Conformer-specific hydrogen atom tunnelling in trifluoromethylhydroxycarbene

NASA Astrophysics Data System (ADS)

Mardyukov, Artur; Quanz, Henrik; Schreiner, Peter R.

2017-01-01

Conformational control of organic reactions is at the heart of the biomolecular sciences. To achieve a particular reactivity, one of many conformers may be selected, for instance, by a (bio)catalyst, as the geometrically most suited and appropriately reactive species. The equilibration of energetically close-lying conformers is typically assumed to be facile and less energetically taxing than the reaction under consideration itself: this is termed the 'Curtin-Hammett principle'. Here, we show that the trans conformer of trifluoromethylhydroxycarbene preferentially rearranges through a facile quantum-mechanical hydrogen tunnelling pathway, while its cis conformer is entirely unreactive. Hence, this presents the first example of a conformer-specific hydrogen tunnelling reaction. The Curtin-Hammett principle is not applicable, due to the high barrier between the two conformers.

An Individualized 3-Dimensional Designed and Printed Conformer After Dermis Fat Grafting for Complex Sockets.

PubMed

Mourits, Daphne L; Remmers, Jelmer S; Tan, Stevie H; Moll, Annette C; Hartong, Dyonne T

2018-04-03

To introduce a novel technique to design individually customized conformers for postenucleation sockets with dermis fat implants. We use a 3-dimensional scan of the frontal face/orbit and eyelid contour to design an individualized conformer. This polymethylmetacrylate printed conformer is adapted to patients' socket, palpebral fissures, horizontal eyelid aperture, curvature of the eyelids, and mean diameter of patients' contralateral eye. Sutures through holes in the inferior part of the conformer and in the extension can be placed to fixate the conformer and anchor fornix deepening sutures. A correct fitting conformer can be printed and attached to the socket and eyelids. The shape of this conformer can be used subsequently postsurgically to design the ocular prosthesis. Presurgical planning is important to anticipate for a functional socket to adequately fit an artificial eye. The presented technique using 3-dimensional imaging, designing, and printing promises to prevent conformer extrusion and forniceal shortening.

Microscopic insights into the NMR relaxation based protein conformational entropy meter

PubMed Central

Kasinath, Vignesh; Sharp, Kim A.; Wand, A. Joshua

2013-01-01

Conformational entropy is a potentially important thermodynamic parameter contributing to protein function. Quantitative measures of conformational entropy are necessary for an understanding of its role but have been difficult to obtain. An empirical method that utilizes changes in conformational dynamics as a proxy for changes in conformational entropy has recently been introduced. Here we probe the microscopic origins of the link between conformational dynamics and conformational entropy using molecular dynamics simulations. Simulation of seven pro! teins gave an excellent correlation with measures of side-chain motion derived from NMR relaxation. The simulations show that the motion of methyl-bearing side-chains are sufficiently coupled to that of other side chains to serve as excellent reporters of the overall side-chain conformational entropy. These results tend to validate the use of experimentally accessible measures of methyl motion - the NMR-derived generalized order parameters - as a proxy from which to derive changes in protein conformational entropy. PMID:24007504

Boundary conformal anomalies on hyperbolic spaces and Euclidean balls

NASA Astrophysics Data System (ADS)

Rodriguez-Gomez, Diego; Russo, Jorge G.

2017-12-01

We compute conformal anomalies for conformal field theories with free conformal scalars and massless spin 1/2 fields in hyperbolic space ℍ d and in the ball B^d , for 2≤d≤7. These spaces are related by a conformal transformation. In even dimensional spaces, the conformal anomalies on ℍ2 n and B^{2n} are shown to be identical. In odd dimensional spaces, the conformal anomaly on B^{2n+1} comes from a boundary contribution, which exactly coincides with that of ℍ2 n + 1 provided one identifies the UV short-distance cutoff on B^{2n+1} with the inverse large distance IR cutoff on ℍ2 n + 1, just as prescribed by the conformal map. As an application, we determine, for the first time, the conformal anomaly coefficients multiplying the Euler characteristic of the boundary for scalars and half-spin fields with various boundary conditions in d = 5 and d = 7.

