. Despite this, the molecular details of the catalytic cycle, a cycle that includes large conformational changes, is not fully understood. In this computational study, we provide molecular dynamics descriptions of conformational changes during the E2→E1 transitions. The motivating point for these calculations was a series of insertion mutants in the A-M3 linker region that led to significant shifts in measured rates between the E2 and E1 states, as shown by experimental characterization. Using coarse-grained dynamic importance sampling within the context of a population shift framework, we sample on the intermediates along the transition pathway to address the mechanism for the conformational changes and the effects of the insertion mutations on the kinetics of the transition. The calculations define an approximation for the relative changes in entropy and enthalpy along the transition. These are found to be important for understanding the experimentally observed differences in rates. In particular, the interactions between cytoplasmic domains, water interactions, and the shifts in protein degrees of freedom with the insertion mutations show mutual compensation for the E2→E1 transitions in wild-type and mutant systems.

  17. Energetics of the Cleft Closing Transition and the Role of Electrostatic Interactions in Conformational Rearrangements of the Glutamate Receptor Ligand Binding Domain

    PubMed Central

    Mamonova, Tatyana; Yonkunas, Michael J.; Kurnikova, Maria G.

    2009-01-01

    The ionotropic glutamate receptors are localized in the pre- and postsynaptic membrane of neurons in the brain. Activation by the principal excitatory neurotransmitter glutamate allows the ligand binding domain to change conformation, communicating opening of the channel for ion conduction. The free energy of the GluR2 S1S2 ligand binding domain (S1S2) closure transition was computed using a combination of thermodynamic integration and umbrella sampling modeling methods. A path that involves lowering the charge on E705 was chosen to clarify the role of this binding site residue. A continuum electrostatic approach in S1S2 is used to show E705, located in the ligand binding cleft, stabilizes the closed conformation of S1S2. In the closed conformation, in the absence of a ligand, S1S2 is somewhat more closed than reported from X-ray structures. A semi-open conformation has been identified which is characterized by disruption of a single cross-cleft interaction and differs only slightly in energy from the fully closed S1S2. The fully open S1S2 conformation exhibits a wide energy well and shares structural similarity to the apo S1S2 crystal structure. Hybrid continuum electrostatics/MD calculations along the chosen closure transition pathway reveal solvation energies, as well as electrostatic interaction energies between two lobes of the protein increase the relative energetic difference between the open and the closed conformational states. By analyzing the role of several cross-cleft contacts as well as other binding site residues we demonstrate how S1S2 interactions facilitate formation of the closed conformation of the ligand binding domain. PMID:18823129

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

    PubMed

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

    2013-10-25

    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 β-sheet and random conformational structures as a function of concentration. However, in the presence of Lyso-C12PC, maximal percentages of α-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 α-helix. PMID:24513206

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

    PubMed

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

    2013-11-15

    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 β-sheet and random conformational structures as a function of concentration. However, in the presence of Lyso-C12PC, maximal percentages of α-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 α-helix. PMID:24383078

  20. Conformation of T4 lysozyme in solution. Hinge-bending motion and the substrate-induced conformational transition studied by site-directed spin labeling.

    PubMed

    Mchaourab, H S; Oh, K J; Fang, C J; Hubbell, W L

    1997-01-14

    T4 lysozyme and mutants thereof crystallize in different conformations that are related to each other by a bend about a hinge in the molecule. This observation suggests that the wild type protein may undergo a hinge-bending motion in solution to allow substrate access to an otherwise closed active site cleft [Faber, H.R., & Matthews, B.W. (1990) Nature 348, 263-266]. To test this hypothesis, either single or pairs of nitroxide side chains were introduced into the protein to monitor tertiary contact interactions and inter-residue distances, respectively, in solution. A set of constraints for these structural parameters was derived from a reference state, a covalent enzyme-substrate adduct where the enzyme is locked in the closed state. In the absence of substrate, differences in both inter-residue distances and tertiary contact interactions relative to this reference state are consistent with a hinge-bending motion that opens the active site cleft. Quantitative analysis of spin-spin interactions between nitroxide pairs reveals an 8 A relative domain movement upon substrate binding. In addition, it is demonstrated that the I3P mutation, which produces a large hinge-bending angle in the crystal, has no effect on the solution conformation. Thus, the hinge motion is not the result of the mutation but is an integral part of T4 lysozyme catalysis in solution, as suggested recently [Zhang, X.J., Wozniak, J.A., & Matthews, B.W. (1995) J. Mol. Biol. 250, 527-552]. The strategy employed here, based on site-directed spin labeling, should be generally applicable to the study of protein conformation and conformational changes in solution.

  1. Calcium wave propagation by calcium-induced calcium release: an unusual excitable system.

    PubMed

    Sneyd, J; Girard, S; Clapham, D

    1993-03-01

    We discuss in detail the behaviour of a model, proposed by Goldbeter et al. (1990. Proc. natn. Acad. Sci. 87, 1461-1465), for intracellular calcium wave propagation by calcium-induced calcium release, focusing our attention on excitability and the propagation of waves in one spatial dimension. The model with no diffusion behaves like a generic excitable system, and threshold behaviour, excitability and oscillations can be understood within this general framework. However, when diffusion is included, the model no longer behaves like a generic excitable system; the fast and slow variables are not distinct and previous results on excitable systems do not necessarily apply. We consider a piecewise linear simplification of the model, and construct travelling pulse and periodic plane wave solutions to the simplified model. The analogous behaviour in the full model is studied numerically. Goldbeter's model for calcium-induced calcium release is an excitable system of a type not previously studied in detail.

  2. Tight conformational coupling between the domains of the enterotoxigenic Escherichia coli fimbrial adhesin CfaE regulates binding state transition.

    PubMed

    Liu, Yang; Esser, Lothar; Interlandi, Gianluca; Kisiela, Dagmara I; Tchesnokova, Veronika; Thomas, Wendy E; Sokurenko, Evgeni; Xia, Di; Savarino, Stephen J

    2013-04-01

    CfaE, the tip adhesin of enterotoxigenic Escherichia coli colonization factor antigen I fimbriae, initiates binding of this enteropathogen to the small intestine. It comprises stacked β-sandwich adhesin (AD) and pilin (PD) domains, with the putative receptor-binding pocket at one pole and an equatorial interdomain interface. CfaE binding to erythrocytes is enhanced by application of moderate shear stress. A G168D replacement along the AD facing the CfaE interdomain region was previously shown to decrease the dependence on shear by increasing binding at lower shear forces. To elucidate the structural basis for this functional change, we studied the properties of CfaE G168D (with a self-complemented donor strand) and solved its crystal structure at 2.6 Å resolution. Compared with native CfaE, CfaE G168D showed a downward shift in peak erythrocyte binding under shear stress and greater binding under static conditions. The thermal melting transition of CfaE G168D occurred 10 °C below that of CfaE. Compared with CfaE, the atomic structure of CfaE G168D revealed a 36% reduction in the buried surface area at the interdomain interface. Despite the location of this single modification in the AD, CfaE G168D exhibited structural derangements only in the adjoining PD compared with CfaE. In molecular dynamics simulations, the G168D mutation was associated with weakened interdomain interactions under tensile force. Taken together, these findings indicate that the AD and PD of CfaE are conformationally tightly coupled and support the hypothesis that opening of the interface plays a critical modulatory role in the allosteric activation of CfaE. PMID:23393133

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

    PubMed

    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

    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.

  4. Phosphoprotein Phosphatase 1 Is Required for Extracellular Calcium-Induced Keratinocyte Differentiation

    PubMed Central

    Fan, Hong; Zeng, Qin; Pennypacker, Sally D.; Xie, Zhongjian

    2016-01-01

    Extracellular calcium is a major regulator of keratinocyte differentiation in vitro and appears to play that role in vivo, but the mechanism is unclear. We have previously demonstrated that, following calcium stimulation, PIP5K1α is recruited by the E-cadherin-β-catenin complex to the plasma membrane where it provides the substrate PIP2 for both PI3K and PLC-γ1. This signaling pathway is critical for calcium-induced generation of second messengers including IP3 and intracellular calcium and keratinocyte differentiation. In this study, we explored the upstream regulatory mechanism by which calcium activates PIP5K1α and the role of this activation in calcium-induced keratinocyte differentiation. We found that treatment of human keratinocytes in culture with calcium resulted in an increase in serine dephosphorylation and PIP5K1α activation. PP1 knockdown blocked extracellular calcium-induced increase in serine dephosphorylation and activity of PIP5K1α and induction of keratinocyte differentiation markers. Knockdown of PLC-γ1, the downstream effector of PIP5K1α, blocked upstream dephosphorylation and PIP5K1α activation induced by calcium. Coimmunoprecipitation revealed calcium induced recruitment of PP1 to the E-cadherin-catenin-PIP5K1α complex in the plasma membrane. These results indicate that PP1 is recruited to the extracellular calcium-dependent E-cadherin-catenin-PIP5K1α complex in the plasma membrane to activate PIP5K1α, which is required for PLC-γ1 activation leading to keratinocyte differentiation. PMID:27340655

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

    PubMed

    Sychev, Sergei V; Ivanov, Vadim T

    2014-08-01

    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 ↑↓β5.6 or ↑↓β7.2 helices (number of residues per turn) and a single-stranded β6.3 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 ↑↓β5.6 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 ↑↓β5.6 → β-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.].

  6. The Highly Conserved Layer-3 Component of the HIV-1 gp120 Inner Domain Is Critical for CD4-Required Conformational Transitions

    PubMed Central

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

    2013-01-01

    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

  7. The intramolecular impact to the sequence specificity of B-->A transition: low energy conformational variations in AA/TT and GG/CC steps.

    PubMed

    Il'icheva, I A; Vlasov, P K; Esipova, N G; Tumanyan, V G

    2010-04-01

    It is well known, that local B--> A transformation in DNA is involved in several biological processes. In vitro B<--> A transition is sequence-specific. The physical basis of this specificity is not known yet. Here we analyze the effect of intramolecular interactions on the structural behavior of the GG/CC and AA/TT steps. These steps exemplify sequence specific bias to the B- or A-form structure. Optimization of potential energy of the molecular systems composed of an octanucleotide, neutralized by Na(+) and solvated with TIP3P water molecules in rectangular box with periodic boundary conditions gives the statistically representative sets of low energy structures for GG/CC and AA/TT steps in the middle of the diverse flanking sequences. Permissible 3D variations of GG/CC and AA/TT, and correlation of the relative motion of base pairs in these steps were analyzed. AA/TT step permits high variability for low energy conformers in the B-form DNA and small variability for low energy conformers in the A-form DNA. In contrast GG/CC step permits high variability for low energy conformers in the A-form DNA and small variability for low energy conformers in the B-form DNA. The relative motion of base pairs in GG/CC step is high correlated, while in AA/TT step this correlation is notably less. Atom-atom interactions inside-the-step always favors the B-form and their component - stacking interactions (atom-atom interactions between nucleic bases) is crucial for the duplex stabilization. Formation of the A-form for both steps is a result of interactions with the flanking sequences and water-cation environment in the box. The average energy difference between conformations presenting B-form and A-form for the GG/CC step is high, while for the AA/TT step it is rather low. Thus, intramolecular interactions in GG/CC and AA/TT steps affect the possible conformational diversity ("conformational entropy") of the A- and B- type structures of DNA step. This determines the known bias of

  8. The Intramolecular Impact to the Sequence Specificity of B→A Transition: Low Energy Conformational Variations in AA/TT and GG/CC Steps.

    PubMed

    Il'icheva, I A; Vlasov, P K; Esipova, N G; Tumanyan, V G

    2010-04-01

    Abstract It is well known, that local B→A transformation in DNA is involved in several biological processes. In vitro B↔A transition is sequence-specific. The physical basis of this specificity is not known yet. Here we analyze the effect of intramolecular interactions on the structural behavior of the GG/CC and AA/TT steps. These steps exemplify sequence specific bias to the B- or A-form structure. Optimization of potential energy of the molecular systems composed of an octanucle-otide, neutralized by Na(+) and solvated with TIP3P water molecules in rectangular box with periodic boundary conditions gives the statistically representative sets of low energy structures for GG/CC and AA/TT steps in the middle of the diverse flanking sequences. Permissible 3D variations of GG/CC and AA/TT, and correlation of the relative motion of base pairs in these steps were analyzed. AA/TT step permits high variability for low energy conformers in the B-form DNA and small variability for low energy conformers in the A-form DNA. In contrast GG/CC step permits high variability for low energy conformers in the A-form DNA and small variability for low energy conformers in the B-form DNA. The relative motion of base pairs in GG/CC step is high correlated, while in AA/TT step this correlation is notably less. Atom-atom interactions inside-the-step always favors the B-form and their component - stacking interactions (atomatom interactions between nucleic bases) is crucial for the duplex stabilization. Formation of the A-form for both steps is a result of interactions with the flanking sequences and water-cation environment in the box. The average energy difference between conformations presenting B-form and A-form for the GG/CC step is high, while for the AA/TT step it is rather low. Thus, intramolecular interactions in GG/CC and AA/TT steps affect the possible conformational diversity ("conformational entropy") of the A- and B- type structures of DNA step. This determines the known

  9. 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

    Stokka, Anne J; Flatmark, Torgeir

    2003-01-01

    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

  10. Secondary structure of prothymosin alpha evidenced for conformational transitions induced by changes in temperature and concentration of n-dodecyltrimethylammonium bromide.

    PubMed

    Pombo, C; Suarez, M J; Nogueira, M; Czarnecki, J; Ruso, J M; Sarmiento, F; Prieto, G

    2001-08-01

    Conformational changes of prothymosin alpha (ProTalpha) induced by changes in temperature and concentration of the denaturant n-dodecyltrimethylammonium bromide (C12TAB) were studied by difference spectroscopy. The conformational transition of ProTalpha by C12TAB was followed as a function of denaturant concentration by absorbance measurements at 230 nm and the data were analyzed to obtain the Gibbs energy of the transition in water (deltaG0(w)) and in a hydrophobic environment (deltaG0(hc)) for saturated protein-surfactant complexes. The value of deltaG0(w) was 6.38 kJ mol(-1) and that for deltaG0(hc), which is not affected by temperature, was -18.62 kJ mol(-1). Changes of absorbance at 230 nm of ProTalpha with temperature can be assumed to resemble a transition in the secondary structure. The parameters characterizing the thermodynamics of unfolding, melting temperature (Tm), enthalpy (deltaHm), entropy (deltaSm) and heat capacity (deltaCp) were determined. The values obtained for Tm, deltaHm, and deltaSm are smaller that those found for other globular proteins; deltaCp was found to be much smaller. These results suggest that ProTalpha exhibits some type of secondary structure under these conditions (10 mM glycine buffer, pH 2.4).

  11. A conformational transition in the structure of a 2'-thiomethyl-modified DNA visualized at high resolution

    SciTech Connect

    Pallan, Pradeep S.; Prakash, Thazha P.; Li, Feng; Eoff, Robert L.; Manoharan, Muthiah; Egli, Martin

    2009-06-17

    Crystal structures of A-form and B-form DNA duplexes containing 2'-S-methyl-uridines reveal that the modified residues adopt a RNA-like C3'-endo pucker, illustrating that the replacement of electronegative oxygen at the 2'-carbon of RNA by sulfur does not appear to fundamentally alter the conformational preference of the sugar in the oligonucleotide context and sterics trump stereoelectronics.

  12. Calcium-induced conformational changes in the regulatory domain of the human mitochondrial ATP-Mg/Pi carrier

    PubMed Central

    Harborne, Steven P.D.; Ruprecht, Jonathan J.; Kunji, Edmund R.S.

    2015-01-01

    The mitochondrial ATP-Mg/Pi carrier imports adenine nucleotides from the cytosol into the mitochondrial matrix and exports phosphate. The carrier is regulated by the concentration of cytosolic calcium, altering the size of the adenine nucleotide pool in the mitochondrial matrix in response to energetic demands. The protein consists of three domains; (i) the N-terminal regulatory domain, which is formed of two pairs of fused calcium-binding EF-hands, (ii) the C-terminal mitochondrial carrier domain, which is involved in transport, and (iii) a linker region with an amphipathic α-helix of unknown function. The mechanism by which calcium binding to the regulatory domain modulates substrate transport in the carrier domain has not been resolved. Here, we present two new crystal structures of the regulatory domain of the human isoform 1. Careful analysis by SEC confirmed that although the regulatory domain crystallised as dimers, full-length ATP-Mg/Pi carrier is monomeric. Therefore, the ATP-Mg/Pi carrier must have a different mechanism of calcium regulation than the architecturally related aspartate/glutamate carrier, which is dimeric. The structure showed that an amphipathic α-helix is bound to the regulatory domain in a hydrophobic cleft of EF-hand 3/4. Detailed bioinformatics analyses of different EF-hand states indicate that upon release of calcium, EF-hands close, meaning that the regulatory domain would release the amphipathic α-helix. We propose a mechanism for ATP-Mg/Pi carriers in which the amphipathic α-helix becomes mobile upon release of calcium and could block the transport of substrates across the mitochondrial inner membrane. PMID:26164100

  13. Calcium-induced conformational changes in the regulatory domain of the human mitochondrial ATP-Mg/Pi carrier.

    PubMed

    Harborne, Steven P D; Ruprecht, Jonathan J; Kunji, Edmund R S

    2015-10-01

    The mitochondrial ATP-Mg/Pi carrier imports adenine nucleotides from the cytosol into the mitochondrial matrix and exports phosphate. The carrier is regulated by the concentration of cytosolic calcium, altering the size of the adenine nucleotide pool in the mitochondrial matrix in response to energetic demands. The protein consists of three domains; (i) the N-terminal regulatory domain, which is formed of two pairs of fused calcium-binding EF-hands, (ii) the C-terminal mitochondrial carrier domain, which is involved in transport, and (iii) a linker region with an amphipathic α-helix of unknown function. The mechanism by which calcium binding to the regulatory domain modulates substrate transport in the carrier domain has not been resolved. Here, we present two new crystal structures of the regulatory domain of the human isoform 1. Careful analysis by SEC confirmed that although the regulatory domain crystallised as dimers, full-length ATP-Mg/Pi carrier is monomeric. Therefore, the ATP-Mg/Pi carrier must have a different mechanism of calcium regulation than the architecturally related aspartate/glutamate carrier, which is dimeric. The structure showed that an amphipathic α-helix is bound to the regulatory domain in a hydrophobic cleft of EF-hand 3/4. Detailed bioinformatics analyses of different EF-hand states indicate that upon release of calcium, EF-hands close, meaning that the regulatory domain would release the amphipathic α-helix. We propose a mechanism for ATP-Mg/Pi carriers in which the amphipathic α-helix becomes mobile upon release of calcium and could block the transport of substrates across the mitochondrial inner membrane. PMID:26164100

  14. Turn-directed α-β conformational transition of α-syn12 peptide at different pH revealed by unbiased molecular dynamics simulations.

    PubMed

    Liu, Lei; Cao, Zanxia

    2013-05-24

    The transition from α-helical to β-hairpin conformations of α-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 β-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.

  15. Effects of poly (ethylene glycol) chains conformational transition on the properties of mixed DMPC/DMPE-PEG thin liquid films and monolayers.

    PubMed

    Georgiev, Georgi As; Sarker, Dipak K; Al-Hanbali, Othman; Georgiev, Georgi D; Lalchev, Zdravko

    2007-10-01

    Foam thin liquid films (TLF) and monolayers at the air-water interface formed by DMPC mixed with DMPE-bonded poly (ethylene glycol)s (DMPE-PEG(550), DMPE-PEG(2000) and DMPE-PEG(5000)) were obtained. The influence of both (i) PEG chain size (evaluated in terms of Mw) and mushroom-to-brush conformational transition and (ii) of the liposome/micelle ratio in the film-forming dispersions, on the interfacial properties of mixed DMPC/DMPE-PEG films was compared. Foam film studies demonstrated that DMPE-PEG addition to foam TLFs caused (i) delayed kinetics of film thinning and black spot expansion and (ii) film stabilization. At the mushroom-to-brush transition, due to steric repulsion increased DMPE-PEG films thickness reached 25 nm while pure DMPC films were only 8 nm thick Newton black films. It was possible to differentiate DMPE-PEG(2000/5000) from DMPE-PEG(550) by the ability to change foam TLF formation mechanism, which could be of great importance for "stealth" liposome design. Monolayer studies showed improved formation kinetics and equilibrium surface tension decrease for DMPE-PEG monolayers compared with DMPC pure films. SEM observations revealed "smoothing" and "sealing" of the defects in the solid-supported layer surface by DMPE-PEGs adsorption, which could explain DMPE-PEGs ability to stabilize TLFs and to decrease monolayer surface tension. All effects in monolayers, foam TLFs and solid-supported layers increased with the increase of PEG Mw and DMPE-PEG concentration. However, at the critical DMPE-PEG concentration (where mushroom-to-brush conformational transition occurred) maximal magnitude of the effects was reached, which only slightly changed at further DMPE-PEG content and micelle/liposome ratio increase.

  16. FTIR/PCA study of propanol in argon matrix: The initial stage of clustering and conformational transitions

    NASA Astrophysics Data System (ADS)

    Doroshenko, Iryna; Balevicius, Vytautas; Pitsevich, George; Aidas, Kestutis; Sablinskas, Valdas; Pogorelov, Valeriy

    2014-12-01

    FTIR spectra of 1-propanol in an argon matrix were studied in the range 11-30 K. Principal component analysis of dynamic FTIR spectra and nonlinear band shape fitting has been carried out. The peaks of monomer, open dimer, mixed propanol-water dimer and those of higher H-bond clusters have been resolved and analyzed. The attribution of certain FTIR peaks has been supported by proper density functional theory calculations. Analyzing dependences of the integral band intensities of various aggregates on temperature it has been deduced that in the initial stage of clustering monomers and dimers are the basic building blocks forming higher H-bond clusters. The peaks assigned to two conformers of monomers and mixed propanol-water dimers were investigated processing the temperature dependences of their integral intensities in Arrhenius plot. The obtained values of 0.18 kJ.mol-1 for propanol monomer and 0.26 kJ.mol-1 for mixed dimer are well comparable with the energy differences between the global minimum conformation of 1-propanol (Gt) and some other energetically higher structures (Tt or Tg).

  17. Self-association promoted conformational transition of (3R,4S,8R,9R)-9-[(3,5-bis(trifluoromethyl)phenyl))-thiourea](9-deoxy)-epi-cinchonine.

    PubMed

    Király, Péter; Soós, Tibor; Varga, Szilárd; Vakulya, Benedek; Tárkányi, Gábor

    2010-01-01

    The conformational diversity of the (3R,4S,8R,9R)-9-[(3,5-bis(trifluoromethyl)phenyl))-thiourea](9-deoxy)-epi-cinchonine organocatalyst is discussed. Low-temperature NMR experiments confirmed a self-association process, which promotes the quinoline rotation between two intramolecularly hydrogen-bonded monomeric conformers of the catalyst. The balanced population of the coexisting monomeric and dimeric species allowed us to conduct a structural study of a rather complex conformational dynamics of the pure catalyst. The study is extended by a comparison with other members of the bifunctional amine-thiourea organocatalyst family. Changes in the molecular structure of the catalysts influence the interplay between intra- and intermolecular hydrogen bonding, and yield different extent of catalyst self-association. By assessing the conformation of the individual states, we established the thermodynamic model of a self-association promoted conformational transition.

  18. Specificity Rendering ‘Hot-Spots’ for Aurora Kinase Inhibitor Design: The Role of Non-Covalent Interactions and Conformational Transitions

    PubMed Central

    Badrinarayan, Preethi; Sastry, G. Narahari

    2014-01-01

    The present study examines the conformational transitions occurring among the major structural motifs of Aurora kinase (AK) concomitant with the DFG-flip and deciphers the role of non-covalent interactions in rendering specificity. Multiple sequence alignment, docking and structural analysis of a repertoire of 56 crystal structures of AK from Protein Data Bank (PDB) has been carried out. The crystal structures were systematically categorized based on the conformational disposition of the DFG-loop [in (DI) 42, out (DO) 5 and out-up (DOU) 9], G-loop [extended (GE) 53 and folded (GF) 3] and αC-helix [in (CI) 42 and out (CO) 14]. The overlapping subsets on categorization show the inter-dependency among structural motifs. Therefore, the four distinct possibilities a) 2W1C (DI, CI, GE) b) 3E5A (DI, CI, GF) c) 3DJ6 (DI, CO, GF) d) 3UNZ (DOU, CO, GF) along with their co-crystals and apo-forms were subjected to molecular dynamics simulations of 40 ns each to evaluate the variations of individual residues and their impact on forming interactions. The non-covalent interactions formed by the 157 AK co-crystals with different regions of the binding site were initially studied with the docked complexes and structure interaction fingerprints. The frequency of the most prominent interactions was gauged in the AK inhibitors from PDB and the four representative conformations during 40 ns. Based on this study, seven major non-covalent interactions and their complementary sites in AK capable of rendering specificity have been prioritized for the design of different classes of inhibitors. PMID:25485544

  19. Structural Exploration and Conformational Transitions in MDM2 upon DHFR Interaction from Homo sapiens: A Computational Outlook for Malignancy via Epigenetic Disruption.

    PubMed

    Banerjee, Arundhati; Ray, Sujay

    2016-01-01

    Structural basis for exploration into MDM2 and MDM2-DHFR interaction plays a vital role in analyzing the obstruction in folate metabolism, nonsynthesis of purines, and further epigenetic regulation in Homo sapiens. Therefore, it leads to suppression of normal cellular behavior and malignancy. This has been earlier documented via yeast two-hybrid assays. So, with a novel outlook, this study explores the molecular level demonstration of the best satisfactory MDM2 model selection after performing manifold modeling techniques. Z-scores and other stereochemical features were estimated for comparison. Further, protein-protein docking was executed with MDM2 and the experimentally validated X-ray crystallographic DHFR. Residual disclosure from the best suited simulated protein complex disclosed 18 side chain and 3 ionic interactions to strongly accommodate MDM2 protein into the pocket-like zone in DHFR due to the positive environment by charged residues. Lysine residues from MDM2 played a predominant role. Moreover, evaluation from varied energy calculations, folding rate, and net area for solvent accessibility implied the active participation of MDM2 with DHFR. Fascinatingly, conformational transitions from coils to helices and β-sheets after interaction with DHFR affirm the conformational strength and firmer interaction of human MDM2-DHFR. Therefore, this probe instigates near-future clinical research and interactive computational investigations with mutations. PMID:27213086

  20. Structural Exploration and Conformational Transitions in MDM2 upon DHFR Interaction from Homo sapiens: A Computational Outlook for Malignancy via Epigenetic Disruption

    PubMed Central

    Banerjee, Arundhati; Ray, Sujay

    2016-01-01

    Structural basis for exploration into MDM2 and MDM2-DHFR interaction plays a vital role in analyzing the obstruction in folate metabolism, nonsynthesis of purines, and further epigenetic regulation in Homo sapiens. Therefore, it leads to suppression of normal cellular behavior and malignancy. This has been earlier documented via yeast two-hybrid assays. So, with a novel outlook, this study explores the molecular level demonstration of the best satisfactory MDM2 model selection after performing manifold modeling techniques. Z-scores and other stereochemical features were estimated for comparison. Further, protein-protein docking was executed with MDM2 and the experimentally validated X-ray crystallographic DHFR. Residual disclosure from the best suited simulated protein complex disclosed 18 side chain and 3 ionic interactions to strongly accommodate MDM2 protein into the pocket-like zone in DHFR due to the positive environment by charged residues. Lysine residues from MDM2 played a predominant role. Moreover, evaluation from varied energy calculations, folding rate, and net area for solvent accessibility implied the active participation of MDM2 with DHFR. Fascinatingly, conformational transitions from coils to helices and β-sheets after interaction with DHFR affirm the conformational strength and firmer interaction of human MDM2-DHFR. Therefore, this probe instigates near-future clinical research and interactive computational investigations with mutations. PMID:27213086

  1. pH Induced Conformational Transitions in the Transforming Growth Factor β-Induced Protein (TGFβIp) Associated Corneal Dystrophy Mutants

    PubMed Central

    Murugan, Elavazhagan; Venkatraman, Anandalakshmi; Lei, Zhou; Mouvet, Victoria; Rui Yi Lim, Rayne; Muruganantham, Nandhakumar; Goh, Eunice; Swee Lim Peh, Gary; Beuerman, Roger W.; Chaurasia, Shyam S.; Rajamani, Lakshminarayanan; Mehta, Jodhbir S.

    2016-01-01

    Most stromal corneal dystrophies are associated with aggregation and deposition of the mutated transforming growth factor-β induced protein (TGFβIp). The 4th_FAS1 domain of TGFβIp harbors ~80% of the mutations that forms amyloidogenic and non-amyloidogenic aggregates. To understand the mechanism of aggregation and the differences between the amyloidogenic and non-amyloidogenic phenotypes, we expressed the 4th_FAS1 domains of TGFβIp carrying the mutations R555W (non-amyloidogenic) and H572R (amyloidogenic) along with the wild-type (WT). R555W was more susceptible to acidic pH compared to H572R and displayed varying chemical stabilities with decreasing pH. Thermal denaturation studies at acidic pH showed that while WT did not undergo any conformational transition, the mutants exhibited a clear pH-dependent irreversible conversion from αβ conformation to β-sheet oligomers. The β-oligomers of both mutants were stable at physiological temperature and pH. Electron microscopy and dynamic light scattering studies showed that β-oligomers of H572R were larger compared to R555W. The β-oligomers of both mutants were cytotoxic to primary human corneal stromal fibroblast (pHCSF) cells. The β-oligomers of both mutants exhibit variations in their morphologies, sizes, thermal and chemical stabilities, aggregation patterns and cytotoxicities. PMID:27030015

  2. Thermodynamic analysis of the disorder-to-α-helical transition of 18.5-kDa myelin basic protein reveals an equilibrium intermediate representing the most compact conformation.

    PubMed

    Vassall, Kenrick A; Jenkins, Andrew D; Bamm, Vladimir V; Harauz, George

    2015-05-22

    The intrinsically disordered, 18.5-kDa isoform of myelin basic protein (MBP) is a peripheral membrane protein that is essential to proper myelin formation in the central nervous system. MBP acts in oligodendrocytes both to adjoin membrane leaflets to each other in forming myelin and as a hub in numerous protein-protein and protein-membrane interaction networks. Like many intrinsically disordered proteins (IDPs), MBP multifunctionality arises from its high conformational plasticity and its ability to undergo reversible disorder-to-order transitions. One such transition is the disorder-to-α-helical conformational change that is induced upon MBP-membrane binding. Here, we have investigated the disorder-to-α-helical transition of MBP-derived α-peptides and the full-length 18.5-kDa protein. This transition was induced through titration of the membrane-mimetic solvent trifluoroethanol into both protein and peptide solutions, and conformational change was monitored using circular dichroism spectroscopy, 1-anilinonaphthalene-8-sulfonic acid binding, tryptophan fluorescence quenching, and Förster (fluorescence) resonance energy transfer measurements. The data suggest that the disorder-to-α-helical transition of MBP follows a 3-state model: disordered↔intermediate↔α-helical, with each of the identified equilibrium states likely representing a conformational ensemble. The disordered state is characterized by slight compaction with little regular secondary structure, whereas the intermediate is also disordered but globally more compact. Surprisingly, the α-helical conformation is less compact than the intermediate. This study suggests that multifunctionality in MBP could arise from differences in the population of energetically distinct ensembles under different conditions and also provides an example of an IDP that undergoes cooperative global conformation change.

  3. Phase Transitions of PYR14-TFSI as a Function of Pressure and Temperature: the Competition between Smaller Volume and Lower Energy Conformer.

    PubMed

    Capitani, F; Trequattrini, F; Palumbo, O; Paolone, A; Postorino, P

    2016-03-24

    A detailed Raman study has been carried out on the ionic liquid 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (PYR14-TFSI) over a wide pressure (0-8 GPa) and temperature (100-300 K) range. The explored thermodynamic region allowed us to study the evolution of the system across different solid and liquid phases. Calculated Raman spectra remarkably helped in the spectral data analysis. In particular, the pressure behavior of the most intense Raman peak and the shape analysis of the ruby fluorescence (used as a local pressure gauge) allowed us to identify a liquid-solid transition around 2.2 GPa at T = 300 K. The low-frequency Raman signal as well as the absence of remarkable spectral shape modifications on crossing the above threshold and the comparison with the spectra of the crystalline phase suggest a glassy nature of the high-pressure phase. A detailed analysis of the pressure dependence of the relative concentration of two conformers of TFSI allowed us to obtain an estimate of the volume variation between trans-TFSI and the smaller cis-TFSI, which is the favored configuration on applying the pressure. Finally, the combined use of both visual inspection and Raman spectroscopy confirmed the peculiar sequence of phase transitions observed as a function of temperature at ambient pressure and the different spectral/morphological characteristics of the two crystalline phases. PMID:26937556

  4. Transition of hemoglobin between two tertiary conformations: The transition constant differs significantly for the major and minor hemoglobins of the Japanese quail (Cortunix cortunix japonica).

    PubMed

    Okonjo, Kehinde Onwochei; Bello, Olugbenga S; Babalola, J Oyebamiji

    2008-03-01

    We demonstrate that 5,5'-dithiobis(2-nitrobenzoate) - DTNB - reacts with only CysF9[93]beta and CysB5[23]beta among the multiple sulfhydryl groups of the major and minor hemoglobins of the Japanese quail (Cortunix cortunix japonica). K(equ), the equilibrium constant for the reaction, does not differ very significantly between the two hemoglobins. It decreases 430-fold between pH approximately 5.6 and pH approximately 9: from a mean of 7+/-1 to a mean of 0.016+/-0.003. Quantitative analyses of the K(equ) data based on published X-ray and temperature-jump evidence for a tertiary structure transition in liganded hemoglobin enable the calculation of K(rt), the equilibrium constant for the r<---->t tertiary structure transition. K(rt) differs significantly between the two hemoglobins: 0.744+/-0.04 for the major, 0.401+/-0.01 for the minor hemoglobin. The mean pK(a)s of the two groups whose ionizations are coupled to the DTNB reaction are about the same as previously reported for mammalian hemoglobins.

  5. Calcium-induced changes in cytoskeleton and motility of cultured human keratinocytes.

    PubMed

    Magee, A I; Lytton, N A; Watt, F M

    1987-09-01

    In normal epidermis keratinocytes migrate upward from the basal layer as they undergo terminal differentiation, yet they also have the capacity for lateral movement during wound healing. The purpose of our experiments was to investigate these two types of movement by manipulating the calcium ion concentration of the medium so that keratinocytes formed monolayers (0.1 mM calcium) or stratified sheets (2.0 mM calcium). Time-lapse video recording indicated that keratinocytes in low-calcium medium were laterally more motile than keratinocytes in normal medium. This was consistent with the ultrastructural appearance of the cells and the lack of desmosomal junctions, determined by scanning and transmission electron microscopy. During calcium-induced stratification keratinocytes moved upward from the basal layer by gliding over their neighbors and forming contacts with other suprabasal cells. Keratinocytes in low-calcium medium migrated into wounds made in the cultures, a process which was inhibited by monensin; however, stratified keratinocytes in normal medium did not enter wounds. Cytochalasin D caused rapid cell rounding and disruption of actin filaments in keratinocytes grown in low-calcium but not in normal medium, indicating more rapid treadmilling of actin and consistent with the greater motility of keratinocytes in low-calcium medium. Our results suggest that desmosome formation may place constraints on the movement of individual keratinocytes and that the actomyosin cytoskeleton is involved in lateral migration.

  6. Troponin I binds polycystin-L and inhibits its calcium-induced channel activation.

    PubMed

    Li, Qiang; Liu, Yan; Shen, Patrick Y; Dai, Xiao-Qing; Wang, Shaohua; Smillie, Lawrence B; Sandford, Richard; Chen, Xing-Zhen

    2003-06-24

    Polycystin-L (PCL) is an isoform of polycystin-2, the product of the second gene associated with autosomal dominant polycystic kidney disease, and functions as a Ca(2+)-regulated nonselective cation channel. We recently demonstrated that polycystin-2 interacts with troponin I, an important regulatory component of the actin microfilament complex in striated muscle cells and an angiogenesis inhibitor. In this study, using the two-microelectrode voltage-clamp technique and Xenopus oocyte expression system, we showed that the calcium-induced PCL channel activation is substantially inhibited by the skeletal and cardiac troponin I (60% and 31% reduction, respectively). Reciprocal co-immunoprecipitation experiments demonstrated that PCL physically associates with the skeletal and cardiac troponin I isoforms in overexpressed Xenopus oocytes and mouse fibroblast NIH 3T3 cells. Furthermore, both native PCL and cardiac troponin I were present in human heart tissues where they indeed associate with each other. GST pull-down and microtiter binding assays showed that the C-terminus of PCL interacts with the troponin I proteins. The yeast two-hybrid assay further verified this interaction and defined the corresponding interacting domains of the PCL C-terminus and troponin I. Taken together, this study suggests that troponin I acts as a regulatory subunit of the PCL channel complex and provides the first direct evidence that PCL is associated with the actin cytoskeleton through troponin I. PMID:12809519

  7. Inhibitory action of oestrogen on calcium-induced mitosis in rat bone marrow and thymus.

    PubMed

    Smith, G R; Gurson, M L; Riddell, A J; Perris, A D

    1975-04-01

    In the male rat injections of CaCl-2 and MgCl-2 stimulated mitosis in bone marrow and thymus tissue. The magnesium salt was also mitogenic in the normal female, but calcium only exerted its mitogenic effect after ovariectomy. Oestradiol, but not progesterone replacement therpy abolished calcium-induced mitosis in the ovariectomized rat. The inability of calcium to stimulate cell division was also apparent in the thyroparathyroidectomized female rat, suggesting the oestradiol blockage did not operate via some indirect action on the calcium homeostatic hormones calcitonin or parathyroid hormone. When thymic lymphocytes derived from male or female rats were isolated and maintained in suspension, increased calcium or magnesium concentrations in the culture medium stimulated the entry of cells into mitosis. Addition of oestradiol to the culture medium abolished the mitogenic effect of increased calcium levels, but had no effect on magnesium-induced proliferation. These experiments suggested that oestradiol might act at the cell surface to prevent the influx of calcium but not magnesium ions into the interior of the cell and thus to block the sequence of biochemical events which led to the initiation of DNA synthesis and culminate in mitosis.

  8. The endocannabinoid 2-arachidonoylglicerol decreases calcium induced cytochrome c release from liver mitochondria.

    PubMed

    Zaccagnino, Patrizia; D'Oria, Susanna; Romano, Luigi Luciano; Di Venere, Almerinda; Sardanelli, Anna Maria; Lorusso, Michele

    2012-04-01

    2-Arachidonoylglicerol (2-AG) is an endocannabinoid that mimics the pharmacological effects of Δ⁹ tetrahydrocannabinol, the psychoactive component of the plant Cannabis sativa. It is present in many mammalian tissues, such as brain, liver, spleen, heart and kidney, where it exerts different biological effects either receptor mediated or independently of receptor activation. This work analyzes the effects of 2-AG on liver mitochondrial functions. It is shown that 2-AG causes a relevant decrease of calcium induced cyclosporine A sensitive cytochrome c release from mitochondria, a process representing an early event of the apoptotic program. Cyclosporin sensitive matrix swelling and ROS production measured under the same conditions are, on the contrary, almost unaffected or even enhanced, respectively, by 2-AG. Furthemore, 2-AG is found to stimulate resting state succinate oxidase activity and to inhibit oligomycin sensitive F₀F₁ ATP synthase activity. All these effects are apparently associated with 2-AG dependent alteration in the fluidity of the mitochondrial membranes, which was measured as generalized polarization of laurdan fluorescence. PMID:22437740

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

    PubMed

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

    2005-08-01

    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

  10. Distinct Roles of the Active-site Mg2+ Ligands, Asp882 and Asp705, of DNA Polymerase I (Klenow Fragment) during the Prechemistry Conformational Transitions*

    PubMed Central

    Bermek, Oya; Grindley, Nigel D. F.; Joyce, Catherine M.

    2011-01-01

    DNA polymerases catalyze the incorporation of deoxynucleoside triphosphates into a growing DNA chain using a pair of Mg2+ ions, coordinated at the active site by two invariant aspartates, whose removal by mutation typically reduces the polymerase activity to barely detectable levels. Using two stopped-flow fluorescence assays that we developed previously, we have investigated the role of the carboxylate ligands, Asp705 and Asp882, of DNA polymerase I (Klenow fragment) in the early prechemistry steps that prepare the active site for catalysis. We find that neither carboxylate is required for an early conformational transition, reported by a 2-aminopurine probe, that takes place in the open ternary complex after binding of the complementary dNTP. However, the subsequent fingers-closing step requires Asp882; this step converts the open ternary complex into the closed conformation, creating the active-site geometry required for catalysis. Crystal structures indicate that the Asp882 position changes very little during fingers-closing; this side chain may therefore serve as an anchor point to receive the dNTP-associated metal ion as the nucleotide is delivered into the active site. The Asp705 carboxylate is not required until after the fingers-closing step, and we suggest that its role is to facilitate the entry of the second Mg2+ into the active site. The two early prechemistry steps that we have studied take place normally at very low Mg2+ concentrations, although higher concentrations are needed for covalent nucleotide addition, consistent with the second metal ion entering the ternary complex after fingers-closing. PMID:21084297

  11. Ionic liquid-induced all-α to α + β conformational transition in cytochrome c with improved peroxidase activity in aqueous medium.

    PubMed

    Bharmoria, Pankaj; Trivedi, Tushar J; Pabbathi, Ashok; Samanta, Anunay; Kumar, Arvind

    2015-04-21

    Choline dioctylsulfosuccinate [Cho][AOT] (a surface active ionic liquid) has been found to induce all-α to α + β conformational transition in the secondary structure of enzyme cytochrome c (Cyt c) with an enhanced peroxidase activity in its aqueous vesicular phase at pH 7.0. [Cho][AOT] interacted with Cyt c distinctly at three critical concentrations (aggregation C1, saturation C2 and vesicular C3) as detected from isothermal titration calorimetric analysis. Oxidation of heme iron was observed from the disappearance of the Q band in the UV-vis spectra of Cyt c upon [Cho][AOT] binding above C3. Circular dichroism analysis (CD) has shown the loss in both the secondary (190-240 nm) and tertiary (250-300 nm) structure of Cyt c in the monomeric regime until C1, followed by their stabilization until the pre-vesicular regime (C1 → C3). Loss in both the secondary and tertiary structure has been observed in the post-vesicular regime with the change in Cyt c conformation from all-α to α + β which is similar to the conformational changes of Cyt c upon binding with mitochondrial membrane (Biochemistry 1998, 37, 6402-6409), thus citing the potential utility of [Cho][AOT] membranes as an artificial analog for in vitro bio-mimicking. Fluorescence correlation spectroscopy (FCS) measurements confirm the unfolding of Cyt c in the vesicular phase. Dynamic light scattering experiments have shown the contraction of [Cho][AOT] vesicles upon Cyt c binding driven by electrostatic interactions observed by charge neutralization from zeta potential measurements. [Cho][AOT] has been found to enhance the peroxidase activity of Cyt c with maximum activity at C3, observed using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt as the substrate in the presence of hydrogen peroxide. This result shows the relevance of tuning ionic liquids to surfactants for bio-mimicking of specific membrane protein-lipid interactions. PMID:25798458

  12. A lattice model Monte Carlo study of coil-to-globule and other conformational transitions of polymer, amphiphile, and solvent

    NASA Astrophysics Data System (ADS)

    Jennings, Deirdre E.; Kuznetsov, Yuri A.; Timoshenko, Edward G.; Dawson, Kenneth A.

    2000-05-01

    A model of polymer-amphiphile-solvent systems on a cubic lattice is used to investigate the phase diagram of such systems. The polymer is treated within the canonical ensemble (T,V,N) and the amphiphile and solvent are treated within the grand canonical ensemble (T,V,μ). Using a range of Monte Carlo moves the phase diagram of polymer-amphiphile-solvent mixtures, as a function of solvent quality (parametrized by χ) and relative chemical potential, μ, is studied for the dilute polymer limit. The effect of increasing the polymer chain length, N, on the critical aggregation concentration (CAC), and the type of polymer-amphiphile complex formed above the CAC are also examined. For some parameters, it is found that the polymer and amphiphile form a polymer-micelle complex at low amphiphile concentrations, and that the polymer coil-to-globule transition point increases with increasing amphiphile concentration. The resulting collapsed globule has a solvent core and is surrounded by a layer of amphiphile. These results are in good qualitative agreement with experimental results for the poly(N-isopropylacrylamide) (PNIPAM)/sodium dodecyl sulfate (SDS) system. At higher amphiphile concentrations, the polymer and amphiphile form several layered structures depending on the strength of the three-body amphiphilic interactions, l. Finally, the effect of the polymer chain length, N, and the strength of the three-body amphiphilic interactions, l, on the stability of the polymer-amphiphile structures is investigated.

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

    PubMed Central

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

    2014-01-01

    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 (ψ88 and ϕ89) 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. PMID:24405377

  14. Conformational transitions linked to active site ligation in human thrombin: effect on the interaction with fibrinogen and the cleavable platelet receptor.

    PubMed

    De Cristofaro, R; De Candia, E; Picozzi, M; Landolfi, R

    1995-01-27

    An experimental strategy based on solution viscosity perturbation allowed us to study the energetics of amide-substrates, p-aminobenzamidine (p-ABZ) and proflavin binding to the catalytic site of two proteolyzed forms of alpha-thrombin, i.e. zeta- and gamma T-thrombin. These thrombin derivatives are cleaved at the Leu144-Gly150 loop and at the fibrinogen recognition exosite (FRS), respectively. A phenomenological analysis of thermodynamic data showed that the amide substrates and p-ABZ interactions with zeta-thrombin were respectively, associated with a chemical compensation (i.e. the linear relationship between entropy and enthalpy of binding) and a hydrophobic phenomenon (i.e. a change in the standard heat capacity). The latter was slightly lower than that previously observed for a alpha-thrombin (0.78 +/- 0.25 versus 1.01 +/- 0.17 kcal/mol K). Both phenomenon were absent in gamma T-thrombin. The interaction of a alpha-, zeta- and gamma T-thrombin with macromolecular substrates that "bridge-bind" to both the catalytic site (CS) and fibrinogen recognition exosite (FRS), such as fibrinogen and the cleavable platelet receptor (CPR), was also evaluated. These interactions were studied by following fibrinopeptide A (FpA) release and by measuring intraplatelet Ca2+ changes induced by thrombin-CPR interaction. It was found that the free energy of activation (RT ln Kcat/Km) for both fibrinogen and CPR hydrolysis followed the same hierarchy, i.e. alpha > zeta > gamma. Moreover, the values of delta Cp for alpha-, zeta- and gamma T-thrombin interaction with p-ABZ were found to be linearly correlated to the free energy of activation for both fibrinogen and CPR cleavage. In conclusion, these data demonstrate that: (1) the Leu144-Gly150 loop and the FRS are both involved in the conformational transition linked to the binding of p-aminobenzamidine to the thrombin active site; (2) the extent of thrombin's capacity to undergo conformational transitions in alpha-, zeta- and gamma

  15. Transitions.

    ERIC Educational Resources Information Center

    Field, David; And Others

    1992-01-01

    Includes four articles: "Career Aspirations" (Field); "Making the Transition to a New Curriculum" (Baker, Householder); "How about a 'Work to School' Transition?" (Glasberg); and "Technological Improvisation: Bringing CNC to Woodworking" (Charles, McDuffie). (SK)

  16. Calcium-induced calcium release contributes to synaptic release from mouse rod photoreceptors

    PubMed Central

    Babai, N.; Morgans, C. W.; Thoreson, WB.

    2009-01-01

    We tested whether calcium-induced calcium release (CICR) contributes to synaptic release from rods in mammalian retina. Electron micrographs and immunofluorescent double labeling for the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) and synaptic ribbon protein, ribeye, showed a close association between ER and synaptic ribbons in mouse rod terminals. Stimulating CICR with 10 μM ryanodine evoked Ca2+ increases in rod terminals from mouse retinal slices visualized using confocal microscopy with the Ca2+-sensitive dye, Fluo-4. Ryanodine also stimulated membrane depolarization of individual mouse rods. Inhibiting CICR with a high concentration of ryanodine (100 μM) reduced the ERG b-wave but not a-wave consistent with inhibition of synaptic transmission from rods. Ryanodine (100 μM) also inhibited light-evoked voltage responses of individual rod bipolar cells (RBCs) and presumptive horizontal cells recorded with perforated patch recording techniques. A presynaptic site of action for ryanodine's effects is further indicated by the finding that ryanodine (100 μM) did not alter currents evoked in voltage-clamped RBCs by puffing the mGluR6 antagonist, (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG), onto bipolar cell dendrites in the presence of the mGluR6 agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4). Ryanodine (100 μM) also inhibited glutamatergic outward currents in RBCs evoked by electrical stimulation of rods using electrodes placed in the outer segment layer. Together, these results indicate that, like amphibian retina, CICR contributes to synaptic release from mammalian (mouse) rods. By boosting synaptic release in darkness, CICR may improve the detection of small luminance changes by post-synaptic neurons. PMID:19932743

  17. Probing the interaction induced conformation transitions in acid phosphatase with cobalt ferrite nanoparticles: Relation to inhibition and bio-activity of Chlorella vulgaris acid phosphatase.

    PubMed

    Ahmad, Farooq; Zhou, Xing; Yao, Hongzhou; Zhou, Ying; Xu, Chao

    2016-09-01

    The present study explored the interaction and kinetics of cobalt ferrite nanoparticles (NPs) with acid phosphatase (ACP) by utilizing diverse range of spectroscopic techniques. The results corroborate, the CoFe2O4 NPs cause fluorescence quenching in ACP by static quenching mechanism. The negative values of van't Hoff thermodynamic expressions (ΔH=-0.3293Jmol(-1)K(-1) and ΔG=-3.960kJmol(-1)K(-1)) corroborate the spontaneity and exothermic nature of static quenching. The positive value of ΔS (13.2893Jmol(-1)K(-1)) corroborate that major contributors of higher and stronger binding affinity among CoFe2O4 NPs with ACP were electrostatic. In addition, FTIR, UV-CD, UV-vis spectroscopy and three dimensional fluorescence (3D) techniques confirmed that CoFe2O4 NPs binding induces microenvironment perturbations leading to secondary and tertiary conformation changes in ACP to a great extent. Furthermore, synchronous fluorescence spectroscopy (SFS) affirmed the comparatively significant changes in microenvironment around tryptophan (Trp) residue by CoFe2O4 NPs. The effect of CoFe2O4 NPs on the activation kinetics of ACP was further examined in Chlorella vulgaris. Apparent Michaelis constant (Km) values of 0.57 and 26.5mM with activation energy values of 0.538 and 3.428kJmol(-1) were determined without and with 200μM CoFe2O4 NPs. Apparent Vmax value of -7Umml(-1) corroborate that enzyme active sites were completely captured by the NPs leaving no space for the substrate. The results confirmed that CoFe2O4 NPs ceased the activity by unfolding of ACP enzyme. This suggests CoFe2O4 NPs perturbed the enzyme activity by transitions in conformation and hence the metabolic activity of ACP. This study provides the pavement for novel and simple approach of using sensitive biomarkers for sensing NPs in environment. PMID:27209386

  18. Divalent cation-induced variations in polyelectrolyte conformation and controlling calcite morphologies: direct observation of the phase transition by atomic force microscopy.

    PubMed

    Pai, Ranjith Krishna; Pillai, Saju

    2008-10-01

    In the biomineralization process, the changes in conformation of organic matrix may be a widespread phenomenon. Investigation of the structural relationship between organic and inorganic materials is the main subject. The approach taken was to extract quantitative information of the variations in polyelectrolyte conformation during the mineralization process using atomic force microscopy. The results infer the evidence of the role of polyelectrolyte conformation in mineralization of calcium carbonate and the methods for understanding the principle that govern biomineralization.

  19. Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins.

    PubMed

    LeMaster, David M; Mustafi, Sourajit M; Brecher, Matthew; Zhang, Jing; Héroux, Annie; Li, Hongmin; Hernández, Griselda

    2015-06-19

    Interchanging Leu-119 for Pro-119 at the tip of the β4-β5 loop in the first FK506 binding domain (FK1) of the FKBP51 and FKBP52 proteins, respectively, has been reported to largely reverse the inhibitory (FKBP51) or stimulatory (FKBP52) effects of these co-chaperones on the transcriptional activity of glucocorticoid and androgen receptor-protein complexes. Previous NMR relaxation studies have identified exchange line broadening, indicative of submillisecond conformational motion, throughout the β4-β5 loop in the FK1 domain of FKBP51, which are suppressed by the FKBP52-like L119P substitution. This substitution also attenuates exchange line broadening in the underlying β2 and β3a strands that is centered near a bifurcated main chain hydrogen bond interaction between these two strands. The present study demonstrates that these exchange line broadening effects arise from two distinct coupled conformational transitions, and the transition within the β2 and β3a strands samples a transient conformation that resembles the crystal structures of the selectively inhibited FK1 domain of FKBP51 recently reported. Although the crystal structures for their series of inhibitors were interpreted as evidence for an induced fit mechanism of association, the presence of a similar conformation being significantly populated in the unliganded FKBP51 domain is more consistent with a conformational selection binding process. The contrastingly reduced conformational plasticity of the corresponding FK1 domain of FKBP52 is consistent with the current model in which FKBP51 binds to both the apo- and hormone-bound forms of the steroid receptor to modulate its affinity for ligand, whereas FKBP52 binds selectively to the latter state.

  20. Effects of PKA Phosphorylation of Cardiac Troponin I and Strong Crossbridge on Conformational Transitions of the N-Domain of Cardiac Troponin C in Regulated Thin Filaments

    PubMed Central

    Dong, Wen-Ji; Jayasundar, Jayant James; An, Jianli; Xing, Jun; Cheung, Herbert C.

    2008-01-01

    Regulation of cardiac muscle function is initiated by binding of Ca2+ to troponin C (cTnC) which induces a series of structural changes in cTnC and other thin filament proteins. These structural changes are further modulated by crossbridge formation and fine tuned by phosphorylation of cTnI. The objective of the present study is to use a new Förster Resonance Energy Transfer-based structural marker to distinguish structural and kinetic effects of Ca2+ binding, crossbridge interaction and protein kinase A phosphorylation of cTnI on the conformational changes of the cTnC N-domain. The FRET-based structural marker was generated by attaching AEDANS to one cysteine of a double-cysteine mutant cTnC(13C/51C) as a FRET donor and attaching DDPM to the other cysteine as the acceptor. The doubly labeled cTnC mutant was reconstituted into the thin filament by adding cTnI, cTnT, tropomyosin and actin. Changes in the distance between Cys13 and Cys51 induced by Ca2+ binding/dissociation were determined by FRET-sensed Ca2+ titration and stopped-flow studies, and time-resolved fluorescence measurements. The results showed that the presence of both Ca2+ and strong binding of myosin head to actin was required to achieve a fully open structure of the cTnC N-domain in regulated thin filaments. Equilibrium and stopped-flow studies suggested that strongly bound myosin head significantly increased the Ca2+ sensitivity and changed the kinetics of the structural transition of the cTnC N-domain. PKA phosphorylation of cTnI impacted the Ca2+ sensitivity and kinetics of the structural transition of the cTnC N-domain but showed no global structural effect on cTnC opening. These results provide an insight into the modulation mechanism of strong crossbridge and cTnI phosphorylation in cardiac thin filament activation/relaxation processes. PMID:17676764

  1. Honeycomb chain-channel (HCC) signature in the calcium-induced Si(111)-(3 × 2) surface

    NASA Astrophysics Data System (ADS)

    Gallus, O.; Pillo, Th.; Starowicz, P.; Baer, Y.

    2002-12-01

    The electronic and structural properties of a calcium-induced chain system on Si(111) have been studied. Low-energy electron diffraction measurements clearly reveal a (3 × 2) periodicity and the Ca coverage is determined to be 1/6 monolayer. Angle-resolved photoemission measurements have been performed with two different light polarizations in order to study the symmetries of the surface states. In both polarizations no band crossing the Fermi level EF is found. The three detected surface state bands are in good agreement with theoretical calculations in the honeycomb chain-channel (HCC) model for an insulating case.

  2. Accounting for conformational flexibility and torsional anharmonicity in the H + CH{sub 3}CH{sub 2}OH hydrogen abstraction reactions: A multi-path variational transition state theory study

    SciTech Connect

    Meana-Pañeda, Rubén; Fernández-Ramos, Antonio

    2014-05-07

    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.

  3. Transits

    NASA Astrophysics Data System (ADS)

    Gilliland, Ronald L.

    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 radial velocity detected object is indeed a planet by allowing precise determination of its mass and radius relative to these stellar quantities. From study of spectroscopic changes during transit it has been possible to probe for individual components of the transiting planets atmosphere. Planet transits are likely to become a primary tool for detection of new planets, especially other Earth-like planets with the Kepler Discovery Mission. Looking ahead, the additional aperture of the James Webb Space Space Telescope promises to allow the first possibility of studying the atmosphere of extra-solar Earth-analogue planets, perhaps even providing the first evidence of direct relevance to the search for signs of life on other planets.

  4. Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells

    PubMed Central

    Hahn, Hyung Jin; Youn, Hae Jeong; Cha, Hwa Jun; Kim, Karam; An, Sungkwan

    2016-01-01

    Background We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. Objective We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. Methods To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. Results Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. Conclusion These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation. PMID:27489424

  5. Atomic View of Calcium-Induced Clustering of Phosphatidylserine in Mixed Lipid Bilayers†

    PubMed Central

    Boettcher, John M.; Davis-Harrison, Rebecca L.; Clay, Mary C.; Nieuwkoop, Andrew J.; Ohkubo, Y. Zenmei; Tajkhorshid, Emad; Morrissey, James H.; Rienstra, Chad M.

    2011-01-01

    Membranes play key regulatory roles in biological processes, with bilayer composition exerting marked effects on binding affinities and catalytic activities of a number of membrane-associated proteins. In particular, proteins involved in diverse processes such as vesicle fusion, intracellular signaling cascades, and blood coagulation interact specifically with anionic lipids such as phosphatidylserine (PS) in the presence of Ca2+ ions. While Ca2+ is suspected to induce PS clustering in mixed phospholipid bilayers, the detailed structural effects of this ion on anionic lipids are not established. In this study, combining magic angle spinning (MAS) solid-state NMR (SSNMR) measurements of isotopically labeled serine headgroups in mixed lipid bilayers with molecular dynamics (MD) simulations of PS lipid bilayers in the presence of different counterions, we provide site-resolved insights into the effects of Ca2+ on the structure and dynamics of lipid bilayers. Ca2+-induced conformational changes of PS in mixed bilayers are observed in both liposomes and Nanodiscs, a nanoscale membrane-mimetic of bilayer patches. Site-resolved multidimensional correlation SSNMR spectra of bilayers containing 13C, 15N-labeled PS demonstrate that Ca2+ ions promote two major PS headgroup conformations, which are well resolved in two-dimensional 13C-13C, 15N-13C and 31P-13C spectra. The results of MD simulations performed on PS lipid bilayers in the presence or absence of Ca2+ provide an atomic view of the conformational effects underlying the observed spectra. PMID:21294564

  6. The conformal bootstrap

    NASA Astrophysics Data System (ADS)

    Poland, David; Simmons-Duffin, David

    2016-06-01

    The conformal bootstrap was proposed in the 1970s as a strategy for calculating the properties of second-order phase transitions. After spectacular success elucidating two-dimensional systems, little progress was made on systems in higher dimensions until a recent renaissance beginning in 2008. We report on some of the main results and ideas from this renaissance, focusing on new determinations of critical exponents and correlation functions in the three-dimensional Ising and O(N) models.

  7. Conformational changes in biopolymers

    NASA Astrophysics Data System (ADS)

    Ivanov, Vassili

    2005-12-01

    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

  8. Calcium-induced dissociation of human plasma factor XIII and the appearance of catalytic activity

    PubMed Central

    Cooke, Rodney D.

    1974-01-01

    1. The Ca2+ dependence of the activity of plasma Factor XIIIa was studied by using the continuous assay based on the incorporation of dansylcadaverine into dephosphorylated acetylated β-casein (β-substrate). The Km for Ca2+ is about 0.170mm. 2. At low concentrations of Ca2+ there was a lag in attaining the steady-state rate. The size of the lag was decreased and eventually abolished if the enzyme was preincubated with a high concentration of Ca2+ before assay. The concentration of Ca2+ required to decrease the lag phase by 50% in 10min depended on the protein concentration: at 0.87mg of protein/ml it required 17mm-Ca2+ and at 0.44mg/ml it needed 10mm-Ca2+. 3. The concentrations of Ca2+ required either to abolish the lag phase in the appearance of enzyme activity or to activate the essential thiol for reaction with 5,5′-dithiobis-(2-nitrobenzoate) in 10min incubation were similar at the same protein concentration. This indicated that Ca2+ induces a conformation change that is responsible for both phenomena. A model is proposed that links this conformation change to the dissociation of the tetrameric enzyme. 4. This was supported by the observation that the addition of excess of b chains to the Factor XIIIa (a′2b2) increased the concentration of Ca2+ required to expose the reactive thiol, and inhibited the Ca2+-dependent aggregation of a′ chains. 5. Platelet Factor XIIIa (a′2) was inhibited by 5,5′-dithiobis-(2-nitrobenzoate) in the absence of Ca2+, and no lag phases were observed in attaining the steady-state rate at low Ca2+ concentrations, thus confirming the model for the activation of the plasma enzyme. 6. The Ca2+ dependence of platelet Factor XIIIa indicated that Ca2+ has an additional role in the enzyme mechanism of the plasma enzyme, perhaps being involved in substrate binding. 7. The dependence of the stability of plasma Factor XIIIa on Ca2+ and protein concentration indicates that the decay in activity is related to the tetramer dissociation. 8

  9. Conformable seal

    DOEpatents

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

    1982-08-10

    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.

  10. Conformational transitions of the phosphodiester backbone in native DNA: two-dimensional magic-angle-spinning 31P-NMR of DNA fibers.

    PubMed Central

    Song, Z; Antzutkin, O N; Lee, Y K; Shekar, S C; Rupprecht, A; Levitt, M H

    1997-01-01

    Solid-state 31P-NMR is used to investigate the orientation of the phosphodiester backbone in NaDNA-, LiDNA-, MgDNA-, and NaDNA-netropsin fibers. The results for A- and B-DNA agree with previous interpretations. We verify that the binding of netropsin to NaDNA stabilizes the B form, and find that in NaDNA, most of the phosphate groups adopt a conformation typical of the A form, although there are minor components with phosphate orientations close to the B form. For LiDNA and MgDNA samples, on the other hand, we find phosphate conformations that are in variance with previous models. These samples display x-ray diffraction patterns that correspond to C-DNA. However, we find two distinct phosphate orientations in these samples, one resembling that in B-DNA, and one displaying a twist of the PO4 groups about the O3-P-O4 bisectors. The latter conformation is not in accordance with previous models of C-DNA structure. Images FIGURE 2 FIGURE 3 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 14 PMID:9284321

  11. Modeling conformational changes in cyclosporin A.

    PubMed Central

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

    1995-01-01

    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. PMID:8535256

  12. Eukaryotic translation initiation factor eIF5 promotes the accuracy of start codon recognition by regulating Pi release and conformational transitions of the preinitiation complex.

    PubMed

    Saini, Adesh K; Nanda, Jagpreet S; Martin-Marcos, Pilar; Dong, Jinsheng; Zhang, Fan; Bhardwaj, Monika; Lorsch, Jon R; Hinnebusch, Alan G

    2014-09-01

    eIF5 is the GTPase activating protein (GAP) for the eIF2 · GTP · Met-tRNAi (Met) ternary complex with a critical role in initiation codon selection. Previous work suggested that the eIF5 mutation G31R/SUI5 elevates initiation at UUG codons by increasing GAP function. Subsequent work implicated eIF5 in rearrangement of the preinitiation complex (PIC) from an open, scanning conformation to a closed state at AUG codons, from which Pi is released from eIF2 · GDP · Pi. To identify eIF5 functions crucial for accurate initiation, we investigated the consequences of G31R on GTP hydrolysis and Pi release, and the effects of intragenic G31R suppressors on these reactions, and on the partitioning of PICs between open and closed states. eIF5-G31R altered regulation of Pi release, accelerating it at UUG while decreasing it at AUG codons, consistent with its ability to stabilize the closed complex at UUG. Suppressor G62S mitigates both defects of G31R, accounting for its efficient suppression of UUG initiation in G31R,G62S cells; however suppressor M18V impairs GTP hydrolysis with little effect on PIC conformation. The strong defect in GTP hydrolysis conferred by M18V likely explains its broad suppression of Sui(-) mutations in numerous factors. We conclude that both of eIF5's functions, regulating Pi release and stabilizing the closed PIC conformation, contribute to stringent AUG selection in vivo.

  13. Dissecting the Calcium-Induced Differentiation of Human Primary Keratinocytes Stem Cells by Integrative and Structural Network Analyses

    PubMed Central

    Toufighi, Kiana; Yang, Jae-Seong; Luis, Nuno Miguel; Aznar Benitah, Salvador; Lehner, Ben; Serrano, Luis; Kiel, Christina

    2015-01-01

    The molecular details underlying the time-dependent assembly of protein complexes in cellular networks, such as those that occur during differentiation, are largely unexplored. Focusing on the calcium-induced differentiation of primary human keratinocytes as a model system for a major cellular reorganization process, we look at the expression of genes whose products are involved in manually-annotated protein complexes. Clustering analyses revealed only moderate co-expression of functionally related proteins during differentiation. However, when we looked at protein complexes, we found that the majority (55%) are composed of non-dynamic and dynamic gene products (‘di-chromatic’), 19% are non-dynamic, and 26% only dynamic. Considering three-dimensional protein structures to predict steric interactions, we found that proteins encoded by dynamic genes frequently interact with a common non-dynamic protein in a mutually exclusive fashion. This suggests that during differentiation, complex assemblies may also change through variation in the abundance of proteins that compete for binding to common proteins as found in some cases for paralogous proteins. Considering the example of the TNF-α/NFκB signaling complex, we suggest that the same core complex can guide signals into diverse context-specific outputs by addition of time specific expressed subunits, while keeping other cellular functions constant. Thus, our analysis provides evidence that complex assembly with stable core components and competition could contribute to cell differentiation. PMID:25946651

  14. Creation of reduced fat foods: influence of calcium-induced droplet aggregation on microstructure and rheology of mixed food dispersions.

    PubMed

    Wu, Bi-cheng; Degner, Brian; McClements, David Julian

    2013-12-15

    The impact of calcium-induced fat droplet aggregation on the microstructure and physicochemical properties of model mixed colloidal dispersions was investigated. These systems consisted of 2 wt% whey protein-coated fat droplets and 4 wt% modified starch granules heated to induce starch swelling (pH 7). Optical and confocal microscopy showed that the fat droplets were dispersed within the interstitial region between the swollen starch granules. The structural organisation of the fat droplets within these interstitial regions could be modulated by controlling the calcium concentration: (i) at a low calcium concentration the droplets were evenly distributed; (ii) at an intermediate calcium concentration they formed a layer around the starch granules; (iii) at a high calcium concentration they formed a network of aggregated droplets. Paste-like materials were produced when the fat droplets formed a three-dimensional network in the interstitial region. The properties of fat droplet-starch granule suspensions can be modulated by altering the electrostatic interactions to alter microstructure.

  15. Sustained release of vascular endothelial growth factor from calcium-induced alginate hydrogels reinforced by heparin and chitosan.

    PubMed

    Lee, K W; Yoon, J J; Lee, J H; Kim, S Y; Jung, H J; Kim, S J; Joh, J W; Lee, H H; Lee, D S; Lee, S K

    2004-10-01

    A possible alternative for immunosuppression is a microencapsulation technique using hydrogels, which have been utilized for cell immobilization and drug delivery systems. Angiogenesis is crucial for delivery of the metabolic products to the host tissues as well as to supply oxygen and nutrients to cells. The local delivery of angiogenic growth factors, such as VEGF and basic FGF, has been recently studied to enhance angiogenesis on peripheral tissue of graft. In this study, we evaluated sustained VEGF release with a model using hydrogels coated with chitosan and heparin in vitro. We fabricated calcium alginate gels and chitosan-coated calcium alginate gels. Heparinized chitosan-coated calcium-induced alginate hydrogel beads were prepared by soaking chitosan-coated calcium alginate gels in heparin solution. We compared the stability and VEGF release manner between three kinds of hydrogels. To compare the stability, 5 mL of each hydrogel was incubated with 20 mL PBS under the rotational culture. Compression forces were measured using a rheometer. The amount of VEGF released from the gels was measured by ELISA. The heparin-coated chitosan alginate hydrogels showed the highest surface stability among the three hydrogels. VEGF from the heparinized gel was released in sustained manner up to 10 days in vitro. Chitosan-coated alginate gels released 90% of loaded VEGF within 5 days. These results suggest that local delivery of VEGF using a heparinized hydrogel may provide a long-term supply of angiogenic growth factor that might induce new vessel formation in vivo.

  16. A quantitative measure for protein conformational heterogeneity

    PubMed Central

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

    2013-01-01

    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. PMID:24089719

  17. Conformational stability of apoflavodoxin.

    PubMed Central

    Genzor, C. G.; Beldarraín, A.; Gómez-Moreno, C.; López-Lacomba, J. L.; Cortijo, M.; Sancho, J.

    1996-01-01

    Flavodoxins are alpha/beta proteins that mediate electron transfer reactions. The conformational stability of apoflavodoxin from Anaboena PCC 7119 has been studied by calorimetry and urea denaturation as a function of pH and ionic strength. At pH > 12, the protein is unfolded. Between pH 11 and pH 6, the apoprotein is folded properly as judged from near-ultraviolet (UV) circular dichroism (CD) and high-field 1H NMR spectra. In this pH interval, apoflavodoxin is a monomer and its unfolding by urea or temperature follows a simple two-state mechanism. The specific heat capacity of unfolding for this native conformation is unusually low. Near its isoelectric point (3.9), the protein is highly insoluble. At lower pH values (pH 3.5-2.0), apoflavodoxin adopts a conformation with the properties of a molten globule. Although apoflavodoxin at pH 2 unfolds cooperatively with urea in a reversible fashion and the fluorescence and far-UV CD unfolding curves coincide, the transition midpoint depends on the concentration of protein, ruling out a simple two-state process at acidic pH. Apoflavodoxin constitutes a promising system for the analysis of the stability and folding of alpha/beta proteins and for the study of the interaction between apoflavoproteins and their corresponding redox cofactors. PMID:8819170

  18. 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

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

    2012-10-23

    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.

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

    SciTech Connect

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

    2014-04-28

    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.

  20. Calcium-induced calcium release and gap junctions mediate large-scale calcium waves in olfactory ensheathing cells in situ.

    PubMed

    Stavermann, Maren; Meuth, Patrick; Doengi, Michael; Thyssen, Anne; Deitmer, Joachim W; Lohr, Christian

    2015-08-01

    Olfactory ensheathing cells (OECs) are a specialised type of glial cells, supporting axon growth and guidance during development and regeneration of the olfactory nerve and the nerve layer of the olfactory bulb. We measured calcium signalling in OECs in olfactory bulb in-toto preparations using confocal and epifluorescence microscopy and the calcium indicator Fluo-4. We identified two subpopulations of olfactory bulb OECs: OECs in the outer sublamina of the nerve layer responded to purinergic neurotransmitters such as adenosine triphosphate with calcium transients, while OECs in the inner sublamina of the nerve layer did not respond to neurotransmitters. However, the latter generated spontaneous calcium waves that covered hundreds of cells. These calcium waves persisted in the presence of tetrodotoxin and in calcium-free saline, but were abolished after calcium store depletion with cyclopiazonic acid or inositol trisphosphate receptor blockage with 2-APB. Calcium waves could be triggered by laser photolysis of caged inositol trisphosphate. Blocking purinoceptors with PPADS had no effect on calcium wave propagation, whereas blocking gap junctions with carbenoxolone or meclofenamic acid entirely suppressed calcium waves. Increasing calcium buffer capacity in OECs with NP-EGTA ("caged" Ca(2+)) prevented calcium wave generation, and laser photolysis of NP-EGTA in a small group of OECs resulted in a calcium increase in the irradiated cells followed by a calcium wave. We conclude that calcium waves in OECs can be initiated by calcium-induced calcium release via InsP3 receptors and propagate through gap junctions, while purinergic signalling is not involved.

  1. Vitamin D receptor is required for dietary calcium-induced repression of calbindin-D9k expression in mice.

    PubMed

    Bolt, Merry J G; Cao, Li-Ping; Kong, Juan; Sitrin, Michael D; Li, Yan Chun

    2005-05-01

    Calbindin (CaBP), the vitamin D-dependent calcium-binding protein, is believed to play an important role in intracellular calcium transport. The aim of this study was to investigate the effect of high dietary calcium on the expression of CaBP-D9k and CaBP-D28k in the presence and absence of a functional vitamin D receptor (VDR). Treatment with the HCa-Lac diet containing 2% calcium, 1.5% phosphorus and 20% lactose reversed the hypocalcemia seen in adult VDR-null mice in 3 weeks but did not significantly change the blood ionized calcium in wild-type mice. This dietary treatment dramatically suppressed both the duodenal and the renal CaBP-D9k expression in wild-type mice at both mRNA and protein levels but had little effect on the expression of the same gene in VDR-null mice. Removal of this diet gradually restored the expression of CaBP-D9k to the untreated level in wild-type mice. Only moderate or little change in CaBP-D28k expression was seen in wild-type and VDR-null mice fed with the HCa-Lac diet. The VDR content in the duodenum or kidney of wild-type mice was not altered by the dietary treatment. These results suggest that calcium regulates CaBP-D9k expression by modulating the circulating 1,25-dihydrxyvitamin D(3) level and that VDR is thus required for the dietary calcium-induced suppression of CaBP-D9k expression. Calcium regulation of the CaBP-D9k level may represent an important mechanism by which animals maintain their calcium balance. PMID:15866228

  2. Intramolecular interactions in the polar headgroup of sphingosine: serinol† †Electronic supplementary information (ESI) available: Ab initio parameters for serinol conformers within 1000 cm–1, measured transition frequencies, typical a-type transition for conformer aa1, interconversion barriers and possible tunnelling pathways. See DOI: 10.1039/c5cc09423b Click here for additional data file.

    PubMed Central

    Loru, Donatella; Peña, Isabel; Alonso, José L.

    2016-01-01

    The intramolecular interactions in the lipid sphingosine have been elucidated through the investigation of the amino alcohol serinol which mimics its polar headgroup. Intricate networks of intramolecular hydrogen bonds involving the hydroxyl groups and the amino group contribute to the stabilisation of five different conformations observed in the broadband rotational spectrum. PMID:26727395

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

    PubMed

    Manna, Moutusi; Mukhopadhyay, Chaitali

    2013-01-01

    Interactions of amyloid-β (Aβ) with neuronal membrane are associated with the progression of Alzheimer's disease (AD). Ganglioside GM1 has been shown to promote the structural conversion of Aβ 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 Aβ monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for Aβ-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a β-hairpin motif was formed at the C-terminus of the GM1-bound Aβ-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 Aβ-dimers, the β-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of Aβ 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 Aβ-GM1 and Aβ-Aβ interactions and demonstrate their importance in the early-stages of GM1-mediated Aβ-oligomerisation on membrane surface.

  4. 40 CFR 93.104 - Frequency of conformity determinations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 21 2013-07-01 2013-07-01 false Frequency of conformity determinations..., Funded or Approved Under Title 23 U.S.C. or the Federal Transit Laws § 93.104 Frequency of conformity... implementation plan. (b) Frequency of conformity determinations for transportation plans. (1) Each...

  5. 40 CFR 93.104 - Frequency of conformity determinations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 21 2012-07-01 2012-07-01 false Frequency of conformity determinations..., Funded or Approved Under Title 23 U.S.C. or the Federal Transit Laws § 93.104 Frequency of conformity... implementation plan. (b) Frequency of conformity determinations for transportation plans. (1) Each...

  6. 40 CFR 93.104 - Frequency of conformity determinations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 20 2014-07-01 2013-07-01 true Frequency of conformity determinations..., Funded or Approved Under Title 23 U.S.C. or the Federal Transit Laws § 93.104 Frequency of conformity... implementation plan. (b) Frequency of conformity determinations for transportation plans. (1) Each...

  7. Kinetics of the Hydrogen Abstraction from Carbon-3 of 1-Butanol by Hydroperoxyl Radical: Multi-Structural Variational Transition-State Calculations of a Reaction with 262 Conformations of the Transition State.

    PubMed

    Seal, Prasenjit; Papajak, Ewa; Truhlar, Donald G

    2012-01-19

    We estimated rate constants for the hydrogen abstraction from carbon-3 of 1-butanol by hydroperoxyl radical, a critically important reaction in the combustion of biofuel. We employed the recently developed multi-structural variational transition-state theory (MS-VTST), which utilizes a multifaceted dividing surface that allows us to include the contributions of multiple structures for reacting species and transition states. First, multiconfigurational Shepard interpolation-based on molecular-mechanics-guided interpolation of electronic-structure Hessian data obtained by the M08 HX/jun-cc-pVTZ electronic model chemistry-was used to obtain the portion of the potential energy surface needed for single-structure variational transition-state theory rate constants including multidimensional tunneling; then, the M08-HX/MG3S electronic model chemistry was used to calculate multi-structural torsional anharmonicity factors to complete the MS-VTST rate constant calculations. The lowest-energy structures of the transition state have strongly bent hydrogen bonds. Our results indicate that neglect of multi-structural anharmonicity would lead to errors of factors of 0.3, 46, and 171 at 200, 1000, and 2400 K for this reaction. PMID:26698116

  8. Conformal operators in QCD

    SciTech Connect

    Makeenko, Y.M.

    1981-03-01

    Utilizing the properties of the representations of the conformal group, we obtain new expressions for the conformal operators composed of spinor or scalar fields of arbitrary dimension in terms of Jacobi polynomials. These expressions generalize the known formulas in terms of Gegenbauer polynomials. Using the conformal Ward identities, we prove the multiplicative renormalizability of conformal operators in the leading logarithmic approximation.

  9. Holographic multiverse and conformal invariance

    SciTech Connect

    Garriga, Jaume; Vilenkin, Alexander E-mail: vilenkin@cosmos.phy.tufts.edu

    2009-11-01

    We consider a holographic description of the inflationary multiverse, according to which the wave function of the universe is interpreted as the generating functional for a lower dimensional Euclidean theory. We analyze a simple model where transitions between inflationary vacua occur through bubble nucleation, and the inflating part of spacetime consists of de Sitter regions separated by thin bubble walls. In this model, we present some evidence that the dual theory is conformally invariant in the UV.

  10. Atomic levers control pyranose ring conformations

    PubMed Central

    Marszalek, Piotr E.; Pang, Yuan-Ping; Li, Hongbin; Yazal, Jamal El; Oberhauser, Andres F.; Fernandez, Julio M.

    1999-01-01

    Atomic force microscope manipulations of single polysaccharide molecules have recently expanded conformational chemistry to include force-driven transitions between the chair and boat conformers of the pyranose ring structure. We now expand these observations to include chair inversion, a common phenomenon in the conformational chemistry of six-membered ring molecules. We demonstrate that by stretching single pectin molecules (1 → 4-linked α-d-galactouronic acid polymer), we could change the pyranose ring conformation from a chair to a boat and then to an inverted chair in a clearly resolved two-step conversion: 4C1 ⇄ boat ⇄ 1C4. The two-step extension of the distance between the glycosidic oxygen atoms O1 and O4 determined by atomic force microscope manipulations is corroborated by ab initio calculations of the increase in length of the residue vector O1O4 on chair inversion. We postulate that this conformational change results from the torque generated by the glycosidic bonds when a force is applied to the pectin molecule. Hence, the glycosidic bonds act as mechanical levers, driving the conformational transitions of the pyranose ring. When the glycosidic bonds are equatorial (e), the torque is zero, causing no conformational change. However, when the glycosidic bond is axial (a), torque is generated, causing a rotation around C—C bonds and a conformational change. This hypothesis readily predicts the number of transitions observed in pyranose monomers with 1a-4a linkages (two), 1a-4e (one), and 1e-4e (none). Our results demonstrate single-molecule mechanochemistry with the capability of resolving complex conformational transitions. PMID:10393918

  11. Evolutionary Conserved Positions Define Protein Conformational Diversity.

    PubMed

    Saldaño, Tadeo E; Monzon, Alexander M; Parisi, Gustavo; Fernandez-Alberti, Sebastian

    2016-03-01

    Conformational diversity of the native state plays a central role in modulating protein function. The selection paradigm sustains that different ligands shift the conformational equilibrium through their binding to highest-affinity conformers. Intramolecular vibrational dynamics associated to each conformation should guarantee conformational transitions, which due to its importance, could possibly be associated with evolutionary conserved traits. Normal mode analysis, based on a coarse-grained model of the protein, can provide the required information to explore these features. Herein, we present a novel procedure to identify key positions sustaining the conformational diversity associated to ligand binding. The method is applied to an adequate refined dataset of 188 paired protein structures in their bound and unbound forms. Firstly, normal modes most involved in the conformational change are selected according to their corresponding overlap with structural distortions introduced by ligand binding. The subspace defined by these modes is used to analyze the effect of simulated point mutations on preserving the conformational diversity of the protein. We find a negative correlation between the effects of mutations on these normal mode subspaces associated to ligand-binding and position-specific evolutionary conservations obtained from multiple sequence-structure alignments. Positions whose mutations are found to alter the most these subspaces are defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. These positions are shown to be evolutionary conserved, mostly buried aliphatic residues localized in regular structural regions of the protein like β-sheets and α-helix. PMID:27008419

  12. Evolutionary Conserved Positions Define Protein Conformational Diversity

    PubMed Central

    Saldaño, Tadeo E.; Monzon, Alexander M.; Parisi, Gustavo; Fernandez-Alberti, Sebastian

    2016-01-01

    Conformational diversity of the native state plays a central role in modulating protein function. The selection paradigm sustains that different ligands shift the conformational equilibrium through their binding to highest-affinity conformers. Intramolecular vibrational dynamics associated to each conformation should guarantee conformational transitions, which due to its importance, could possibly be associated with evolutionary conserved traits. Normal mode analysis, based on a coarse-grained model of the protein, can provide the required information to explore these features. Herein, we present a novel procedure to identify key positions sustaining the conformational diversity associated to ligand binding. The method is applied to an adequate refined dataset of 188 paired protein structures in their bound and unbound forms. Firstly, normal modes most involved in the conformational change are selected according to their corresponding overlap with structural distortions introduced by ligand binding. The subspace defined by these modes is used to analyze the effect of simulated point mutations on preserving the conformational diversity of the protein. We find a negative correlation between the effects of mutations on these normal mode subspaces associated to ligand-binding and position-specific evolutionary conservations obtained from multiple sequence-structure alignments. Positions whose mutations are found to alter the most these subspaces are defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. These positions are shown to be evolutionary conserved, mostly buried aliphatic residues localized in regular structural regions of the protein like β-sheets and α-helix. PMID:27008419

  13. Conformational Interconversions of Amino Acid Derivatives.

    PubMed

    Kaminský, Jakub; Jensen, Frank

    2016-02-01

    Exhaustive conformational interconversions including transition structure analyses of N-acetyl-l-glycine-N-methylamide as well as its alanine, serine, and cysteine analogues have been investigated at the MP2/6-31G** level, yielding a total of 142 transition states. Improved estimates of relative energies were obtained by separately extrapolating the Hartree-Fock and MP2 energies to the basis set limit and adding the difference between CCSD(T) and MP2 results with the cc-pVDZ basis set to the extrapolated MP2 results. The performance of eight empirical force fields (AMBER94, AMBER14SB, MM2, MM3, MMFFs, CHARMM22_CMAP, OPLS_2005, and AMOEBAPRO13) in reproducing ab initio energies of transition states was tested. Our results indicate that commonly used class I force fields employing a fixed partial charge model for the electrostatic interaction provide mean errors in the ∼10 kJ/mol range for energies of conformational transition states for amino acid conformers. Modern reparametrized versions, such as CHARMM22_CMAP, and polarizable force fields, such as AMOEBAPRO13, have slightly lower mean errors, but maximal errors are still in the 35 kJ/mol range. There are differences between the force fields in their ability for reproducing conformational transitions classified according to backbone/side-chain or regions in the Ramachandran angles, but the data set is likely too small to draw any general conclusions. Errors in conformational interconversion barriers by ∼10 kJ/mol suggest that the commonly used force field may bias certain types of transitions by several orders of magnitude in rate and thus lead to incorrect dynamics in simulations. It is therefore suggested that information for conformational transition states should be included in parametrizations of new force fields. PMID:26691979

  14. Platelet-activating factor in Iberian pig spermatozoa: receptor expression and role as enhancer of the calcium-induced acrosome reaction.