Methods in Enzymology: “Flexible backbone sampling methods to model and design protein alternative conformations”

PubMed Central

Ollikainen, Noah; Smith, Colin A.; Fraser, James S.; Kortemme, Tanja

2013-01-01

Sampling alternative conformations is key to understanding how proteins work and engineering them for new functions. However, accurately characterizing and modeling protein conformational ensembles remains experimentally and computationally challenging. These challenges must be met before protein conformational heterogeneity can be exploited in protein engineering and design. Here, as a stepping stone, we describe methods to detect alternative conformations in proteins and strategies to model these near-native conformational changes based on backrub-type Monte Carlo moves in Rosetta. We illustrate how Rosetta simulations that apply backrub moves improve modeling of point mutant side chain conformations, native side chain conformational heterogeneity, functional conformational changes, tolerated sequence space, protein interaction specificity, and amino acid co-variation across protein-protein interfaces. We include relevant Rosetta command lines and RosettaScripts to encourage the application of these types of simulations to other systems. Our work highlights that critical scoring and sampling improvements will be necessary to approximate conformational landscapes. Challenges for the future development of these methods include modeling conformational changes that propagate away from designed mutation sites and modulating backbone flexibility to predictively design functionally important conformational heterogeneity. PMID:23422426

PubChem3D: Conformer generation

PubMed Central

2011-01-01

Background PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling. Results Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall average accuracy of reproduction of bioactive conformations was remarkably linear with respect to both non-hydrogen atom count ("size") and effective rotor count ("flexibility"). Using these as independent variables, a regression equation was developed to predict the RMSD accuracy of a theoretical ensemble to reproduce bioactive conformations. The equation was modified to give a minimum RMSD conformer sampling value to help ensure that 90% of the sampled theoretical models should contain at least one conformer within the RMSD sampling value to a "bioactive" conformation. Conclusion Optimal parameters for conformer generation using OMEGA were explored and determined. An equation was developed that provides an RMSD sampling value to use that is based on the relative accuracy to reproduce bioactive conformations. The optimal conformer generation parameters and RMSD sampling values determined are used by the PubChem3D project to generate theoretical conformer models. PMID:21272340

Laser probes of the potential energy landscapes and conformational isomerization dynamics of flexible biomolecules

NASA Astrophysics Data System (ADS)

Dian, Brian; Clarkson, Jasper; Zwier, Timothy

2003-03-01

Using a combination of 2-color resonant two-photon ionization (R2PI), laser-induced fluorescence excitation (LIF), resonant ion-dip infrared spectroscopy (RIDIRS), fluorescence-dip infrared spectroscopy (FDIRS), and UV-UV hole-burning spectroscopy, the conformational preferences of a series of flexible biomolecules, including melatonin, N-acetyl-tryptophan methyl amide (NATMA), and their close analogs, have been determined in a molecular beam. These molecules are sufficiently complex to have hundreds of conformational minima, yet small enough that their potential energy landscapes can be explored in some detail. Once the conformational preferences of the molecules are established, these molecules are then studied using infrared-ultraviolet hole-filling and IR-induced population transfer spectroscopy. These methods utilize selective infrared excitation of single conformations of the molecule in the early portions of a gas-phase expansion, followed by collisional re-cooling of the excited population into its conformational minima for subsequent conformation-specific detection. Efficient isomerization is induced by the infrared excitation that redistributes population between the same conformations that have population in the absence of infrared excitation. Examples will be given in which the quantum yields for transfer of the population into the various conformational minima depend both on which conformation is excited and on which hydride stretch vibration is excited within a given conformation; that is, they are both conformation-selective and mode-selective.

Increased conformity offers diminishing returns for reducing total knee replacement wear.

PubMed

Fregly, Benjamin J; Marquez-Barrientos, Carlos; Banks, Scott A; DesJardins, John D

2010-02-01

Wear remains a significant problem limiting the lifespan of total knee replacements (TKRs). Though increased conformity between TKR components has the potential to decrease wear, the optimal amount and planes of conformity have not been investigated. Furthermore, differing conformities in the medial and lateral compartments may provide designers the opportunity to address both wear and kinematic design goals simultaneously. This study used a computational model of a Stanmore knee simulator machine and a previously validated wear model to investigate this issue for simulated gait. TKR geometries with different amounts and planes of conformity on the medial and lateral sides were created and tested in two phases. The first phase utilized a wide range of sagittal and coronal conformity combinations to blanket a physically realistic design space. The second phase performed a focused investigation of the conformity conditions from the first phase to which predicted wear volume was sensitive. For the first phase, sagittal but not coronal conformity was found to have a significant effect on predicted wear volume. For the second phase, increased sagittal conformity was found to decrease predicted wear volume in a nonlinear fashion, with reductions gradually diminishing as conformity increased. These results suggest that TKR geometric design efforts aimed at minimizing wear should focus on sagittal rather than coronal conformity and that at least moderate sagittal conformity is desirable in both compartments.