    PubMed

    Bragado, M J; Gil, M C; Garcia-Marin, L J

    2011-12-01

    Platelet-activating factor (PAF) is a phospholipid involved in reproductive physiology. PAF receptor is expressed in some mammalian spermatozoa species where it plays a role in these germ-cell-specific processes. The aim of this study is to identify PAF receptor in Iberian pig spermatozoa and to evaluate PAF's effects on motility, viability and acrosome reaction. Semen samples from Iberian boars were used. PAF receptor identification was performed by Western blotting. Spermatozoa motility was analysed by computer-assisted sperm analysis system, whereas spermatozoa viability and acrosome reaction were evaluated by flow cytometry. Different PAF concentrations added to non-capacitating medium during 60 min have no effect on any spermatozoa motility parameter measured. Acrosome reaction was rapid and potently induced by 1 μm calcium ionophore A23187 showing an effect at 60 min and maximum at 240 min. PAF added to a capacitating medium is not able to induce spermatozoa acrosome reaction at any time studied. However, PAF, in the presence of A23187, significantly accelerates and enhances the calcium-induced acrosome reaction in a concentration-dependent manner in Iberian boar spermatozoa. Exogenous PAF does not affect at all spermatozoa viability, whereas slightly exacerbated the A23187-induced loss in viability. This work demonstrates that PAF receptor is expressed in Iberian pig spermatozoa and that its stimulation by PAF regulates the calcium-induced acrosome reaction. This work contributes to further elucidate the physiological regulation of the most relevant spermatozoa functions for successful fertilization: acrosome reaction. PMID:22023717

  15. Concurrence of replicative senescence and elevated expression of p16(INK4A) with subculture-induced but not calcium-induced differentiation in normal human oral keratinocytes.

    PubMed

    Lee, G; Park, B S; Han, S E; Oh, J E; You, Y O; Baek, J H; Kim, G S; Min, B M

    2000-10-01

    Primary normal human oral keratinocytes (NHOKs) undergo differentiation in the presence of calcium concentrations higher than 0.15 mM in vitro, which is useful in investigating the mechanisms involved in the differentiation of epithelial cells. Serial subculture of NHOKs to the postmitotic stage also induces terminal differentiation. However, the detailed mechanisms of both differentiation processes remain substantially unknown. To investigate the molecular differences in these processes, NHOKs were induced to differentiate by exposure to 1.2 mM of calcium and by serial subculture to the postmitotic stage. To study whether the cells were induced to differentiate and to undergo replicative senescence, the amount of cellular involucrin and the expression of senescence-associated beta-galactosidase (SA-beta-gal) were measured respectively. The expression of replicative senescence-associated genes and the activity of telomerase from the differentiated cells were also determined. Both calcium treatment and serial subculture to the postmitotic stage notably elevated the cellular involucrin. The percentage of SA-beta-gal-positive cells was significantly elevated by the continued subculture, but such changes were not observed in keratinocytes exposed to calcium. The concentration of cellular p16(INK4A) protein was progressively increased by the continued subculture but was not changed by calcium treatment. On the other hand, the concentrations of cellular p53 were similar in both differentiation processes. However, telomerase activity was lost in NHOKs that had undergone differentiation by both calcium treatment and serial subculture. The results indicate that calcium-induced differentiation of NHOKs has similar characteristics to their serial subculture-induced differentiation, but that the differentiation processes are not identical, because calcium-induced differentiation does not concur with either replicative senescence or the gradually increased concentration of p16

  16. Toward TeV Conformality

    SciTech Connect

    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

    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.

  17. Transition state complexes of the Klebsiella pneumoniae nitrogenase proteins. Spectroscopic properties of aluminium fluoride-stabilized and beryllium fluoride-stabilized MgADP complexes reveal conformational differences of the Fe protein.

    PubMed

    Miller, R W; Eady, R R; Fairhurst, S A; Gormal, C A; Smith, B E

    2001-02-01

    Stable inactive 2 : 1 complexes of the Klebsiella pneumoniae nitrogenase components (Kp2/Kp1) were prepared with ADP or the fluorescent ADP analogue, 2'(3')-O-[N-methylanthraniloyl] ADP and AlF(4)(-) or BeF(3)(-) ions. By analogy with published crystallographic data [Schindelin et al. (1997) Nature 387, 370-376)], we suggest that the metal fluoride ions replaced phosphate at the two ATP-binding sites of the iron protein, Kp2. The beryllium (BeF(x)) and aluminium (AlF(4)(-)) containing complexes are proposed to correspond to the ATP-bound state and the hydrolytic transition states, respectively, by analogy with the equivalent complexes of myosin [Fisher et al. (1995) Biochemistry 34, 8960-8972]. (31)P NMR spectroscopy showed that during the initial stages of complex formation, MgADP bound to the complexed Kp2 in a manner similar to that reported for isolated Kp2. This process was followed by a second step that caused broadening of the (31)P NMR signals and, in the case of the AlF4- complex, slow hydrolysis of some of the excess ADP to AMP and inorganic phosphate. The purified BeFx complex contained 3.8 +/- 0.1 MgADP per mol Kp1. With the AlF(4)(-) complex, MgAMP and adenosine (from MgAMP hydrolysis) replaced part of the bound MgADP although four AlF(4)(-) ions were retained, demonstrating that full occupancy by MgADP is not required for the stability of the complex. The fluorescence emission maximum of 2'(3')-O-[N-methylanthraniloyl] ADP was blue-shifted by 6-8 nm in both metal fluoride complexes and polarization was 6-9 times that of the free analogue. The fluorescence yield of bound 2'(3')-O-[N-methylanthraniloyl] ADP was enhanced by 40% in the AlF(4)(-) complex relative to the solvent but no increase in fluorescence was observed in the BeFx complex. Resonance energy transfer from conserved tyrosine residues located in proximity to the Kp2 nucleotide-binding pocket was marked in the AlF(4)(-) complex but minimal in the BeFx fluoride complex, illustrating a clear

  18. Mapping Conformational Dynamics of Proteins Using Torsional Dynamics Simulations

    PubMed Central

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

    2013-01-01

    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

  19. Mapping conformational dynamics of proteins using torsional dynamics simulations.

    PubMed

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

    2013-05-01

    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 Ca(2+)-bound to the Ca(2+)-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

  20. CONSENSUS AND CONFORMITY.

    ERIC Educational Resources Information Center

    ALLEN, VERNON L.; LEVINE, JOHN M.

    IN THIS STUDY, PROFESSOR ALLEN EMPLOYS TWO METHODS OF BREAKING GROUP CONSENSUS, AND HE MEASURES THE EFFECTS ON THE RESPONSES OF COLLEGE SUBJECTS TO BOTH OBJECTIVE AND SUBJECTIVE STIMULI. THE RESULTS SUGGEST THE NEED FOR MODIFICATION OF EXISTING THEORIES OF CONFORMITY BEHAVIOR. IN ADDITION, THESE RESULTS EMPHASIZE THE DIFFERENCES IN CONFORMITY OF…

  1. Dynamics and Conformational Energetics of a Peptide Hormone: Vasopressin

    NASA Astrophysics Data System (ADS)

    Hagler, A. T.; Osguthorpe, D. J.; Dauber-Osguthorpe, P.; Hempel, J. C.

    1985-03-01

    A theoretical methodology for use in conjunction with experiment was applied to the neurohypophyseal hormone lysine vasopressin for elucidation of its accessible molecular conformations and associated flexibility, conformational transitions, and dynamics. Molecular dynamics and energy minimization techniques make possible a description of the conformational properties of a peptide in terms of the precise positions of atoms, their fluctuations in time, and the interatomic forces acting on them. Analysis of the dynamic trajectory of lysine vasopressin shows the ability of a flexible peptide hormone to undergo spontaneous conformational transitions. The excursions of an individual phenylalanine residue exemplify the dynamic flexibility and multiple conformational states available to small peptide hormones and their component residues, even within constraints imposed by a cyclic hexapeptide ring.

  2. High-resolution KMM radiative Auger x-ray emission spectra of calcium induced by synchrotron radiation

    SciTech Connect

    Cao, W.; Dousse, J.-Cl.; Berset, M.; Fennane, K.; Hoszowska, J.; Maillard, Y.-P.; Szlachetko, M.; Kavcic, M.; Bucar, K.; Budnar, M.; Zitnik, M.; Szlachetko, J.

    2011-04-15

    The KMM radiative Auger (RA) x-ray spectra of solid Ca were induced by monochromatic synchrotron radiation and measured with a high-resolution von Hamos bent crystal spectrometer. Two excitation energies were employed, one in the near K threshold region and the second well above the K absorption edge. The KMM RA spectral structure and relative intensity with respect to the diagram K{beta}{sub 1,3} (K-M{sub 3,2}) line are found to be independent of the excitation energy. The overall RA structure resembles the density of unoccupied s, p, and d states. Due to solid-state effects, however, spectral features resulting from the major discrete shake-up transitions could not be resolved. For the total KMM RA to K{beta}{sub 1,3} yield ratio, a value of 0.053(3) is obtained. The latter is compared to theoretical predictions and available experimental data obtained by various types of target excitation.

  3. Logarithmic conformal field theory

    NASA Astrophysics Data System (ADS)

    Gainutdinov, Azat; Ridout, David; Runkel, Ingo

    2013-12-01

    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

  4. Discovering conformational sub-states relevant to protein function

    SciTech Connect

    Agarwal, Pratul K; Ramanathan, Arvind

    2011-01-01

    Internal motions enable proteins to explore a range of conformations, even in the vicinity of native state. The role of conformational fluctuations in the designated function of a protein is widely debated. Emerging evidence suggests that sub-groups within the range of conformations (or sub-states) contain properties that may be functionally relevant. However, low populations in these sub-states and the transient nature of conformational transitions between these sub-states present significant challenges for their identification and characterization. To overcome these challenges we have developed a new computational technique, quasi-anharmonic analysis (QAA). QAA utilizes higher-order statistics of protein motions to identify sub-states in the conformational landscape. Further, the focus on anharmonicity allows identification of conformational fluctuations that enable transitions between sub-states. QAA applied to equilibrium simulations of human ubiquitin and T4 lysozyme reveals functionally relevant sub-states and protein motions involved in molecular recognition. In combination with a reaction pathway sampling method, QAA characterizes conformational sub-states associated with cis/trans peptidyl-prolyl isomerization catalyzed by the enzyme cyclophilin A. In these three proteins, QAA allows identification of conformational sub-states, with critical structural and dynamical features relevant to protein function. Overall, QAA provides a novel framework to intuitively understand the biophysical basis of conformational diversity and its relevance to protein function.

  5. 40 CFR 93.114 - Criteria and procedures: Currently conforming transportation plan and TIP.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... conforming transportation plan and TIP. 93.114 Section 93.114 Protection of Environment ENVIRONMENTAL..., Programs, and Projects Developed, Funded or Approved Under Title 23 U.S.C. or the Federal Transit Laws § 93... currently conforming transportation plan and currently conforming TIP at the time of project approval, or...

  6. 40 CFR 93.114 - Criteria and procedures: Currently conforming transportation plan and TIP.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... conforming transportation plan and TIP. 93.114 Section 93.114 Protection of Environment ENVIRONMENTAL..., Programs, and Projects Developed, Funded or Approved Under Title 23 U.S.C. or the Federal Transit Laws § 93... currently conforming transportation plan and currently conforming TIP at the time of project approval, or...

  7. Assemblies of Conformal Tanks

    NASA Technical Reports Server (NTRS)

    DeLay, Tom

    2009-01-01

    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.

  8. Essential role of conformational selection in ligand binding

    PubMed Central

    Vogt, Austin D.; Pozzi, Nicola; Chen, Zhiwei; Di Cera, Enrico

    2013-01-01

    Two competing and mutually exclusive mechanisms of ligand recognition – conformational selection and induced fit - have dominated our interpretation of ligand binding in biological macromolecules for almost six decades. Conformational selection posits the pre-existence of multiple conformations of the macromolecule from which the ligand selects the optimal one. Induced fit, on the other hand, postulates the existence of conformational rearrangements of the original conformation into an optimal one that is induced by binding of the ligand. In the former case, conformational transitions precede the binding event; in the latter, conformational changes follow the binding step. Kineticists have used a facile criterion to distinguish between the two mechanisms based on the dependence of the rate of relaxation to equilibrium, kobs, on the ligand concentration, [L]. A value of kobs decreasing hyperbolically with [L] is seen as diagnostic of conformational selection, while a value of kobs increasing hyperbolically with [L] is considered diagnostic of induced fit. However, this simple conclusion is only valid in the rather unrealistic assumption of conformational transitions being much slower than binding and dissociation events. In general, induced fit only produces values of kobs that increase with [L] but conformational selection is more versatile and is associated with values of kobs that increase, decrease with or are independent of [L]. The richer repertoire of kinetic properties of conformational selection applies to kinetic mechanisms with single or multiple saturable relaxations and explains the behavior of nearly all experimental systems reported in the literature thus far. Conformational selection is always sufficient and often necessary to account for the relaxation kinetics of ligand binding to a biological macromolecule and is therefore an essential component of any binding mechanism. On the other hand, induced fit is never necessary and only sufficient in a

  9. Two-Dimensional Heterospectral Correlation Analysis of the Redox-Induced Conformational Transition in Cytochrome c Using Surface-Enhanced Raman and Infrared Absorption Spectroscopies on a Two-Layer Gold Surface

    PubMed Central

    2013-01-01

    The heme protein cytochrome c adsorbed to a two-layer gold surface modified with a self-assembled monolayer of 2-mercaptoethanol was analyzed using a two-dimensional (2D) heterospectral correlation analysis that combined surface-enhanced infrared absorption spectroscopy (SEIRAS) and surface-enhanced Raman spectroscopy (SERS). Stepwise increasing electric potentials were applied to alter the redox state of the protein and to induce conformational changes within the protein backbone. We demonstrate herein that 2D heterospectral correlation analysis is a particularly suitable and useful technique for the study of heme-containing proteins as the two spectroscopies address different portions of the protein. Thus, by correlating SERS and SEIRAS data in a 2D plot, we can obtain a deeper understanding of the conformational changes occurring at the redox center and in the supporting protein backbone during the electron transfer process. The correlation analyses are complemented by molecular dynamics calculations to explore the intramolecular interactions. PMID:23930980

  10. The modulation of action potential generation by calcium-induced calcium release is enhanced by mitochondrial inhibitors in mudpuppy parasympathetic neurons.

    PubMed

    Barstow, K L; Locknar, S A; Merriam, L A; Parsons, R L

    2004-01-01

    Previously, we demonstrated that outward currents activated by calcium-induced calcium release (CICR) opposed depolarization-induced action potential (AP) generation in dissociated mudpuppy parasympathetic neurons [J Neurophysiol 88 (2002) 1119]. In the present study, we tested whether AP generation by depolarizing current ramps could be altered by dissipating the mitochondrial membrane potential and thus interrupting mitochondrial Ca2+ buffering. Exposure to the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP; 2 microM) alone or in combination with the mitochondrial ATP synthase inhibitor oligomycin (8 microg/ml), increased the latency to AP generation. Exposure to the electron transport chain inhibitor rotenone (10 microM) alone or in combination with oligomycin (8 microg/ml) similarly increased the latency to AP generation. CCCP and oligomycin or rotenone and oligomycin treatment caused rhodamine 123 loss from mitochondria within a few minutes, confirming that the mitochondrial membrane potential was dissipated during drug exposure. Oligomycin alone had no effect on the latency to AP generation and did not cause loss of rhodamine 123 from mitochondria. The increase in latency induced by CCCP and oligomycin was similar when recordings were made with either the perforated patch or standard whole cell patch recording configuration. Exposure to the endoplasmic reticulum Ca-ATPase inhibitor thapsigargin (1 microM), decreased the latency to AP generation. In cells pretreated with thapsigargin to eliminate CICR, CCCP and oligomycin had no effect on AP latency. Pretreatment with iberiotoxin (IBX; 100 nM), an inhibitor of large conductance, calcium- and voltage-activated potassium channels, reduced the extent of the CCCP- and oligomycin-induced increase in latency to AP generation. These results indicate that treatment with CCCP or rotenone to dissipate the mitochondrial membrane potential, a condition which should minimize sequestration of Ca2+ by

  11. Calcium-induced proline accumulation contributes to amelioration of NaCl injury and expression of glutamine synthetase in greater duckweed (Spirodela polyrhiza L.).

    PubMed

    Cheng, Tai-Sheng; Hung, Meng-Ju; Cheng, Yen-I; Cheng, Lee-Ju

    2013-11-15

    The calcium-mediated proline accumulation is a critical response under NaCl stress and the function of the induced proline as a glutamine synthetase (GS) protectant in greater duckweed was investigated. The plants were treated with solutions containing 100mM NaCl, 200 mM NaCl, 200 mM NaCl plus 10mM CaCl2, or 10mM CaCl2 alone for 4 days. At the end of the experiment, the fronds of inoculum treated with 200 mM NaCl showed the chlorotic effect, higher glutamate dehydrogenase (NADH-GDH) activity and lower GS activity. At the lower salinity, the activities of GS and NADH-GDH were not altered markedly. A significant accumulation of proline was not found under either low or high salinity. The activity of Δ(1)-pyrroline-5-carboxylate reductase (P5CR) was enhanced only at 200 mM NaCl but remained unchanged at 100mM NaCl. The activity of Δ(1)-pyrroline-5-carboxylate synthetase (P5CS) did not change under salinity-stressed. Addition of CaCl2 to the salt stressed plants not only lowered NaCl injury but also showed an elevated level of proline contents in response to the salinity treatment. In addition, both GS activity and corresponding polypeptides were expressed close to the level of control. Exogenous proline protects GS2 and the 32 kDa protein in photosystem II reaction center (D1) from H2O2-induced redox degradation in the chloroplast lysates of duckweed. The results suggest that calcium-induced proline accumulation may play an important role as a GS protectant under NaCl exposure in S. polyrhiza.

  12. Charged conformal Killing spinors

    SciTech Connect

    Lischewski, Andree

    2015-01-15

    We study the twistor equation on pseudo-Riemannian Spin{sup c}-manifolds whose solutions we call charged conformal Killing spinors (CCKSs). We derive several integrability conditions for the existence of CCKS and study their relations to spinor bilinears. A construction principle for Lorentzian manifolds admitting CCKS with nontrivial charge starting from CR-geometry is presented. We obtain a partial classification result in the Lorentzian case under the additional assumption that the associated Dirac current is normal conformal and complete the classification of manifolds admitting CCKS in all dimensions and signatures ≤5 which has recently been initiated in the study of supersymmetric field theories on curved space.

  13. Molecular dynamics studies of the conformation of sorbitol

    PubMed Central

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

    2009-01-01

    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. PMID:19744646

  14. Extended conformal field theories

    NASA Astrophysics Data System (ADS)

    Taormina, Anne

    1990-08-01

    Some extended conformal field theories are briefly reviewed. They illustrate how non minimal models of the Virasoro algebra (c≥1) can become minimal with respect to a larger algebra. The accent is put on N-extended superconformal algebras, which are relevant in superstring compactification.

  15. Quantifying polypeptide conformational space: sensitivity to conformation and ensemble definition.

    PubMed

    Sullivan, David C; Lim, Carmay

    2006-08-24

    Quantifying the density of conformations over phase space (the conformational distribution) is needed to model important macromolecular processes such as protein folding. In this work, we quantify the conformational distribution for a simple polypeptide (N-mer polyalanine) using the cumulative distribution function (CDF), which gives the probability that two randomly selected conformations are separated by less than a "conformational" distance and whose inverse gives conformation counts as a function of conformational radius. An important finding is that the conformation counts obtained by the CDF inverse depend critically on the assignment of a conformation's distance span and the ensemble (e.g., unfolded state model): varying ensemble and conformation definition (1 --> 2 A) varies the CDF-based conformation counts for Ala(50) from 10(11) to 10(69). In particular, relatively short molecular dynamics (MD) relaxation of Ala(50)'s random-walk ensemble reduces the number of conformers from 10(55) to 10(14) (using a 1 A root-mean-square-deviation radius conformation definition) pointing to potential disconnections in comparing the results from simplified models of unfolded proteins with those from all-atom MD simulations. Explicit waters are found to roughen the landscape considerably. Under some common conformation definitions, the results herein provide (i) an upper limit to the number of accessible conformations that compose unfolded states of proteins, (ii) the optimal clustering radius/conformation radius for counting conformations for a given energy and solvent model, (iii) a means of comparing various studies, and (iv) an assessment of the applicability of random search in protein folding.

  16. Logarithmic conformal field theory

    NASA Astrophysics Data System (ADS)

    Gainutdinov, Azat; Ridout, David; Runkel, Ingo

    2013-12-01

    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

  17. Protein Conformational Populations and Functionally Relevant Sub-states

    SciTech Connect

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

    2013-01-01

    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.

  18. Characterization of DNA conformation inside bacterial viruses

    NASA Astrophysics Data System (ADS)

    Petrov, Anton S.; Locker, C. Rebecca; Harvey, Stephen C.

    2009-08-01

    In this study we develop a formalism to describe the organization of DNA inside bacteriophage capsids during genome packaging. We have previously shown that DNA inside bacteriophage phi29 (ϕ29) is organized into folded toroids [A. S. Petrov and S. C. Harvey, Structure 15, 21 (2007)], whereas epsilon15 (ɛ15) reveals the coaxial organization of the genetic material [A. S. Petrov, K. Lim-Hing, and S. C. Harvey, Structure 15, 807 (2007)]. We now show that each system undergoes two consecutive transitions. The first transition corresponds to the formation of global conformations and is analogous to a disorder-order conformational transition. The second transition is characterized by a significant loss of DNA mobility at the local level leading to glasslike dynamic behavior. Packing genetic material inside bacteriophages can be used as a general model to study the behavior of semiflexible chains inside confined spaces, and the proposed formalism developed here can be used to study other systems of linear polymer chains confined to closed spaces.

  19. How to Distinguish Conformational Selection and Induced Fit Based on Chemical Relaxation Rates.

    PubMed

    Paul, Fabian; Weikl, Thomas R

    2016-09-01

    Protein binding often involves conformational changes. Important questions are whether a conformational change occurs prior to a binding event ('conformational selection') or after a binding event ('induced fit'), and how conformational transition rates can be obtained from experiments. In this article, we present general results for the chemical relaxation rates of conformational-selection and induced-fit binding processes that hold for all concentrations of proteins and ligands and, thus, go beyond the standard pseudo-first-order approximation of large ligand concentration. These results allow to distinguish conformational-selection from induced-fit processes-also in cases in which such a distinction is not possible under pseudo-first-order conditions-and to extract conformational transition rates of proteins from chemical relaxation data. PMID:27636092

  20. How to Distinguish Conformational Selection and Induced Fit Based on Chemical Relaxation Rates

    PubMed Central

    2016-01-01

    Protein binding often involves conformational changes. Important questions are whether a conformational change occurs prior to a binding event (‘conformational selection’) or after a binding event (‘induced fit’), and how conformational transition rates can be obtained from experiments. In this article, we present general results for the chemical relaxation rates of conformational-selection and induced-fit binding processes that hold for all concentrations of proteins and ligands and, thus, go beyond the standard pseudo-first-order approximation of large ligand concentration. These results allow to distinguish conformational-selection from induced-fit processes—also in cases in which such a distinction is not possible under pseudo-first-order conditions—and to extract conformational transition rates of proteins from chemical relaxation data. PMID:27636092

  1. Conformational flexibility of aspartame.

    PubMed

    Toniolo, Claudio; Temussi, Pierandrea

    2016-05-01

    L-Aspartyl-L-phenylalanine methyl ester, better known as aspartame, is not only one of the most used artificial sweeteners, but also a very interesting molecule with respect to the correlation between molecular structure and taste. The extreme conformational flexibility of this dipeptide posed a huge difficulty when researchers tried to use it as a lead compound to design new sweeteners. In particular, it was difficult to take advantage of its molecular model as a mold to infer the shape of the, then unknown, active site of the sweet taste receptor. Here, we follow the story of the 3D structural aspects of aspartame from early conformational studies to recent docking into homology models of the receptor. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 376-384, 2016. PMID:27038223

  2. Conformal complementarity maps

    NASA Astrophysics Data System (ADS)

    Barbón, José L. F.; Rabinovici, Eliezer

    2013-12-01

    We study quantum cosmological models for certain classes of bang/crunch singularities, using the duality between expanding bubbles in AdS with a FRW interior cosmology and perturbed CFTs on de Sitter space-time. It is pointed out that horizon complementarity in the AdS bulk geometries is realized as a conformal transformation in the dual deformed CFT. The quantum version of this map is described in full detail in a toy model involving conformal quantum mechanics. In this system the complementarity map acts as an exact duality between eternal and apocalyptic Hamiltonian evolutions. We calculate the commutation relation between the Hamiltonians corresponding to the different frames. It vanishes only on scale invariant states.

  3. Multiscale conformal pattern transfer.

    PubMed

    Lodewijks, Kristof; Miljkovic, Vladimir; Massiot, Inès; Mekonnen, Addis; Verre, Ruggero; Olsson, Eva; Dmitriev, Alexandre

    2016-01-01

    We demonstrate a method for seamless transfer from a parent flat substrate of basically any lithographic top-down or bottom-up pattern onto essentially any kind of surface. The nano- or microscale patterns, spanning macroscopic surface areas, can be transferred with high conformity onto a large variety of surfaces when such patterns are produced on a thin carbon film, grown on top of a sacrificial layer. The latter allows lifting the patterns from the flat parent substrate onto a water-air interface to be picked up by the host surface of choice. We illustrate the power of this technique by functionalizing broad range of materials including glass, plastics, metals, rough semiconductors and polymers, highlighting the potential applications in in situ colorimetry of the chemistry of materials, anti-counterfeit technologies, biomolecular and biomedical studies, light-matter interactions at the nanoscale, conformal photovoltaics and flexible electronics. PMID:27329824

  4. Multiscale conformal pattern transfer

    PubMed Central

    Lodewijks, Kristof; Miljkovic, Vladimir; Massiot, Inès; Mekonnen, Addis; Verre, Ruggero; Olsson, Eva; Dmitriev, Alexandre

    2016-01-01

    We demonstrate a method for seamless transfer from a parent flat substrate of basically any lithographic top-down or bottom-up pattern onto essentially any kind of surface. The nano- or microscale patterns, spanning macroscopic surface areas, can be transferred with high conformity onto a large variety of surfaces when such patterns are produced on a thin carbon film, grown on top of a sacrificial layer. The latter allows lifting the patterns from the flat parent substrate onto a water-air interface to be picked up by the host surface of choice. We illustrate the power of this technique by functionalizing broad range of materials including glass, plastics, metals, rough semiconductors and polymers, highlighting the potential applications in in situ colorimetry of the chemistry of materials, anti-counterfeit technologies, biomolecular and biomedical studies, light-matter interactions at the nanoscale, conformal photovoltaics and flexible electronics. PMID:27329824

  5. Multiscale conformal pattern transfer

    NASA Astrophysics Data System (ADS)

    Lodewijks, Kristof; Miljkovic, Vladimir; Massiot, Inès; Mekonnen, Addis; Verre, Ruggero; Olsson, Eva; Dmitriev, Alexandre

    2016-06-01

    We demonstrate a method for seamless transfer from a parent flat substrate of basically any lithographic top-down or bottom-up pattern onto essentially any kind of surface. The nano- or microscale patterns, spanning macroscopic surface areas, can be transferred with high conformity onto a large variety of surfaces when such patterns are produced on a thin carbon film, grown on top of a sacrificial layer. The latter allows lifting the patterns from the flat parent substrate onto a water-air interface to be picked up by the host surface of choice. We illustrate the power of this technique by functionalizing broad range of materials including glass, plastics, metals, rough semiconductors and polymers, highlighting the potential applications in in situ colorimetry of the chemistry of materials, anti-counterfeit technologies, biomolecular and biomedical studies, light-matter interactions at the nanoscale, conformal photovoltaics and flexible electronics.

  6. Conformational flexibility of aspartame.

    PubMed

    Toniolo, Claudio; Temussi, Pierandrea

    2016-05-01

    L-Aspartyl-L-phenylalanine methyl ester, better known as aspartame, is not only one of the most used artificial sweeteners, but also a very interesting molecule with respect to the correlation between molecular structure and taste. The extreme conformational flexibility of this dipeptide posed a huge difficulty when researchers tried to use it as a lead compound to design new sweeteners. In particular, it was difficult to take advantage of its molecular model as a mold to infer the shape of the, then unknown, active site of the sweet taste receptor. Here, we follow the story of the 3D structural aspects of aspartame from early conformational studies to recent docking into homology models of the receptor. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 376-384, 2016.

  7. Conformal scalar field wormholes

    NASA Technical Reports Server (NTRS)

    Halliwell, Jonathan J.; Laflamme, Raymond

    1989-01-01

    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.

  8. Conformations of organophosphine oxides

    SciTech Connect

    De Silva, Nuwan; Zahariev, Federico; Hay, Benjamin P.; Gordon, Mark S.; Windus, Theresa L.

    2015-07-17

    The conformations of a series of organophosphine oxides, OP(CH3)2R, where R = methyl, ethyl, isopropyl, tert-butyl, vinyl, and phenyl, are predicted using the MP2/cc-pVTZ level of theory. Comparison of potential energy surfaces for rotation about P–C bonds with crystal structure data reveals a strong correlation between predicted location and energetics of minima and histograms of dihedral angle distributions observed in the solid state. In addition, the most stable conformers are those that minimize the extent of steric repulsion between adjacent rotor substituents, and the torsional barriers tend to increase with the steric bulk of the rotating alkyl group. MM3 force field parameters were adjusted to fit the MP2 results, providing a fast and accurate model for predicting organophosphine oxides shapes—an essential part of understanding the chemistry of these compounds. As a result, the predictive power of the modified MM3 model was tested against MP2/cc-pVTZ conformations for triethylphosphine oxide, OP(CH2CH3)3, and triphenylphosphine oxide, OP(Ph)3.

  9. Conformations of organophosphine oxides

    DOE PAGESBeta

    De Silva, Nuwan; Zahariev, Federico; Hay, Benjamin P.; Gordon, Mark S.; Windus, Theresa L.

    2015-07-17

    The conformations of a series of organophosphine oxides, OP(CH3)2R, where R = methyl, ethyl, isopropyl, tert-butyl, vinyl, and phenyl, are predicted using the MP2/cc-pVTZ level of theory. Comparison of potential energy surfaces for rotation about P–C bonds with crystal structure data reveals a strong correlation between predicted location and energetics of minima and histograms of dihedral angle distributions observed in the solid state. In addition, the most stable conformers are those that minimize the extent of steric repulsion between adjacent rotor substituents, and the torsional barriers tend to increase with the steric bulk of the rotating alkyl group. MM3 forcemore » field parameters were adjusted to fit the MP2 results, providing a fast and accurate model for predicting organophosphine oxides shapes—an essential part of understanding the chemistry of these compounds. As a result, the predictive power of the modified MM3 model was tested against MP2/cc-pVTZ conformations for triethylphosphine oxide, OP(CH2CH3)3, and triphenylphosphine oxide, OP(Ph)3.« less

  10. Mapping L1 Ligase ribozyme conformational switch

    PubMed Central

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

    2012-01-01

    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. PMID:22771572

  11. Conformation and hydration of aspartame.

    PubMed

    Kang, Y K

    1991-07-01

    Conformational free energy calculations using an empirical potential (ECEPP/2) and the hydration shell model were carried out on the neutral, acidic, zwitterionic, and basic forms of aspartame in the hydrated state. The results indicate that as the molecule becomes more charged, the number of low energy conformations becomes smaller and the molecule becomes less flexible. The calculated free energies of hydration of charged aspartames show that hydration has a significant effect on the conformation in solution. Only two feasible conformations were found for the zwitterionic form, and these are consistent with the conformations deduced from NMR and X-ray diffraction experiments. The calculated free energy difference between these two conformations was 1.25 kcal/mol. The less favored of the two solvated conformations can be expected to be stabilized by hydrophobic interaction of the phenyl groups in the crystal.

  12. Conformal superalgebras via tractor calculus

    NASA Astrophysics Data System (ADS)

    Lischewski, Andree

    2015-01-01

    We use the manifestly conformally invariant description of a Lorentzian conformal structure in terms of a parabolic Cartan geometry in order to introduce a superalgebra structure on the space of twistor spinors and normal conformal vector fields formulated in purely algebraic terms on parallel sections in tractor bundles. Via a fixed metric in the conformal class, one reproduces a conformal superalgebra structure that has been considered in the literature before. The tractor approach, however, makes clear that the failure of this object to be a Lie superalgebra in certain cases is due to purely algebraic identities on the spinor module and to special properties of the conformal holonomy representation. Moreover, it naturally generalizes to higher signatures. This yields new formulas for constructing new twistor spinors and higher order normal conformal Killing forms out of existing ones, generalizing the well-known spinorial Lie derivative. Moreover, we derive restrictions on the possible dimension of the space of twistor spinors in any metric signature.

  13. Leaf growth is conformal

    NASA Astrophysics Data System (ADS)

    Alim, Karen; Armon, Shahaf; Shraiman, Boris I.; Boudaoud, Arezki

    2016-10-01

    Growth pattern dynamics lie at the heart of morphogenesis. Here, we investigate the growth of plant leaves. We compute the conformal transformation that maps the contour of a leaf at a given stage onto the contour of the same leaf at a later stage. Based on the mapping we predict the local displacement field in the leaf blade and find it to agree with the experimentally measured displacement field to 92%. This approach is applicable to any two-dimensional system with locally isotropic growth, enabling the deduction of the whole growth field just from observation of the tissue contour.

  14. Leaf growth is conformal.

    PubMed

    Alim, Karen; Armon, Shahaf; Shraiman, Boris I; Boudaoud, Arezki

    2016-01-01

    Growth pattern dynamics lie at the heart of morphogenesis. Here, we investigate the growth of plant leaves. We compute the conformal transformation that maps the contour of a leaf at a given stage onto the contour of the same leaf at a later stage. Based on the mapping we predict the local displacement field in the leaf blade and find it to agree with the experimentally measured displacement field to 92%. This approach is applicable to any two-dimensional system with locally isotropic growth, enabling the deduction of the whole growth field just from observation of the tissue contour. PMID:27597439

  15. OSI Conformance Testing for Bibliographic Applications.

    ERIC Educational Resources Information Center

    Arbez, Gilbert; Swain, Leigh

    1990-01-01

    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)

  16. Movement of elongation factor G between compact and extended conformations.

    PubMed

    Salsi, Enea; Farah, Elie; Netter, Zoe; Dann, Jillian; Ermolenko, Dmitri N

    2015-01-30

    Previous structural studies suggested that ribosomal translocation is accompanied by large interdomain rearrangements of elongation factor G (EF-G). Here, we follow the movement of domain IV of EF-G relative to domain II of EF-G using ensemble and single-molecule Förster resonance energy transfer. Our results indicate that ribosome-free EF-G predominantly adopts a compact conformation that can also, albeit infrequently, transition into a more extended conformation in which domain IV moves away from domain II. By contrast, ribosome-bound EF-G predominantly adopts an extended conformation regardless of whether it is interacting with pretranslocation ribosomes or with posttranslocation ribosomes. Our data suggest that ribosome-bound EF-G may also occasionally sample at least one more compact conformation. GTP hydrolysis catalyzed by EF-G does not affect the relative stability of the observed conformations in ribosome-free and ribosome-bound EF-G. Our data support a model suggesting that, upon binding to a pretranslocation ribosome, EF-G moves from a compact to a more extended conformation. This transition is not coupled to but likely precedes both GTP hydrolysis and mRNA/tRNA translocation.

  17. Movement of Elongation Factor G between Compact and Extended Conformations

    PubMed Central

    Salsi, Enea; Farah, Elie; Netter, Zoe; Dann, Jillian; Ermolenko, Dmitri N.

    2014-01-01

    Previous structural studies suggested that ribosomal translocation is accompanied by large interdomain rearrangements of elongation factor G (EF-G). Here, we follow the movement of domain IV of EF-G relative to domain II of EF-G using ensemble and single-molecule Förster resonance energy transfer (smFRET). Our results indicate that ribosome-free EF-G predominantly adopts a compact conformation that can also, albeit infrequently, transition into a more extended conformation in which domain IV moves away from domain II. By contrast, ribosome-bound EF-G predominantly adopts an extended conformation regardless of whether it is interacting with pre- or posttranslocation ribosomes. Our data suggest that ribosome-bound EF-G may also occasionally sample at least one more compact conformation. GTP hydrolysis catalyzed by EF-G does not affect the relative stability of the observed conformations in ribosome-free and ribosome-bound EF-G. Our data support a model suggesting that, upon binding to a pretranslocation ribosome, EF-G moves from a compact to a more extended conformation. This transition is not coupled to, but likely precedes both GTP hydrolysis and mRNA/tRNA translocation. PMID:25463439

  18. Conformational ensembles and sampled energy landscapes: Analysis and comparison.

    PubMed

    Cazals, Frédéric; Dreyfus, Tom; Mazauric, Dorian; Roth, Christine-Andrea; Robert, Charles H

    2015-06-15

    We present novel algorithms and software addressing four core problems in computational structural biology, namely analyzing a conformational ensemble, comparing two conformational ensembles, analyzing a sampled energy landscape, and comparing two sampled energy landscapes. Using recent developments in computational topology, graph theory, and combinatorial optimization, we make two notable contributions. First, we present a generic algorithm analyzing height fields. We then use this algorithm to perform density-based clustering of conformations, and to analyze a sampled energy landscape in terms of basins and transitions between them. In both cases, topological persistence is used to manage (geometric) frustration. Second, we introduce two algorithms to compare transition graphs. The first is the classical earth mover distance metric which depends only on local minimum energy configurations along with their statistical weights, while the second incorporates topological constraints inherent to conformational transitions. Illustrations are provided on a simplified protein model (BLN69), whose frustrated potential energy landscape has been thoroughly studied. The software implementing our tools is also made available, and should prove valuable wherever conformational ensembles and energy landscapes are used. PMID:25994596

  19. The detection of conformational disorder by thermal analysis

    SciTech Connect

    Wunderlich, B.

    1988-01-01

    Conformational disorder in crystals is found in many molecules that possess a plurality of conformational isomers. Typical examples are linear macromolecules such as polyethylene, polytetrafluoroethylene and trans-1,4-polybutadiene; and small molecules such as paraffins, cycloparaffins, soaps, lipids and many liquid-crystal forming molecules. Conformational motion is often coupled with the cooperative creation of disorder. In this case a heat and entropy of transition is observed by thermal analysis. Levels of transition entropies can be estimated, assuming most of the disorder can be traced to conformational isomerism. In case there is conformational disorder frozen-in at low temperature, thermal analysis can be used to find the glass transition of a condis crystal. An Advanced Thermal Analysis System has been developed, and will be described that permits a detailed interpretation of the thermal analysis traces. It rests with the establishment of high quality heat capacity for the rigid solid state (vibration only) and the mobile liquid state (vibrations and large amplitude cooperative motion). 36 refs., 3 figs.

  20. Conformational ensembles and sampled energy landscapes: Analysis and comparison.

    PubMed

    Cazals, Frédéric; Dreyfus, Tom; Mazauric, Dorian; Roth, Christine-Andrea; Robert, Charles H

    2015-06-15

    We present novel algorithms and software addressing four core problems in computational structural biology, namely analyzing a conformational ensemble, comparing two conformational ensembles, analyzing a sampled energy landscape, and comparing two sampled energy landscapes. Using recent developments in computational topology, graph theory, and combinatorial optimization, we make two notable contributions. First, we present a generic algorithm analyzing height fields. We then use this algorithm to perform density-based clustering of conformations, and to analyze a sampled energy landscape in terms of basins and transitions between them. In both cases, topological persistence is used to manage (geometric) frustration. Second, we introduce two algorithms to compare transition graphs. The first is the classical earth mover distance metric which depends only on local minimum energy configurations along with their statistical weights, while the second incorporates topological constraints inherent to conformational transitions. Illustrations are provided on a simplified protein model (BLN69), whose frustrated potential energy landscape has been thoroughly studied. The software implementing our tools is also made available, and should prove valuable wherever conformational ensembles and energy landscapes are used.

  1. A novel approach to the study of conformality in the SU(3) theory with multiple flavors

    SciTech Connect

    Brower, R.; Hasenfratz, A.; Rebbi, C. Weinberg, E.; Witzel, O.

    2015-03-15

    We investigate the transition between spontaneous chiral symmetry breaking and conformal behavior in the SU(3) theory with multiple fermion flavors. We propose a new strategy for studying this transition. Instead of changing the number of flavors, we lift the mass of a subset of the fermions, keeping the rest of the fermions near the massless chiral limit in order to probe the transition.

  2. Targeting Inactive Enzyme Conformation

    PubMed Central

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

    2009-01-01

    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. PMID:19012396

  3. Conformally symmetric traversable wormholes

    SciTech Connect

    Boehmer, Christian G.; Harko, Tiberiu; Lobo, Francisco S. N.

    2007-10-15

    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.

  4. Eikonalization of conformal blocks

    SciTech Connect

    Fitzpatrick, A. Liam; Kaplan, Jared; Walters, Matthew T.; Wang, Junpu

    2015-09-03

    Classical field configurations such as the Coulomb potential and Schwarzschild solution are built from the t-channel exchange of many light degrees of freedom. We study the CFT analog of this phenomenon, which we term the 'eikonalization' of conformal blocks. We show that when an operator T appears in the OPE Ο(x)Ο(0), then the large spin Fock space states [TT···T] also appear in this OPE with a computable coefficient. The sum over the exchange of these Fock space states in an correlator build the classical 'T field' in the dual AdS description. In some limits the sum of all Fock space exchanges can be represented as the exponential of a single T exchange in the 4-pt correlator of O. Our results should be useful for systematizing 1/ℓ perturbation theory in general CFTs and simplifying the computation of large spin OPE coefficients. As examples we obtain the leading log ℓ dependence of Fock space conformal block coefficients, and we directly compute the OPE coefficients of the simplest ‘triple-trace’ operators.