Conformers, infrared spectrum, UV-induced photochemistry, and near-IR-induced generation of two rare conformers of matrix-isolated phenylglycine.

PubMed

Borba, Ana; Gómez-Zavaglia, Andrea; Fausto, Rui

2014-10-21

The conformational space of α-phenylglycine (PG) have been investigated theoretically at both the DFT/B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of approximation. Seventeen different minima were found on the investigated potential energy surfaces, which are characterized by different dominant intramolecular interactions: type I conformers are stabilized by hydrogen bonds of the type N-H···O=C, type II by a strong O-H···N hydrogen bond, type III by weak N-H···O-H hydrogen bonds, and type IV by a C=O···H-C contact. The calculations indicate also that entropic effects are relevant in determining the equilibrium populations of the conformers of PG in the gas phase, in particular in the case of conformers of type II, where the strong intramolecular O-H···N hydrogen bond considerably diminishes entropy by reducing the conformational mobility of the molecule. In consonance with the relative energies of the conformers and barriers for conformational interconversion, only 3 conformers of PG were observed for the compound isolated in cryogenic Ar, Xe, and N2 matrices: the conformational ground state (ICa), and forms ICc and IITa. All other significantly populated conformers existing in the gas phase prior to deposition convert either to conformer ICa or to conformer ICc during matrix deposition. The experimental observation of ICc had never been achieved hitherto. Narrowband near-IR irradiation of the first overtone of νOH vibrational mode of ICa and ICc in nitrogen matrices (at 6910 and 6930 cm(-1), respectively) led to selective generation of two additional conformers of high-energy, ITc and ITa, respectively, which were also observed experimentally for the first time. In addition, these experiments also provided the key information for the detailed vibrational characterization of the 3 conformers initially present in the matrices. On the other hand, UV irradiation (λ = 255 nm) of PG isolated in a xenon matrix revealed that PG undergoes facile photofragmentation through two photochemical pathways that are favored for different initial conformations of the reactant: (a) decarboxylation, leading to CO2 plus benzylamine (the dominant photofragmentation channel in PG cis-COOH conformers ICa and ICc) and (b) decarbonylation, with generation of CO plus benzonitrile, H2O and H2 (prevalent in the case of the trans-COOH conformer, IITa).

Conformers, infrared spectrum, UV-induced photochemistry, and near-IR-induced generation of two rare conformers of matrix-isolated phenylglycine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borba, Ana, E-mail: anaborba@ci.uc.pt; Fausto, Rui; Gómez-Zavaglia, Andrea

The conformational space of α-phenylglycine (PG) have been investigated theoretically at both the DFT/B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of approximation. Seventeen different minima were found on the investigated potential energy surfaces, which are characterized by different dominant intramolecular interactions: type I conformers are stabilized by hydrogen bonds of the type N–H···O=C, type II by a strong O–H···N hydrogen bond, type III by weak N–H···O–H hydrogen bonds, and type IV by a C=O···H–C contact. The calculations indicate also that entropic effects are relevant in determining the equilibrium populations of the conformers of PG in the gas phase, in particular in the casemore » of conformers of type II, where the strong intramolecular O–H···N hydrogen bond considerably diminishes entropy by reducing the conformational mobility of the molecule. In consonance with the relative energies of the conformers and barriers for conformational interconversion, only 3 conformers of PG were observed for the compound isolated in cryogenic Ar, Xe, and N{sub 2} matrices: the conformational ground state (ICa), and forms ICc and IITa. All other significantly populated conformers existing in the gas phase prior to deposition convert either to conformer ICa or to conformer ICc during matrix deposition. The experimental observation of ICc had never been achieved hitherto. Narrowband near-IR irradiation of the first overtone of νOH vibrational mode of ICa and ICc in nitrogen matrices (at 6910 and 6930 cm{sup −1}, respectively) led to selective generation of two additional conformers of high-energy, ITc and ITa, respectively, which were also observed experimentally for the first time. In addition, these experiments also provided the key information for the detailed vibrational characterization of the 3 conformers initially present in the matrices. On the other hand, UV irradiation (λ = 255 nm) of PG isolated in a xenon matrix revealed that PG undergoes facile photofragmentation through two photochemical pathways that are favored for different initial conformations of the reactant: (a) decarboxylation, leading to CO{sub 2} plus benzylamine (the dominant photofragmentation channel in PG cis-COOH conformers ICa and ICc) and (b) decarbonylation, with generation of CO plus benzonitrile, H{sub 2}O and H{sub 2} (prevalent in the case of the trans-COOH conformer, IITa)« less

Conformational analysis of oligosaccharides and polysaccharides using molecular dynamics simulations.