  5. Eikonalization of conformal blocks

    DOE PAGESBeta

    Fitzpatrick, A. Liam; Kaplan, Jared; Walters, Matthew T.; Wang, Junpu

    2015-09-03

    Classical field configurations such as the Coulomb potential and Schwarzschild solution are built from the t-channel exchange of many light degrees of freedom. We study the CFT analog of this phenomenon, which we term the 'eikonalization' of conformal blocks. We show that when an operator T appears in the OPE Ο(x)Ο(0), then the large spin Fock space states [TT···T]ℓ also appear in this OPE with a computable coefficient. The sum over the exchange of these Fock space states in an correlator build the classical 'T field' in the dual AdS description. In some limits the sum of all Fock spacemore » exchanges can be represented as the exponential of a single T exchange in the 4-pt correlator of O. Our results should be useful for systematizing 1/ℓ perturbation theory in general CFTs and simplifying the computation of large spin OPE coefficients. As examples we obtain the leading log ℓ dependence of Fock space conformal block coefficients, and we directly compute the OPE coefficients of the simplest ‘triple-trace’ operators.« less

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

    NASA Astrophysics Data System (ADS)

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

    2009-12-01

    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.

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

    NASA Astrophysics Data System (ADS)

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

    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.

  8. In silico Exploration of the Conformational Universe of GPCRs.

    PubMed

    Rodríguez-Espigares, Ismael; Kaczor, Agnieszka A; Selent, Jana

    2016-07-01

    The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design. PMID:27492237

  9. In silico Exploration of the Conformational Universe of GPCRs.

    PubMed

    Rodríguez-Espigares, Ismael; Kaczor, Agnieszka A; Selent, Jana

    2016-07-01

    The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design.

  10. Intramolecular conformational changes optimize protein kinase C signaling.

    PubMed

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

    2014-04-24

    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.

  11. Intramolecular conformational changes optimize protein kinase C signaling.

    PubMed

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

    2014-04-24

    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

  12. Conformations of Low-Molecular-Weight Lignin Polymers in Water.

    PubMed

    Petridis, Loukas; Smith, Jeremy C

    2016-02-01

    Low-molecular-weight lignin binds to cellulose during the thermochemical pretreatment of biomass for biofuel production, which prevents the efficient hydrolysis of the cellulose to sugars. The binding properties of lignin are influenced strongly by the conformations it adopts. Here, we use molecular dynamics simulations in aqueous solution to investigate the dependence of the shape of lignin polymers on chain length and temperature. Lignin is found to adopt collapsed conformations in water at 300 and 500 K. However, at 300 K, a discontinuous transition is found in the shape of the polymer as a function of the chain length. Below a critical degree of polymerization, Nc =15, the polymer adopts less spherical conformations than above Nc. The transition disappears at high temperatures (500 K) at which only spherical shapes are adopted. An implication relevant to cellulosic biofuel production is that lignin will self-aggregate even at high pretreatment temperatures.

  13. Conformations of low-molecular-weight lignin polymers in water

    DOE PAGESBeta

    Petridis, Loukas; Smith, Jeremy C.

    2016-01-13

    Low-molecular-weight lignin binds to cellulose during the thermochemical pretreatment of biomass for biofuel production, which prevents the efficient hydrolysis of the cellulose to sugars. The binding properties of lignin are influenced strongly by the conformations it adopts. Here, we use molecular dynamics simulations in aqueous solution to investigate the dependence of the shape of lignin polymers on chain length and temperature. Lignin is found to adopt collapsed conformations in water at 300 and 500 K. However, at 300 K, a discontinuous transition is found in the shape of the polymer as a function of the chain length. Below a criticalmore » degree of polymerization, Nc=15, the polymer adopts less spherical conformations than above Nc. The transition disappears at high temperatures (500 K) at which only spherical shapes are adopted. As a result, an implication relevant to cellulosic biofuel production is that lignin will self-aggregate even at high pretreatment temperatures.« less

  14. Recent Advances in Conformal Gravity

    NASA Astrophysics Data System (ADS)

    O'Brien, James; Chaykov, Spasen

    2016-03-01

    In recent years, significant advances have been made in alternative gravitational theories. Although MOND remains the leading candidate among the alternative models, Conformal Gravity has been studied by Mannheim and O'Brien to solve the rotation curve problem without the need for dark matter. Recently, Mannheim, O'Brien and Chaykov have begun solving other gravitational questions in Conformal Gravity. In this presentation, we highlight the new work of Conformal Gravity's application to random motions of clusters (the original Zwicky problem), gravitational bending of light, gravitational lensing and a very recent survey of dwarf galaxy rotation curves. We will show in each case that Conformal Gravity can provide an accurate explanation and prediction of the data without the need for dark matter. Coupled with the fact that Conformal Gravity is a fully re-normalizable metric theory of gravity, these results help to push Conformal Gravity onto a competitive stage against other alternative models.

  15. Fermion-scalar conformal blocks

    DOE PAGESBeta

    Iliesiu, Luca; Kos, Filip; Poland, David; Pufu, Silviu S.; Simmons-Duffin, David; Yacoby, Ran

    2016-04-13

    In this study, we compute the conformal blocks associated with scalar-scalar-fermionfermion 4-point functions in 3D CFTs. Together with the known scalar conformal blocks, our result completes the task of determining the so-called ‘seed blocks’ in three dimensions. In addition, conformal blocks associated with 4-point functions of operators with arbitrary spins can now be determined from these seed blocks by using known differential operators.

  16. Killing and conformal Killing tensors

    NASA Astrophysics Data System (ADS)

    Heil, Konstantin; Moroianu, Andrei; Semmelmann, Uwe

    2016-08-01

    We introduce an appropriate formalism in order to study conformal Killing (symmetric) tensors on Riemannian manifolds. We reprove in a simple way some known results in the field and obtain several new results, like the classification of conformal Killing 2-tensors on Riemannian products of compact manifolds, Weitzenböck formulas leading to non-existence results, and construct various examples of manifolds with conformal Killing tensors.

  17. Parafermionic conformal field theory on the lattice

    NASA Astrophysics Data System (ADS)

    Mong, Roger S. K.; Clarke, David J.; Alicea, Jason; Lindner, Netanel H.; Fendley, Paul

    2014-11-01

    Finding the precise correspondence between lattice operators and the continuum fields that describe their long-distance properties is a largely open problem for strongly interacting critical points. Here, we solve this problem essentially completely in the case of the three-state Potts model, which exhibits a phase transition described by a strongly interacting ‘parafermion’ conformal field theory. Using symmetry arguments, insights from integrability, and extensive simulations, we construct lattice analogues of nearly all the relevant and marginal physical fields governing this transition. This construction includes chiral fields such as the parafermion. Along the way we also clarify the structure of operator product expansions between order and disorder fields, which we confirm numerically. Our results both suggest a systematic methodology for attacking non-free field theories on the lattice and find broader applications in the pursuit of exotic topologically ordered phases of matter.

  18. Reflections on conformal spectra

    NASA Astrophysics Data System (ADS)

    Kim, Hyungrok; Kravchuk, Petr; Ooguri, Hirosi

    2016-04-01

    We use modular invariance and crossing symmetry of conformal field theory to reveal approximate reflection symmetries in the spectral decompositions of the partition function in two dimensions in the limit of large central charge and of the four-point function in any dimension in the limit of large scaling dimensions Δ0 of external operators. We use these symmetries to motivate universal upper bounds on the spectrum and the operator product expansion coefficients, which we then derive by independent techniques. Some of the bounds for four-point functions are valid for finite Δ0 as well as for large Δ0. We discuss a similar symmetry in a large spacetime dimension limit. Finally, we comment on the analogue of the Cardy formula and sparse light spectrum condition for the four-point function.

  19. Capturing Chromosome Conformation

    NASA Astrophysics Data System (ADS)

    Dekker, Job; Rippe, Karsten; Dekker, Martijn; Kleckner, Nancy

    2002-02-01

    We describe an approach to detect the frequency of interaction between any two genomic loci. Generation of a matrix of interaction frequencies between sites on the same or different chromosomes reveals their relative spatial disposition and provides information about the physical properties of the chromatin fiber. This methodology can be applied to the spatial organization of entire genomes in organisms from bacteria to human. Using the yeast Saccharomyces cerevisiae, we could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis. We also analyzed yeast chromosome III at the G1 stage of the cell cycle. We found that chromatin is highly flexible throughout. Furthermore, functionally distinct AT- and GC-rich domains were found to exhibit different conformations, and a population-average 3D model of chromosome III could be determined. Chromosome III emerges as a contorted ring.

  20. Replacement between conformity and counter-conformity in consumption decisions.

    PubMed

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

    2013-02-01

    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

  1. Replacement between conformity and counter-conformity in consumption decisions.

    PubMed

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

    2013-02-01

    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.

  2. Fe-heme conformations in ferric myoglobin.

    PubMed Central

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

    1998-01-01

    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. PMID:9826636

  3. The Principle of Maximum Conformality

    SciTech Connect

    Brodsky, Stanley J; Giustino, Di; /SLAC

    2011-04-05

    A key problem in making precise perturbative QCD predictions is the uncertainty in determining the renormalization scale of the running coupling {alpha}{sub s}({mu}{sup 2}). It is common practice to guess a physical scale {mu} = Q which is of order of a typical momentum transfer Q in the process, and then vary the scale over a range Q/2 and 2Q. This procedure is clearly problematic since the resulting fixed-order pQCD prediction will depend on the renormalization scheme, and it can even predict negative QCD cross sections at next-to-leading-order. Other heuristic methods to set the renormalization scale, such as the 'principle of minimal sensitivity', give unphysical results for jet physics, sum physics into the running coupling not associated with renormalization, and violate the transitivity property of the renormalization group. Such scale-setting methods also give incorrect results when applied to Abelian QED. Note that the factorization scale in QCD is introduced to match nonperturbative and perturbative aspects of the parton distributions in hadrons; it is present even in conformal theory and thus is a completely separate issue from renormalization scale setting. The PMC provides a consistent method for determining the renormalization scale in pQCD. The PMC scale-fixed prediction is independent of the choice of renormalization scheme, a key requirement of renormalization group invariance. The results avoid renormalon resummation and agree with QED scale-setting in the Abelian limit. The PMC global scale can be derived efficiently at NLO from basic properties of the PQCD cross section. The elimination of the renormalization scheme ambiguity using the PMC will not only increases the precision of QCD tests, but it will also increase the sensitivity of colliders to new physics beyond the Standard Model.

  4. Conformal gravity and time

    NASA Astrophysics Data System (ADS)

    Hazboun, Jeffrey Shafiq

    2014-10-01

    Cartan geometry provides a rich formalism from which to look at various geometrically motivated extensions to general relativity. In this manuscript, we start by motivating reasons to extend the theory of general relativity. We then introduce the reader to our technique, called the quotient manifold method, for extending the geometry of spacetime. We will specifically look at the class of theories formed from the various quotients of the conformal group. Starting with the conformal symmetries of Euclidean space, we construct a manifold where time manifests as a part of the geometry. Though there is no matter present in the geome- try studied here, geometric terms analogous to dark energy and dark matter appear when we write down the Einstein tensor. Specifically, the quotient of the conformal group of Euclidean four-space by its Weyl subgroup results in a geometry possessing many of the properties of relativistic phase space, including both a natural symplectic form and nondegenerate Killing metric. We show the general solution possesses orthogonal Lagrangian submanifolds, with the induced metric and the spin connection on the submanifolds necessarily Lorentzian, despite the Euclidean starting point. By examining the structure equations of the biconformal space in an orthonormal frame adapted to its phase space properties, we also find two new tensor fields exist in this geometry, not present in Riemannian geometry. The first is a combination of the Weyl vector with the scale factor on the metric, and determines the time-like directions on the submanifolds. The second comes from the components of the spin connection, symmetric with respect to the new metric. Though this field comes from the spin connection, it transforms ho- mogeneously. Finally, we show in the absence of Cartan curvature or sources, the configuration space has geometric terms equivalent to a perfect fluid and a cosmological constant. We complete the analysis of this homogeneous space by

  5. Conformal Transformations and Space Travel.

    PubMed

    Gupta, S N

    1961-10-27

    Conformal transformations are applied to the motion of a space ship experiencing a constant acceleration. The role of proper time is interpreted in terms of atomic periods, and the relationship between the conformal transformations and the general theory of relativity is clarified.

  6. Counselor Identity: Conformity or Distinction?

    ERIC Educational Resources Information Center

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    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.

  7. [Conformal radiotherapy: principles and classification].

    PubMed

    Rosenwald, J C; Gaboriaud, G; Pontvert, D

    1999-01-01

    'Conformal radiotherapy' is the name fixed by usage and given to a new form of radiotherapy resulting from the technological improvements observed during, the last ten years. While this terminology is now widely used, no precise definition can be found in the literature. Conformal radiotherapy refers to an approach in which the dose distribution is more closely 'conformed' or adapted to the actual shape of the target volume. However, the achievement of a consensus on a more specific definition is hampered by various difficulties, namely in characterizing the degree of 'conformality'. We have therefore suggested a classification scheme be established on the basis of the tools and the procedures actually used for all steps of the process, i.e., from prescription to treatment completion. Our classification consists of four levels: schematically, at level 0, there is no conformation (rectangular fields); at level 1, a simple conformation takes place, on the basis of conventional 2D imaging; at level 2, a 3D reconstruction of the structures is used for a more accurate conformation; and level 3 includes research and advanced dynamic techniques. We have used our personal experience, contacts with colleagues and data from the literature to analyze all the steps of the planning process, and to define the tools and procedures relevant to a given level. The corresponding tables have been discussed and approved at the European level within the Dynarad concerted action. It is proposed that the term 'conformal radiotherapy' be restricted to procedures where all steps are at least at level 2.

  8. A Conformance Testing Relation for Symbolic Timed Automata

    NASA Astrophysics Data System (ADS)

    von Styp, Sabrina; Bohnenkamp, Henrik; Schmaltz, Julien

    We introduce Symbolic Timed Automata, an amalgamation of symbolic transition systems and timed automata, which allows to express nondeterministic data-dependent control flow with inputs and outputs and real-time behaviour. In particular, input data can influence the timing behaviour. We define two semantics for STA, a concrete one as timed labelled transition systems and another one on a symbolic level. We show that the symbolic semantics is complete and correct w.r.t. the concrete one. Finally, we introduce symbolic conformance relation stioco , which is an extension of the well-known ioco conformance relation. Relation stioco is defined using FO-logic on a purely symbolic level. We show that stioco corresponds on the concrete semantic level to Krichen and Tripakis' implementation relation tioco for timed labelled transition systems.

  9. Recursion relations for conformal blocks

    NASA Astrophysics Data System (ADS)

    Penedones, João; Trevisani, Emilio; Yamazaki, Masahito

    2016-09-01

    In the context of conformal field theories in general space-time dimension, we find all the possible singularities of the conformal blocks as functions of the scaling dimension Δ of the exchanged operator. In particular, we argue, using representation theory of parabolic Verma modules, that in odd spacetime dimension the singularities are only simple poles. We discuss how to use this information to write recursion relations that determine the conformal blocks. We first recover the recursion relation introduced in [1] for conformal blocks of external scalar operators. We then generalize this recursion relation for the conformal blocks associated to the four point function of three scalar and one vector operator. Finally we specialize to the case in which the vector operator is a conserved current.

  10. Conformational dynamics of Thermus aquaticus DNA polymerase I during catalysis.

    PubMed

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

    2014-08-12

    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

  11. Conformal Fermi Coordinates

    SciTech Connect

    Dai, Liang; Pajer, Enrico; Schmidt, Fabian E-mail: Enrico.pajer@gmail.com

    2015-11-01

    Fermi Normal Coordinates (FNC) are a useful frame for isolating the locally observable, physical effects of a long-wavelength spacetime perturbation. Their cosmological application, however, is hampered by the fact that they are only valid on scales much smaller than the horizon. We introduce a generalization that we call Conformal Fermi Coordinates (CFC). CFC preserve all the advantages of FNC, but in addition are valid outside the horizon. They allow us to calculate the coupling of long- and short-wavelength modes on all scales larger than the sound horizon of the cosmological fluid, starting from the epoch of inflation until today, by removing the complications of the second order Einstein equations to a large extent, and eliminating all gauge ambiguities. As an application, we present a calculation of the effect of long-wavelength tensor modes on small scale density fluctuations. We recover previous results, but clarify the physical content of the individual contributions in terms of locally measurable effects and ''projection'' terms.

  12. Dynamics of protein conformations

    NASA Astrophysics Data System (ADS)

    Stepanova, Maria

    2010-10-01

    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.

  13. Necessary Condition for Emergent Symmetry from the Conformal Bootstrap

    NASA Astrophysics Data System (ADS)

    Nakayama, Yu; Ohtsuki, Tomoki

    2016-09-01

    We use the conformal bootstrap program to derive the necessary conditions for emergent symmetry enhancement from discrete symmetry (e.g., Zn ) to continuous symmetry [e.g., U (1 )] under the renormalization group flow. In three dimensions, in order for Z2 symmetry to be enhanced to U (1 ) symmetry, the conformal bootstrap program predicts that the scaling dimension of the order parameter field at the infrared conformal fixed point must satisfy Δ1>1.08 . We also obtain the similar necessary conditions for Z3 symmetry with Δ1>0.580 and Z4 symmetry with Δ1>0.504 from the simultaneous conformal bootstrap analysis of multiple four-point functions. As applications, we show that our necessary conditions impose severe constraints on the nature of the chiral phase transition in QCD, the deconfinement criticality in Néel valence bond solid transitions, and anisotropic deformations in critical O (n ) models. We prove that some fixed points proposed in the literature are unstable under the perturbation that cannot be forbidden by the discrete symmetry. In these situations, the second-order phase transition with enhanced symmetry cannot happen.

  14. Towards conformal loop quantum gravity

    NASA Astrophysics Data System (ADS)

    H-T Wang, Charles

    2006-03-01

    A discussion is given of recent developments in canonical gravity that assimilates the conformal analysis of gravitational degrees of freedom. The work is motivated by the problem of time in quantum gravity and is carried out at the metric and the triad levels. At the metric level, it is shown that by extending the Arnowitt-Deser-Misner (ADM) phase space of general relativity (GR), a conformal form of geometrodynamics can be constructed. In addition to the Hamiltonian and Diffeomorphism constraints, an extra first class constraint is introduced to generate conformal transformations. This phase space consists of York's mean extrinsic curvature time, conformal three-metric and their momenta. At the triad level, the phase space of GR is further enlarged by incorporating spin-gauge as well as conformal symmetries. This leads to a canonical formulation of GR using a new set of real spin connection variables. The resulting gravitational constraints are first class, consisting of the Hamiltonian constraint and the canonical generators for spin-gauge and conformorphism transformations. The formulation has a remarkable feature of being parameter-free. Indeed, it is shown that a conformal parameter of the Barbero-Immirzi type can be absorbed by the conformal symmetry of the extended phase space. This gives rise to an alternative approach to loop quantum gravity that addresses both the conceptual problem of time and the technical problem of functional calculus in quantum gravity.

  15. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but

  16. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2002-02-28

    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.

  17. Conformational Landscape of Nicotinoids: Solving the "conformational - Rity" of Anabasine

    NASA Astrophysics Data System (ADS)

    Lesarri, Alberto; Cocinero, Emilio J.; Evangelisti, Luca; Suenram, Richard D.; Caminati, Walther; Grabow, Jens-Uwe

    2010-06-01

    The conformational landscape of the alkaloid anabasine (neonicotine) has been investigated using rotational spectroscopy and ab initio calculations. The results allow a detailed comparison of the structural properties of the prototype piperidinic and pyrrolidinic nicotinoids (anabasine vs. nicotine). Anabasine adopts two most stable conformations in isolation conditions, for which we determined accurate rotational and nuclear quadrupole coupling parameters. The preferred conformations are characterized by an equatorial pyridine moiety and additional N-H equatorial stereochemistry at the piperidine ring (Eq-Eq). The two rings of anabasine are close to a bisecting arrangement, with the observed conformations differing in a ca. 180° rotation of the pyridine subunit, denoted either Syn or Anti. The preference of anabasine for the Eq-Eq-Syn conformation has been established by relative intensity measurements (Syn/Anti˜5(2)). The conformational preferences of free anabasine are directed by a N\\cdot\\cdot\\cdotH-C weak hydrogen bond interaction between the nitrogen lone pair at piperidine and the closest hydrogen bond in pyridine, with N\\cdot\\cdot\\cdotN distances ranging from 4.750 Å (Syn) to 4.233 Å (Anti). R. J. Lavrich, R. D. Suenram, D. F. Plusquellic and S. Davis, 58^th OSU Int. Symp. on Mol. Spectrosc., Columbus, OH, 2003, Comm. RH13.

  18. Molecular insight into conformational transmission of human P-glycoprotein

    SciTech Connect

    Chang, Shan-Yan; Liu, Fu-Feng E-mail: ysun@tju.edu.cn; Dong, Xiao-Yan; Sun, Yan E-mail: ysun@tju.edu.cn

    2013-12-14

    P-glycoprotein (P-gp), a kind of ATP-binding cassette transporter, can export candidates through a channel at the two transmembrane domains (TMDs) across the cell membranes using the energy released from ATP hydrolysis at the two nucleotide-binding domains (NBDs). Considerable evidence has indicated that human P-gp undergoes large-scale conformational changes to export a wide variety of anti-cancer drugs out of the cancer cells. However, molecular mechanism of the conformational transmission of human P-gp from the NBDs to the TMDs is still unclear. Herein, targeted molecular dynamics simulations were performed to explore the atomic detail of the conformational transmission of human P-gp. It is confirmed that the conformational transition from the inward- to outward-facing is initiated by the movement of the NBDs. It is found that the two NBDs move both on the two directions (x and y). The movement on the x direction leads to the closure of the NBDs, while the movement on the y direction adjusts the conformations of the NBDs to form the correct ATP binding pockets. Six key segments (KSs) protruding from the TMDs to interact with the NBDs are identified. The relative movement of the KSs along the y axis driven by the NBDs can be transmitted through α-helices to the rest of the TMDs, rendering the TMDs to open towards periplasm in the outward-facing conformation. Twenty eight key residue pairs are identified to participate in the interaction network that contributes to the conformational transmission from the NBDs to the TMDs of human P-gp. In addition, 9 key residues in each NBD are also identified. The studies have thus provided clear insight into the conformational transmission from the NBDs to the TMDs in human P-gp.

  19. Molecular insight into conformational transmission of human P-glycoprotein

    NASA Astrophysics Data System (ADS)

    Chang, Shan-Yan; Liu, Fu-Feng; Dong, Xiao-Yan; Sun, Yan

    2013-12-01

    P-glycoprotein (P-gp), a kind of ATP-binding cassette transporter, can export candidates through a channel at the two transmembrane domains (TMDs) across the cell membranes using the energy released from ATP hydrolysis at the two nucleotide-binding domains (NBDs). Considerable evidence has indicated that human P-gp undergoes large-scale conformational changes to export a wide variety of anti-cancer drugs out of the cancer cells. However, molecular mechanism of the conformational transmission of human P-gp from the NBDs to the TMDs is still unclear. Herein, targeted molecular dynamics simulations were performed to explore the atomic detail of the conformational transmission of human P-gp. It is confirmed that the conformational transition from the inward- to outward-facing is initiated by the movement of the NBDs. It is found that the two NBDs move both on the two directions (x and y). The movement on the x direction leads to the closure of the NBDs, while the movement on the y direction adjusts the conformations of the NBDs to form the correct ATP binding pockets. Six key segments (KSs) protruding from the TMDs to interact with the NBDs are identified. The relative movement of the KSs along the y axis driven by the NBDs can be transmitted through α-helices to the rest of the TMDs, rendering the TMDs to open towards periplasm in the outward-facing conformation. Twenty eight key residue pairs are identified to participate in the interaction network that contributes to the conformational transmission from the NBDs to the TMDs of human P-gp. In addition, 9 key residues in each NBD are also identified. The studies have thus provided clear insight into the conformational transmission from the NBDs to the TMDs in human P-gp.

  20. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2004-09-30

    This report describes work performed during the third and final year of the project, ''Conformance Improvement Using Gels.'' Corefloods revealed throughput dependencies of permeability reduction by polymers and gels that were much more prolonged during oil flow than water flow. This behavior was explained using simple mobility ratio arguments. A model was developed that quantitatively fits the results and predicts ''clean up'' times for oil productivity when production wells are returned to service after application of a polymer or gel treatment. X-ray computed microtomography studies of gels in strongly water-wet Berea sandstone and strongly oil-wet porous polyethylene suggested that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than gel-ripping or gel-displacement mechanisms. In contrast, analysis of data from the University of Kansas suggests that the gel-ripping or displacement mechanisms are more important in more permeable, strongly water-wet sandpacks. These findings help to explain why aqueous gels can reduce permeability to water more than to oil under different conditions. Since cement is the most commonly used material for water shutoff, we considered when gels are preferred over cements. Our analysis and experimental results indicated that cement cannot be expected to completely fill (top to bottom) a vertical fracture of any width, except near the wellbore. For vertical fractures with apertures less than 4 mm, the cement slurry will simply not penetrate very far into the fracture. For vertical fractures with apertures greater than 4 mm, the slurry may penetrate a substantial distance into the bottom part of the fracture. However, except near the wellbore, the upper part of the fracture will remain open due to gravity segregation. We compared various approaches to plugging fractures using gels, including (1) varying polymer content, (2) varying placement (extrusion) rate, (3) using partially formed gels, (4

  1. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2004-03-01

    This technical progress report describes work performed from September 1, 2003, through February 29, 2004, for the project, ''Conformance Improvement Using Gels.'' We examined the properties of several ''partially formed'' gels that were formulated with a combination of high and low molecular weight HPAM polymers. After placement in 4-mm-wide fractures, these gels required about 25 psi/ft for brine to breach the gel (the best performance to date in fractures this wide). After this breach, stabilized residual resistance factors decreased significantly with increased flow rate. Also, residual resistance factors were up to 9 times greater for water than for oil. Nevertheless, permeability reduction factors were substantial for both water and oil flow. Gel with 2.5% chopped fiberglass effectively plugged 4-mm-wide fractures if a 0.5-mm-wide constriction was present. The ability to screen-out at a constriction appears crucial for particulate incorporation to be useful in plugging fractures. In addition to fiberglass, we examined incorporation of polypropylene fibers into gels. Once dispersed in brine or gelant, the polypropylene fibers exhibited the least gravity segregation of any particulate that we have tested to date. In fractures with widths of at least 2 mm, 24-hr-old gels (0.5% high molecular weight HPAM) with 0.5% fiber did not exhibit progressive plugging during placement and showed extrusion pressure gradients similar to those of gels without the fiber. The presence of the fiber roughly doubled the gel's resistance to first breach by brine flow. The breaching pressure gradients were not as large as for gels made with high and low molecular weight polymers (mentioned above). However, their material requirements and costs (i.e., polymer and/or particulate concentrations) were substantially lower than for those gels. A partially formed gel made with 0.5% HPAM did not enter a 0.052-mm-wide fracture when applying a pressure gradient of 65 psi/ft. This result

  2. Radial coordinates for conformal blocks

    NASA Astrophysics Data System (ADS)

    Hogervorst, Matthijs; Rychkov, Slava

    2013-05-01

    We develop the theory of conformal blocks in CFTd expressing them as power series with Gegenbauer polynomial coefficients. Such series have a clear physical meaning when the conformal block is analyzed in radial quantization: individual terms describe contributions of descendants of a given spin. Convergence of these series can be optimized by a judicious choice of the radial quantization origin. We argue that the best choice is to insert the operators symmetrically. We analyze in detail the resulting “ρ-series” and show that it converges much more rapidly than for the commonly used variable z. We discuss how these conformal block representations can be used in the conformal bootstrap. In particular, we use them to derive analytically some bootstrap bounds whose existence was previously found numerically.

  3. Conformal mapping of rectangular heptagons

    SciTech Connect

    Bogatyrev, Andrei B

    2012-12-31

    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.

  4. Lattice Simulations and Infrared Conformality

    DOE PAGESBeta

    Appelquist, Thomas; Fleming, George T.; Lin, Meifeng; Neil, Ethan T.; Schaich, David A

    2011-09-01

    We examine several recent lattice-simulation data sets, asking whether they are consistent with infrared conformality. We observe, in particular, that for an SU(3) gauge theory with 12 Dirac fermions in the fundamental representation, recent simulation data can be described assuming infrared conformality. Lattice simulations include a fermion mass m which is then extrapolated to zero, and we note that this data can be fit by a small-m expansion, allowing a controlled extrapolation. We also note that the conformal hypothesis does not work well for two theories that are known or expected to be confining and chirally broken, and that itmore » does work well for another theory expected to be infrared conformal.« less

  5. Solution NMR conformation of glycosaminoglycans.

    PubMed

    Pomin, Vitor H

    2014-04-01

    Nuclear magnetic resonance (NMR) spectroscopy has been giving a pivotal contribution to the progress of glycomics, mostly by elucidating the structural, dynamical, conformational and intermolecular binding aspects of carbohydrates. Particularly in the field of conformation, NOE resonances, scalar couplings, residual dipolar couplings, and chemical shift anisotropy offsets have been the principal NMR parameters utilized. Molecular dynamics calculations restrained by NMR-data input are usually employed in conjunction to generate glycosidic bond dihedral angles. Glycosaminoglycans (GAGs) are a special class of sulfated polysaccharides extensively studied worldwide. Besides regulating innumerous physiological processes, these glycans are also widely explored in the global market as either clinical or nutraceutical agents. The conformational aspects of GAGs are key regulators to the quality of interactions with the functional proteins involved in biological events. This report discusses the solution conformation of each GAG type analyzed by one or more of the above-mentioned methods.

  6. Scale invariance vs conformal invariance

    NASA Astrophysics Data System (ADS)

    Nakayama, Yu

    2015-03-01

    In this review article, we discuss the distinction and possible equivalence between scale invariance and conformal invariance in relativistic quantum field theories. Under some technical assumptions, we can prove that scale invariant quantum field theories in d = 2 space-time dimensions necessarily possess the enhanced conformal symmetry. The use of the conformal symmetry is well appreciated in the literature, but the fact that all the scale invariant phenomena in d = 2 space-time dimensions enjoy the conformal property relies on the deep structure of the renormalization group. The outstanding question is whether this feature is specific to d = 2 space-time dimensions or it holds in higher dimensions, too. As of January 2014, our consensus is that there is no known example of scale invariant but non-conformal field theories in d = 4 space-time dimensions under the assumptions of (1) unitarity, (2) Poincaré invariance (causality), (3) discrete spectrum in scaling dimensions, (4) existence of scale current and (5) unbroken scale invariance in the vacuum. We have a perturbative proof of the enhancement of conformal invariance from scale invariance based on the higher dimensional analogue of Zamolodchikov's c-theorem, but the non-perturbative proof is yet to come. As a reference we have tried to collect as many interesting examples of scale invariance in relativistic quantum field theories as possible in this article. We give a complementary holographic argument based on the energy-condition of the gravitational system and the space-time diffeomorphism in order to support the claim of the symmetry enhancement. We believe that the possible enhancement of conformal invariance from scale invariance reveals the sublime nature of the renormalization group and space-time with holography. This review is based on a lecture note on scale invariance vs conformal invariance, on which the author gave lectures at Taiwan Central University for the 5th Taiwan School on Strings and

  7. Photocontrol of protein conformation in a Langmuir monolayer

    NASA Astrophysics Data System (ADS)

    Cicuta, Pietro; Hopkinson, Ian; Petrov, Peter G.

    2001-12-01

    We report a method to control the conformation of a weak polyampholyte (the protein β-casein) in Langmuir monolayers by light, even though the protein is not photosensitive. Our approach is to couple the monolayer state to a photochemical reaction excited in the liquid subphase. The conformational transition of the protein molecule is triggered through its sensitivity to a subphase bulk field (pH in this study), changing in the course of the photochemical process. Thus, reaction of photoaquation of the ferrocyanide ion, which increases the subphase pH from 7.0 to about 8.3, produces a change in the surface monolayer pressure, ΔΠ, between -0.5 and +1.5 mN/m (depending on the surface concentration), signalling a conformational switch. The approach proposed here can be used to selectively target and influence different interfacial properties by light, without embedding photosensitizers in the matrix.

  8. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2003-09-01

    This report describes work performed during the second year of the project, ''Conformance Improvement Using Gels.'' The project has two objectives. The first objective is to identify gel compositions and conditions that substantially reduce flow through fractures that allow direct channeling between wells, while leaving secondary fractures open so that high fluid injection and production rates can be maintained. The second objective is to optimize treatments in fractured production wells, where the gel must reduce permeability to water much more than that to oil. Pore-level images from X-ray computed microtomography were re-examined for Berea sandstone and porous polyethylene. This analysis suggests that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than a gel-ripping mechanism. This finding helps to explain why aqueous gels can reduce permeability to water more than to oil. We analyzed a Cr(III)-acetate-HPAM gel treatment in a production well in the Arbuckle formation. The availability of accurate pressure data before, during, and after the treatment was critical for the analysis. After the gel treatment, water productivity was fairly constant at about 20% of the pre-treatment value. However, oil productivity was stimulated by a factor of 18 immediately after the treatment. During the six months after the treatment, oil productivity gradually decreased to approach the pre-treatment value. To explain this behavior, we proposed that the fracture area open to oil flow was increased substantially by the gel treatment, followed by a gradual closing of the fractures during subsequent production. For a conventional Cr(III)-acetate-HPAM gel, the delay between gelant preparation and injection into a fracture impacts the placement, leakoff, and permeability reduction behavior. Formulations placed as partially formed gels showed relatively low pressure gradients during placement, and yet substantially reduced the flow capacity of

  9. The conformations of cyclic (1-->2)-beta-D-glucans: application of multidimensional clustering analysis to conformational data sets obtained by Metropolis Monte Carlo calculations.

    PubMed

    York, W S; Thomsen, J U; Meyer, B

    1993-10-01

    Sets containing up to 1.3 x 10(6) energetically accessible conformations of linear (1-->2)-beta-D-glucan oligosaccharides were obtained by Metropolis Monte Carlo (MMC) calculations performed with the GEGOP (GEometry of GlycOProteins) program. Quantitative analyses of the data sets (which were expressed in terms of the glycosidic dihedral angle coordinates) were obtained by two different clustering methods: (i) the three-distance hierarchical clustering method (3-DM), published by Jure Zupan, and (ii) a nonhierarchical clustering method (Population-Density Projection, PDP) which, through a segmentation analysis of two-dimensional projections of the population-density surface, establishes a partitioning of conformational space into a set of "cluster regions", followed by a clustering step where each conformation of the data set is assigned to one of these regions. Computer programs (MCLUST and PDPCLUST) were developed to perform the 3-DM and PDP analyses, respectively. The two types of analysis provided very similar sets of conformational families (clusters), which could be expressed as combinations of distinct conformations of the glycosidic torsional angles (phi, psi) centered at (50 degrees, 10 degrees) for conformation A, (40 degrees, 160 degrees) for conformation B, (55 degrees, -160 degrees) for conformation B', and (170 degrees, 10 degrees) for conformation C. The analysis provided the populations of the families, along with relative rates for transitions between families. Examination of the frequencies of the A, B, and C glycosidic bond conformations with respect to their relative positions in the sequence revealed the tendency of the (1-->2)-beta-D-glucan to adopt conformational repeating structures of the general form [AnB], where n = 3 or 6. These repeating structures combine in an energetically cooperative fashion to give low-energy cyclic conformations having, for example C5 symmetry [AAAB]5 for the eicosamer, and C3 symmetry [AAAAAAB]3 for the

  10. Indomethacin polymorphs: Experimental and conformational analysis.

    PubMed

    Aceves-Hernandez, J M; Nicolás-Vázquez, I; Aceves, F J; Hinojosa-Torres, J; Paz, M; Castaño, V M

    2009-07-01

    Thermal analysis of indomethacin alpha and gamma polymorphs presents a temperature transition at 429.2 and 435.8 K, respectively, although with X-ray diffraction or near infra-red spectroscopy phase transformations were not registered. DSC method for the indomethacin amorphous solid shows an endothermic event; however, the conformational analysis at higher temperature shows a rotational change which may explain such endothermic peak. By heating the gamma polymorph at 483 K (210 degrees C) for 30 min and then quenching into liquid nitrogen the amorphous solid was obtained. The alpha form shows the highest intrinsic dissolution rate, while the lowest rate was for the amorphous indomethacin. Theoretical calculations (ab initio, Hartree-Fock and density functional theory, DFT) indicate that the double interaction is responsible for the observed difference in solubility.

  11. To conform or not to conform: spontaneous conformity diminishes the sensitivity to monetary outcomes.

    PubMed

    Yu, Rongjun; Sun, Sai

    2013-01-01

    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.

  12. 40 CFR 93.154 - Conformity analysis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Conformity analysis. 93.154 Section 93...) DETERMINING CONFORMITY OF FEDERAL ACTIONS TO STATE OR FEDERAL IMPLEMENTATION PLANS Determining Conformity of General Federal Actions to State or Federal Implementation Plans § 93.154 Conformity analysis. Any...

  13. Conformational elasticity can facilitate TALE-DNA recognition.

    PubMed

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

    2014-01-01

    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.

  14. Induction of protein conformational change inside the charged electrospray droplet.

    PubMed

    Banerjee, Shibdas

    2013-02-01

    The behavior of the analyte molecules inside the neutral core of the charged electrospray (ES) droplet is not unambiguously known to date. The possibility of protein conformational change inside the charged ES droplet has been investigated. The ES droplets encapsulating the protein molecules were exposed to the acetic acid vapor in the ionization chamber to absorb the acetic acid vapor. Because of the faster evaporation of water than that of acetic acid, the droplets became enriched with acetic acid and thus altered the solvent environment (e.g. pH and polarity) of the final charged droplets from where the naked charged analytes (proteins) are formed. Thus, the perturbation of the ES droplet solvent environment resulted in the protein conformational change (unfolding) during the short lifespan of the ES droplet and that is reflected by the multimodal charge state distribution in the corresponding mass spectra. Further, the extent of this conformational change inside the ES droplet was found to be related to the structural flexibility of the protein. Although the protein conformational change inside the ES droplet has been driven by using acetic acid vapor in the present study, the results would help in the near future to understand the spontaneity of the conformational change of the analyte on the millisecond timescale of phase transition in the natural way of ES process.

  15. HAMP domain conformers that propagate opposite signals in bacterial chemoreceptors.

    PubMed

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

    2013-01-01

    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.

  16. Hierarchical Conformational Analysis of Native Lysozyme Based on Sub-Millisecond Molecular Dynamics Simulations

    PubMed Central

    Wang, Kai; Long, Shiyang; Tian, Pu

    2015-01-01

    Hierarchical organization of free energy landscape (FEL) for native globular proteins has been widely accepted by the biophysics community. However, FEL of native proteins is usually projected onto one or a few dimensions. Here we generated collectively 0.2 milli-second molecular dynamics simulation trajectories in explicit solvent for hen egg white lysozyme (HEWL), and carried out detailed conformational analysis based on backbone torsional degrees of freedom (DOF). Our results demonstrated that at micro-second and coarser temporal resolutions, FEL of HEWL exhibits hub-like topology with crystal structures occupying the dominant structural ensemble that serves as the hub of conformational transitions. However, at 100ns and finer temporal resolutions, conformational substates of HEWL exhibit network-like topology, crystal structures are associated with kinetic traps that are important but not dominant ensembles. Backbone torsional state transitions on time scales ranging from nanoseconds to beyond microseconds were found to be associated with various types of molecular interactions. Even at nanoseconds temporal resolution, the number of conformational substates that are of statistical significance is quite limited. These observations suggest that detailed analysis of conformational substates at multiple temporal resolutions is both important and feasible. Transition state ensembles among various conformational substates at microsecond temporal resolution were observed to be considerably disordered. Life times of these transition state ensembles are found to be nearly independent of the time scales of the participating torsional DOFs. PMID:26057625

  17. Transition Planning

    ERIC Educational Resources Information Center

    Statfeld, Jenna L.

    2011-01-01

    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…

  18. Universality class in conformal inflation

    SciTech Connect

    Kallosh, Renata; Linde, Andrei E-mail: alinde@stanford.edu

    2013-07-01

    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.

  19. Identification of Serine Conformers by Matrix-Isolation IR Spectroscopy Aided by Near-Infrared Laser-Induced Conformational Change, 2D Correlation Analysis, and Quantum Mechanical Anharmonic Computations.

    PubMed

    Najbauer, Eszter E; Bazsó, Gábor; Apóstolo, Rui; Fausto, Rui; Biczysko, Malgorzata; Barone, Vincenzo; Tarczay, György

    2015-08-20

    The conformers of α-serine were investigated by matrix-isolation IR spectroscopy combined with NIR laser irradiation. This method, aided by 2D correlation analysis, enabled unambiguously grouping the spectral lines to individual conformers. On the basis of comparison of at least nine experimentally observed vibrational transitions of each conformer with empirically scaled (SQM) and anharmonic (GVPT2) computed IR spectra, six conformers were identified. In addition, the presence of at least one more conformer in Ar matrix was proved, and a short-lived conformer with a half-life of (3.7 ± 0.5) × 10(3) s in N2 matrix was generated by NIR irradiation. The analysis of the NIR laser-induced conversions revealed that the excitation of the stretching overtone of both the side chain and the carboxylic OH groups can effectively promote conformational changes, but remarkably different paths were observed for the two kinds of excitations. PMID:26201050

  20. Conformation-sensitive capillary electrophoresis.

    PubMed

    Ashton, Emma Jane

    2011-01-01

    Conformation-sensitive capillary electrophoresis (CSCE) is a rapid, high-throughput screening method that can be applied to any region of a genome for detection of sequence variants. Slab gel-based conformation-sensitive gel electrophoresis was first described by Ganguly et al., and the transfer from slab gels to capillaries for higher throughput was reported by Rozycka et al. CSCE is based on the principle that DNA homoduplexes and heteroduplexes migrate at different rates during electrophoresis under mildly denaturing conditions. Fragments showing an altered peak morphology compared to the wild type are then sequenced to determine the precise nature of the sequence variant detected.

  1. Cyclic AMP Analog Blocks Kinase Activation by Stabilizing Inactive Conformation: Conformational Selection Highlights a New Concept in Allosteric Inhibitor Design*

    PubMed Central

    Badireddy, Suguna; Yunfeng, Gao; Ritchie, Mark; Akamine, Pearl; Wu, Jian; Kim, Choel W.; Taylor, Susan S.; Qingsong, Lin; Swaminathan, Kunchithapadam; Anand, Ganesh S.