PubMed

Frank, Martin

2015-01-01

Complex carbohydrates usually have a large number of rotatable bonds and consequently a large number of theoretically possible conformations can be generated (combinatorial explosion). The application of systematic search methods for conformational analysis of carbohydrates is therefore limited to disaccharides and trisaccharides in a routine analysis. An alternative approach is to use Monte-Carlo methods or (high-temperature) molecular dynamics (MD) simulations to explore the conformational space of complex carbohydrates. This chapter describes how to use MD simulation data to perform a conformational analysis (conformational maps, hydrogen bonds) of oligosaccharides and how to build realistic 3D structures of large polysaccharides using Conformational Analysis Tools (CAT).

Exposing hidden alternative backbone conformations in X-ray crystallography using qFit

DOE PAGES

Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry; ...

2015-10-27

Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechainmore » conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Furthermore, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems.« less

Nickel porphyrins for memory optical applications

DOEpatents

Shelnutt, John A.; Jia, Songling; Medforth, Craig; Holten, Dewey; Nelson, Nora Y.; Smith, Kevin M.

2000-01-01

The present invention relates to a nickel-porphyrin derivative in a matrix, the nickel-porphyrin derivative comprising at least two conformational isomers, a lower-energy-state conformer and a higher-energy-state conformer, such that when the higher-energy-state conformer is generated from the lower-energy-state conformer following absorption of a photon of suitable energy, the time to return to the lower-energy-state conformer is greater than 40 nanoseconds at approximately room temperature. The nickel-porphyrin derivative is useful in optical memory applications.

Conformational flexibility of two RNA trimers explored by computational tools and database search.

PubMed

Fadrná, Eva; Koca, Jaroslav

2003-04-01

Two RNA sequences, AAA and AUG, were studied by the conformational search program CICADA and by molecular dynamics (MD) in the framework of the AMBER force field, and also via thorough PDB database search. CICADA was used to provide detailed information about conformers and conformational interconversions on the energy surfaces of the above molecules. Several conformational families were found for both sequences. Analysis of the results shows differences, especially between the energy of the single families, and also in flexibility and concerted conformational movement. Therefore, several MD trajectories (altogether 16 ns) were run to obtain more details about both the stability of conformers belonging to different conformational families and about the dynamics of the two systems. Results show that the trajectories strongly depend on the starting structure. When the MD start from the global minimum found by CICADA, they provide a stable run, while MD starting from another conformational family generates a trajectory where several different conformational families are visited. The results obtained by theoretical methods are compared with the thorough database search data. It is concluded that all except for the highest energy conformational families found in theoretical result also appear in experimental data. Registry numbers: adenylyl-(3' --> 5')-adenylyl-(3' --> 5')-adenosine [917-44-2] adenylyl-(3' --> 5')-uridylyl-(3' --> 5')-guanosine [3494-35-7].

Conformational study of 2-phenylethylamine by molecular-beam Fourier transform microwave spectroscopy.

PubMed

López, Juan C; Cortijo, Vanessa; Blanco, Susana; Alonso, Jose L

2007-08-28

The conformational preferences of the simplest amine neurotransmitter 2-phenylethylamine have been investigated using molecular beam Fourier transform microwave (MB-FTMW) spectroscopy. Two new conformers have been observed together with the two previously reported by Godfrey et al. [J. Am. Chem. Soc., 1995, 117, 8204]. The (14)N nuclear quadrupole hyperfine structure has been resolved for all four conformers. Comparison of the experimental rotational and quadrupole coupling constants with those calculated theoretically provides a conclusive test for the identification of all conformers. The two most stable conformers present a gauche (folded) disposition of the alkyl-amine chain and are stabilised by a weak NH...pi interaction between the amino group and the aromatic ring. The other two conformers show an anti (extended) arrangement of the alkyl-amine chain. Tunnelling splittings have been observed in the spectrum of one of the anti conformers. The post expansion relative abundances in the supersonic jet have been also investigated and related to the conformer energies.

Modeling the Conformation-Specific Infrared Spectra of N-Alkylbenzenes

NASA Astrophysics Data System (ADS)

Tabor, Daniel P.; Sibert, Edwin; Hewett, Daniel M.; Korn, Joseph A.; Zwier, Timothy S.