    2011-01-01

    The regulatory (R) subunit of protein kinase A serves to modulate the activity of protein kinase A in a cAMP-dependent manner and exists in two distinct and structurally dissimilar, end point cAMP-bound “B” and C-subunit-bound “H”-conformations. Here we report mechanistic details of cAMP action as yet unknown through a unique approach combining x-ray crystallography with structural proteomics approaches, amide hydrogen/deuterium exchange and ion mobility mass spectrometry, applied to the study of a stereospecific cAMP phosphorothioate analog and antagonist((Rp)-cAMPS). X-ray crystallography shows cAMP-bound R-subunit in the B form but surprisingly the antagonist Rp-cAMPS-bound R-subunit crystallized in the H conformation, which was previously assumed to be induced only by C-subunit-binding. Apo R-subunit crystallized in the B form as well but amide exchange mass spectrometry showed large differences between apo, agonist and antagonist-bound states of the R-subunit. Further ion mobility reveals the apo R-subunit as an ensemble of multiple conformations with collisional cross-sectional areas spanning both the agonist and antagonist-bound states. Thus contrary to earlier studies that explained the basis for cAMP action through “induced fit” alone, we report evidence for conformational selection, where the ligand-free apo form of the R-subunit exists as an ensemble of both B and H conformations. Although cAMP preferentially binds the B conformation, Rp-cAMPS interestingly binds the H conformation. This reveals the unique importance of the equatorial oxygen of the cyclic phosphate in mediating conformational transitions from H to B forms highlighting a novel approach for rational structure-based drug design. Ideal inhibitors such as Rp-cAMPS are those that preferentially “select” inactive conformations of target proteins by satisfying all “binding” constraints alone without inducing conformational changes necessary for activation. PMID:21081668

  2. Patterns and conformations in molecularly thin films

    NASA Astrophysics Data System (ADS)

    Basnet, Prem B.

    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

  3. NIR Laser Radiation Induced Conformational Changes and Tunneling Lifetimes of High-Energy Conformers of Amino Acids in Low-Temperature Matrices

    NASA Astrophysics Data System (ADS)

    Bazso, Gabor; Najbauer, Eszter E.; Magyarfalvi, Gabor; Tarczay, Gyorgy

    2013-06-01

    We review our recent results on combined matrix isolation FT-IR and NIR laser irradiation studies on glycine alanine, and cysteine. The OH and the NH stretching overtones of the low-energy conformers of these amino acids deposited in Ar, Kr, Xe, and N_{2} matrices were irradiated. At the expense of the irradiated conformer, other conformers were enriched and new, high-energy, formerly unobserved conformers were formed in the matrices. This enabled the separation and unambiguous assignment of the vibrational transitions of the different conformers. The main conversion paths and their efficiencies are described qualitatively showing that there are significant differences in different matrices. It was shown that the high-energy conformer decays in the matrix by H-atom tunneling. The lifetimes of the high-energy conformers in different matrices were measured. Based on our results we conclude that some theoretically predicted low-energy conformers of amino acids are likely even absent in low-energy matrices due to fast H-atom tunneling. G. Bazso, G. Magyarfalvi, G. Tarczay J. Mol. Struct. 1025 (Light-Induced Processes in Cryogenic Matrices Special Issue) 33-42 (2012). G. Bazso, G. Magyarfalvi, G. Tarczay J. Phys. Chem. A 116 (43) 10539-10547 (2012). G. Bazso, E. E. Najbauer, G. Magyarfalvi, G. Tarczay J. Phys. Chem. A in press, DOI: 10.1021/jp400196b. E. E. Najbauer, G. Bazso, G. Magyarfalvi, G. Tarczay in preparation.

  4. Physical studies of conformational plasticity in a recombinant prion protein.

    PubMed

    Zhang, H; Stockel, J; Mehlhorn, I; Groth, D; Baldwin, M A; Prusiner, S B; James, T L; Cohen, F E

    1997-03-25

    PrP(Sc) is known to be the major, if not the only, component of the infectious prion. Limited proteolysis of PrP(Sc) produces an N-terminally truncated polypeptide of about 142 residues, designated PrP 27-30. Recently, a recombinant protein (rPrP) of 142 residues corresponding to the Syrian hamster PrP 27-30 was expressed in Escherichia coli and purified (Mehlhorn et al., 1996). rPrP has been refolded into both alpha-helical and beta-sheet structures as well as various intermediates in aqueous buffers. The beta-sheet state and two pH-dependent alpha-helical states were characterized by CD and NMR. The alpha-helical conformation occurred only after the formation of an intramolecular disulfide bond, whereas the beta-sheet form was accessible either with or without the disulfide. Of the different alpha-helical forms studied, only those refolded in the pH range 5-8 were substantially soluble at physiological pH, exhibiting similar conformations and monomeric analytical sedimentation profiles throughout the above pH range. Furthermore, refolded alpha-rPrP showed NMR chemical shift dispersion typical of proteins with native conformations, although 2D NMR indicated large segments of conformational flexibility. It displayed a cooperative thermal denaturation transition; at elevated temperatures, it converted rapidly and irreversibly to the thermodynamically more stable beta-sheet form. Unfolding of alpha-rPrP by GdnHCl revealed a two-phase transition with a relatively stable folding intermediate at 2 M GdnHCl. The deltaG values were estimated to be 1.9 +/- 0.4 kcal/mol for the first phase and 6.5 +/- 1.2 kcal/mol for the second, consistent with a folding core surrounded by significant segments of flexible conformation. By NMR, alpha-rPrP(acid) isolated at pH 2 without refolding exhibited heterogeneous line widths, consistent with an acid-denatured molten globular state. We conclude that to the extent that rPrP constitutes a relevant folding domain of PrP(C), the various

  5. Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection

    PubMed Central

    Buscaglia, Robert; Miller, M. Clarke; Dean, William L.; Gray, Robert D.; Lane, Andrew N.; Trent, John O.; Chaires, Jonathan B.

    2013-01-01

    Polyethylene glycols (PEGs) are widely used to perturb the conformations of nucleic acids, including G-quadruplexes. The mechanism by which PEG alters G-quadruplex conformation is poorly understood. We describe here studies designed to determine how PEG and other co-solutes affect the conformation of the human telomeric quadruplex. Osmotic stress studies using acetonitrile and ethylene glycol show that conversion of the ‘hybrid’ conformation to an all-parallel ‘propeller’ conformation is accompanied by the release of about 17 water molecules per quadruplex and is energetically unfavorable in pure aqueous solutions. Sedimentation velocity experiments show that the propeller form is hydrodynamically larger than hybrid forms, ruling out a crowding mechanism for the conversion by PEG. PEGs do not alter water activity sufficiently to perturb quadruplex hydration by osmotic stress. PEG titration experiments are most consistent with a conformational selection mechanism in which PEG binds more strongly to the propeller conformation, and binding is coupled to the conformational transition between forms. Molecular dynamics simulations show that PEG binding to the propeller form is sterically feasible and energetically favorable. We conclude that PEG does not act by crowding and is a poor mimic of the intranuclear environment, keeping open the question of the physiologically relevant quadruplex conformation. PMID:23804761

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

    PubMed

    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

    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 β-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.

  7. Temperature: Human Regulating, Ants Conforming

    ERIC Educational Resources Information Center

    Clopton, Joe R.

    2007-01-01

    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.

  8. Conformal coating using parylene polymers.

    PubMed

    Noordegraaf, J

    1997-01-01

    Parylene, a conformal polymer film, is being used increasingly in Europe to provide environmental and dielectric isolation. Application areas include electronic circuitry, sensors, and medical substrates. This article describes the variants of parylene and their characteristics, together with the process and applications of parylene coating. PMID:10167681

  9. Caspase Allostery and Conformational Selection.

    PubMed

    Clark, A Clay

    2016-06-01

    The role of caspase proteases in regulated processes such as apoptosis and inflammation has been studied for more than two decades, and the activation cascades are known in detail. Apoptotic caspases also are utilized in critical developmental processes, although it is not known how cells maintain the exquisite control over caspase activity in order to retain subthreshold levels required for a particular adaptive response while preventing entry into apoptosis. In addition to active site-directed inhibitors, caspase activity is modulated by post-translational modifications or metal binding to allosteric sites on the enzyme, which stabilize inactive states in the conformational ensemble. This review provides a comprehensive global view of the complex conformational landscape of caspases and mechanisms used to select states in the ensemble. The caspase structural database provides considerable detail on the active and inactive conformations in the ensemble, which provide the cell multiple opportunities to fine tune caspase activity. In contrast, the current database on caspase modifications is largely incomplete and thus provides only a low-resolution picture of global allosteric communications and their effects on the conformational landscape. In recent years, allosteric control has been utilized in the design of small drug compounds or other allosteric effectors to modulate caspase activity.

  10. The conformational analysis of 2-halocyclooctanones.

    PubMed

    Rozada, Thiago C; Gauze, Gisele F; Rosa, Fernanda A; Favaro, Denize C; Rittner, Roberto; Pontes, Rodrigo M; Basso, Ernani A

    2015-02-25

    The establishment of the most stable structures of eight membered rings is a challenging task to the field of conformational analysis. In this work, a series of 2-halocyclooctanones were synthesized (including fluorine, chlorine, bromine and iodine derivatives) and submitted to conformational studies using a combination of theoretical calculation and infrared spectroscopy. For each compound, four conformations were identified as the most important ones. These conformations are derived from the chair-boat conformation of cyclooctanone. The pseudo-equatorial (with respect to the halogen) conformer is preferred in vacuum and in low polarity solvents for chlorine, bromine and iodine derivatives. For 2-fluorocyclooctanone, the preferred conformation in vacuum is pseudo-axial. In acetonitrile, the pseudo-axial conformer becomes the most stable for the chlorine derivative. According to NBO calculations, the conformational preference is not dictated by electron delocalization, but by classical electrostatic repulsions.

  11. Conformational studies of nucleic acids

    SciTech Connect

    Pearlman, D.A.

    1984-11-01

    Techniques are developed for thorough examinations of the conformational energetics of nucleic acids and their constituents. The first one is a method for modeling the furanose sugar ring in nucleic acids. This method allows the coordinates corresponding to any sugar conformation to be generated rapidly and unambiguously from just the phase angle of pseudorotation. Taking advantage of this simplification, we carry out the first calculations to completely explore the conformational spaces available to the eight commonly occurring nucleosides using experimentally consistent furanose geometries and an appropriate classical potential energy force field. Results are in excellent agreement with experiment. We also develop empirically fit multiple correlation functions between the torsion angles of nucleic acids. This reduces the number of conformations which need to be considered in a thorough energetic survey for a nucleic acid. Such surveys are then carried out for two single-stranded nucleic acid tetramers: d(ApApApA) and ApApApA. We create energy contour maps for each of the 21 possible torsion angle pairs in a nucleotide repeating unit. The maps are quite consistent with the experimental distribution of oligonucleotide data and provide rationalizations for several experimentally observed angle-angle correlations. Complete energy minimization is carried out on all local minima found in the surveys. Both the maps and minimizations indicate DNA and RNA to be highly polymorphic. Conformational changes in DNA upon damage by uv radiation are also studied using energy minimization techniques. Finally, we derive a set of partial charges for a nucleotide (2'-deoxycytidine 5'-monophosphate monohydrate) from high resolution x-ray data.

  12. Trickle-Down Preferences: Preferential Conformity to High Status Peers in Fashion Choices.

    PubMed

    Galak, Jeff; Gray, Kurt; Elbert, Igor; Strohminger, Nina

    2016-01-01

    How much do our choices represent stable inner preferences versus social conformity? We examine conformity and consistency in sartorial choices surrounding a common life event of new norm exposure: relocation. A large-scale dataset of individual purchases of women's shoes (16,236 transactions) across five years and 2,007 women reveals a balance of conformity and consistency, moderated by changes in location socioeconomic status. Women conform to new local norms (i.e., average heel size) when moving to relatively higher status locations, but mostly ignore new local norms when moving to relatively lower status locations. In short, at periods of transition, it is the fashion norms of the rich that trickle down to consumers. These analyses provide the first naturalistic large-scale demonstration of the tension between psychological conformity and consistency, with real decisions in a highly visible context.

  13. Trickle-Down Preferences: Preferential Conformity to High Status Peers in Fashion Choices

    PubMed Central

    Galak, Jeff; Gray, Kurt; Elbert, Igor; Strohminger, Nina

    2016-01-01

    How much do our choices represent stable inner preferences versus social conformity? We examine conformity and consistency in sartorial choices surrounding a common life event of new norm exposure: relocation. A large-scale dataset of individual purchases of women’s shoes (16,236 transactions) across five years and 2,007 women reveals a balance of conformity and consistency, moderated by changes in location socioeconomic status. Women conform to new local norms (i.e., average heel size) when moving to relatively higher status locations, but mostly ignore new local norms when moving to relatively lower status locations. In short, at periods of transition, it is the fashion norms of the rich that trickle down to consumers. These analyses provide the first naturalistic large-scale demonstration of the tension between psychological conformity and consistency, with real decisions in a highly visible context. PMID:27144595

  14. Fake conformal symmetry in unimodular gravity

    NASA Astrophysics Data System (ADS)

    Oda, Ichiro

    2016-08-01

    We study Weyl symmetry (local conformal symmetry) in unimodular gravity. It is shown that the Noether currents for both Weyl symmetry and global scale symmetry vanish exactly as in conformally invariant scalar-tensor gravity. We clearly explain why in the class of conformally invariant gravitational theories, the Noether currents vanish by starting with conformally invariant scalar-tensor gravity. Moreover, we comment on both classical and quantum-mechanical equivalences in Einstein's general relativity, conformally invariant scalar-tensor gravity, and the Weyl-transverse gravity. Finally, we discuss the Weyl current in the conformally invariant scalar action and see that it is also vanishing.

  15. Stochastic ensembles, conformationally adaptive teamwork, and enzymatic detoxification.

    PubMed

    Atkins, William M; Qian, Hong

    2011-05-17

    It has been appreciated for a long time that enzymes exist as conformational ensembles throughout multiple stages of the reactions they catalyze, but there is renewed interest in the functional implications. The energy landscape that results from conformationlly diverse poteins is a complex surface with an energetic topography in multiple dimensions, even at the transition state(s) leading to product formation, and this represents a new paradigm. At the same time there has been renewed interest in conformational ensembles, a new paradigm concerning enzyme function has emerged, wherein catalytic promiscuity has clear biological advantages in some cases. "Useful", or biologically functional, promiscuity or the related behavior of "multifunctionality" can be found in the immune system, enzymatic detoxification, signal transduction, and the evolution of new function from an existing pool of folded protein scaffolds. Experimental evidence supports the widely held assumption that conformational heterogeneity promotes functional promiscuity. The common link between these coevolving paradigms is the inherent structural plasticity and conformational dynamics of proteins that, on one hand, lead to complex but evolutionarily selected energy landscapes and, on the other hand, promote functional promiscuity. Here we consider a logical extension of the overlap between these two nascent paradigms: functionally promiscuous and multifunctional enzymes such as detoxification enzymes are expected to have an ensemble landscape with more states accessible on multiple time scales than substrate specific enzymes. Two attributes of detoxification enzymes become important in the context of conformational ensembles: these enzymes metabolize multiple substrates, often in substrate mixtures, and they can form multiple products from a single substrate. These properties, combined with complex conformational landscapes, lead to the possibility of interesting time-dependent, or emergent

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

    PubMed Central

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

    2014-01-01

    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. PMID:24551117

  17. Transiting Exoplanets

    NASA Astrophysics Data System (ADS)

    Haswell, Carole A.

    2010-07-01

    1. Our solar system from afar; 2. Exoplanet discoveries by the transit method; 3. What the transit lightcurve tells us; 4. The transiting exoplanet population; 5. Transmission spectroscopy and Rossiter-McLaughlin effect; 6. Secondary eclipses and phase variations; 7. Transit timing variations and orbital dynamics; 8. Brave new worlds: the future; Index.

  18. Conformal Killing-Yano tensors for the Plebanski-Demianski family of solutions

    SciTech Connect

    Kubiznak, David; Krtous, Pavel

    2007-10-15

    We present explicit expressions for the conformal Killing-Yano tensors for the Plebanski-Demianski family of type D solutions in four dimensions. Some physically important special cases are discussed in more detail. In particular, it is demonstrated how the conformal Killing-Yano tensor becomes the Killing-Yano tensor for the solutions without acceleration. A possible generalization into higher dimensions is studied. Whereas the transition from the nonaccelerating to accelerating solutions in four dimensions is achieved by the conformal rescaling of the metric, we show that such a procedure is not sufficiently general in higher dimensions - only the maximally symmetric spacetimes in 'accelerated' coordinates are obtained.

  19. Molecular dynamics simulations of conformation changes of HIV-1 regulatory protein on graphene

    NASA Astrophysics Data System (ADS)

    Zhao, Daohui; Li, Libo; He, Daohang; Zhou, Jian

    2016-07-01

    The fragment of viral protein R (Vpr), Vpr13-33, plays an important role in regulating nuclear importing of HIV genes through channel formation in which it adopts a leucine-zipper-like alpha-helical conformation. A recent experimental study reported that helical Vpr13-33 would transform to β-sheet or random coil structures and aggregate on the surface of graphene or graphene oxide through hydrophobic interactions. Due to experimental limitations, however, there is still a considerable lack of understanding on the adsorption dynamics at the early stage of the conformational transition at water-graphene interface and the underlying driving force at molecular level. In this study, atomistic molecular dynamics simulations were used to explore the conformation transition phenomena. Vpr13-33 kept α-helical structure in solution, but changed to β-sheet structure when strongly adsorbed onto graphene. Preferential adsorption of Vpr13-33 on graphene is dominated by hydrophobic interactions. The cluster analysis identified the most significant populated conformation and the early stage of structure conversion from α-helical to β-sheet was found, but the full β-sheet propagation was not observed. Free energy landscape analysis further complemented the transformation analysis of peptide conformations. These findings are consistent with experimental results, and give a molecular level interpretation for the reduced cytotoxicity of Vpr13-33 to some extent upon graphene exposure. Meanwhile, this study provides some significant insights into the detailed mechanism of graphene-induced protein conformation transition.

  20. Conformal Gravity rotation curves with a conformal Higgs halo

    NASA Astrophysics Data System (ADS)

    Horne, Keith

    2016-06-01

    We discuss the effect of a conformally coupled Higgs field on conformal gravity (CG) predictions for the rotation curves of galaxies. The Mannheim-Kazanas (MK) metric is a valid vacuum solution of CG's fourth-order Poisson equation if and only if the Higgs field has a particular radial profile, S(r) = S0 a/(r + a), decreasing from S0 at r = 0 with radial scalelength a. Since particle rest masses scale with S(r)/S0, their world lines do not follow time-like geodesics of the MK metric gμν, as previously assumed, but rather those of the Higgs-frame MK metric tilde{g}_{μ ν }=Ω ^2 g_{μ ν }, with the conformal factor Ω(r) = S(r)/S0. We show that the required stretching of the MK metric exactly cancels the linear potential that has been invoked to fit galaxy rotation curves without dark matter. We also formulate, for spherical structures with a Higgs halo S(r), the CG equations that must be solved for viable astrophysical tests of CG using galaxy and cluster dynamics and lensing.

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

    NASA Astrophysics Data System (ADS)

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

    2006-08-01

    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.

  2. Conformal Window and Correlation Functions in Lattice Conformal QCD

    NASA Astrophysics Data System (ADS)

    Iwasaki, Y.

    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)/tα, 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

  3. Conformal triality of the Kepler problem

    NASA Astrophysics Data System (ADS)

    Cariglia, Marco

    2016-08-01

    We show that the Kepler problem is projectively equivalent to null geodesic motion on the conformal compactification of Minkowski-4 space. This space realises the conformal triality of Minkowski, dS and AdS spaces.

  4. Gauge natural formulation of conformal gravity

    SciTech Connect

    Campigotto, M.; Fatibene, L.

    2015-03-15

    We consider conformal gravity as a gauge natural theory. We study its conservation laws and superpotentials. We also consider the Mannheim and Kazanas spherically symmetric vacuum solution and discuss conserved quantities associated to conformal and diffeomorphism symmetries.

  5. Killing Initial Data on spacelike conformal boundaries

    NASA Astrophysics Data System (ADS)

    Paetz, Tim-Torben

    2016-08-01

    We analyze Killing Initial Data on Cauchy surfaces in conformally rescaled vacuum space-times satisfying Friedrich's conformal field equations. As an application, we derive the KID equations on a spacelike ℐ-.

  6. Alternative Conformations of Cytochrome c: Structure, Function, and Detection.

    PubMed

    Hannibal, Luciana; Tomasina, Florencia; Capdevila, Daiana A; Demicheli, Verónica; Tórtora, Verónica; Alvarez-Paggi, Damián; Jemmerson, Ronald; Murgida, Daniel H; Radi, Rafael

    2016-01-26

    Cytochrome c (cyt c) is a cationic hemoprotein of ∼100 amino acid residues that exhibits exceptional functional versatility. While its primary function is electron transfer in the respiratory chain, cyt c is also recognized as a key component of the intrinsic apoptotic pathway, the mitochondrial oxidative protein folding machinery, and presumably as a redox sensor in the cytosol, along with other reported functions. Transition to alternative conformations and gain-of-peroxidase activity are thought to further enable the multiple functions of cyt c and its translocation across cellular compartments. In vitro, direct interactions of cyt c with cardiolipin, post-translational modifications such as tyrosine nitration, phosphorylation, methionine sulfoxidation, mutations, and even fine changes in electrical fields lead to a variety of conformational states that may be of biological relevance. The identification of these alternative conformations and the elucidation of their functions in vivo continue to be a major challenge. Here, we unify the knowledge of the structural flexibility of cyt c that supports functional moonlighting and review biochemical and immunochemical evidence confirming that cyt c undergoes conformational changes during normal and altered cellular homeostasis.

  7. Supramolecular hydrogels based on short peptides linked with conformational switch.

    PubMed

    Huang, Yucheng; Qiu, Zhenjun; Xu, Yanmei; Shi, Junfeng; Lin, Hongkun; Zhang, Yan

    2011-04-01

    Short peptides appropriately linked with an azobenzene conformational switch were found to be motif and pH dependant supramolecular hydrogelators. The hydrogelation properties of the short peptides linked with the conformational switch were studied in detail with respect to dependence on amino acid residue, pH and salt effect. The presence of amino acids with aromatic side chains such as Phe and Tyr was found to be favorable for the short peptides to gel water at an appropriate pH range. Cationic amino acid residues such as Arg and Lys in the short peptides were found to be unfavorable for hydrogelation. pH and salt effect were also found to be important factors for the hydrogelation properties of the short peptides. A series of short peptides with bioactive sequences were linked with the conformational switch and their hydrogelation properties were investigated. Photoresponsive supramolecular hydrogels were realized based on the E-/Z- transition of the conformational switch upon light irradiation. Proper combination of amino acid residues in the short peptides resulted in smart supramolecular hydrogels with responses to multiple stimuli.

  8. Alternative Conformations of Cytochrome c: Structure, Function, and Detection.

    PubMed

    Hannibal, Luciana; Tomasina, Florencia; Capdevila, Daiana A; Demicheli, Verónica; Tórtora, Verónica; Alvarez-Paggi, Damián; Jemmerson, Ronald; Murgida, Daniel H; Radi, Rafael

    2016-01-26

    Cytochrome c (cyt c) is a cationic hemoprotein of ∼100 amino acid residues that exhibits exceptional functional versatility. While its primary function is electron transfer in the respiratory chain, cyt c is also recognized as a key component of the intrinsic apoptotic pathway, the mitochondrial oxidative protein folding machinery, and presumably as a redox sensor in the cytosol, along with other reported functions. Transition to alternative conformations and gain-of-peroxidase activity are thought to further enable the multiple functions of cyt c and its translocation across cellular compartments. In vitro, direct interactions of cyt c with cardiolipin, post-translational modifications such as tyrosine nitration, phosphorylation, methionine sulfoxidation, mutations, and even fine changes in electrical fields lead to a variety of conformational states that may be of biological relevance. The identification of these alternative conformations and the elucidation of their functions in vivo continue to be a major challenge. Here, we unify the knowledge of the structural flexibility of cyt c that supports functional moonlighting and review biochemical and immunochemical evidence confirming that cyt c undergoes conformational changes during normal and altered cellular homeostasis. PMID:26720007

  9. Structuring and sampling complex conformation space: Weighted ensemble dynamics simulations.

    PubMed

    Gong, Linchen; Zhou, Xin

    2009-08-01

    Based on multiple simulation trajectories, which started from dispersively selected initial conformations, the weighted ensemble dynamics method is designed to robustly and systematically explore the hierarchical structure of complex conformational space through the spectral analysis of the variance-covariance matrix of trajectory-mapped vectors. The nondegenerate ground state of the matrix directly predicts the ergodicity of simulation data. The ground state could be adopted as statistical weights of trajectories to correctly reconstruct the equilibrium properties, even though each trajectory only explores part of the conformational space. Otherwise, the degree of degeneracy simply gives the number of metastable states of the system under the time scale of individual trajectory. Manipulation on the eigenvectors leads to the classification of trajectories into nontransition ones within the states and transition ones between them. The transition states may also be predicted without a priori knowledge of the system. We demonstrate the application of the general method both to the system with a one-dimensional glassy potential and with the one of alanine dipeptide in explicit solvent.

  10. Temperature-cycle microscopy reveals single-molecule conformational heterogeneity.

    PubMed

    Yuan, Haifeng; Gaiduk, Alexander; Siekierzycka, Joanna R; Fujiyoshi, Satoru; Matsushita, Michio; Nettels, Daniel; Schuler, Benjamin; Seidel, Claus A M; Orrit, Michel

    2015-03-01

    Our previous temperature-cycle study reported FRET transitions between different states on FRET-labeled polyprolines [Yuan et al., PCCP, 2011, 13, 1762]. The conformational origin of such transitions, however, was left open. In this work, we apply temperature-cycle microscopy of single FRET-labeled polyproline and dsDNA molecules and compare their responses to resolve the conformational origin of different FRET states. We observe different steady-state FRET distributions and different temperature-cycle responses in the two samples. Our temperature-cycle results on single molecules resemble the results in steady-state measurements but reveal a dark state which could not be observed otherwise. By comparing the timescales and probabilities of different FRET states in temperature-cycle traces, we assign the conformational heterogeneity reflected by different FRET states to linker dynamics, dye-chain and dye-dye interactions. The dark state and low-FRET state are likely due to dye-dye interactions at short separations.

  11. Structuring and sampling complex conformation space: Weighted ensemble dynamics simulations

    NASA Astrophysics Data System (ADS)

    Gong, Linchen; Zhou, Xin

    2009-08-01

    Based on multiple simulation trajectories, which started from dispersively selected initial conformations, the weighted ensemble dynamics method is designed to robustly and systematically explore the hierarchical structure of complex conformational space through the spectral analysis of the variance-covariance matrix of trajectory-mapped vectors. The nondegenerate ground state of the matrix directly predicts the ergodicity of simulation data. The ground state could be adopted as statistical weights of trajectories to correctly reconstruct the equilibrium properties, even though each trajectory only explores part of the conformational space. Otherwise, the degree of degeneracy simply gives the number of metastable states of the system under the time scale of individual trajectory. Manipulation on the eigenvectors leads to the classification of trajectories into nontransition ones within the states and transition ones between them. The transition states may also be predicted without a priori knowledge of the system. We demonstrate the application of the general method both to the system with a one-dimensional glassy potential and with the one of alanine dipeptide in explicit solvent.

  12. Electrochemical evidence on the molten globule conformation of cytochrome c.

    PubMed

    Pineda, T; Sevilla, J M; Román, A J; Blázquez, M

    1997-12-01

    To explore a new approach for characterizing the molten globule conformation, cyclic voltammetric studies of salt induced transitions at acidic pH of cyt c have been carried out. The use of modified electrodes has made the observation of direct electrochemistry in native cyt c possible. However, most of these electrodes do not show reversible responses at acidic pH, due to the fact that, for this system, a deprotonated electrode surface is needed. In these studies, we have used a 6-mercaptopurine and cysteine-modified gold electrodes which are effective for direct rapid electron transfer to cyt c, even in acid solutions. The change in the absorption bands of cyt c are used to monitor the conformational states and, hence, to compare the voltammetric results. Under the experimental conditions where the A state of cyt c is obtained, a reversible voltammetric signal is observed. The midpoint peak potentials are found to be very close to the formal potential of native cyt c. Results are discussed in terms of a cooperative two-state transition between the acid unfolded and the globular acidic states of cyt c. This finding establishes, for the first time, the similarity of both the native and the molten globule-like conformations in terms of its redox properties. PMID:9434113

  13. Electrochemical evidence on the molten globule conformation of cytochrome c.

    PubMed

    Pineda, T; Sevilla, J M; Román, A J; Blázquez, M

    1997-12-01

    To explore a new approach for characterizing the molten globule conformation, cyclic voltammetric studies of salt induced transitions at acidic pH of cyt c have been carried out. The use of modified electrodes has made the observation of direct electrochemistry in native cyt c possible. However, most of these electrodes do not show reversible responses at acidic pH, due to the fact that, for this system, a deprotonated electrode surface is needed. In these studies, we have used a 6-mercaptopurine and cysteine-modified gold electrodes which are effective for direct rapid electron transfer to cyt c, even in acid solutions. The change in the absorption bands of cyt c are used to monitor the conformational states and, hence, to compare the voltammetric results. Under the experimental conditions where the A state of cyt c is obtained, a reversible voltammetric signal is observed. The midpoint peak potentials are found to be very close to the formal potential of native cyt c. Results are discussed in terms of a cooperative two-state transition between the acid unfolded and the globular acidic states of cyt c. This finding establishes, for the first time, the similarity of both the native and the molten globule-like conformations in terms of its redox properties.

  14. [Conformal radiotherapy of brain tumors].

    PubMed

    Haie-Meder, C; Beaudré, A; Breton, C; Biron, B; Cordova, A; Dubray, B; Mazeron, J J

    1999-01-01

    Conformal irradiation of brain tumours is based on the three-dimensional reconstruction of the targeted volumes and at-risk organ images, the three-dimensional calculation of the dose distribution and a treatment device (immobilisation, beam energy, collimation, etc.) adapted to the high precision required by the procedure. Each step requires an appropriate methodology and a quality insurance program. Specific difficulties in brain tumour management are related to GTV and CTV definition depending upon the histological type, the quality of the surgical resection and the medical team. Clinical studies have reported dose escalation trials, mostly in high-grade gliomas and tumours at the base of the skull. Clinical data are now providing a better knowledge of the tolerance of normal tissues. As for small tumours, the implementation of beam intensity modulation is likely to narrow the gap between conformal and stereotaxic radiotherapy. PMID:10572510

  15. The Conformational Behaviour of Glucosamine

    NASA Astrophysics Data System (ADS)

    Peña, Isabel; Kolesniková, Lucie; Cabezas, Carlos; Bermúdez, Celina; Berdakin, Matías; Simao, Alcides; Alonso, José L.

    2014-06-01

    A laser ablation method has been successfully used to vaporize the bioactive amino monosaccharide D-glucosamine. Three cyclic α-4C1 pyranose forms have been identified using a combination of CP-FTMW and LA-MB-FTMW spectroscopy. Stereoelectronic hyperconjugative factors, like those associated with anomeric or gauche effects, as well as the cooperative OH\\cdotsO, OH\\cdotsN and NH\\cdotsO chains, extended along the entire molecule, are the main factors driving the conformational behavior. All observed conformers exhibit a counter-clockwise arrangement (cc) of the network of intramolecular hydrogen bonds. The results are compared with those recently obtained for D-glucose. J. L. Alonso, M. A. Lozoya, I. Peña, J. C. López, C. Cabezas, S. Mata, S. Blanco, Chem. Sci. 2014, 5, 515.

  16. The conformational cycle of kinesin.

    PubMed Central

    Cross, R A; Crevel, I; Carter, N J; Alonso, M C; Hirose, K; Amos, L A

    2000-01-01

    The stepping mechanism of kinesin can be thought of as a programme of conformational changes. We briefly review protein chemical, electron microscopic and transient kinetic evidence for conformational changes, and working from this evidence, outline a model for the mechanism. In the model, both kinesin heads initially trap Mg x ADP. Microtubule binding releases ADP from one head only (the trailing head). Subsequent ATP binding and hydrolysis by the trailing head progressively accelerate attachment of the leading head, by positioning it closer to its next site. Once attached, the leading head releases its ADP and exerts a sustained pull on the trailing head. The rate of closure of the molecular gate which traps ADP on the trailing head governs its detachment rate. A speculative but crucial coordinating feature is that this rate is strain sensitive, slowing down under negative strain and accelerating under positive strain. PMID:10836499

  17. Anomalous dimensions of conformal baryons

    NASA Astrophysics Data System (ADS)

    Pica, Claudio; Sannino, Francesco

    2016-10-01

    We determine the anomalous dimensions of baryon operators for the three-color theory as functions of the number of massless flavors within the conformal window to the maximum known order in perturbation theory. We show that the anomalous dimension of the baryon is controllably small, within the δ expansion, for a wide range of number of flavors. We also find that this is always smaller than the anomalous dimension of the fermion mass operator. These findings challenge the partial compositeness paradigm.

  18. Stabilizing the boat conformation of cyclohexane rings

    SciTech Connect

    Dasgupta, S.; Goddard, W.A. III; Moldowan, J.M.; Carlson, R.M.K.; Goddard, W.A. III.

    1995-06-21

    In calculating the energetics for various conformers of the A, B, and C series of hopanoid hydrocarbons present in mature oil reservoirs, we find that the B series prefers the boat conformation (by 1.3-2.5 kcal/mol) for the D cyclohexane ring. We analyze the structural elements responsible for stabilizing this boat conformation, identify the key features, and illustrate how one might stabilize boat conformations of other systems. 5 refs., 3 figs., 2 tabs.

  19. Anomalies, conformal manifolds, and spheres

    NASA Astrophysics Data System (ADS)

    Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar; Schwimmer, Adam; Seiberg, Nathan; Theisen, Stefan

    2016-03-01

    The two-point function of exactly marginal operators leads to a universal contribution to the trace anomaly in even dimensions. We study aspects of this trace anomaly, emphasizing its interpretation as a sigma model, whose target space {M} is the space of conformal field theories (a.k.a. the conformal manifold). When the underlying quantum field theory is supersymmetric, this sigma model has to be appropriately supersymmetrized. As examples, we consider in some detail {N}=(2,2) and {N}=(0,2) supersymmetric theories in d = 2 and {N}=2 supersymmetric theories in d = 4. This reasoning leads to new information about the conformal manifolds of these theories, for example, we show that the manifold is Kähler-Hodge and we further argue that it has vanishing Kähler class. For {N}=(2,2) theories in d = 2 and {N}=2 theories in d = 4 we also show that the relation between the sphere partition function and the Kähler potential of {M} follows immediately from the appropriate sigma models that we construct. Along the way we find several examples of potential trace anomalies that obey the Wess-Zumino consistency conditions, but can be ruled out by a more detailed analysis.

  20. Conformal Invariance of Graphene Sheets.

    PubMed

    Giordanelli, I; Posé, N; Mendoza, M; Herrmann, H J

    2016-03-10

    Suspended graphene sheets exhibit correlated random deformations that can be studied under the framework of rough surfaces with a Hurst (roughness) exponent 0.72 ± 0.01. Here, we show that, independent of the temperature, the iso-height lines at the percolation threshold have a well-defined fractal dimension and are conformally invariant, sharing the same statistical properties as Schramm-Loewner evolution (SLEκ) curves with κ = 2.24 ± 0.07. Interestingly, iso-height lines of other rough surfaces are not necessarily conformally invariant even if they have the same Hurst exponent, e.g. random Gaussian surfaces. We have found that the distribution of the modulus of the Fourier coefficients plays an important role on this property. Our results not only introduce a new universality class and place the study of suspended graphene membranes within the theory of critical phenomena, but also provide hints on the long-standing question about the origin of conformal invariance in iso-height lines of rough surfaces.

  1. Limit cycles and conformal invariance

    NASA Astrophysics Data System (ADS)

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

    2013-01-01

    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.

  2. The Conformational Landscape of Serinol

    NASA Astrophysics Data System (ADS)

    Sanz, M. Eugenia; Loru, Donatella; Peña, Isabel; Alonso, José L.

    2014-06-01

    The rotational spectrum of the amino alcohol serinol CH_2OH--CH(NH_2)--CH_2OH, which constitutes the hydrophilic head of the lipid sphingosine, has been investigated using chirped-pulsed Fourier transform microwave spectroscopy in combination with laser ablation Five different forms of serinol have been observed and conclusively identified by the comparison between the experimental values of their rotational and 14N quadrupole coupling constants and those predicted by ab initio calculations. In all observed conformers several hydrogen bonds are established between the two hydroxyl groups and the amino groups in a chain or circular arrangement. The most abundant conformer is stabilised by O--H···N and N--H···O hydrogen bonds forming a chain rather than a cycle. One of the detected conformers presents a tunnelling motion of the hydrogen atoms of the functional groups similar to that observed in glycerol. S. Mata, I. Peña, C. Cabezas, J. C. López, J. L. Alonso, J. Mol. Spectrosc. 2012, 280, 91 V. V. Ilyushin, R. A. Motiyenko, F. J. Lovas, D. F. Plusquellic, J. Mol. Spectrosc. 2008, 251, 129.

  3. Anomalies, conformal manifolds, and spheres

    DOE PAGESBeta

    Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar; Schwimmer, Adam; Seiberg, Nathan; Theisen, Stefan

    2016-03-04

    The two-point function of exactly marginal operators leads to a universal contribution to the trace anomaly in even dimensions. We study aspects of this trace anomaly, emphasizing its interpretation as a sigma model, whose target space $M$ is the space of conformal field theories (a.k.a. the conformal manifold). When the underlying quantum field theory is supersymmetric, this sigma model has to be appropriately supersymmetrized. As examples, we consider in some detail $N$ = (2; 2) and $N$ = (0; 2) supersymmetric theories in d = 2 and $N$ = 2 supersymmetric theories in d = 4. This reasoning leads tomore » new information about the conformal manifolds of these theories, for example, we show that the manifold is K ahler-Hodge and we further argue that it has vanishing K ahler class. For $N$ = (2; 2) theories in d = 2 and N = 2 theories in d = 4 we also show that the relation between the sphere partition function and the K ahler potential of $M$ follows immediately from the appropriate sigma models that we construct. Ultimately, along the way we find several examples of potential trace anomalies that obey the Wess-Zumino consistency conditions, but can be ruled out by a more detailed analysis.« less

  4. Electrophysiological precursors of social conformity.

    PubMed

    Shestakova, Anna; Rieskamp, Jörg; Tugin, Sergey; Ossadtchi, Alexey; Krutitskaya, Janina; Klucharev, Vasily

    2013-10-01

    Humans often change their beliefs or behavior due to the behavior or opinions of others. This study explored, with the use of human event-related potentials (ERPs), whether social conformity is based on a general performance-monitoring mechanism. We tested the hypothesis that conflicts with a normative group opinion evoke a feedback-related negativity (FRN) often associated with performance monitoring and subsequent adjustment of behavior. The experimental results show that individual judgments of facial attractiveness were adjusted in line with a normative group opinion. A mismatch between individual and group opinions triggered a frontocentral negative deflection with the maximum at 200 ms, similar to FRN. Overall, a conflict with a normative group opinion triggered a cascade of neuronal responses: from an earlier FRN response reflecting a conflict with the normative opinion to a later ERP component (peaking at 380 ms) reflecting a conforming behavioral adjustment. These results add to the growing literature on neuronal mechanisms of social influence by disentangling the conflict-monitoring signal in response to the perceived violation of social norms and the neural signal of a conforming behavioral adjustment.

  5. Conformal Invariance of Graphene Sheets

    PubMed Central

    Giordanelli, I.; Posé, N.; Mendoza, M.; Herrmann, H. J.

    2016-01-01

    Suspended graphene sheets exhibit correlated random deformations that can be studied under the framework of rough surfaces with a Hurst (roughness) exponent 0.72 ± 0.01. Here, we show that, independent of the temperature, the iso-height lines at the percolation threshold have a well-defined fractal dimension and are conformally invariant, sharing the same statistical properties as Schramm-Loewner evolution (SLEκ) curves with κ = 2.24 ± 0.07. Interestingly, iso-height lines of other rough surfaces are not necessarily conformally invariant even if they have the same Hurst exponent, e.g. random Gaussian surfaces. We have found that the distribution of the modulus of the Fourier coefficients plays an important role on this property. Our results not only introduce a new universality class and place the study of suspended graphene membranes within the theory of critical phenomena, but also provide hints on the long-standing question about the origin of conformal invariance in iso-height lines of rough surfaces. PMID:26961723

  6. Electrophysiological precursors of social conformity.

    PubMed

    Shestakova, Anna; Rieskamp, Jörg; Tugin, Sergey; Ossadtchi, Alexey; Krutitskaya, Janina; Klucharev, Vasily

    2013-10-01

    Humans often change their beliefs or behavior due to the behavior or opinions of others. This study explored, with the use of human event-related potentials (ERPs), whether social conformity is based on a general performance-monitoring mechanism. We tested the hypothesis that conflicts with a normative group opinion evoke a feedback-related negativity (FRN) often associated with performance monitoring and subsequent adjustment of behavior. The experimental results show that individual judgments of facial attractiveness were adjusted in line with a normative group opinion. A mismatch between individual and group opinions triggered a frontocentral negative deflection with the maximum at 200 ms, similar to FRN. Overall, a conflict with a normative group opinion triggered a cascade of neuronal responses: from an earlier FRN response reflecting a conflict with the normative opinion to a later ERP component (peaking at 380 ms) reflecting a conforming behavioral adjustment. These results add to the growing literature on neuronal mechanisms of social influence by disentangling the conflict-monitoring signal in response to the perceived violation of social norms and the neural signal of a conforming behavioral adjustment. PMID:22683703

  7. On the cohomology of Leibniz conformal algebras

    NASA Astrophysics Data System (ADS)

    Zhang, Jiao

    2015-04-01

    We construct a new cohomology complex of Leibniz conformal algebras with coefficients in a representation instead of a module. The low-dimensional cohomology groups of this complex are computed. Meanwhile, we construct a Leibniz algebra from a Leibniz conformal algebra and prove that the category of Leibniz conformal algebras is equivalent to the category of equivalence classes of formal distribution Leibniz algebras.

  8. Flexible ligand docking using conformational ensembles.

    PubMed Central

    Lorber, D. M.; Shoichet, B. K.