2016-06-01

Conformation-specific UV-IR double resonance spectra are presented for n-alkylbenzenes. With the aid of a local mode Hamiltonian that includes the effects of stretch-bend Fermi coupling, the spectra of ethyl, n-propyl, and n-butylbenzene are assigned to individual conformers. These molecules allow for further development of the work on a first principles method for calculating alkyl stretch spectra. Due to the consistency of the anharmonic couplings from conformer to conformer, construction of the model Hamiltonian for a given conformer only requires a harmonic frequency calculation at the conformer's minimum geometry as an input. The model Hamiltonian can be parameterized with either density functional theory or MP2 electronic structure calculations. The relative strengths and weaknesses of these methods are evaluated, including their predictions of the relative energetics of the conformers. Finally, the IR spectra for conformers that have the alkyl chain bend back and interact with the π cloud of the benzene ring are modeled.

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 Central

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

2018-01-01

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, 6 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-live of (3.7±0.5)·103 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

Density-based clustering of small peptide conformations sampled from a molecular dynamics simulation.

PubMed

Kim, Minkyoung; Choi, Seung-Hoon; Kim, Junhyoung; Choi, Kihang; Shin, Jae-Min; Kang, Sang-Kee; Choi, Yun-Jaie; Jung, Dong Hyun

2009-11-01

This study describes the application of a density-based algorithm to clustering small peptide conformations after a molecular dynamics simulation. We propose a clustering method for small peptide conformations that enables adjacent clusters to be separated more clearly on the basis of neighbor density. Neighbor density means the number of neighboring conformations, so if a conformation has too few neighboring conformations, then it is considered as noise or an outlier and is excluded from the list of cluster members. With this approach, we can easily identify clusters in which the members are densely crowded in the conformational space, and we can safely avoid misclustering individual clusters linked by noise or outliers. Consideration of neighbor density significantly improves the efficiency of clustering of small peptide conformations sampled from molecular dynamics simulations and can be used for predicting peptide structures.

Conformational Heterogeneity of Unbound Proteins Enhances Recognition in Protein-Protein Encounters.

PubMed

Pallara, Chiara; Rueda, Manuel; Abagyan, Ruben; Fernández-Recio, Juan

2016-07-12

To understand cellular processes at the molecular level we need to improve our knowledge of protein-protein interactions, from a structural, mechanistic, and energetic point of view. Current theoretical studies and computational docking simulations show that protein dynamics plays a key role in protein association and support the need for including protein flexibility in modeling protein interactions. Assuming the conformational selection binding mechanism, in which the unbound state can sample bound conformers, one possible strategy to include flexibility in docking predictions would be the use of conformational ensembles originated from unbound protein structures. Here we present an exhaustive computational study about the use of precomputed unbound ensembles in the context of protein docking, performed on a set of 124 cases of the Protein-Protein Docking Benchmark 3.0. Conformational ensembles were generated by conformational optimization and refinement with MODELLER and by short molecular dynamics trajectories with AMBER. We identified those conformers providing optimal binding and investigated the role of protein conformational heterogeneity in protein-protein recognition. Our results show that a restricted conformational refinement can generate conformers with better binding properties and improve docking encounters in medium-flexible cases. For more flexible cases, a more extended conformational sampling based on Normal Mode Analysis was proven helpful. We found that successful conformers provide better energetic complementarity to the docking partners, which is compatible with recent views of binding association. In addition to the mechanistic considerations, these findings could be exploited for practical docking predictions of improved efficiency.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry

Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechainmore » conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Furthermore, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems.« less

Immirzi parameter without Immirzi ambiguity: Conformal loop quantization of scalar-tensor gravity

NASA Astrophysics Data System (ADS)

Veraguth, Olivier J.; Wang, Charles H.-T.

2017-10-01

Conformal loop quantum gravity provides an approach to loop quantization through an underlying conformal structure i.e. conformally equivalent class of metrics. The property that general relativity itself has no conformal invariance is reinstated with a constrained scalar field setting the physical scale. Conformally equivalent metrics have recently been shown to be amenable to loop quantization including matter coupling. It has been suggested that conformal geometry may provide an extended symmetry to allow a reformulated Immirzi parameter necessary for loop quantization to behave like an arbitrary group parameter that requires no further fixing as its present standard form does. Here, we find that this can be naturally realized via conformal frame transformations in scalar-tensor gravity. Such a theory generally incorporates a dynamical scalar gravitational field and reduces to general relativity when the scalar field becomes a pure gauge. In particular, we introduce a conformal Einstein frame in which loop quantization is implemented. We then discuss how different Immirzi parameters under this description may be related by conformal frame transformations and yet share the same quantization having, for example, the same area gaps, modulated by the scalar gravitational field.