    1998-01-01

    Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation. PMID:9568900

  9. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  10. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  11. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  12. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  13. 40 CFR 51.854 - Conformity analysis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 2 2010-07-01 2010-07-01 false Conformity analysis. 51.854 Section 51... FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Determining Conformity of General Federal Actions to State or Federal Implementation Plans § 51.854 Conformity analysis. Link to...

  14. Effect of monovalent salt on the conformation of polyelectrolyte-surfactant complexes

    NASA Astrophysics Data System (ADS)

    Diehl, A.; Kuhn, P. S.

    2009-01-01

    We study the conformation of polyelectrolyte-surfactant complexes in the presence of monovalent salt. A simple model for the formation of these structures is presented in the framework of the Debye-Hückel-Bjerrum-Manning and Flory theories, with the hydrophobic interactions between the hydrocarbon tails of surfactant molecules treated in the spirit of van der Waals theory as an effective attraction. The extension of the polyelectrolyte-surfactant complexes is analyzed as a function of the salt concentration and a discrete conformational transition between a compact globule and an elongated coil is found, in agreement with experimental results for the unfolding transition of a DNA-cationic surfactant complex.

  15. Direct measurement of the energy thresholds to conformational isomerization in tryptamine: experiment and theory.

    PubMed

    Clarkson, Jasper R; Dian, Brian C; Moriggi, Loïck; DeFusco, Albert; McCarthy, Valerie; Jordan, Kenneth D; Zwier, Timothy S

    2005-06-01

    The methods of stimulated emission pumping-hole filling spectroscopy (SEP-HFS) and stimulated emission pumping population transfer spectroscopy (SEP-PTS) were applied to the conformation-specific study of conformational isomerization in tryptamine [TRA, 3-(2-aminoethyl)indole]. These experimental methods employ stimulated emission pumping to selectively excite a fraction of the population of a single conformation of TRA to well-defined ground-state vibrational levels. This produces single conformations with well-defined internal energy, tunable over a range of energies from near the zero-point level to well above the lowest barriers to conformational isomerization. When the SEP step overcomes a barrier to isomerization, a fraction of the excited population isomerizes to form that product. By carrying out SEP excitation early in a supersonic expansion, these product molecules are subsequently cooled to their zero-point vibrational levels, where they can be detected downstream with a third tunable laser that probes the ground-state population of a particular product conformer via a unique ultraviolet transition using laser-induced fluorescence. The population transfer spectra (recorded by tuning the SEP dump laser while holding the pump and probe lasers fixed) exhibit sharp onsets that directly determine the energy thresholds for conformational isomerization in a given reactant-product conformer pair. In the absence of tunneling effects, the first observed transition in a given X-Y PTS constitutes an upper bound to the energy barrier to conformational isomerization, while the last transition not observed constitutes a lower bound. The bounds for isomerizing conformer A of tryptamine to B(688-748 cm(-1)), C(1)(860-1000 cm(-1)), C(2)(1219-1316 cm(-1)), D(1219-1282 cm(-1)), E(1219-1316 cm(-1)), and F(688-748 cm(-1)) are determined. In addition, thresholds for isomerizing from B to A(<1562 cm(-1)), B to F(562-688 cm(-1)), and out of C(2) to B(<747 cm(-1)) are also

  16. Direct measurement of the energy thresholds to conformational isomerization in Tryptamine: Experiment and theory

    NASA Astrophysics Data System (ADS)

    Clarkson, Jasper R.; Dian, Brian C.; Moriggi, Loïck; DeFusco, Albert; McCarthy, Valerie; Jordan, Kenneth D.; Zwier, Timothy S.

    2005-06-01

    The methods of stimulated emission pumping-hole filling spectroscopy (SEP-HFS) and stimulated emission pumping population transfer spectroscopy (SEP-PTS) were applied to the conformation-specific study of conformational isomerization in tryptamine [TRA, 3-(2-aminoethyl)indole]. These experimental methods employ stimulated emission pumping to selectively excite a fraction of the population of a single conformation of TRA to well-defined ground-state vibrational levels. This produces single conformations with well-defined internal energy, tunable over a range of energies from near the zero-point level to well above the lowest barriers to conformational isomerization. When the SEP step overcomes a barrier to isomerization, a fraction of the excited population isomerizes to form that product. By carrying out SEP excitation early in a supersonic expansion, these product molecules are subsequently cooled to their zero-point vibrational levels, where they can be detected downstream with a third tunable laser that probes the ground-state population of a particular product conformer via a unique ultraviolet transition using laser-induced fluorescence. The population transfer spectra (recorded by tuning the SEP dump laser while holding the pump and probe lasers fixed) exhibit sharp onsets that directly determine the energy thresholds for conformational isomerization in a given reactant-product conformer pair. In the absence of tunneling effects, the first observed transition in a given X -Y PTS constitutes an upper bound to the energy barrier to conformational isomerization, while the last transition not observed constitutes a lower bound. The bounds for isomerizing conformer A of tryptamine to B(688-748cm-1), C(1)(860-1000cm-1), C(2)(1219-1316cm-1), D(1219-1282cm-1), E(1219-1316cm-1), and F(688-748cm-1) are determined. In addition, thresholds for isomerizing from B to A(<1562cm-1), B to F(562-688cm-1), and out of C(2) to B(<747cm-1) are also determined. The A →B and B

  17. Myosin and Tropomyosin Stabilize the Conformation of Formin-nucleated Actin Filaments*

    PubMed Central

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

    2012-01-01

    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

  18. Measuring Conformational Dynamics of Single Biomolecules Using Nanoscale Electronic Devices

    NASA Astrophysics Data System (ADS)

    Akhterov, Maxim V.; Choi, Yongki; Sims, Patrick C.; Olsen, Tivoli J.; Gul, O. Tolga; Corso, Brad L.; Weiss, Gregory A.; Collins, Philip G.

    2014-03-01

    Molecular motion can be a rate-limiting step of enzyme catalysis, but motions are typically too quick to resolve with fluorescent single molecule techniques. Recently, we demonstrated a label-free technique that replaced fluorophores with nano-electronic circuits to monitor protein motions. The solid-state electronic technique used single-walled carbon nanotube (SWNT) transistors to monitor conformational motions of a single molecule of T4 lysozyme while processing its substrate, peptidoglycan. As lysozyme catalyzes the hydrolysis of glycosidic bonds, two protein domains undergo 8 Å hinge bending motion that generates an electronic signal in the SWNT transistor. We describe improvements to the system that have extended our temporal resolution to 2 μs . Electronic recordings at this level of detail directly resolve not just transitions between open and closed conformations but also the durations for those transition events. Statistical analysis of many events determines transition timescales characteristic of enzyme activity and shows a high degree of variability within nominally identical chemical events. The high resolution technique can be readily applied to other complex biomolecules to gain insights into their kinetic parameters and catalytic function.

  19. Conformance Testing: Measurement Decision Rules

    NASA Technical Reports Server (NTRS)

    Mimbs, Scott M.

    2010-01-01

    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

  20. The Biological Bases of Conformity

    PubMed Central

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

    2012-01-01

    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. PMID:22712006

  1. Conformance Verification of Privacy Policies

    NASA Astrophysics Data System (ADS)

    Fu, Xiang

    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.

  2. Chromosome Conformation Capture in Drosophila.

    PubMed

    Li, Hua-Bing

    2016-01-01

    Linear chromatin fiber is packed inside the nuclei as a complex three-dimensional structure, and the organization of the chromatin has important roles in the appropriate spatial and temporal regulation of gene expression. To understand how chromatin organizes inside nuclei, and how regulatory proteins physically interact with genes, chromosome conformation capture (3C) technique provides a powerful and sensitive tool to detect both short- and long-range DNA-DNA interaction. Here I describe the 3C technique to detect the DNA-DNA interactions mediated by insulator proteins that are closely related to PcG in Drosophila, which is also broadly applicable to other systems. PMID:27659987

  3. Net charge per residue modulates conformational ensembles of intrinsically disordered proteins

    PubMed Central

    Mao, Albert H.; Crick, Scott L.; Vitalis, Andreas; Chicoine, Caitlin L.; Pappu, Rohit V.

    2010-01-01

    Intrinsically disordered proteins (IDPs) adopt heterogeneous ensembles of conformations under physiological conditions. Understanding the relationship between amino acid sequence and conformational ensembles of IDPs can help clarify the role of disorder in physiological function. Recent studies revealed that polar IDPs favor collapsed ensembles in water despite the absence of hydrophobic groups—a result that holds for polypeptide backbones as well. By studying highly charged polypeptides, a different archetype of IDPs, we assess how charge content modulates the intrinsic preference of polypeptide backbones for collapsed structures. We characterized conformational ensembles for a set of protamines in aqueous milieus using molecular simulations and fluorescence measurements. Protamines are arginine-rich IDPs involved in the condensation of chromatin during spermatogenesis. Simulations based on the ABSINTH implicit solvation model predict the existence of a globule-to-coil transition, with net charge per residue serving as the discriminating order parameter. The transition is supported by quantitative agreement between simulation and experiment. Local conformational preferences partially explain the observed trends of polymeric properties. Our results lead to the proposal of a schematic protein phase diagram that should enable prediction of polymeric attributes for IDP conformational ensembles using easily calculated physicochemical properties of amino acid sequences. Although sequence composition allows the prediction of polymeric properties, interresidue contact preferences of protamines with similar polymeric attributes suggest that certain details of conformational ensembles depend on the sequence. This provides a plausible mechanism for specificity in the functions of IDPs. PMID:20404210

  4. Phase transition in the Sznajd model with independence

    NASA Astrophysics Data System (ADS)

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

    2011-11-01

    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.

  5. Theory for the conformational changes of double-stranded chain molecules

    NASA Astrophysics Data System (ADS)

    Chen, Shi-Jie; Dill, Ken A.

    1998-09-01

    We develop statistical mechanical theory to predict the thermodynamic properties of chain molecules having noncovalent double-stranded conformations, as in RNA molecules and β-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 β-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.

  6. Conformational gating of DNA conductance

    PubMed Central

    Artés, Juan Manuel; Li, Yuanhui; Qi, Jianqing; Anantram, M. P.; Hihath, Joshua

    2015-01-01

    DNA is a promising molecule for applications in molecular electronics because of its unique electronic and self-assembly properties. Here we report that the conductance of DNA duplexes increases by approximately one order of magnitude when its conformation is changed from the B-form to the A-form. This large conductance increase is fully reversible, and by controlling the chemical environment, the conductance can be repeatedly switched between the two values. The conductance of the two conformations displays weak length dependencies, as is expected for guanine-rich sequences, and can be fit with a coherence-corrected hopping model. These results are supported by ab initio electronic structure calculations that indicate that the highest occupied molecular orbital is more disperse in the A-form DNA case. These results demonstrate that DNA can behave as a promising molecular switch for molecular electronics applications and also provide additional insights into the huge dispersion of DNA conductance values found in the literature. PMID:26648400

  7. Metrics with Galilean conformal isometry

    SciTech Connect

    Bagchi, Arjun; Kundu, Arnab

    2011-03-15

    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.

  8. Charged gravastars admitting conformal motion

    NASA Astrophysics Data System (ADS)

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

    2011-07-01

    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.

  9. Conformational gating of DNA conductance.

    PubMed

    Artés, Juan Manuel; Li, Yuanhui; Qi, Jianqing; Anantram, M P; Hihath, Joshua

    2015-01-01

    DNA is a promising molecule for applications in molecular electronics because of its unique electronic and self-assembly properties. Here we report that the conductance of DNA duplexes increases by approximately one order of magnitude when its conformation is changed from the B-form to the A-form. This large conductance increase is fully reversible, and by controlling the chemical environment, the conductance can be repeatedly switched between the two values. The conductance of the two conformations displays weak length dependencies, as is expected for guanine-rich sequences, and can be fit with a coherence-corrected hopping model. These results are supported by ab initio electronic structure calculations that indicate that the highest occupied molecular orbital is more disperse in the A-form DNA case. These results demonstrate that DNA can behave as a promising molecular switch for molecular electronics applications and also provide additional insights into the huge dispersion of DNA conductance values found in the literature. PMID:26648400

  10. Conformal inflation coupled to matter

    SciTech Connect

    Brax, Philippe

    2014-05-01

    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.

  11. Parity Doubling and the S Parameter Below the Conformal Window

    SciTech Connect

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

    2011-10-21

    We describe a lattice simulation of the masses and decay constants of the lowest-lying vector and axial resonances, and the electroweak S parameter, in an SU(3) gauge theory with N{sub f} = 2 and 6 fermions in the fundamental representation. The spectrum becomes more parity doubled and the S parameter per electroweak doublet decreases when N{sub f} is increased from 2 to 6, motivating study of these trends as N{sub f} is increased further, toward the critical value for transition from confinement to infrared conformality.

  12. Intrinsic time in Wheeler-DeWitt conformal superspace

    NASA Astrophysics Data System (ADS)

    Pavlov, A. E.; Pervushin, V. N.

    In Geometrodynamics, the York's extrinsic time, constructed of the tensor of extrinsic curvature and the Misner's intrinsic time, built of the spatial metric tensor, coexist. In our paper, we prove the preference of selecting the internal time. To extract the intrinsic time, we generalize the Dirac's mapping of transition to conformal variables. In Friedmann cosmology, the many-fingered intrinsic time obtains a sense of a global time of the Universe. An accounting of metric scalar linear perturbations leads to adding some corrections not dominated to the effective energy density in the Hubble law. The metric vector and tensor perturbations do not influence the internal time in linear approximation.

  13. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation

    NASA Astrophysics Data System (ADS)

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W.; Lin, Jialing; Li, Jianing

    2016-07-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.

  14. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation

    PubMed Central

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W.; Lin, Jialing; Li, Jianing

    2016-01-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation. PMID:27381287

  15. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation.

    PubMed

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W; Lin, Jialing; Li, Jianing

    2016-01-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model - using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation. PMID:27381287

  16. Characterizing Active Site Conformational Heterogeneity along the Trajectory of an Enzymatic Phosphoryl Transfer Reaction.

    PubMed

    Zeymer, Cathleen; Werbeck, Nicolas D; Zimmermann, Sabine; Reinstein, Jochen; Hansen, D Flemming

    2016-09-12

    States along the phosphoryl transfer reaction catalyzed by the nucleoside monophosphate kinase UmpK were captured and changes in the conformational heterogeneity of conserved active site arginine side-chains were quantified by NMR spin-relaxation methods. In addition to apo and ligand-bound UmpK, a transition state analog (TSA) complex was utilized to evaluate the extent to which active site conformational entropy contributes to the transition state free energy. The catalytically essential arginine side-chain guanidino groups were found to be remarkably rigid in the TSA complex, indicating that the enzyme has evolved to restrict the conformational freedom along its reaction path over the energy landscape, which in turn allows the phosphoryl transfer to occur selectively by avoiding side reactions. PMID:27534930

  17. Conformational dynamics in substrate-binding domains influences transport in the ABC importer GlnPQ.

    PubMed

    Gouridis, Giorgos; Schuurman-Wolters, Gea K; Ploetz, Evelyn; Husada, Florence; Vietrov, Ruslan; de Boer, Marijn; Cordes, Thorben; Poolman, Bert

    2015-01-01

    The conformational dynamics in ABC transporters is largely elusive. The ABC importer GlnPQ from Lactococcus lactis has different covalently linked substrate-binding domains (SBDs), thus making it an excellent model system to elucidate the dynamics and role of the SBDs in transport. We demonstrate by single-molecule spectroscopy that the two SBDs intrinsically transit from open to closed ligand-free conformation, and the proteins capture their amino acid ligands via an induced-fit mechanism. High-affinity ligands elicit transitions without changing the closed-state lifetime, whereas low-affinity ligands dramatically shorten it. We show that SBDs in the closed state compete for docking onto the translocator, but remarkably the effect is strongest without ligand. We find that the rate-determining steps depend on the SBD and the amino acid transported. We conclude that the lifetime of the closed conformation controls both SBD docking to the translocator and substrate release.

  18. Conformational Dynamics of the Single Lipopolysaccharide O-Antigen in Solution.

    PubMed

    Galochkina, Tatiana; Zlenko, Dmitry; Nesterenko, Alexey; Kovalenko, Ilya; Strakhovskaya, Marina; Averyanov, Alexander; Rubin, Andrey

    2016-09-19

    The O-antigen is the most variable and highly immunogenic part of the lipopolysaccharide molecule that covers the surface of Gram-negative bacteria and makes up the first line of cellular defense. To provide insight into the details of the O-antigen arrangement on the membrane surface, we simulated its behavior in solution by molecular dynamics. We developed the energetically favorable O-antigen conformation by analyzing free-energy distributions for its disaccharide fragments. Starting from this conformation, we simulated the behavior of the O-antigen chain on long timescales. Depending on the force field and temperature, the single molecule can undergo reversible or irreversible coil-to-globule transitions. The mechanism of these transitions is related either to the rotation of the carbohydrate residues around O-glycosidic bonds or to flips of the pyranose rings. We found that the presence of rhamnose in the O-antigen chain crucially increases its conformational mobility.

  19. Conformational Dynamics of the Single Lipopolysaccharide O-Antigen in Solution.

    PubMed

    Galochkina, Tatiana; Zlenko, Dmitry; Nesterenko, Alexey; Kovalenko, Ilya; Strakhovskaya, Marina; Averyanov, Alexander; Rubin, Andrey

    2016-09-19

    The O-antigen is the most variable and highly immunogenic part of the lipopolysaccharide molecule that covers the surface of Gram-negative bacteria and makes up the first line of cellular defense. To provide insight into the details of the O-antigen arrangement on the membrane surface, we simulated its behavior in solution by molecular dynamics. We developed the energetically favorable O-antigen conformation by analyzing free-energy distributions for its disaccharide fragments. Starting from this conformation, we simulated the behavior of the O-antigen chain on long timescales. Depending on the force field and temperature, the single molecule can undergo reversible or irreversible coil-to-globule transitions. The mechanism of these transitions is related either to the rotation of the carbohydrate residues around O-glycosidic bonds or to flips of the pyranose rings. We found that the presence of rhamnose in the O-antigen chain crucially increases its conformational mobility. PMID:27304860

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

    PubMed

    Oang, Key Young; Kim, Jong Goo; Yang, Cheolhee; Kim, Tae Wu; Kim, Youngmin; Kim, Kyung Hwan; Kim, Jeongho; Ihee, Hyotcherl

    2014-03-01

    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. PMID:24761190

  1. Characterizing Active Site Conformational Heterogeneity along the Trajectory of an Enzymatic Phosphoryl Transfer Reaction

    PubMed Central

    Zeymer, Cathleen; Werbeck, Nicolas D.; Zimmermann, Sabine

    2016-01-01

    Abstract States along the phosphoryl transfer reaction catalyzed by the nucleoside monophosphate kinase UmpK were captured and changes in the conformational heterogeneity of conserved active site arginine side‐chains were quantified by NMR spin‐relaxation methods. In addition to apo and ligand‐bound UmpK, a transition state analog (TSA) complex was utilized to evaluate the extent to which active site conformational entropy contributes to the transition state free energy. The catalytically essential arginine side‐chain guanidino groups were found to be remarkably rigid in the TSA complex, indicating that the enzyme has evolved to restrict the conformational freedom along its reaction path over the energy landscape, which in turn allows the phosphoryl transfer to occur selectively by avoiding side reactions. PMID:27534930

  2. Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase

    PubMed Central

    Sutto, Ludovico; Gervasio, Francesco Luigi

    2013-01-01

    Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are frequently found in many cancers. It has been suggested that changes in the equilibrium between its active and inactive conformations are linked to its oncogenic potential. Here, we quantify the effects of some of the most common single (L858R and T790M) and double (T790M-L858R) oncogenic mutations on the conformational free-energy landscape of the EGFR kinase domain by using massive molecular dynamics simulations together with parallel tempering, metadynamics, and one of the best force-fields available. Whereas the wild-type EGFR catalytic domain monomer is mostly found in an inactive conformation, our results show a clear shift toward the active conformation for all of the mutants. The L858R mutation stabilizes the active conformation at the expense of the inactive conformation and rigidifies the αC-helix. The T790M gatekeeper mutant favors activation by stabilizing a hydrophobic cluster. Finally, T790M with L858R shows a significant positive epistasis effect. This combination not only stabilizes the active conformation, but in nontrivial ways changes the free-energy landscape lowering the transition barriers. PMID:23754386

  3. Conformational selection or induced-fit? A critical appraisal of the kinetic mechanism†

    PubMed Central

    Vogt, Austin D.; Di Cera, Enrico

    2013-01-01

    For almost five decades, two competing mechanisms of ligand recognition – conformational selection and induced-fit - have dominated our interpretation of ligand binding in biological macromolecules. When binding/dissociation events are fast compared to conformational transitions, the rate of approach to equilibrium, kobs, becomes diagnostic of conformational selection or induced-fit based on whether it decreases or increases with the ligand concentration, [L]. However, this simple conclusion based on the rapid-equilibrium approximation is not valid in general. Here we show that conformational selection is associated with a rich repertoire of kinetic properties, with kobs decreasing or increasing with [L] depending on the relative magnitude of the rate of ligand dissociation, koff, and the rate of conformational isomerization, kr. We prove that, even for the simplest two-step mechanism of ligand binding, a decrease of kobs with [L] is unequivocal evidence of conformational selection, but an increase of kobs with [L] is not unequivocal evidence of induced-fit. Ligand binding to glucokinase, thrombin and its precursor prethrombin-2 are used as relevant examples. We conclude that conformational selection as a mechanism for ligand binding to its target may be far more common than currently believed. PMID:22775458

  4. Measuring the mechanical properties of molecular conformers

    NASA Astrophysics Data System (ADS)

    Jarvis, S. P.; Taylor, S.; Baran, J. D.; Champness, N. R.; Larsson, J. A.; Moriarty, P.

    2015-09-01

    Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules.

  5. 40 CFR 93.106 - Content of transportation plans and timeframe of conformity determinations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... timeframe of conformity determinations. 93.106 Section 93.106 Protection of Environment ENVIRONMENTAL..., Programs, and Projects Developed, Funded or Approved Under Title 23 U.S.C. or the Federal Transit Laws § 93... significant project if the project is included in the TIP or the project requires approval before...

  6. Gramicidin conformational studies with mixed-chain unsaturated phospholipid bilayer systems

    SciTech Connect

    Cox, K.J.; Ho, Cojen; Lombardi, J.V.; Stubbs, C.D. )

    1992-02-04

    The transition of gramicidin from a nonchannel to a channel form was investigated using mixed-chain phosphatidylcholine lipid bilayers. Gramicidin and phospholipids were codispersed, after removal of the solvents chloroform/methanol or trifluoroethanol which resulted in nonchannel and channel conformations, respectively, as confirmed using circular dichroism (CD). The fluorescence emission maxima of the nonchannel form were shifted toward shorter wavelengths by heating at 60C (for 0-12 h), which converted it to a channel form, again as confirmed by CD. The channel form did not respond to heat treatment. Heat treatment also increased the fluorescence anisotropy of the nonchannel gramicidin tryptophans. The rate of transition from the nonchannel to channel conformation was found to be faster is phosphatidylethanolamine was present in combination with phosphatidylcholine compared to phosphatidylcholine alone. Using the fluorescence anisotropy of the membrane lipid probe, 1,6-diphenyl-1,3,5-hexatriene, it was also shown that the motional properties of the surrounding lipid acyl chains differed for the channel and nonchannel gramicidin conformations. The possibility that lipids tending to favor the hexagonal phase (H{sub II}) would enhance the rate of the nonchannel to channel transition was supported by {sup 31}P NMR which revealed the presence of some H{sub II} lipids in the channel preparations. The results of this study suggest that gramicidin may serve as a useful model for similar conformational transitions in other more complex membrane proteins.

  7. Photomodulation of conformational states. II. Mono- and bicyclic peptides with (4-aminomethyl)phenylazobenzoic acid as backbone constituent.

    PubMed

    Renner, C; Cramer, J; Behrendt, R; Moroder, L

    2000-12-01

    It has been reported that backbone cyclization of octapeptides with the photoresponsive (4-aminomethyl)phenylazobenzoic acid imparts sufficient restraints to induce and stabilize ordered conformations of the peptide backbone in both the cis- and trans-azo-isomers (L. Ulysse, J. Cubillos, and J. Chmielewski, Journal of the American Chemical Society, 1995, Vol. 117, pp. 8466-8467). Correspondingly, the active-site octapeptide fragment H-Ala-Cys-Ala-Thr-Cys-Asp-Gly-Phe-OH [134-141] of thioredoxin reductase, with its high preference for a 3(10)-helix turn conformation centered on the Thr-Cys sequence, was backbone cyclized with this azobenzene moiety in the attempt to design a photoresponsive system where the conformational states of the peptide backbone are dictated by the configuration of the azobenzene and can be further modulated by the disulfide bridge. Nuclear magnetic resonance conformational analysis of the monocyclic compound clearly revealed the presence of two conformational families in both the cis- and trans-azo configuration. Of the higher populated conformational families, the structure of the trans-isomer seems like a pretzel-like folding, while the cis-isomer relaxes into a significantly less defined conformational state that does not exhibit any regular structural elements. Further restrictions imparted by disulfide bridging of the peptide moiety leads to an even better defined conformation for the trans-azo-isomer, whereas the cis-isomer can be described as a frustrated system without pronounced energy minima and thus with little conformational preferences. Our findings would suggest that this photoresponsive peptide template may not be of general usefulness for light-induced conformational transitions between two well-defined conformational states at least under the experimental conditions employed, even in the bicyclic form. However, trans --> cis isomerization of the bicyclic peptide is accompanied by a switch from a well-defined conformation to

  8. Conformal Electromagnetic Particle in Cell: A Review

    SciTech Connect

    Meierbachtol, Collin S.; Greenwood, Andrew D.; Verboncoeur, John P.; Shanker, Balasubramaniam

    2015-10-26

    We review conformal (or body-fitted) electromagnetic particle-in-cell (EM-PIC) numerical solution schemes. Included is a chronological history of relevant particle physics algorithms often employed in these conformal simulations. We also provide brief mathematical descriptions of particle-tracking algorithms and current weighting schemes, along with a brief summary of major time-dependent electromagnetic solution methods. Several research areas are also highlighted for recommended future development of new conformal EM-PIC methods.

  9. Terbium luminescence-lifetime heterogeneity and protein equilibrium conformational dynamics.

    PubMed Central

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

    1987-01-01

    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. PMID:3470740

  10. Conformal frame dependence of inflation

    SciTech Connect

    Domènech, Guillem; Sasaki, Misao E-mail: misao@yukawa.kyoto-u.ac.jp

    2015-04-01

    Physical equivalence between different conformal frames in scalar-tensor theory of gravity is a known fact. However, assuming that matter minimally couples to the metric of a particular frame, which we call the matter Jordan frame, the matter point of view of the universe may vary from frame to frame. Thus, there is a clear distinction between gravitational sector (curvature and scalar field) and matter sector. In this paper, focusing on a simple power-law inflation model in the Einstein frame, two examples are considered; a super-inflationary and a bouncing universe Jordan frames. Then we consider a spectator curvaton minimally coupled to a Jordan frame, and compute its contribution to the curvature perturbation power spectrum. In these specific examples, we find a blue tilt at short scales for the super-inflationary case, and a blue tilt at large scales for the bouncing case.

  11. Conformal approach to cylindrical DLA

    NASA Astrophysics Data System (ADS)

    Taloni, A.; Caglioti, E.; Loreto, V.; Pietronero, L.

    2006-09-01

    We extend the conformal mapping approach elaborated for the radial diffusion limited aggregation model (DLA) to cylindrical geometry. We introduce in particular a complex function which allows a cylindrical cluster to be grown using as an intermediate step a radial aggregate. The aggregate grown exhibits the same self-affine features as the original cylindrical DLA. The specific choice of the transformation allows us to study the relationship between the radial and the cylindrical geometry. In particular the cylindrical aggregate can be seen as a radial aggregate with particles of size increasing with the radius. On the other hand, the radial aggregate can be seen as a cylindrical aggregate with particles of size decreasing with the height. This framework, which shifts the point of view from the geometry to the size of the particles, can open the way to more quantitative studies on the relationship between radial and cylindrical DLA.

  12. Conformable eddy current array delivery

    NASA Astrophysics Data System (ADS)

    Summan, Rahul; Pierce, Gareth; Macleod, Charles; Mineo, Carmelo; Riise, Jonathan; Morozov, Maxim; Dobie, Gordon; Bolton, Gary; Raude, Angélique; Dalpé, Colombe; Braumann, Johannes

    2016-02-01

    The external surface of stainless steel containers used for the interim storage of nuclear material may be subject to Atmospherically Induced Stress Corrosion Cracking (AISCC). The inspection of such containers poses a significant challenge due to the large quantities involved; therefore, automating the inspection process is of considerable interest. This paper reports upon a proof-of-concept project concerning the automated NDT of a set of test containers containing artificially generated AISCCs. An Eddy current array probe with a conformable padded surface from Eddyfi was used as the NDT sensor and end effector on a KUKA KR5 arc HW robot. A kinematically valid cylindrical raster scan path was designed using the KUKA|PRC path planning software. Custom software was then written to interface measurement acquisition from the Eddyfi hardware with the motion control of the robot. Preliminary results and analysis are presented from scanning two canisters.

  13. Approaching Conformality with Ten Flavors

    SciTech Connect

    Appelquist, Thomas; Brower, Richard C.; Buchoff, Michael I.; Cheng, Michael; Cohen, Saul D.; Fleming, George T.; Kiskis, Joe; Lin, Meifeng; Na, Heechang; Neil, Ethan T.; Osborn, James C.

    2012-04-01

    We present first results for lattice simulations, on a single volume, of the low-lying spectrum of an SU(3) Yang-Mills gauge theory with N{sub f} = 10 light fermions in the fundamental representation. Fits to the fermion mass dependence of various observables are found to be globally consistent with the hypothesis that this theory is within or just outside the strongly-coupled edge of the conformal window, with mass anomalous dimension {gamma}* {approx} 1 over the range of scales simulated. We stress that we cannot rule out the possibility of spontaneous chiral-symmetry breaking at scales well below our infrared cutoff. We discuss important systematic effects, including finite-volume corrections, and consider directions for future improvement.

  14. Electromagnetic characterization of conformal antennas

    NASA Technical Reports Server (NTRS)

    Volakis, John L.; Kempel, Leo C.; Alexanian, Angelos; Jin, J. M.; Yu, C. L.; Woo, Alex C.

    1992-01-01

    The ultimate objective of this project is to develop a new technique which permits an accurate simulation of microstrip patch antennas or arrays with various feed, superstrate and/or substrate configurations residing in a recessed cavity whose aperture is planar, cylindrical or otherwise conformed to the substructure. The technique combines the finite element and boundary integral methods to formulate a system suitable for solution via the conjugate gradient method in conjunction with the fast Fourier transform. The final code is intended to compute both scattering and radiation patterns of the structure with an affordable memory demand. With upgraded capabilities, the four included papers examined the radar cross section (RCS), input impedance, gain, and resonant frequency of several rectangular configurations using different loading and substrate/superstrate configurations.

  15. Rotational Spectroscopy Unveils Eleven Conformers of Adrenaline

    NASA Astrophysics Data System (ADS)

    Cabezas, C.; Cortijo, V.; Mata, S.; Lopez, J. C.; Alonso, J. L.

    2013-06-01

    Recent improvements in our LA-MB-FTMW instrumentation have allowed the characterization of eleven and eight conformers for the neurotransmitters adrenaline and noradrenaline respectively. The observation of this rich conformational behavior is in accordance with the recent observation of seven conformers for dopamine and in sharp contrast with the conformational reduction proposed for catecholamines. C. Cabezas, I. Peña, J. C. López, J. L. Alonso J. Phys. Chem. Lett. 2013, 4, 486. H. Mitsuda, M. Miyazaki, I. B. Nielsen, P. Carcabal,C. Dedonder, C. Jouvet, S. Ishiuchi, M. Fujii J. Phys. Chem. Lett. 2010, 1, 1130.

  16. Pyrrolidine nucleotide analogs with a tunable conformation

    PubMed Central

    Poštová Slavětínská, Lenka; Rejman, Dominik

    2014-01-01

    Summary Conformational preferences of the pyrrolidine ring in nucleotide analogs 7–14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle. PMID:25246956

  17. Fabrication challenges associated with conformal optics

    NASA Astrophysics Data System (ADS)

    Schaefer, John; Eichholtz, Richard A.; Sulzbach, Frank C.

    2001-09-01

    A conformal optic is typically an optical window that conforms smoothly to the external shape of a system platform to improve aerodynamics. Conformal optics can be on-axis, such as an ogive missile dome, or off-axis, such as in a free form airplane wing. A common example of conformal optics is the automotive head light window that conforms to the body of the car aerodynamics and aesthetics. The unusual shape of conformal optics creates tremendous challenges for design, manufacturing, and testing. This paper will discuss fabrication methods that have been successfully demonstrated to produce conformal missile domes and associated wavefront corrector elements. It will identify challenges foreseen with more complex free-form configurations. Work presented in this paper was directed by the Precision Conformal Optics Consortium (PCOT). PCOT is comprised of both industrial and academic members who teamed to develop and demonstrate conformal optical systems suitable for insertion into future military programs. The consortium was funded under DARPA agreement number MDA972-96-9-08000.

  18. Dissecting Protein Configurational Entropy into Conformational and Vibrational Contributions.

    PubMed

    Chong, Song-Ho; Ham, Sihyun

    2015-10-01

    Quantifying how the rugged nature of the underlying free-energy landscape determines the entropic cost a protein must incur upon folding and ligand binding is a challenging problem. Here, we present a novel computational approach that dissects the protein configurational entropy on the basis of the classification of protein dynamics on the landscape into two separate components: short-term vibrational dynamics related to individual free-energy wells and long-term conformational dynamics associated with transitions between wells. We apply this method to separate the configurational entropy of the protein villin headpiece subdomain into its conformational and vibrational components. We find that the change in configurational entropy upon folding is dominated by the conformational entropy despite the fact that the magnitude of the vibrational entropy is the significantly larger component in each of the folded and unfolded states, which is in accord with the previous empirical estimations. The straightforward applicability of our method to unfolded proteins promises a wide range of applications, including those related to intrinsically disordered proteins.

  19. Conformational Dynamics of o-Fluoro-Substituted Z-Azobenzene.

    PubMed

    Rastogi, S K; Rogers, R A; Shi, J; Gao, C; Rinaldi, P L; Brittain, W J

    2015-11-20

    A conformational analysis of o-fluoro Z-azobenzene reveals a slight preference for aromatic C-F/π interaction. Density functional theory (DFT) indicates that the conformation with a C-F/π interaction is preferred by approximately 0.3-0.5 kcal/mol. Ground-state conformations were corroborated with X-ray crystallography. (Z)-Azobenzene (Z-AB) with at least one o-fluoro per ring displays (19)F-(19)F through-space (TS) coupling. 2D J-resolved NMR was used to distinguish through-bond from TS coupling ((TS)JFF). (TS)JFF decreases as the temperature is lowered and the multiplets coalesce into broad singlets. We hypothesize that the coalescence temperature (Tc) corresponds to the barrier for phenyl rotation. The experimentally determined barrier of 8-10 kcal/mol has been qualitatively verified by DFT where transition states with a bisected geometry were identified with zero-point energies of 6-9 kcal/mol relative to ground state. These values are significantly higher that values estimated from previous theoretical studies but lie within a reasonable range for phenyl rotation in hydrocarbon systems.

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

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

    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.

  1. Conformational equilibria and large-amplitude motions in dimers of carboxylic acids: rotational spectrum of acetic acid-difluoroacetic acid.

    PubMed

    Gou, Qian; Feng, Gang; Evangelisti, Luca; Caminati, Walther

    2014-10-01

    We report the rotational spectra of two conformers of the acetic acid-difluoroacetic acid adduct (CH3COOH-CHF2COOH) and supply information on its internal dynamics. The two conformers differ from each other, depending on the trans or gauche orientation of the terminal -CHF2 group. Both conformers display splittings of the rotational transitions, due to the internal rotation of the methyl group of acetic acid. The corresponding barriers are determined to be V3(trans)=99.8(3) and V3(gauche)=90.5(9) cm(-1) (where V3 is the methyl rotation barrier height). The gauche form displays a further doubling of the rotational transitions, due to the tunneling motion of the -CHF2 group between its two equivalent conformations. The corresponding B2 barrier is estimated to be 108(2) cm(-1). The increase in the distance between the two monomers upon OH→OD deuteration (the Ubbelohde effect) is determined.

  2. Transitional Care

    ERIC Educational Resources Information Center

    Naylor, Mary; Keating, Stacen A.

    2008-01-01

    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…

  3. Newborn transition.

    PubMed

    Graves, Barbara W; Haley, Mary Mumford

    2013-01-01

    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.

  4. Conformational readout of RNA by small ligands

    PubMed Central

    Kligun, Efrat; Mandel-Gutfreund, Yael

    2013-01-01

    RNA molecules have highly versatile structures that can fold into myriad conformations, providing many potential pockets for binding small molecules. The increasing number of available RNA structures, in complex with proteins, small ligands and in free form, enables the design of new therapeutically useful RNA-binding ligands. Here we studied RNA ligand complexes from 10 RNA groups extracted from the protein data bank (PDB), including adaptive and non-adaptive complexes. We analyzed the chemical, physical, structural and conformational properties of binding pockets around the ligand. Comparing the properties of ligand-binding pockets to the properties of computed pockets extracted from all available RNA structures and RNA-protein interfaces, revealed that ligand-binding pockets, mainly the adaptive pockets, are characterized by unique properties, specifically enriched in rare conformations of the nucleobase and the sugar pucker. Further, we demonstrate that nucleotides possessing the rare conformations are preferentially involved in direct interactions with the ligand. Overall, based on our comprehensive analysis of RNA-ligand complexes, we suggest that the unique conformations adopted by RNA nucleotides play an important role in RNA recognition by small ligands. We term the recognition of a binding site by a ligand via the unique RNA conformations “RNA conformational readout.” We propose that “conformational readout” is a general way by which RNA binding pockets are recognized and selected from an ensemble of different RNA states. PMID:23618839

  5. Conformational Sampling of Peptides in Cellular Environments☆

    PubMed Central

    Tanizaki, Seiichiro; Clifford, Jacob; Connelly, Brian D.; Feig, Michael

    2008-01-01

    Abstract Biological systems provide a complex environment that can be understood in terms of its dielectric properties. High concentrations of macromolecules and cosolvents effectively reduce the dielectric constant of cellular environments, thereby affecting the conformational sampling of biomolecules. To examine this effect in more detail, the conformational preference of alanine dipeptide, poly-alanine, and melittin in different dielectric environments is studied with computer simulations based on recently developed generalized Born methodology. Results from these simulations suggest that extended conformations are favored over α-helical conformations at the dipeptide level at and below dielectric constants of 5–10. Furthermore, lower-dielectric environments begin to significantly stabilize helical structures in poly-alanine at ɛ = 20. In the more complex peptide melittin, different dielectric environments shift the equilibrium between two main conformations: a nearly fully extended helix that is most stable in low dielectrics and a compact, V-shaped conformation consisting of two helices that is preferred in higher dielectric environments. An additional conformation is only found to be significantly populated at intermediate dielectric constants. Good agreement with previous studies of different peptides in specific, less-polar solvent environments, suggest that helix stabilization and shifts in conformational preferences in such environments are primarily due to a reduced dielectric environment rather than specific molecular details. The findings presented here make predictions of how peptide sampling may be altered in dense cellular environments with reduced dielectric response. PMID:17905846

  6. 40 CFR 52.938 - General conformity.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Implementation Plan (SIP). The Commonwealth of Kentucky incorporated by reference regulations 40 CFR part 51... 40 Protection of Environment 3 2010-07-01 2010-07-01 false General conformity. 52.938 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Kentucky § 52.938 General conformity. The...

  7. 14 CFR 17.45 - Conforming amendments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Conforming amendments. 17.45 Section 17.45 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PROCEDURAL RULES PROCEDURES FOR PROTESTS AND CONTRACTS DISPUTES Finality and Review § 17.45 Conforming amendments. The...

  8. Conformity to Peer Pressure in Preschool Children

    ERIC Educational Resources Information Center

    Haun, Daniel B. M.; Tomasello, Michael

    2011-01-01

    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…

  9. Regulatory Conformance Checking: Logic and Logical Form

    ERIC Educational Resources Information Center

    Dinesh, Nikhil

    2010-01-01

    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…

  10. CCProf: exploring conformational change profile of proteins

    PubMed Central

    Chang, Che-Wei; Chou, Chai-Wei; Chang, Darby Tien-Hao

    2016-01-01

    In many biological processes, proteins have important interactions with various molecules such as proteins, ions or ligands. Many proteins undergo conformational changes upon these interactions, where regions with large conformational changes are critical to the interactions. This work presents the CCProf platform, which provides conformational changes of entire proteins, named conformational change profile (CCP) in the context. CCProf aims to be a platform where users can study potential causes of novel conformational changes. It provides 10 biological features, including conformational change, potential binding target site, secondary structure, conservation, disorder propensity, hydropathy propensity, sequence domain, structural domain, phosphorylation site and catalytic site. All these information are integrated into a well-aligned view, so that researchers can capture important relevance between different biological features visually. The CCProf contains 986 187 protein structure pairs for 3123 proteins. In addition, CCProf provides a 3D view in which users can see the protein structures before and after conformational changes as well as binding targets that induce conformational changes. All information (e.g. CCP, binding targets and protein structures) shown in CCProf, including intermediate data are available for download to expedite further analyses. Database URL: http://zoro.ee.ncku.edu.tw/ccprof/ PMID:27016699

  11. Technidilaton at the conformal edge

    SciTech Connect

    Hashimoto, Michio; Yamawaki, Koichi

    2011-01-01

    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

  12. Technidilaton at the conformal edge

    NASA Astrophysics Data System (ADS)

    Hashimoto, Michio; Yamawaki, Koichi

    2011-01-01

    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 ⟨θμμ⟩ and to the technigluon condensate ⟨αGμν2⟩, 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 α replaced by the two-loop running coupling α(μ) having the Caswell-Banks-Zaks infrared fixed point α*: α(μ)≃α=α* for the infrared region m<μ<ΛTC, where ΛTC is the intrinsic scale (analogue of ΛQCD of QCD) relevant to the perturbative scale anomaly. We find that -⟨θμμ⟩/m4→const≠0 and ⟨αGμν2⟩/m4→(α/αcr-1)-3/2→∞ in the criticality limit m/ΛTC˜exp⁡(-π/(α/αcr-1)1/2)→0 (α=α*↘αcr, or Nf↗Nfcr) (“conformal edge”). Our result precisely reproduces the formal identity ⟨θμμ⟩=(β(α)/4α2)⟨αGμν2⟩, where β(α)=ΛTC(∂α)/(∂ΛTC)=-(2αcr/π)·(α/αcr-1)3/2 is the nonperturbative beta function corresponding to the above essential singularity scaling of m/ΛTC. Accordingly, the partially conserved dilatation current implies (MTD/m)2(FTD/m)2=-4⟨θμμ⟩/m4→const≠0 at criticality limit, where MTD is the mass of TD and FTD the decay constant of TD. We thus conclude that at criticality limit the TD could become a “true (massless) Nambu-Goldstone boson” MTD/m→0, only when m/FTD→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.