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

Use of 1–4 interaction scaling factors to control the conformational equilibrium between α-helix and β-strand

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pang, Yuan-Ping, E-mail: pang@mayo.edu

Highlights: • 1–4 interaction scaling factors are used to adjust conformational energy. • This article reports the effects of these factors on protein conformations. • Reducing these factors changes a helix to a strand in molecular dynamics simulation. • Increasing these factors causes the reverse conformational change. • These factors control the conformational equilibrium between helix and strand. - Abstract: 1–4 interaction scaling factors are used in AMBER forcefields to reduce the exaggeration of short-range repulsion caused by the 6–12 Lennard-Jones potential and a nonpolarizable charge model and to obtain better agreements of small-molecule conformational energies with experimental data. However,more » the effects of these scaling factors on protein secondary structure conformations have not been investigated until now. This article reports the finding that the 1–4 interactions among the protein backbone atoms separated by three consecutive covalent bonds are more repulsive in the α-helix conformation than in two β-strand conformations. Therefore, the 1–4 interaction scaling factors of protein backbone torsions ϕ and ψ control the conformational equilibrium between α-helix and β-strand. Molecular dynamics simulations confirm that reducing the ϕ and ψ scaling factors readily converts the α-helix conformation of AcO-(AAQAA){sub 3}-NH{sub 2} to a β-strand conformation, and the reverse occurs when these scaling factors are increased. These results suggest that the ϕ and ψ scaling factors can be used to generate the α-helix or β-strand conformation in situ and to control the propensities of a forcefield for adopting secondary structure elements.« less

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 proteins. PMID:23663843

Mapping conformational dynamics of proteins using torsional dynamics simulations.

PubMed

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

2013-05-07

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 proteins. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Conformational dynamics of the molecular chaperone Hsp90

PubMed Central

Krukenberg, Kristin A.; Street, Timothy O.; Lavery, Laura A.; Agard, David A.

2016-01-01

The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1–2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organism-dependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90’s conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90’s conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics. PMID:21414251

DOE Office of Scientific and Technical Information (OSTI.GOV)

Topping, R.J.; Stone, M.P.; Brush, C.K.

The {sup 1}H NMR spectrum of the tetradeoxynucleotide d(TpCpGpA) was examined as a function of temperature, pH, and concentration. At pH 7 and above the solution conformation for this oligodeoxynucleotide appears to be a mixture of random coil and Watson-Crick duplex. At 25{degree}C, a pH titration of d(TpCpGaA) shown that distinct conformational changes occur as the pH is lowered below 7.0. These conformational changes are reversible upon readjusting the pH to neutrality, indicating the presence of a pH-dependent set of conformational equilibria. At 25{degree}C, the various conformational state in the mixture are in rapid exchange on the NMR time scale.more » Examination of the titration curve shown the presence of distinct conformational states at pH greater than 7, and between pH 4 and pH 5. When the pH titration is repeated at 5{degree}C, the conformational equilibria are in slow exchange on the NMR time scale; distinct signals from each conformational state are observable. The stable conformational state present between pH 4 and pH 5 represents an ordered conformation of d(TpCpGpA) which dissociates to a less ordered structure upon raising the temperature. The ordered conformation differs from the Watson-Crick helix, as is shown from nuclear Overhauser enhancement experiments, as well as chemical shift data. These results indicate that their ordered conformation is similar to the conformation of d(TpCpGpA) observed between pH 4 and pH 5. In the present case it is likely that stabilization of an ordered duplex conformation for d(TpCpGpA) is achieved by protonation of cytosine. A possible model which could explain the data involves formation of Hoogsteen C{sup +}:G base pairs.« less

Dynamic clustering threshold reduces conformer ensemble size while maintaining a biologically relevant ensemble

NASA Astrophysics Data System (ADS)