  13. Temperature dependence of the 31P chemical shifts of nucleic acids. A prode of phosphate ester torsional conformations.

    PubMed

    Gorenstein, D G; Findlay, J B; Momii, R K; Luxon, B A; Kar, D

    1976-08-24

    The temperature dependence of the 31P chemical shifts of the ribodinucleoside monophosphates, ApA, GpC, CpC, UpU, and ApU, of the deoxyribonucleic acids, d-ApT, TpT, d-ApA, and d-pApT, and of the homopolyribonucleic acids poly(G), poly(U), poly(A) is shown to provide information on the helix-coli transition in nucleic acids. The base stacked, helical structure with a gauche,gauche phosphate ester torsional conformation is 0.2-0.6 ppm upfield from the random coil conformation. In contrast, the 31P chemical shifts of dimethyl and diethyl phosphate do not change significantly with temperature. These results support our earlier hypothesis that 31P shifts are sensitive probes of torsional conformations with phosphate esters in gauche,gauche conformations having 31P shifts upfield from nongauche conformations.

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

    NASA Technical Reports Server (NTRS)

    Hofer, Richard R. (Inventor)

    2013-01-01

    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.

  15. Superintegrability of d-Dimensional Conformal Blocks.

    PubMed

    Isachenkov, Mikhail; Schomerus, Volker

    2016-08-12

    We observe that conformal blocks of scalar four-point functions in a d-dimensional conformal field theory can be mapped to eigenfunctions of a two-particle hyperbolic Calogero-Sutherland Hamiltonian. The latter describes two coupled Pöschl-Teller particles. Their interaction, whose strength depends smoothly on the dimension d, is known to be superintegrable. Our observation enables us to exploit the rich mathematical literature on Calogero-Sutherland models in deriving various results for conformal field theory. These include an explicit construction of conformal blocks in terms of Heckman-Opdam hypergeometric functions. We conclude with a short outlook, in particular, on the consequences of integrability for the theory of conformal blocks. PMID:27563949

  16. Performance of Conformable Ablators in Aerothermal Environments

    NASA Technical Reports Server (NTRS)

    Thornton, J.; Fan, W.; Skokova, K.; Stackpoole, M.; Beck, R.; Chavez-Garcia, J.

    2012-01-01

    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.

  17. Superintegrability of d -Dimensional Conformal Blocks

    NASA Astrophysics Data System (ADS)

    Isachenkov, Mikhail; Schomerus, Volker

    2016-08-01

    We observe that conformal blocks of scalar four-point functions in a d -dimensional conformal field theory can be mapped to eigenfunctions of a two-particle hyperbolic Calogero-Sutherland Hamiltonian. The latter describes two coupled Pöschl-Teller particles. Their interaction, whose strength depends smoothly on the dimension d , is known to be superintegrable. Our observation enables us to exploit the rich mathematical literature on Calogero-Sutherland models in deriving various results for conformal field theory. These include an explicit construction of conformal blocks in terms of Heckman-Opdam hypergeometric functions. We conclude with a short outlook, in particular, on the consequences of integrability for the theory of conformal blocks.

  18. Vibrational and vibronic spectra of tryptamine conformers

    NASA Astrophysics Data System (ADS)

    Mayorkas, Nitzan; Bernat, Amir; Izbitski, Shay; Bar, Ilana

    2013-03-01

    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.

  19. Dolastatin 11 conformations, analogues and pharmacophore.

    PubMed

    Ali, Md Ahad; Bates, Robert B; Crane, Zackary D; Dicus, Christopher W; Gramme, Michelle R; Hamel, Ernest; Marcischak, Jacob; Martinez, David S; McClure, Kelly J; Nakkiew, Pichaya; Pettit, George R; Stessman, Chad C; Sufi, Bilal A; Yarick, Gayle V

    2005-07-01

    Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.

  20. Conformational implications of asparagine-linked glycosylation.

    PubMed Central

    Imperiali, B; Rickert, K W

    1995-01-01

    The effects of cotranslational protein modification on the process of protein folding are poorly understood. Time-resolved fluorescence energy transfer has been used to assess the impact of glycosylation on the conformational dynamics of flexible oligopeptides. The peptide sequences examined are selected from glycoproteins of known three-dimensional structure. The energy transfer modulation associated with N-linked glycosylation is consistent with the glycopeptides sampling different conformational profiles in water. Results show that glycosylation causes the modified peptides to adopt a different ensemble of conformations, and for some peptides this change may lead to conformations that are more compact and better approximate the conformation of these peptides in the final folded protein. This result further implies that cotranslational glycosylation can trigger the timely formation of structural nucleation elements and thus assist in the complex process of protein folding. PMID:7816856

  1. Protein biosynthesis with conformationally restricted amino acids

    SciTech Connect

    Mendel, D. Lawrence Berkeley Lab., CA ); Ellman, J.; Schultz, P.G. )

    1993-05-19

    The incorporation of conformationally constrained amino acids into peptides is a powerful approach for generating structurally defined peptides as conformational probes and bioactive agents. The ability to site-specifically introduce constrained amino acids into large polypeptide chains would provide a similar opportunity to probe the flexibility, conformation, folding and stability of proteins. To this end, we have examined the competence of the Escherichia coli protein biosynthetic machinery to incorporate a number of these unnatural amino acids into the 164 residue protein T4 lysozyme (T4L). Results clearly demonstrate that the protein biosynthetic machinery can accommodate a wide variety of conformationally constrained amino acids. The expansion of structural motifs that can be biosynthetically incorporated into proteins to include a large number of conformationally constrained amino acids significantly increases the power of mutagenesis methods as probes of protein structure and function and provides additional insights into the steric requirements of the translational machinery. 13 refs., 2 figs.

  2. Conformational changes in human serum albumin induced by sodium perfluorooctanoate in aqueous solutions.

    PubMed

    Messina, Paula V; Prieto, Gerardo; Ruso, Juan M; Sarmiento, Félix

    2005-08-18

    Conformational changes in the bulk solution and at the air-aqueous interface of human serum albumin (HSA) induced by changes in concentration of sodium perfluorooctanoate (C(7)F(15)COO(-)Na(+)) were studied by difference spectroscopy, zeta-potential data, and axisymmetric drop shape analysis. zeta-potential was used to monitor the formation of the HSA-C(7)F(15)COO(-)Na(+) complex and the surface charge of the complex. The conformational transition of HSA in the bulk solution was followed as a function of denaturant concentration by absorbance measurements at 280 nm. The data were analyzed to obtain values for the Gibbs energies of the transition in water (DeltaG(0)(W)) and in a hydrophobic environment (DeltaG(0)(hc)) pertaining to saturated protein-surfactant complexes. The conformational changes that surfactants induce in HSA molecules alter its absorption behavior at the air-water interface. Dynamic surface measurements were used to evaluate this behavior. At low [C(7)F(15)COO(-)Na(+)], proteins present three adsorption regimes: induction time, monolayer saturation, and interfacial gelation. When surfactant concentration increases and conformational changes in the bulk solution occur, the adsorption regimes disappear. HSA molecules in an intermediate conformational state migrate to the air-water interface and form a unique monolayer. At high [C(7)F(15)COO(-)Na(+)], the adsorption of denatured molecules exhibits a behavior analogous to that of dilute solutions.

  3. Mapping the temperature-dependent conformational landscapes of the dynamic enzymes cyclophilin A and urease

    NASA Astrophysics Data System (ADS)

    Thorne, Robert; Keedy, Daniel; Warkentin, Matthew; Fraser, James; Moreau, David; Atakisi, Hakan; Rau, Peter

    Proteins populate complex, temperature-dependent ensembles of conformations that enable their function. Yet in X-ray crystallographic studies, roughly 98% of structures have been determined at 100 K, and most refined to only a single conformation. A combination of experimental methods enabled by studies of ice formation and computational methods for mining low-density features in electron density maps have been applied to determine the evolution of the conformational landscapes of the enzymes cyclophilin A and urease between 300 K and 100 K. Minority conformations of most side chains depopulate on cooling from 300 to ~200 K, below which subsequent conformational evolution is quenched. The characteristic temperatures for this depopulation are highly heterogeneous throughout each enzyme. The temperature-dependent ensemble of the active site flap in urease has also been mapped. These all-atom, site-resolved measurements and analyses rule out one interpretation of the protein-solvent glass transition, and give an alternative interpretation of a dynamical transition identified in site-averaged experiments. They demonstrate a powerful approach to structural characterization of the dynamic underpinnings of protein function. Supported by NSF MCB-1330685.

  4. Conforming Morse-Smale Complexes

    SciTech Connect

    Gyulassy, Attila; Gunther, David; Levine, Joshua A.; Tierny, Julien; Pascucci, Valerio

    2014-08-11

    Morse-Smale (MS) complexes have been gaining popularity as a tool for feature-driven data analysis and visualization. However, the quality of their geometric embedding and the sole dependence on the input scalar field data can limit their applicability when expressing application-dependent features. In this paper we introduce a new combinatorial technique to compute an MS complex that conforms to both an input scalar field and an additional, prior segmentation of the domain. The segmentation constrains the MS complex computation guaranteeing that boundaries in the segmentation are captured as separatrices of the MS complex. We demonstrate the utility and versatility of our approach with two applications. First, we use streamline integration to determine numerically computed basins/mountains and use the resulting segmentation as an input to our algorithm. This strategy enables the incorporation of prior flow path knowledge, effectively resulting in an MS complex that is as geometrically accurate as the employed numerical integration. Our second use case is motivated by the observation that often the data itself does not explicitly contain features known to be present by a domain expert. We introduce edit operations for MS complexes so that a user can directly modify their features while maintaining all the advantages of a robust topology-based representation.

  5. Conforming Morse-Smale Complexes.

    PubMed

    Gyulassy, Attila; Günther, David; Levine, Joshua A; Tierny, Julien; Pascucci, Valerio

    2014-12-01

    Morse-Smale (MS) complexes have been gaining popularity as a tool for feature-driven data analysis and visualization. However, the quality of their geometric embedding and the sole dependence on the input scalar field data can limit their applicability when expressing application-dependent features. In this paper we introduce a new combinatorial technique to compute an MS complex that conforms to both an input scalar field and an additional, prior segmentation of the domain. The segmentation constrains the MS complex computation guaranteeing that boundaries in the segmentation are captured as separatrices of the MS complex. We demonstrate the utility and versatility of our approach with two applications. First, we use streamline integration to determine numerically computed basins/mountains and use the resulting segmentation as an input to our algorithm. This strategy enables the incorporation of prior flow path knowledge, effectively resulting in an MS complex that is as geometrically accurate as the employed numerical integration. Our second use case is motivated by the observation that often the data itself does not explicitly contain features known to be present by a domain expert. We introduce edit operations for MS complexes so that a user can directly modify their features while maintaining all the advantages of a robust topology-based representation.

  6. Conformal Higgs, or Techni-Dilaton -- Composite Higgs Near Conformality

    NASA Astrophysics Data System (ADS)

    Yamawaki, Koichi

    2011-01-01

    In contrast to the folklore that Technicolor (TC) is a "Higgsless theory", we shall discuss existence of a composite Higgs boson, Techni-Dilaton (TD), a pseudo-Nambu-Goldstone boson of the scale invariance in the Scale-invariant/Walking/Conformal TC (SWC TC) which generates a large anomalous dimension γm ≃ 1 in a wide region from the dynamical mass m = {O} ({TeV}) of the techni-fermion all the way up to the intrinsic scale ΛTC of the SWC TC (analogue of ΛQCD), where ΛTC is taken typically as the scale of the Extended TC scale ΛETC: ΛTC ≃ ΛETC 103 TeV (≫ m). All the techni-hadrons have mass on the same order {O}(m), which in SWC TC is extremely smaller than the intrinsic scale ΛTC ≃ ΛETC, in sharp contrast to QCD where both are of the same order. The mass of TD arises from the non-perturbative scale anomaly associated with the techni-fermion mass generation and is typically 500-600 GeV, even smaller than other techni-hadrons of the same order of {O}(m), in another contrast to QCD which is believed to have no scalar bar qq bound state lighter than other hadrons. We discuss the TD mass in various methods, Gauged NJL model via ladder Schwinger-Dyson (SD) equation, straightforward calculations in the ladder SD/ Bethe-Salpeter equation, and the holographic approach including techni-gluon condensate. The TD may be discovered in LHC.

  7. Dimerization transitions in spin-1 chains

    NASA Astrophysics Data System (ADS)

    Chepiga, Natalia; Affleck, Ian; Mila, Frédéric

    2016-06-01

    We study spontaneous dimerization transitions in a Heisenberg spin-1 chain with additional next-nearest-neighbor and three-site interactions using extensive numerical simulations and a conformal field-theory analysis. We show that the transition can be second order in the Wess-Zumino-Witten (WZW) SU (2) 2 or Ising universality class, or first order. We argue that these features are generic because of a marginal operator in the WZW SU (2) 2 model and because of two topologically distinct nondimerized phases with or without edge states. We also provide explicit numerical evidence of conformal towers of singlets inside the spin gap at the Ising transition. Implications for other models are briefly discussed.

  8. Perceived Symbols of Authority and Their Influence on Conformity.

    ERIC Educational Resources Information Center

    Bushman, Brad J.

    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%…

  9. 47 CFR 2.1072 - Limitation on Declaration of Conformity.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Limitation on Declaration of Conformity. 2.1072... Conformity § 2.1072 Limitation on Declaration of Conformity. (a) The Declaration of Conformity signifies that...'s rules. (b) A Declaration of Conformity by the responsible party is effective until a...

  10. Conformational Changes Underlying Desensitization of the Pentameric Ligand-gated Ion Channel ELIC

    PubMed Central

    Kinde, Monica N.; Chen, Qiang; Lawless, Matthew J.; Mowrey, David D.; Xu, Jiawei; Saxena, Sunil; Xu, Yan; Tang, Pei

    2015-01-01

    SUMMARY Structural rearrangements underlying functional transitions of pentameric ligand-gated ion channels (pLGICs) are not fully understood. Using 19F NMR and ESR spectroscopy, we found that ELIC, a pLGIC from Erwinia chrysanthemi, expanded the extracellular end and contracted the intracellular end of its pore during transition from the resting to an apparent desensitized state. Importantly, the contraction at the intracellular end of the pore likely forms a gate to restrict ion transport in the desensitized state. This gate differs from the hydrophobic gate present in the resting state. Conformational changes of the TM2-TM3 loop were limited to the N-terminal end. The TM4 helices and the TM3-TM4 loop appeared relatively insensitive to agonist-mediated structural rearrangement. These results indicate that conformational changes accompanying functional transitions are not uniform among different ELIC regions. This work also revealed the co-existence of multiple conformations for a given state and suggested asymmetric conformational arrangements in a homomeric pLGIC. PMID:25960405

  11. Direct Neutron Scattering Measurements of Grafted Polymer Chain Conformations from Functionalized Nanoparticles

    NASA Astrophysics Data System (ADS)

    Hore, Michael J. A.; Hammouda, Boualem

    2014-03-01

    The conformations of grafted polymers play an important role in determining the physical properties of polymer nanocomposites. Small-angle neutron scattering (SANS) is performed to quantify the conformation of poly(methyl methacrylate)(Mw > 27,000 g/mol) and polystyrene chains (Mw > 57,000 g/mol) which are attached to iron oxide nanoparticles (Rnp = 2 . 5 nm, σ = 0 . 73 chains/nm2) and small fractal aggregates (R ~ 11 nm, σ = 0 . 2 chains/nm2), respectively. Unlike light scattering or microscopy, SANS can directly measure the grafted polymer chain conformations. In a homopolymer melt, we find the grafted chains adopt stretched conformations near the nanoparticle surface, and transition to ideal, random coils past a cutoff distance rc, in agreement with scaling arguments in the literature. We find the conformation of the polymer chains is largely unaffected by the ratio of the degree of polymerization of the matrix (P) to that of the brush (N). Finally, we extend this work to measure grafted polymer conformation in solution as a function of solvent quality, and find the grafted chains behave as swollen coils with an excluded volume parameter ν that decreases as the solvent cools to the Θ temperature.

  12. Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin.

    PubMed Central

    Caves, L. S.; Evanseck, J. D.; Karplus, M.

    1998-01-01

    Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory. PMID:9541397

  13. Conformational landscapes of DNA polymerase I and mutator derivatives establish fidelity checkpoints for nucleotide insertion.

    PubMed

    Hohlbein, Johannes; Aigrain, Louise; Craggs, Timothy D; Bermek, Oya; Potapova, Olga; Shoolizadeh, Pouya; Grindley, Nigel D F; Joyce, Catherine M; Kapanidis, Achillefs N

    2013-01-01

    The fidelity of DNA polymerases depends on conformational changes that promote the rejection of incorrect nucleotides before phosphoryl transfer. Here, we combine single-molecule FRET with the use of DNA polymerase I and various fidelity mutants to highlight mechanisms by which active-site side chains influence the conformational transitions and free-energy landscape that underlie fidelity decisions in DNA synthesis. Ternary complexes of high fidelity derivatives with complementary dNTPs adopt mainly a fully closed conformation, whereas a conformation with a FRET value between those of open and closed is sparsely populated. This intermediate-FRET state, which we attribute to a partially closed conformation, is also predominant in ternary complexes with incorrect nucleotides and, strikingly, in most ternary complexes of low-fidelity derivatives for both correct and incorrect nucleotides. The mutator phenotype of the low-fidelity derivatives correlates well with reduced affinity for complementary dNTPs and highlights the partially closed conformation as a primary checkpoint for nucleotide selection.

  14. ClustENM: ENM-Based Sampling of Essential Conformational Space at Full Atomic Resolution

    PubMed Central

    Kurkcuoglu, Zeynep; Bahar, Ivet; Doruker, Pemra

    2016-01-01

    Accurate sampling of conformational space and, in particular, the transitions between functional substates has been a challenge in molecular dynamic (MD) simulations of large biomolecular systems. We developed an Elastic Network Model (ENM)-based computational method, ClustENM, for sampling large conformational changes of biomolecules with various sizes and oligomerization states. ClustENM is an iterative method that combines ENM with energy minimization and clustering steps. It is an unbiased technique, which requires only an initial structure as input, and no information about the target conformation. To test the performance of ClustENM, we applied it to six biomolecular systems: adenylate kinase (AK), calmodulin, p38 MAP kinase, HIV-1 reverse transcriptase (RT), triosephosphate isomerase (TIM), and the 70S ribosomal complex. The generated ensembles of conformers determined at atomic resolution show good agreement with experimental data (979 structures resolved by X-ray and/or NMR) and encompass the subspaces covered in independent MD simulations for TIM, p38, and RT. ClustENM emerges as a computationally efficient tool for characterizing the conformational space of large systems at atomic detail, in addition to generating a representative ensemble of conformers that can be advantageously used in simulating substrate/ligand-binding events. PMID:27494296

  15. Representation of target-bound drugs by computed conformers: implications for conformational libraries

    PubMed Central

    Günther, Stefan; Senger, Christian; Michalsky, Elke; Goede, Andrean; Preissner, Robert

    2006-01-01

    Background The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. Results Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space. A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. Conclusion Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site [1]. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available. PMID:16764718

  16. Transition path theory analysis of c-Src kinase activation.

    PubMed

    Meng, Yilin; Shukla, Diwakar; Pande, Vijay S; Roux, Benoît

    2016-08-16

    Nonreceptor tyrosine kinases of the Src family are large multidomain allosteric proteins that are crucial to cellular signaling pathways. In a previous study, we generated a Markov state model (MSM) to simulate the activation of c-Src catalytic domain, used as a prototypical tyrosine kinase. The long-time kinetics of transition predicted by the MSM was in agreement with experimental observations. In the present study, we apply the framework of transition path theory (TPT) to the previously constructed MSM to characterize the main features of the activation pathway. The analysis indicates that the activating transition, in which the activation loop first opens up followed by an inward rotation of the αC-helix, takes place via a dense set of intermediate microstates distributed within a fairly broad "transition tube" in a multidimensional conformational subspace connecting the two end-point conformations. Multiple microstates with negligible equilibrium probabilities carry a large transition flux associated with the activating transition, which explains why extensive conformational sampling is necessary to accurately determine the kinetics of activation. Our results suggest that the combination of MSM with TPT provides an effective framework to represent conformational transitions in complex biomolecular systems. PMID:27482115

  17. Global structure of conformal theories in the SU(3) gauge theory

    NASA Astrophysics Data System (ADS)

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

    2014-06-01

    We investigate SU(3) gauge theories in four dimensions with Nf fundamental fermions on a lattice using the Wilson fermion. Clarifying the vacuum structure in terms of Polyakov loops in spatial directions and properties of temporal propagators using a new method that we call "local analysis," we conjecture that the "conformal region" exists together with the confining region and the deconfining region in the phase structure parametrized by β and K, both in the cases of the large Nf QCD within the conformal window (referred as conformal QCD) with an IR cutoff and small Nf QCD at T/Tc>1 with Tc being the chiral transition temperature (referred to as high-temperature QCD). Our numerical simulation on a lattice of the size 163×64 shows the following evidence of the conjecture. In the conformal region, we find that the vacuum is the nontrivial Z(3) twisted vacuum modified by nonperturbative effects and that temporal propagators of mesons behave at large t as a power-law-corrected Yukawa-type decaying form. The transition from the conformal region to the deconfining region or the confining region is a sharp transition between different vacua, and therefore, it suggests a first-order transition both in conformal QCD and high-temperature QCD. To confirm the conjecture and distinguish it from the possibility of crossover phenomena, we need to take the continuum/thermodynamic limit, which we do not attempt in this work. Within our fixed-lattice simulation, we find that there is a precise correspondence between conformal QCD and high-temperature QCD in the temporal propagators under the change of the parameters Nf and T/Tc, respectively: one boundary is close to meson states, and the other is close to free quark states. In particular, conformal QCD with Nf=7 corresponds to high-temperature QCD with Nf=2 at T˜2Tc, both of which are in close relation to a meson unparticle model. From this, we estimate the anomalous mass dimension γ*=1.2(1) for Nf=7. We also show that the

  18. Using Solutes and Kinetics to Probe Large Conformational Changes in the Steps of Transcription Initiation

    PubMed Central

    Ruff, Emily; Kontur, Wayne S.; Record, M. Thomas

    2014-01-01

    Summary Small solutes are useful probes of large conformational changes in RNA polymerase (RNAP)-promoter interactions and other biopolymer processes. In general, a large effect of a solute on an equilibrium constant (or rate constant) indicates a large change in water-accessible biopolymer surface area in the corresponding step (or transition state), resulting from conformational changes, interface formation, or both. Here, we describe nitrocellulose filter binding assays from series used to determine the urea dependence of open complex formation and dissociation with Escherichia coli RNAP and λPR promoter DNA. Then, we describe the subsequent data analysis and interpretation of these solute effects. PMID:25665568

  19. Solvent microenvironments and copper binding alters the conformation and toxicity of a prion fragment.

    PubMed

    Inayathullah, Mohammed; Satheeshkumar, K S; Malkovskiy, Andrey V; Carre, Antoine L; Sivanesan, Senthilkumar; Hardesty, Jasper O; Rajadas, Jayakumar

    2013-01-01

    The secondary structures of amyloidogenic proteins are largely influenced by various intra and extra cellular microenvironments and metal ions that govern cytotoxicity. The secondary structure of a prion fragment, PrP(111-126), was determined using circular dichroism (CD) spectroscopy in various microenvironments. The conformational preferences of the prion peptide fragment were examined by changing solvent conditions and pH, and by introducing external stress (sonication). These physical and chemical environments simulate various cellular components at the water-membrane interface, namely differing aqueous environments and metal chelating ions. The results show that PrP(111-126) adopts different conformations in assembled and non-assembled forms. Aging studies on the PrP(111-126) peptide fragment in aqueous buffer demonstrated a structural transition from random coil to a stable β-sheet structure. A similar, but significantly accelerated structural transition was observed upon sonication in aqueous environment. With increasing TFE concentrations, the helical content of PrP(111-126) increased persistently during the structural transition process from random coil. In aqueous SDS solution, PrP(111-126) exhibited β-sheet conformation with greater α-helical content. No significant conformational changes were observed under various pH conditions. Addition of Cu(2+) ions inhibited the structural transition and fibril formation of the peptide in a cell free in vitro system. The fact that Cu(2+) supplementation attenuates the fibrillar assemblies and cytotoxicity of PrP(111-126) was witnessed through structural morphology studies using AFM as well as cytotoxicity using MTT measurements. We observed negligible effects during both physical and chemical stimulation on conformation of the prion fragment in the presence of Cu(2+) ions. The toxicity of PrP(111-126) to cultured astrocytes was reduced following the addition of Cu(2+) ions, owing to binding affinity of copper

  20. Kinetics and thermodyamics of the rate limiting conformational change in the actomyosin V mechanochemical cycle

    PubMed Central

    Jacobs, Donald J.; Trivedi, Darshan; David, Charles; Yengo, Christopher M.

    2011-01-01

    We used FRET to examine the kinetics and thermodynamics of structural changes associated with ADP release in myosin V, which is thought to be a strain sensitive step in many muscle and non-muscle myosins. We also explore essential dynamics using FIRST/FRODA starting with three different myosin V X-ray crystal structures to examine intrinsic flexibility and correlated motions. Our steady-state and time resolved FRET analysis demonstrates a temperature dependent reversible conformational change in the nucleotide binding pocket. Our kinetic results demonstrate that the nucleotide binding pocket goes from a closed to an open conformation prior to the release of ADP while the actin binding cleft remains closed. Interestingly, we find that the temperature dependence of the maximum actin-activated myosin V ATPase rate is similar to the pocket opening step, demonstrating this is the rate limiting structural transition in the ATPase cycle. Thermodynamic analysis demonstrates the transition from the open to closed nucleotide binding pocket conformation is unfavorable because of a decrease in entropy. The intrinsic flexibility analysis is consistent with conformational entropy playing a role in this transition as the MV.ADP structure is highly flexible compared to the MV.APO structure. Our experimental and modeling studies support the conclusion of a novel post-power-stroke actomyosin.ADP state in which the nucleotide binding pocket and actin binding cleft are closed. The novel state may be important for strain sensitivity as the transition from the closed to open nucleotide binding pocket conformation may be altered by lever arm position. PMID:21315083

  1. Conformation sensitive charge transport in conjugated polymers

    SciTech Connect

    Mattias Andersson, L.; Hedström, Svante; Persson, Petter

    2013-11-18

    Temperature dependent charge carrier mobility measurements using field effect transistors and density functional theory calculations are combined to show how the conformation dependent frontier orbital delocalization influences the hole- and electron mobilities in a donor-acceptor based polymer. A conformationally sensitive lowest unoccupied molecular orbital results in an electron mobility that decreases with increasing temperature above room temperature, while a conformationally stable highest occupied molecular orbital is consistent with a conventional hole mobility behavior and also proposed to be one of the reasons for why the material works well as a hole transporter in amorphous bulk heterojunction solar cells.

  2. The conformal window from the worldline formalism

    NASA Astrophysics Data System (ADS)

    Armoni, Adi

    2010-02-01

    We use the worldline formalism to derive a universal relation for the lower boundary of the conformal window in non-supersymmetric QCD-like theories. The derivation relies on the convergence of the expansion of the fermionic determinant in terms of Wilson loops. The expansion shares a similarity with the lattice strong coupling expansion and the genus expansion in string theory. Our result relates the lower boundary of the conformal window in theories with different representations and different gauge groups. Finally, we use SQCD to estimate the boundary of the conformal window in QCD-like theories and compare it with other approaches.

  3. Novel Approach to Conformal FINFET Extension Doping

    SciTech Connect

    Zschaetzsch, G.; Vandervorst, W.; Hoffmann, T. Y.; Horiguchi, N.; Hautala, J.; Shao, Y.

    2011-01-07

    This paper presents a novel strategy to achieve conformal FINFET extension doping with low tilt-angle beam-line ion implantation. The process relies on the self-aligned cap layer formation exclusively on top of the FIN to tune doping levels in this particular area by partial dopant trapping. The conformality itself is evaluated for n- and p-type dopants by a novel extraction method applied to FIN resistor test structures. Furthermore, the process was integrated into a full NMOS device flow and compared to a highly tilted and more conformal As implant condition.

  4. Conformational and Vibrational Studies of Triclosan

    NASA Astrophysics Data System (ADS)

    Özişik, Haci; Bayari, S. Haman; Saǧlam, Semran

    2010-01-01

    The conformational equilibrium of triclosan (5-chloro-2-(2, 4-dichlorophenoxy) phenol) have been calculated using density functional theory (DFTe/B3LYP/6-311++G(d, p)) method. Four different geometries were found to correspond to energy minimum conformations. The IR spectrum of triclosan was measured in the 4000-400 cm-1 region. We calculated the harmonic frequencies and intensities of the most stable conformers in order to assist in the assignment of the vibrational bands in the experimental spectrum. The fundamental vibrational modes were characterized depending on their total energy distribution (TED%) using scaled quantum mechanical (SQM) force field method.

  5. Conformable Fractional Nikiforov—Uvarov Method

    NASA Astrophysics Data System (ADS)

    Karayer, H.; Demirhan, D.; Büyükkılıç, F.

    2016-07-01

    We introduce conformable fractional Nikiforov—Uvarov (NU) method by means of conformable fractional derivative which is the most natural definition in non-integer calculus. Since, NU method gives exact eigenstate solutions of Schrödinger equation (SE) for certain potentials in quantum mechanics, this method is carried into the domain of fractional calculus to obtain the solutions of fractional SE. In order to demonstrate the applicability of the conformable fractional NU method, we solve fractional SE for harmonic oscillator potential, Woods—Saxon potential, and Hulthen potential.

  6. Anticholinergic substances: A single consistent conformation

    PubMed Central

    Pauling, Peter; Datta, Narayandas

    1980-01-01

    An interactive computer-graphics analysis of 24 antagonists of acetylcholine at peripheral autonomic post-ganglionic (muscarinic) nervous junctions and at similar junctions in the central nervous system, the crystal structures of which are known, has led to the determination of a single, consistent, energetically favorable conformation for all 24 substances, although their observed crystal structure conformations vary widely. The absolute configuration and the single, consistent (ideal) conformation of the chemical groups required for maximum anticholinergic activity are described quantitatively. Images PMID:16592775

  7. Conformity and Dissonance in Generalized Voter Models

    NASA Astrophysics Data System (ADS)

    Page, Scott E.; Sander, Leonard M.; Schneider-Mizell, Casey M.

    2007-09-01

    We generalize the voter model to include social forces that produce conformity among voters and avoidance of cognitive dissonance of opinions within a voter. The time for both conformity and consistency (which we call the exit time) is, in general, much longer than for either process alone. We show that our generalized model can be applied quite widely: it is a form of Wright's island model of population genetics, and is related to problems in the physical sciences. We give scaling arguments, numerical simulations, and analytic estimates for the exit time for a range of relative strengths in the tendency to conform and to avoid dissonance.

  8. Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

    PubMed Central

    Floquet, Nicolas; Costa, Mauricio G.S.; Batista, Paulo R.; Renault, Pedro; Bisch, Paulo M.; Raussin, Florent; Martinez, Jean; Morris, May C.; Perahia, David

    2015-01-01

    Cyclin-dependent kinases (CDKs) and their associated regulatory cyclins are central for timely regulation of cell-cycle progression. They constitute attractive pharmacological targets for development of anticancer therapeutics, since they are frequently deregulated in human cancers and contribute to sustained, uncontrolled tumor proliferation. Characterization of their structural/dynamic features is essential to gain in-depth insight into structure-activity relationships. In addition, the identification of druggable pockets or key intermediate conformations yields potential targets for the development of novel classes of inhibitors. Structural studies of CDK2/cyclin A have provided a wealth of information concerning monomeric/heterodimeric forms of this kinase. There is, however, much less structural information for other CDK/cyclin complexes, including CDK4/cyclin D1, which displays an alternative (open) position of the cyclin partner relative to CDK, contrasting with the closed CDK2/cyclin A conformation. In this study, we carried out normal-mode analysis and enhanced sampling simulations with our recently developed method, molecular dynamics with excited normal modes, to understand the conformational equilibrium on these complexes. Interestingly, the lowest-frequency normal mode computed for each complex described the transition between the open and closed conformations. Exploration of these motions with an explicit-solvent representation using molecular dynamics with excited normal modes confirmed that the closed conformation is the most stable for the CDK2/cyclin A complex, in agreement with their experimentally available structures. On the other hand, we clearly show that an open↔closed equilibrium may exist in CDK4/cyclin D1, with closed conformations resembling that captured for CDK2/cyclin A. Such conformational preferences may result from the distinct distributions of frustrated contacts in each complex. Using the same approach, the putative roles of

  9. Toward Focusing Conformational Ensembles on Bioactive Conformations: A Molecular Mechanics/Quantum Mechanics Study.

    PubMed

    Avgy-David, Hannah H; Senderowitz, Hanoch

    2015-10-26

    The identification of bound conformations, namely, conformations adopted by ligands when binding their target is critical for target-based and ligand-based drug design. Bound conformations could be obtained computationally from unbound conformational ensembles generated by conformational search tools. However, these tools also generate many nonrelevant conformations thus requiring a focusing mechanism. To identify such a mechanism, this work focuses on a comparison of energies and structural properties of bound and unbound conformations for a set of FDA approved drugs whose complexes are available in the PDB. Unbound conformational ensembles were initially obtained with three force fields. These were merged, clustered, and reminimized using the same force fields and four QM methods. Bound conformations of all ligands were represented by their crystal structures or by approximations to these structures. Energy differences were calculated between global minima of the unbound state or the Boltzmann averaged energies of the unbound ensemble and the approximated bound conformations. Ligand conformations which resemble the X-ray conformation (RMSD < 1.0 Å) were obtained in 91%-97% and 96%-98% of the cases using the ensembles generated by the individual force fields and the reminimized ensembles, respectively, yet only in 52%-56% (original ensembles) and 47%-65% (reminimized ensembles) as global energy minima. The energy window within which the different methods identified the bound conformation (approximated by its closest local energy minimum) was found to be at 4-6 kcal/mol with respect to the global minimum and marginally lower with respect to a Boltzmann averaged energy of the unbound ensemble. Better approximations to the bound conformation obtained with a constrained minimization using the crystallographic B-factors or with a newly developed Knee Point Detection (KPD) method gave lower values (2-5 kcal/mol). Overall, QM methods gave lower energy differences than

  10. Conformational landscape of diisopropyl ketone: quantum chemical calculations validated by microwave spectroscopy.

    PubMed

    Zhao, Yueyue; Mouhib, Halima; Stahl, Wolfgang

    2013-01-17

    We report on the gas-phase structure of the most abundant conformer of diisopropyl ketone, (CH(3))(2)HC-CO-CH(CH(3))(2), as observed by molecular beam Fourier transform microwave spectroscopy. The gas-phase structures of five conformers of diisopropyl ketone were optimized using ab initio calculations at the MP2/6-311++G(d,p) level of theory. The natures of the stationary points were verified using harmonic frequency calculations. The only conformer observed in the supersonic jet possesses C(2) symmetry and appears as an enantiomeric pair. From the microwave spectrum, a set of three highly accurate rotational constants, five centrifugal distortion constants, and three sextic centrifugal distortion constants were determined. The structure of the observed conformer was optimized again at different levels of theory using the HF, MP2, and B3LYP methods. The theoretical constants of the C(2) conformer were subsequently validated using the experimental constants. To understand the transitions of one conformer to the others, the isopropyl groups were rotated against each other. The resulting two-dimensional potential energy surface shows nicely the symmetry of the conformational landscape and also indicates the enantiomeric pairs of the conformers. The barriers to internal rotation of the methyl groups were determined to be 1052 and 905 cm(-1) at the MP2/6-311++G(d,p) and the B3LYP/6-311++G(d,p) levels, respectively. In agreement with the theoretical predictions, no internal rotation patterns could be observed in the microwave spectrum.

  11. Conformational influence of the ribose 2'-hydroxyl group: crystal structures of DNA-RNA chimeric duplexes

    NASA Technical Reports Server (NTRS)

    Egli, M.; Usman, N.; Rich, A.

    1993-01-01

    We have crystallized three double-helical DNA-RNA chimeric duplexes and determined their structures by X-ray crystallography at resolutions between 2 and 2.25 A. The two self-complementary duplexes [r(G)d(CGTATACGC)]2 and [d(GCGT)r(A)d(TACGC)]2, as well as the Okazaki fragment d(GGGTATACGC).r(GCG)d(TATACCC), were found to adopt A-type conformations. The crystal structures are non-isomorphous, and the crystallographic environments for the three chimeras are different. A number of intramolecular interactions of the ribose 2'-hydroxyl groups contribute to the stabilization of the A-conformation. Hydrogen bonds between 2'-hydroxyls and 5'-oxygens or phosphate oxygens, in addition to the previously observed hydrogen bonds to 1'-oxygens of adjacent riboses and deoxyriboses, are observed in the DNA-RNA chimeric duplexes. The crystalline chimeric duplexes do not show a transition between the DNA A- and B-conformations. CD spectra suggest that the Okazaki fragment assumes an A-conformation in solution as well. In this molecule the three RNA residues may therefore lock the complete decamer in the A-conformation. Crystals of an all-DNA strand with the same sequence as the self-complementary chimeras show a morphology which is different from those of the chimera crystals. Moreover, the oligonucleotide does not match any of the sequence characteristics of DNAs usually adopting the A-conformation in the crystalline state (e.g., octamers with short alternating stretches of purines and pyrimidines). In DNA-RNA chimeric duplexes, it is therefore possible that a single RNA residue can drive the conformational equilibrium toward the A-conformation.

  12. On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

    SciTech Connect

    Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Fernandez-Alberti, Sebastian; Roitberg, Adrian E.

    2015-06-28

    The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

  13. On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

    NASA Astrophysics Data System (ADS)

    Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Roitberg, Adrian E.; Fernandez-Alberti, Sebastian

    2015-06-01

    The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

  14. Conformational Dynamics in FKBP Domains: Relevance to Molecular Signaling and Drug Design.

    PubMed

    LeMaster, David M; Hernandez, Griselda

    2015-01-01

    Among the 22 FKBP domains in the human genome, FKBP12.6 and the first FKBP domains (FK1) of FKBP51 and FKBP52 are evolutionarily and structurally most similar to the archetypical FKBP12. As such, the development of inhibitors with selectivity among these four FKBP domains poses a significant challenge for structure-based design. The pleiotropic effects of these FKBP domains in a range of signaling processes such as the regulation of ryanodine receptor calcium channels by FKBP12 and FKBP12.6 and steroid receptor regulation by the FK1 domains of FKBP51 and FKBP52 amply justify the efforts to develop selective therapies. In contrast to their close structural similarities, these four FKBP domains exhibit a substantial diversity in their conformational flexibility. A number of distinct conformational transitions have been characterized for FKBP12 spanning timeframes from 20 s to 10 ns and in each case these dynamics have been shown to markedly differ from the conformational behavior for one or more of the other three FKBP domains. Protein flexibilitybased inhibitor design could draw upon the transitions that are significantly populated in only one of the targeted proteins. Both the similarities and differences among these four proteins valuably inform the understanding of how dynamical effects propagate across the FKBP domains as well as potentially how such intramolecular transitions might couple to the larger scale transitions that are central to the signaling complexes in which these FKBP domains function.

  15. Membrane-Induced Dichotomous Conformation of Amyloid β with the Disordered N-Terminal Segment Followed by the Stable C-Terminal β Structure

    PubMed Central

    Yagi-Utsumi, Maho; Kato, Koichi; Nishimura, Katsuyuki

    2016-01-01

    Various neurodegenerative disorders are ascribed to pathogenic molecular processes involving conformational transitions of amyloidogenic proteins into toxic aggregates characterized by their β structures. Accumulating evidence indicates that neuronal cell membranes provide platforms for such conformational transitions of pathogenic proteins as best exemplified by amyloid β (Aβ). Therefore, membrane-bound Aβ species can be promising targets for the development of novel drugs for Alzheimer’s disease. In the present study, solid-state nuclear magnetic resonance spectroscopy has elucidated the membrane-induced conformation of Aβ, in which the disordered N-terminal segment is followed by the stable C-terminal β strand. The data provides an insight into the molecular processes of the conformational transition of Aβ coupled with its assembly into parallel β structures. PMID:26731546

  16. Electroweak phase transition in ultraminimal technicolor

    SciTech Connect

    Jaervinen, Matti; Sannino, Francesco; Ryttov, Thomas A.

    2009-05-01

    We unveil the temperature-dependent electroweak phase transition in new extensions of the standard model in which the electroweak symmetry is spontaneously broken via strongly coupled, nearly conformal dynamics achieved by the means of multiple matter representations. In particular, we focus on the low energy effective theory introduced to describe ultra minimal walking technicolor at the phase transition. Using the one-loop effective potential with ring improvement, we identify regions of parameter space, which yield a strong first-order transition. A striking feature of the model is the existence of a second phase transition associated to the electroweak-singlet sector. The interplay between these two transitions leads to an extremely rich phase diagram.

  17. Exploring structural phase transitions of ion crystals

    PubMed Central

    Yan, L. L.; Wan, W.; Chen, L.; Zhou, F.; Gong, S. J.; Tong, X.; Feng, M.