Yongye, Austin B.; Bender, Andreas; Martínez-Mayorga, Karina

2010-08-01

Representing the 3D structures of ligands in virtual screenings via multi-conformer ensembles can be computationally intensive, especially for compounds with a large number of rotatable bonds. Thus, reducing the size of multi-conformer databases and the number of query conformers, while simultaneously reproducing the bioactive conformer with good accuracy, is of crucial interest. While clustering and RMSD filtering methods are employed in existing conformer generators, the novelty of this work is the inclusion of a clustering scheme (NMRCLUST) that does not require a user-defined cut-off value. This algorithm simultaneously optimizes the number and the average spread of the clusters. Here we describe and test four inter-dependent approaches for selecting computer-generated conformers, namely: OMEGA, NMRCLUST, RMS filtering and averaged- RMS filtering. The bioactive conformations of 65 selected ligands were extracted from the corresponding protein:ligand complexes from the Protein Data Bank, including eight ligands that adopted dissimilar bound conformations within different receptors. We show that NMRCLUST can be employed to further filter OMEGA-generated conformers while maintaining biological relevance of the ensemble. It was observed that NMRCLUST (containing on average 10 times fewer conformers per compound) performed nearly as well as OMEGA, and both outperformed RMS filtering and averaged- RMS filtering in terms of identifying the bioactive conformations with excellent and good matches (0.5 < RMSD < 1.0 Å). Furthermore, we propose thresholds for OMEGA root-mean square filtering depending on the number of rotors in a compound: 0.8, 1.0 and 1.4 for structures with low (1-4), medium (5-9) and high (10-15) numbers of rotatable bonds, respectively. The protocol employed is general and can be applied to reduce the number of conformers in multi-conformer compound collections and alleviate the complexity of downstream data processing in virtual screening experiments.

Predicting bioactive conformations and binding modes of macrocycles

NASA Astrophysics Data System (ADS)

Anighoro, Andrew; de la Vega de León, Antonio; Bajorath, Jürgen

2016-10-01

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.

Homologous ligands accommodated by discrete conformations of a buried cavity

PubMed Central

Merski, Matthew; Fischer, Marcus; Balius, Trent E.; Eidam, Oliv; Shoichet, Brian K.

2015-01-01

Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design. PMID:25847998

Homologous ligands accommodated by discrete conformations of a buried cavity.

PubMed

Merski, Matthew; Fischer, Marcus; Balius, Trent E; Eidam, Oliv; Shoichet, Brian K

2015-04-21

Conformational change in protein-ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design.

Cyclo-biphenalenyl Biradicaloid Molecular Materials: Conformation, Tautomerization, Magnetism, and Thermochromism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Jingsong; Meunier, Vincent; Tian, Yong-Hui

2010-01-01

Phenalenyl and its derivatives have recently attracted a great deal of interest as a result of a two-electron multicenter (2e/mc) - bonding between two -stacked phenalenyl units. The 2e/mc bonded -dimers are close in energy to the -dimers of phenalenyl and therefore fickle properties may emerge from bond fluctuation, yielding smart -functional materials. Here, we examine the valence tautomerization of two cyclo-biphenalenyl biradicaloid molecular materials with chair and boat conformations by spin-restricted (R) and unrestricted (U) DFT using the M06 and B3LYP functionals. We found that the chair conformation involves a 2e/4c - bonded structure, whereas the boat conformation involvesmore » a 2e/12c - bonded structure on their potential energy surfaces. The global minimum for the chair conformation is the -bonded structure, whereas it is the - bonded structure for the boat conformation. The chair conformation exhibits a stepwise [3,3]-sigmatropic rearrangement, and calculations predict a negligible paramagnetic susceptibility near room temperature. In comparison, the paramagnetism of the boat conformation should be observable by SQUID and ESR. According to the energy differences of the respective - and -dimers of the two conformations and the UV-vis calculations, the color of the chair conformation is expected to become darker, whereas that of the boat conformation should become lighter with increasing temperature.« less

Coexisting stable conformations of gaseous protein ions.

PubMed Central

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

1993-01-01

For further insight into the role of solvent in protein conformer stabilization, the structural and dynamic properties of protein ions in vacuo have been probed by hydrogen-deuterium exchange in a Fourier-transform mass spectrometer. Multiply charged ions generated by electrospray ionization of five proteins show exchange reactions with 2H2O at 10(-7) torr (1 torr = 133.3 Pa) exhibiting pseudo-first-order kinetics. Gas-phase compactness of the S-S cross-linked RNase A relative to denatured S-derivatized RNase A is indicated by exchange of 35 and 135 hydrogen atoms, respectively. For pure cytochrome c ions, the existence of at least three distinct gaseous conformers is indicated by the substantially different values--52, 113, and 74--of reactive H atoms; the observation of these same values for ions of a number--2, 7, and 5, respectively--of different charge states indicates conformational insensitivity to coulombic forces. For each of these conformers, the compactness in vacuo indicated by these values corresponds directly to that of a known conformer structure in the solution from which the conformer ions are produced by electrospray. S-derivatized RNase A ions also exist as at least two gaseous conformers exchanging 50-140 H atoms. Gaseous conformer ions are isometrically stable for hours; removal of solvent greatly increases conformational rigidity. More specific ion-molecule reactions could provide further details of conformer structures. Images PMID:8381533

Invariant classification of second-order conformally flat superintegrable systems

NASA Astrophysics Data System (ADS)

Capel, J. J.; Kress, J. M.