    2016-01-01

    Phase transitions have been a research focus in many-body physics over past decades. Cold ions, under strong Coulomb repulsion, provide a repealing paradigm of exploring phase transitions in stable confinement by electromagnetic field. We demonstrate various conformations of up to sixteen laser-cooled 40Ca+ ion crystals in a home-built surface-electrode trap, where besides the usually mentioned structural phase transition from the linear to the zigzag, two additional phase transitions to more complicated two-dimensional configurations are identified. The experimental observation agrees well with the numerical simulation. Heating due to micromotion of the ions is analysed by comparison of the numerical simulation with the experimental observation. Our investigation implies very rich and complicated many-body behaviour in the trapped-ion systems and provides effective mechanism for further exploring quantum phase transitions and quantum information processing with ultracold trapped ions. PMID:26865229

  18. Conformational dynamics of peptide T molecule

    NASA Astrophysics Data System (ADS)

    Akverdieva, Gulnare; Godjayev, Niftali; Akyuz, Sevim

    2002-05-01

    Using a method of the theoretical conformational analysis, a conformational dynamics of the side chains of the amino acid residues of peptide T, a competitor of the human immuno-deficiency virus in the binding to human T cells, was investigated. For this purpose, the conformational maps of the potential surfaces were constructed over the angles of the side chains for the preferable conformations of peptide T molecule. Permissible deviations of these angles from the optimal values were determined. It has been found that the angles of the side chains of the amino acid residues involved in physiologically active fragment Thr4-Thr8 are more rigid than in the other segment of the molecule. This fact confirms the existence of such a regular structure as β-turn revealed previously in studies of the spatial structure of the peptide T molecule.

  19. Energy maps for glycosidic linkage conformations.

    PubMed

    French, Alfred D

    2015-01-01

    Glycosidic linkage conformations are the main factors in determining the shapes of disaccharide, oligosaccharide, and polysaccharide molecules. The conformations are expressed in terms of the torsion angles about the bonds from each ring of the disaccharide moiety to its glycosidic oxygen atom, and the probability of a given conformation is often expressed in terms of its free or potential energy. The energy surface or map for a disaccharide is a display of the energy plotted against the two torsion angles. Successful mapping allows a particular kind of energy calculation to provide the energy values for each conformation and avoids possible pitfalls. Although different methods are discussed, the main emphasis of this chapter is on the technical production of the maps and their exploitation in further understanding the shape of the molecule in question.

  20. The Conformational Behaviour of the Odorant Dihydrocarveol

    NASA Astrophysics Data System (ADS)

    Loru, Donatella; Jarman, Natasha; Sanz, M. Eugenia

    2016-06-01

    The odorant dihydrocarveol (C10H18O) has been investigated in the gas phase using a 2-8 GHz chirped-pulse Fourier transform microwave spectrometer. Dihydrocarveol was purchased as a mixture of n-, iso-, neo-, and neoiso- isomers. The sample was placed in a bespoke heating nozzle at about 85°C and seeded in Ne at 5 bar. Three conformers were observed and their rotational constants were determined. By comparing the experimental rotational constants with those calculated ab initio the three conformers were identified as belonging to n-dihydrocarveol. In all three conformers the isopropenyl group is in equatorial position with respect to the six-membered ring, and the OH group maintains the same configuration. The conformers differ in the orientation of the isopropenyl group.

  1. Conformational NMR Study of Bistriazolyl Anion Receptors.

    PubMed

    Makuc, Damjan; Merckx, Tamara; Dehaen, Wim; Plavec, Janez

    2016-01-01

    Conformational features of pyridine- and pyrimidine-based bistriazolyl anion receptors dissolved in acetonitrile-d3 were assessed by multidimensional, heteronuclear NMR spectroscopy. NOESY correlation signals suggested preorganization of both host molecules in solution in the absence of anions. In addition, only a single set of signals was observed in the 1H NMR spectra, which suggested a symmetrical conformation of anion receptors or their conformational exchange that is fast on the NMR time-scale. Furthermore, the predominant conformations of the pyridine- and pyrimidine-based anion receptors are preserved upon addition of chloride, bromide, and acetate anions. Chemical shift changes observed upon addition of anions showed that the NH (thio)urea and triazole protons are involved in anion-receptor interactions through hydrogen bonding. PMID:27640375

  2. Conformational Electroresistance and Hysteresis in Nanoclusters

    SciTech Connect

    Li, Xiangguo; Zhang, Xiaoguang; Cheng, Hai-Ping

    2014-07-02

    Among many mechanisms proposed for electroresistance, ones involving structural changes are the least understood because of challenges of controllability and repeatability. Yet structural changes can cause dramatic changes in electronic properties, leading to multiple ways in which conduction paths can be opened and closed, not limited to filament movement or variation in molecular conductance. Here we show at least another way: conformational dependence of the Coulomb charging energy of a nanocluster, where charging induced conformational distortion changes the blockade voltage, which in turn leads to a giant electroresistance. This intricate interplay between charging and conformation change is demonstrated in a nanocluster Zn3O4 by combining a first-principles calculation with a temperature dependent transport model. The predicted hysteretic Coulomb blockade staircase in the current-voltage curve adds another dimension to the rich phenomenon of tunneling electroresistance. The new mechanism also provides a better controlled and repeatable platform to study conformational electroresistance.

  3. Conformational Electroresistance and Hysteresis in Nanoclusters

    DOE PAGESBeta

    Li, Xiangguo; Zhang, Xiaoguang; Cheng, Hai-Ping

    2014-07-02

    Among many mechanisms proposed for electroresistance, ones involving structural changes are the least understood because of challenges of controllability and repeatability. Yet structural changes can cause dramatic changes in electronic properties, leading to multiple ways in which conduction paths can be opened and closed, not limited to filament movement or variation in molecular conductance. Here we show at least another way: conformational dependence of the Coulomb charging energy of a nanocluster, where charging induced conformational distortion changes the blockade voltage, which in turn leads to a giant electroresistance. This intricate interplay between charging and conformation change is demonstrated in amore » nanocluster Zn3O4 by combining a first-principles calculation with a temperature dependent transport model. The predicted hysteretic Coulomb blockade staircase in the current-voltage curve adds another dimension to the rich phenomenon of tunneling electroresistance. The new mechanism also provides a better controlled and repeatable platform to study conformational electroresistance.« less

  4. Nanoporous films: From conventional to the conformal

    SciTech Connect

    Allendorf, Mark D.; Stavila, Vitalie

    2015-12-14

    Here, thin and continuous films of porous metal-organic frameworks can now be conformally deposited on various substrates using a vapor-phase synthesis approach that departs from conventional solution-based routes.

  5. Structure of The Planar Galilean Conformal Algebra

    NASA Astrophysics Data System (ADS)

    Gao, Shoulan; Liu, Dong; Pei, Yufeng

    2016-08-01

    In this paper, we compute the low-dimensional cohomology groups of the planar Galilean conformal algebra introduced by Bagchi and Goparkumar. Consequently we determine its derivations, central extensions, and automorphisms.

  6. Social conformity despite individual preferences for distinctiveness.

    PubMed

    Smaldino, Paul E; Epstein, Joshua M

    2015-03-01

    We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.

  7. Conformable apparatus in a drill string

    SciTech Connect

    Hall, David R.; Hall, Jr., H. Tracy; Pixton, David S.; Fox, Joe

    2007-08-28

    An apparatus in a drill string comprises an internally upset drill pipe. The drill pipe comprises a first end, a second end, and an elongate tube intermediate the first and second ends. The elongate tube and the ends comprising a continuous an inside surface with a plurality of diameters. A conformable metal tube is disposed within the drill pipe intermediate the ends thereof and terminating adjacent to the ends of the drill pipe. The conformable metal tube substantially conforms to the continuous inside surface of the metal tube. The metal tube may comprise a non-uniform section which is expanded to conform to the inside surface of the drill pipe. The non-uniform section may comprise protrusions selected from the group consisting of convolutions, corrugations, flutes, and dimples. The non-uniform section extends generally longitudinally along the length of the tube. The metal tube may be adapted to stretch as the drill pipes stretch.

  8. Scale-invariant breaking of conformal symmetry

    NASA Astrophysics Data System (ADS)

    Dymarsky, Anatoly; Zhiboedov, Alexander

    2015-10-01

    Known examples of unitary relativistic scale but not conformal-invariant field theories (SFTs) can be embedded into conventional conformal field theories (CFTs). We show that any SFT which is a subsector of a unitary CFT is a free theory. Our discussion applies to an arbitrary number of spacetime dimensions and explains triviality of known SFTs in four spacetime dimensions. We comment on examples of unitary SFTs which are not captured by our construction.

  9. On being loud and proud: non-conformity and counter-conformity to group norms.

    PubMed

    Hornsey, Matthew J; Majkut, Louise; Terry, Deborah J; McKimmie, Blake M

    2003-09-01

    Most experiments on conformity have been conducted in relation to judgments of physical reality; surprisingly few papers have experimentally examined the influence of group norms on social issues with a moral component. In response to this, participants were told that they were either in a minority or in a majority relative to their university group in terms of their attitudes toward recognition of gay couples in law (Expt 1: N = 205) and a government apology to Aborigines (Expt 2: N = 110). In both experiments, it was found that participants who had a weak moral basis for their attitude conformed to the group norm on private behaviours. In contrast, those who had a strong moral basis for their attitude showed non-conformity on private behaviours and counter-conformity on public behaviours. Incidences of non-conformity and counter-conformity are discussed with reference to theory and research on normative influence.

  10. Conformational properties of oxazoline-amino acids

    NASA Astrophysics Data System (ADS)

    Staś, Monika; Broda, Małgorzata A.; Siodłak, Dawid

    2016-04-01

    Oxazoline-amino acids (Xaa-Ozn) occur in natural peptides of potentially important bioactivity. The conformations of the model compounds: Ac-(S)-Ala-Ozn(4R-Me), Ac-(S)-Ala-Ozn(4S-Me), and (gauche+, gauche-, anti) Ac-(S)-Val-Ozn(4R-Me) were studied at meta-hybrid M06-2X/6-311++G(d,p) method including solvent effect. Boc-L-Ala-L-Ozn-4-COOMe and Boc-L-Val-L-Ozn-4-COOMe were synthesized and studied by FT-IR and NMR-NOE methods. The conformations in crystal state were gathered from the Cambridge Structural Data Base. The main conformational feature of the oxazoline amino acids is the conformation β2 (ϕ,ψ ∼ -161°, -6°), which predominates in weakly polar environment and still is accessible in polar surrounding. The changes of the conformational preferences towards the conformations αR (ϕ,ψ ∼ -70°, -15°) and then β (ϕ,ψ ∼ -57°, -155°) are observed with increase of the environment polarity.

  11. Rapid roll inflation with conformal coupling

    SciTech Connect

    Kofman, Lev; Mukohyama, Shinji

    2008-02-15

    Usual inflation is realized with a slow rolling scalar field minimally coupled to gravity. In contrast, we consider dynamics of a scalar with a flat effective potential, conformally coupled to gravity. Surprisingly, it contains an attractor inflationary solution with the rapidly rolling inflaton field. We discuss models with the conformal inflaton with a flat potential (including hybrid inflation). There is no generation of cosmological fluctuations from the conformally coupled inflaton. We consider realizations of modulated (inhomogeneous reheating) or curvaton cosmological fluctuations in these models. We also implement these unusual features for the popular string-theoretic warped inflationary scenario, based on the interacting D3-D3 branes. The original warped brane inflation suffers a large inflaton mass due to conformal coupling to 4-dimensional gravity. Instead of considering this as a problem and trying to cure it with extra engineering, we show that warped inflation with the conformally coupled, rapidly rolling inflaton is yet possible with N=37 efoldings, which requires low-energy scales 1-100 TeV of inflation. Coincidentally, the same warping numerology can be responsible for the hierarchy. It is shown that the scalars associated with angular isometries of the warped geometry of compact manifold (e.g. S{sup 3} of Klebanov-Strassler (KS) geometry) have solutions identical to conformally coupled modes and also cannot be responsible for cosmological fluctuations. We discuss other possibilities.

  12. Controlling complex networks with conformity behavior

    NASA Astrophysics Data System (ADS)

    Wang, Xu-Wen; Nie, Sen; Wang, Wen-Xu; Wang, Bing-Hong

    2015-09-01

    Controlling complex networks accompanied by common conformity behavior is a fundamental problem in social and physical science. Conformity behavior that individuals tend to follow the majority in their neighborhood is common in human society and animal communities. Despite recent progress in understanding controllability of complex networks, the existent controllability theories cannot be directly applied to networks associated with conformity. Here we propose a simple model to incorporate conformity-based decision making into the evolution of a network system, which allows us to employ the exact controllability theory to explore the controllability of such systems. We offer rigorous theoretical results of controllability for representative regular networks. We also explore real networks in different fields and some typical model networks, finding some interesting results that are different from the predictions of structural and exact controllability theory in the absence of conformity. We finally present an example of steering a real social network to some target states to further validate our controllability theory and tools. Our work offers a more realistic understanding of network controllability with conformity behavior and can have potential applications in networked evolutionary games, opinion dynamics and many other complex networked systems.

  13. Measuring the mechanical properties of molecular conformers

    PubMed Central

    Jarvis, S. P.; Taylor, S.; Baran, J. D.; Champness, N. R.; Larsson, J. A.; Moriarty, P.

    2015-01-01

    Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules. PMID:26388232

  14. Electronic transitions of cobalt monoboride

    NASA Astrophysics Data System (ADS)

    Ng, Y. W.; Pang, H. F.; Cheung, A. S.-C.

    2011-11-01

    Electronic transition spectrum of cobalt monoboride (CoB) in the visible region between 495 and 560 nm has been observed and analyzed using laser-induced fluorescence spectroscopy. CoB molecule was produced by the reaction of laser-ablated cobalt atom and diborane (B2H6) seeded in argon. Fifteen vibrational bands with resolved rotational structure have been recorded, which included transitions of both Co10B and Co11B isotopic species. Our analysis showed that the observed transition bands are ΔΩ = 0 transitions with Ω″ = 2 and Ω″ = 3 lower states. Four transition systems have been assigned, namely, the [18.1]3Π2-X3Δ2, the [18.3]3Φ3-X3Δ3, the [18.6]3- X3Δ3, and the [19.0]2-X3Δ2 systems. The bond length, ro, of the X 3Δ3 state of CoB is determined to be 1.705 Å. The observed rotational lines showed unresolved hyperfine structure arising from the nuclei, which conforms to the Hund's case (aβ) coupling scheme. This work represents the first experimental investigation of the CoB spectrum.

  15. Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization

    PubMed Central

    Guasch, Alicia; Aranguren-Ibáñez, Álvaro; Pérez-Luque, Rosa; Aparicio, David; Martínez-Høyer, Sergio; Mulero, M. Carmen; Serrano-Candelas, Eva

    2015-01-01

    A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis- isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans- conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates. PMID:26248042

  16. Autophosphorylation Activity of a Soluble Hexameric Histidine Kinase Correlates with the Shift in Protein Conformational Equilibrium

    PubMed Central

    Wojnowska, Marta; Yan, Jun; Sivalingam, Ganesh N.; Cryar, Adam; Gor, Jayesh; Thalassinos, Konstantinos; Djordjevic, Snezana

    2013-01-01

    Summary In a commonly accepted model, in response to stimuli, bacterial histidine kinases undergo a conformational transition between an active and inactive form. Structural information on histidine kinases is limited. By using ion mobility-mass spectrometry (IM-MS), we demonstrate an exchange between two conformational populations of histidine kinase ExsG that are linked to different levels of kinase activity. ExsG is an atypical signaling protein that incorporates an uncommon histidine kinase catalytic core at the C terminus preceded by an N-terminal “receiver domain” that is normally associated with the response regulator proteins in two-component signal transduction systems. IM-MS analysis and enzymatic assays indicate that phosphorylation of the ExsG receiver domain stabilizes the “compact” form of the protein and inhibits kinase core activity; in contrast, nucleotide binding required for kinase activity is associated with the more open conformation of ExsG. PMID:24210218

  17. Health care for gender variant or gender non-conforming children.

    PubMed

    Forcier, Michelle M; Haddad, Emily

    2013-04-01

    Most children explore various aspects of gender and sexuality as children. Youth with consistent, persistent, and insistent gender non-conformity or gender dysphoria are important to identify in the pre- and early-pubertal years as early intervention and support may be lifesaving. Those whose gender non-conformity persists into puberty and adolescence are most likely to identify as transgender. Blocking pubertal development at Tanner stage 2 for pre-pubertal, gender non-conforming children is a relatively new but reversible and highly beneficial strategy to delay puberty, giving patients and families time to come up with a transition plan. Early identification, collaborative support from healthcare providers and mental health clinicians, and supportive interventions for both children and families grappling with gender variance may improve social and mental health outcomes for what has traditionally been considered a high-risk, vulnerable population.

  18. Metamaterials-based label-free nanosensor for conformation and affinity biosensing.

    PubMed

    Cao, Cuong; Zhang, Jun; Wen, Xinglin; Dodson, Stephanie L; Dao, Nguyen Thuan; Wong, Lai Mun; Wang, Shijie; Li, Shuzhou; Phan, Anh Tuân; Xiong, Qihua

    2013-09-24

    Analysis of molecular interaction and conformational dynamics of biomolecules is of paramount importance in understanding their vital functions in complex biological systems, disease detection, and new drug development. Plasmonic biosensors based upon surface plasmon resonance and localized surface plasmon resonance have become the predominant workhorse for detecting accumulated biomass caused by molecular binding events. However, unlike surface-enhanced Raman spectroscopy (SERS), the plasmonic biosensors indeed are not suitable tools to interrogate vibrational signatures of conformational transitions required for biomolecules to interact. Here, we show that highly tunable plasmonic metamaterials can offer two transducing channels for parallel acquisition of optical transmission and sensitive SERS spectra at the biointerface, simultaneously probing the conformational states and binding affinity of biomolecules, e.g., G-quadruplexes, in different environments. We further demonstrate the use of the metamaterials for fingerprinting and detection of the arginine-glycine-glycine domain of nucleolin, a cancer biomarker that specifically binds to a G-quadruplex, with the picomolar sensitivity.

  19. Metric transition

    NASA Technical Reports Server (NTRS)

    1992-01-01

    This report describes NASA's metric transition in terms of seven major program elements. Six are technical areas involving research, technology development, and operations; they are managed by specific Program Offices at NASA Headquarters. The final program element, Institutional Management, covers both NASA-wide functional management under control of NASA Headquarters and metric capability development at the individual NASA Field Installations. This area addresses issues common to all NASA program elements, including: Federal, state, and local coordination; standards; private industry initiatives; public-awareness initiatives; and employee training. The concluding section identifies current barriers and impediments to metric transition; NASA has no specific recommendations for consideration by the Congress.

  20. Microwave spectrum, structure, tautomeric, and conformational composition of 4-vinylimidazole

    NASA Astrophysics Data System (ADS)

    Godfrey, Peter D.; Robertson, Evan G.

    2012-08-01

    The microwave spectra of the two conformers each, of the 1H and 3H tautomers of 4-vinylimidazole, have been measured in the 48-72 GHz spectral region. The 4-vinylimidazole was generated in situ by the facile decarboxylation of urocanic acid at its vaporization temperature of 220 °C. The recognition of this reaction casts doubt on the reliability of a previous published spectroscopic study apparently mistakenly thought to be of uncontaminated vaporized urocanic acid, a natural product of great interest in skin cancer etiology. Quantum chemical theoretical predictions of the structures of each of ten possible conformers/tautomers of urocanic acid and four of 4-vinylimidazole were performed at the ab initio MP2/cc-pVTZ level, with vibrational predictions at the B3LYP/cc-pVTZ and M062X/cc-pVTZ levels. The predicted values of rotational constants for all the urocanic acid species were found to be quite inconsistent with those of the four observed spectra. For the 4-vinylimidazole isomers, the calculated relative energies suggested that all four species would have substantial equilibrium mole fractions at 220 °C. The isomers were identified by matching the observed and calculated rotational constants. The resulting assignment was found to be consistent with the predicted and observed 14N nuclear quadrupole hyperfine multiplet patterns for a suitable rotational transition, and with the observed versus empirically calculated inertial defects. With one exception, the predicted structures were found to be planar. Resembling the case of 1-vinylimidazole, where one conformer is nonplanar, one isomer of 4-vinylimidazole was found to be quasiplanar. This seems to belong to a class of spontaneous symmetry-breaking observed in the molecular structure of some otherwise planar vinyl aromatic compounds.

  1. Initiation factor 2 stabilizes the ribosome in a semirotated conformation

    PubMed Central

    Ling, Clarence; Ermolenko, Dmitri N.

    2015-01-01

    Intersubunit rotation and movement of the L1 stalk, a mobile domain of the large ribosomal subunit, have been shown to accompany the elongation cycle of translation. The initiation phase of protein synthesis is crucial for translational control of gene expression; however, in contrast to elongation, little is known about the conformational rearrangements of the ribosome during initiation. Bacterial initiation factors (IFs) 1, 2, and 3 mediate the binding of initiator tRNA and mRNA to the small ribosomal subunit to form the initiation complex, which subsequently associates with the large subunit by a poorly understood mechanism. Here, we use single-molecule FRET to monitor intersubunit rotation and the inward/outward movement of the L1 stalk of the large ribosomal subunit during the subunit-joining step of translation initiation. We show that, on subunit association, the ribosome adopts a distinct conformation in which the ribosomal subunits are in a semirotated orientation and the L1 stalk is positioned in a half-closed state. The formation of the semirotated intermediate requires the presence of an aminoacylated initiator, fMet-tRNAfMet, and IF2 in the GTP-bound state. GTP hydrolysis by IF2 induces opening of the L1 stalk and the transition to the nonrotated conformation of the ribosome. Our results suggest that positioning subunits in a semirotated orientation facilitates subunit association and support a model in which L1 stalk movement is coupled to intersubunit rotation and/or IF2 binding. PMID:26668356

  2. Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation

    PubMed Central

    Dehnes, Yvette; Shan, Jufang; Beuming, Thijs; Shi, Lei; Weinstein, Harel; Javitch, Jonathan A.

    2014-01-01

    The dopamine transporter (DAT), a member of the neurotransmitter:sodium symporter family, mediates the reuptake of dopamine at the synaptic cleft. DAT is the primary target for psychostimulants such as cocaine and amphetamine. We previously demonstrated that cocaine binding and dopamine transport alter the accessibility of Cys342 in the third intracellular loop (IL3). To study the conformational changes associated with the functional mechanism of the transporter, we made cysteine substitution mutants, one at a time, from Phe332 to Ser351 in IL3 of the background DAT construct, X7C, in which 7 endogenous cysteines were mutated. The accessibility of the 20 engineered cysteines to polar charged sulfhydryl reagents was studied in the absence and presence of cocaine or dopamine. Of the 11 positions that reacted with methanethiosulfonate ethyl ammonium, as evidenced by inhibition of ligand binding, 5 were protected against this inhibition by cocaine and dopamine (S333C, S334C, N336C, M342C and T349C), indicating that reagent accessibility is affected by conformational changes associated with inhibitor and substrate binding. In some of the cysteine mutants, transport activity is disrupted, but can be rescued by the presence of zinc, most likely because the distribution between inward- and outward-facing conformations is restored by zinc binding. The experimental data were interpreted in the context of molecular models of DAT in both the inward- and outward-facing conformations. Differences in the solvent accessible surface area for individual IL3 residues calculated for these states correlate well with the experimental accessibility data, and suggest that protection by ligand binding results from the stabilization of the outward-facing configuration. Changes in the residue interaction networks observed from the molecular dynamics simulations also revealed the critical roles of several positions during the conformational transitions. We conclude that the IL3 region of DAT

  3. VEGFR-2 conformational switch in response to ligand binding

    PubMed Central

    Sarabipour, Sarvenaz; Ballmer-Hofer, Kurt; Hristova, Kalina

    2016-01-01

    VEGFR-2 is the primary regulator of angiogenesis, the development of new blood vessels from pre-existing ones. VEGFR-2 has been hypothesized to be monomeric in the absence of bound ligand, and to undergo dimerization and activation only upon ligand binding. Using quantitative FRET and biochemical analysis, we show that VEGFR-2 forms dimers also in the absence of ligand when expressed at physiological levels, and that these dimers are phosphorylated. Ligand binding leads to a change in the TM domain conformation, resulting in increased kinase domain phosphorylation. Inter-receptor contacts within the extracellular and TM domains are critical for the establishment of the unliganded dimer structure, and for the transition to the ligand-bound active conformation. We further show that the pathogenic C482R VEGFR-2 mutant, linked to infantile hemangioma, promotes ligand-independent signaling by mimicking the structure of the ligand-bound wild-type VEGFR-2 dimer. DOI: http://dx.doi.org/10.7554/eLife.13876.001 PMID:27052508

  4. A spin label study of conformational changes in cytochrome c.

    PubMed

    Postnikova, G B; Gorbunova, N P; Volkenstein, M V

    1983-04-01

    Spin-labeled pig heart cytochromes c singly modified at Met-65, Tyr-74 and at one of the lysine residues, Lys-72 or Lys-73, were investigated by the ESR method under conditions of different ligand and redox states of the heme and at various pH values. Replacement of Met-80 by the external ligand, cyanide, was shown to produce a sharp increase in the mobility of all the three bound labels while reduction of the spin-labeled ferricytochromes c did not cause any marked changes in their ESR spectra. In the pH range 6-13, two conformational transitions in ferricytochrome c were observed which preceded its alkaline denaturation: the first with pK 9.3 registered by the spin label at the Met-65 position, and the second with pK 11.1 registered by the labels bound to Tyr-74 and Lys-72(73). The conformational changes in the 'left-hand part' of ferricytochrome c are most probably induced in both cases by the exchange of internal protein ligands at the sixth coordination site of the heme.

  5. Alkyl CH Stretch Vibrations as a Probe of Conformational Preferences

    NASA Astrophysics Data System (ADS)

    Sibert, Edwin L. Sibert, Iii; Buchanan, Evan G.; Zwier, Timothy S.

    2013-06-01

    Theoretical IR spectra of 1,2-diphenoxyethane (C_6H_5-O-CH_2-CH_2-O-C_6H_5 DPOE) and 1,2-diphenylethane (C_6H_5-CH_2-CH_2-C_6H_5 DPE) are presented and compared to results of single-conformation spectroscopy of jet cooled molecules. The theoretical transition energies and intensites are obtained from a model based on a local mode Hamiltonian that includes all local cubic stretch-bend couplings that are then projected onto the normal modes. The model parameters are obtained from density functional theory methods. Full dimensional calculations are compared to those of reduced dimensions that include anharmonic CH streches Fermi coupled to scissor modes. Excellent agreement is found. Scale factors of select terms in the reduced dimensional Hamiltonian are determined by fitting the theoretical Hamiltonian to the anti DPE spectrum. Using the same scaling, Hamiltonians for other conformers of the above molecules are generated and used to predict structures by comparing to experimentally determined spectra in the alkyl CH stretch region. The level patterns in the resulting spectra are elucidated in terms of the model parameters. The model results are extended to interpret the spectra of more complicated macrocycles containing multiple -CH_2CH_2- ethano bridges such as the dibenzo-15-crown-5 ether and 2,2,2-paracyclophane.

  6. Magnetic tweezers force calibration for molecules that exhibit conformational switching

    NASA Astrophysics Data System (ADS)

    Jacobson, David R.; Saleh, Omar A.

    2016-09-01

    High spatial and temporal resolution magnetic tweezers experiments allow for the direct calibration of pulling forces applied to short biomolecules. In one class of experiments, a force is applied to a structured RNA or protein to induce an unfolding transition; when the force is maintained at particular values, the molecule can exhibit conformational switching between the folded and unfolded states or between intermediate states. Here, we analyze the degree to which common force calibration approaches, involving the fitting of model functions to the Allan variance or power spectral density of the bead trajectory, are biased by this conformational switching. We find significant effects in two limits: that of large molecular extension changes between the two states, in which alternative fitting functions must be used, and that of very fast switching kinetics, in which the force calibration cannot be recovered due to the slow diffusion time of the magnetic bead. We use simulations and high-resolution RNA hairpin data to show that most biophysical experiments do not occur in either of these limits.

  7. Conformational Variety of Polyanionic Peptides At Low Salt Concentrations

    NASA Astrophysics Data System (ADS)

    Bertrand, Marylène; Brack, André

    1997-12-01

    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 β-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 α-helix. Solid amorphous CdS generates water soluble β-sheets, as well. Sequential poly(Leu-Glu-Glu-Leu) adopts an α-helix in the presence of divalent cations. The sequence-dependent conformational diversity was extended to poly(Asp-Leu) and poly(Leu-Asp-Asp-Leu).

  8. The Building Game: From Enumerative Combinatorics to Conformational Diffusion

    NASA Astrophysics Data System (ADS)

    Johnson-Chyzhykov, Daniel; Menon, Govind

    2016-08-01

    We study a discrete attachment model for the self-assembly of polyhedra called the building game. We investigate two distinct aspects of the model: (i) enumerative combinatorics of the intermediate states and (ii) a notion of Brownian motion for the polyhedral linkage defined by each intermediate that we term conformational diffusion. The combinatorial configuration space of the model is computed for the Platonic, Archimedean, and Catalan solids of up to 30 faces, and several novel enumerative results are generated. These represent the most exhaustive computations of this nature to date. We further extend the building game to include geometric information. The combinatorial structure of each intermediate yields a systems of constraints specifying a polyhedral linkage and its moduli space. We use a random walk to simulate a reflected Brownian motion in each moduli space. Empirical statistics of the random walk may be used to define the rates of transition for a Markov process modeling the process of self-assembly.

  9. From Stability to Mobility: African Secondary School Aged Adolescents' Transition to Mainstream Schooling

    ERIC Educational Resources Information Center

    Gunasekera, Sashya; Houghton, Stephen; Glasgow, Kenneth; Boyle, Christopher

    2014-01-01

    Setting clear achievable goals that enhance reputational status has been shown to direct the energies of adolescents into socially conforming or non-conforming activities. It appears to be the case that following transition from Intensive English Centres (IECs) into mainstream schooling, students from African refugee backgrounds experience…

  10. Conformational heterogeneity in closed and open states of the KcsA potassium channel in lipid bicelles.

    PubMed

    Kim, Dorothy M; Dikiy, Igor; Upadhyay, Vikrant; Posson, David J; Eliezer, David; Nimigean, Crina M

    2016-08-01

    The process of ion channel gating-opening and closing-involves local and global structural changes in the channel in response to external stimuli. Conformational changes depend on the energetic landscape that underlies the transition between closed and open states, which plays a key role in ion channel gating. For the prokaryotic, pH-gated potassium channel KcsA, closed and open states have been extensively studied using structural and functional methods, but the dynamics within each of these functional states as well as the transition between them is not as well understood. In this study, we used solution nuclear magnetic resonance (NMR) spectroscopy to investigate the conformational transitions within specific functional states of KcsA. We incorporated KcsA channels into lipid bicelles and stabilized them into a closed state by using either phosphatidylcholine lipids, known to favor the closed channel, or mutations designed to trap the channel shut by disulfide cross-linking. A distinct state, consistent with an open channel, was uncovered by the addition of cardiolipin lipids. Using selective amino acid labeling at locations within the channel that are known to move during gating, we observed at least two different slowly interconverting conformational states for both closed and open channels. The pH dependence of these conformations and the predictable disruptions to this dependence observed in mutant channels with altered pH sensing highlight the importance of conformational heterogeneity for KcsA gating. PMID:27432996

  11. Conformations of an adenine bulge in a DNA octamer and its influence on DNA structure from molecular dynamics simulations.

    PubMed Central

    Feig, M; Zacharias, M; Pettitt, B M

    2001-01-01

    Molecular dynamics simulations have been applied to the DNA octamer d(GCGCA-GAAC). d(GTTCGCGC), which has an adenine bulge at the center to determine the pathway for interconversion between the stacked and extended forms. These forms are known to be important in the molecular recognition of bulges. From a total of ~35 ns of simulation time with the most recent CHARMM27 force field a variety of distinct conformations and subconformations are found. Stacked and fully looped-out forms are in excellent agreement with experimental data from NMR and x-ray crystallography. Furthermore, in a number of conformations the bulge base associates with the minor groove to varying degrees. Transitions between many of the conformations are observed in the simulations and used to propose a complete transition pathway between the stacked and fully extended conformations. The effect on the surrounding DNA sequence is investigated and biological implications of the accessible conformational space and the suggested transition pathway are discussed, in particular for the interaction of the MS2 replicase operator RNA with its coat protein. PMID:11423420

  12. Structure and conformation of cyclopentene, cycloheptene and trans-cyclooctene

    NASA Astrophysics Data System (ADS)

    Leong, Max K.; Mastryukov, Vladimir S.; Boggs, James E.

    1998-04-01

    The molecular geometries of different conformations of cycloalkenes, C nH 2 n-2 , with n = 5, 7 and 8 were optimized by restricted Hartree-Fock calculations using the 6-31G∗ basis set followed by second-order Møller-Plesset perturbation theory (MP2) treatment of electron correlation. For cyclopentene, C 5H 8, the potential function for the ring-puckering motion was constructed, followed by solving for the vibrational eigenvalues in terms of distributed Gaussian bases. Good agreement was obtained with the observed frequencies in the far-infrared spectrum of the molecule. For cycloheptene, C 7H 12, geometries were optimized for the chair, boat, twist-boat, and three possible transition states. The chair-chair interconversion mechanism was investigated and compared with available experimental evidence and with the results of a previous molecular mechanics calculation. The computed potential barrier compares well with NMR evidence, but the conformation of the relevant transition state is found to be different from the one assumed in the experimental study. The structure of the smallest isolable trans-cycloalkene, trans-cyclooctene, C 8H 14, was optimized, yielding a structure in reasonable agreement with a previous gas phase electron diffraction study. The agreement includes the pyramidality of the olefinic carbon atoms which was also compared with available X-ray data on related compounds. The bond angles and torsion angles were in better agreement with the experiment than were those obtained in earlier molecular mechanics studies, although it is remarkable how well that method works for these highly strained cyclic systems.

  13. A Kinesin Motor In A Force-producing Conformation

    SciTech Connect

    Heuston, E.; Bronner, C; Kull, F; Endow, S

    2010-01-01

    Kinesin motors hydrolyze ATP to produce force and move along microtubules, converting chemical energy into work by a mechanism that is only poorly understood. Key transitions and intermediate states in the process are still structurally uncharacterized, and remain outstanding questions in the field. Perturbing the motor by introducing point mutations could stabilize transitional or unstable states, providing critical information about these rarer states. Here we show that mutation of a single residue in the kinesin-14 Ncd causes the motor to release ADP and hydrolyze ATP faster than wild type, but move more slowly along microtubules in gliding assays, uncoupling nucleotide hydrolysis from force generation. A crystal structure of the motor shows a large rotation of the stalk, a conformation representing a force-producing stroke of Ncd. Three C-terminal residues of Ncd, visible for the first time, interact with the central {beta}-sheet and dock onto the motor core, forming a structure resembling the kinesin-1 neck linker, which has been proposed to be the primary force-generating mechanical element of kinesin-1. Force generation by minus-end Ncd involves docking of the C-terminus, which forms a structure resembling the kinesin-1 neck linker. The mechanism by which the plus- and minus-end motors produce force to move to opposite ends of the microtubule appears to involve the same conformational changes, but distinct structural linkers. Unstable ADP binding may destabilize the motor-ADP state, triggering Ncd stalk rotation and C-terminus docking, producing a working stroke of the motor.

  14. Conformational space of clindamycin studied by ab initio and full-atom molecular dynamics.

    PubMed

    Kulczycka-Mierzejewska, Katarzyna; Trylska, Joanna; Sadlej, Joanna

    2016-01-01

    Molecular dynamics (MD) simulations allow determining internal flexibility of molecules at atomic level. Using ab initio Born-Oppenheimer molecular dynamics (BOMD), one can simulate in a reasonable time frame small systems with hundreds of atoms, usually in vacuum. With quantum mechanics/molecular mechanics (QM/MM) or full-atom molecular dynamics (FAMD), the influence of the environment can also be simulated. Here, we compare three types of MD calculations: ab initio BOMD, hybrid QM/MM, and classical FAMD. As a model system, we use a small antibiotic molecule, clindamycin, which is one of the lincosamide antibiotics. Clindamycin acquires two energetically stable forms and we investigated the transition between these two experimentally known conformers. We performed 60-ps BOMD simulations in vacuum, 50-ps QM/MM, and 100-ns FAMD in explicit water. The transition between two antibiotic conformers was observed using both BOMD and FAMD methods but was not noted in the QM/MM simulations. PMID:26733483

  15. Multiple stable conformations account for reversible concentration-dependent oligomerization and autoinhibition of a metamorphic metallopeptidase.

    PubMed

    López-Pelegrín, Mar; Cerdà-Costa, Núria; Cintas-Pedrola, Anna; Herranz-Trillo, Fátima; Bernadó, Pau; Peinado, Juan R; Arolas, Joan L; Gomis-Rüth, F Xavier

    2014-09-26

    Molecular plasticity controls enzymatic activity: the native fold of a protein in a given environment is normally unique and at a global free-energy minimum. Some proteins, however, spontaneously undergo substantial fold switching to reversibly transit between defined conformers, the "metamorphic" proteins. Here, we present a minimal metamorphic, selective, and specific caseinolytic metallopeptidase, selecase, which reversibly transits between several different states of defined three-dimensional structure, which are associated with loss of enzymatic activity due to autoinhibition. The latter is triggered by sequestering the competent conformation in incompetent but structured dimers, tetramers, and octamers. This system, which is compatible with a discrete multifunnel energy landscape, affords a switch that provides a reversible mechanism of control of catalytic activity unique in nature.

  16. Cyclic Constraints on Conformational Flexibility in γ-PEPTIDES: Conformation-Specific IR and UV Spectroscopy

    NASA Astrophysics Data System (ADS)

    Walsh, Patrick S.; Kusaka, Ryoji; Zwier, Timothy S.; Fisher, Brian F.; Gellman, Samuel H.

    2013-06-01

    Spectroscopic studies of flexible peptides in the gas phase can provide insight to their inherent structural preferences in the absence of solvent. Recently, there has been increased attention paid to synthetic foldamers containing non-natural residues that can be specifically engineered to robustly form particular secondary structures. These engineered peptides have potential in therapeutic drug design because they are resistant to enzymatic degradation. Specifically, the Gellman group has synthesized a γ-peptide with a six membered cyclic constraint in the γ^{4}-γ^{3} position and an ethyl group at the γ^{2} position (γ_{ACHC}). The three stereocenters have a well-defined chirality [S,S,S]. These two features constrain the relative orientation of adjacent amide groups, thereby favoring a particular "pitch" to the turn. Solution phase results indicate that constrained γ-peptides induce the formation of a 14-helix. Ac-γ_{ACHC}-NHBz, its monohydrate and Ac-γ_{ACHC}-γ_{ACHC}-NHBz have been studied using ultraviolet (UV) and infrared (IR) double-resonance methods to obtain conformation-specific spectra under jet-cooled conditions in the gas phase. IR spectra in the hydride stretch (3300-3750 cm^{-1}), amide I/II and OH bend (1400-1800 cm^{-1}) were recorded and compared to predictions using density functional methods (DFT) and harmonic frequency calculations. We will compare the present results on constrained γ-peptides with corresponding results on unconstrained analogs. Data obtained for the monohydrated water cluster of Ac-γ_{ACHC}-NHBz will also be presented, including assignment of the water bend fundamental, which appears in the midst of transitions due to the amide II vibrations. L. Guo, W. Zhang, A. G. Reidenbach, M. W. Giuliano, I. A. Guzei, L. C. Spencer and S. H. Gellman Angew. Chem. Int. Ed. 2011, 50, 5843-5846

  17. The Relationship between Creativity and Conformity among Preschool Children.

    ERIC Educational Resources Information Center

    Van Hook, Cheryl W.; Tegano, Deborah W.

    2002-01-01

    This study investigated the relationship between creativity and conformity (social conformity and impersonal conformity) with 45 preschool children. Findings support the hypothesis that highly conforming and highly nonconforming children do not score as highly on creativity measurements as children in the freedom of expression group (i.e., not…

  18. 47 CFR 2.906 - Declaration of Conformity.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Declaration of Conformity. 2.906 Section 2.906... Conformity. (a) A Declaration of Conformity is a procedure where the responsible party, as defined in § 2.909... of Conformity attaches to all items subsequently marketed by the responsible party which...

  19. Effects of conformational ordering on protein/polyelectrolyte electrostatic complexation: ionic binding and chain stiffening

    PubMed Central

    Cao, Yiping; Fang, Yapeng; Nishinari, Katsuyoshi; Phillips, Glyn O.

    2016-01-01

    Coupling of electrostatic complexation with conformational transition is rather general in protein/polyelectrolyte interaction and has important implications in many biological processes and practical applications. This work studied the electrostatic complexation between κ-carrageenan (κ-car) and type B gelatin, and analyzed the effects of the conformational ordering of κ-car induced upon cooling in the presence of potassium chloride (KCl) or tetramethylammonium iodide (Me4NI). Experimental results showed that the effects of conformational ordering on protein/polyelectrolyte electrostatic complexation can be decomposed into ionic binding and chain stiffening. At the initial stage of conformational ordering, electrostatic complexation can be either suppressed or enhanced due to the ionic bindings of K+ and I− ions, which significantly alter the charge density of κ-car or occupy the binding sites of gelatin. Beyond a certain stage of conformational ordering, i.e., helix content θ > 0.30, the effect of chain stiffening, accompanied with a rapid increase in helix length ζ, becomes dominant and tends to dissociate the electrostatic complexation. The effect of chain stiffening can be theoretically interpreted in terms of double helix association. PMID:27030165

  20. Distinct contracted conformations of the Tcra/Tcrd locus during Tcra and Tcrd recombination

    PubMed Central

    Shih, Han-Yu

    2010-01-01

    Studies have suggested that antigen receptor loci adopt contracted conformations to promote long-distance interactions between gene segments during V(D)J recombination. The Tcra/Tcrd locus is unique because it undergoes highly divergent Tcrd and Tcra recombination programs in CD4−CD8− double negative (DN) and CD4+CD8+ double positive (DP) thymocytes, respectively. Using three-dimensional fluorescence in situ hybridization, we asked whether these divergent recombination programs are supported by distinct conformational states of the Tcra/Tcrd locus. We found that the 3′ portion of the locus is contracted in DN and DP thymocytes but not in B cells. Remarkably, the 5′ portion of the locus is contracted in DN thymocytes but is decontracted in DP thymocytes. We propose that the fully contracted conformation in DN thymocytes allows Tcrd rearrangements involving Vδ gene segments distributed over 1 Mb, whereas the unique 3′-contracted, 5′-decontracted conformation in DP thymocytes biases initial Tcra rearrangements to the most 3′ of the available Vα gene segments. This would maintain a large pool of distal 5′ Vα gene segments for subsequent rounds of recombination. Thus, distinct contracted conformations of the Tcra/Tcrd locus may facilitate a transition from a Tcrd to a Tcra mode of recombination during thymocyte development. PMID:20696701