2014-12-01

In this paper we continue the work of Kalnins et al in classifying all second-order conformally-superintegrable (Laplace-type) systems over conformally flat spaces, using tools from algebraic geometry and classical invariant theory. The results obtained show, through Stäckel equivalence, that the list of known nondegenerate superintegrable systems over three-dimensional conformally flat spaces is complete. In particular, a seven-dimensional manifold is determined such that each point corresponds to a conformal class of superintegrable systems. This manifold is foliated by the nonlinear action of the conformal group in three dimensions. Two systems lie in the same conformal class if and only if they lie in the same leaf of the foliation. This foliation is explicitly described using algebraic varieties formed from representations of the conformal group. The proof of these results rely heavily on Gröbner basis calculations using the computer algebra software packages Maple and Singular.

Conformational changes in matrix-isolated 6-methoxyindole: Effects of the thermal and infrared light excitations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lopes Jesus, A. J.; CQC, Faculty of Pharmacy, University of Coimbra, 3004-295 Coimbra; Reva, I., E-mail: reva@qui.uc.pt

2016-03-28

Conformational changes induced thermally or upon infrared excitation of matrix-isolated 6-methoxyindole were investigated. Narrowband near-infrared excitation of the first overtone of the N–H stretching vibration of each one of the two identified conformers is found to induce a selective large-scale conversion of the pumped conformer into the other one. This easily controllable bidirectional process consists in the intramolecular reorientation of the methoxy group and allowed a full assignment of the infrared spectra of the two conformers. Matrices with different conformational compositions prepared by narrow-band irradiations were subsequently used to investigate the effects of both thermal and broadband infrared excitations onmore » the conformational mixtures. Particular attention is given to the influence of the matrix medium (Ar vs. Xe) and conformational effects of exposition of the sample to the spectrometer light source during the measurements.« less

Force-Manipulation Single-Molecule Spectroscopy Studies of Enzymatic Dynamics

NASA Astrophysics Data System (ADS)

Lu, H. Peter; He, Yufan; Lu, Maolin; Cao, Jin; Guo, Qing

2014-03-01

Subtle conformational changes play a crucial role in protein functions, especially in enzymatic reactions involving complex substrate-enzyme interactions and chemical reactions. We applied AFM-enhanced and magnetic tweezers-correlated single-molecule spectroscopy to study the mechanisms and dynamics of enzymatic reactions involved with kinase and lysozyme proteins. Enzymatic reaction turnovers and the associated structure changes of individual protein molecules were observed simultaneously in real-time by single-molecule FRET detections. Our single-molecule spectroscopy measurements of enzymatic conformational dynamics have revealed time bunching effect and intermittent coherence in conformational state change dynamics involving in enzymatic reaction cycles. The coherent conformational state dynamics suggests that the enzymatic catalysis involves a multi-step conformational motion along the coordinates of substrate-enzyme complex formation and product releasing. Our results support a multiple-conformational state model, being consistent with a complementary conformation selection and induced-fit enzymatic loop-gated conformational change mechanism in substrate-enzyme active complex formation.

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.

Linear Response Path Following: A Molecular Dynamics Method To Simulate Global Conformational Changes of Protein upon Ligand Binding.

PubMed

Tamura, Koichi; Hayashi, Shigehiko

2015-07-14

Molecular functions of proteins are often fulfilled by global conformational changes that couple with local events such as the binding of ligand molecules. High molecular complexity of proteins has, however, been an obstacle to obtain an atomistic view of the global conformational transitions, imposing a limitation on the mechanistic understanding of the functional processes. In this study, we developed a new method of molecular dynamics (MD) simulation called the linear response path following (LRPF) to simulate a protein's global conformational changes upon ligand binding. The method introduces a biasing force based on a linear response theory, which determines a local reaction coordinate in the configuration space that represents linear coupling between local events of ligand binding and global conformational changes and thus provides one with fully atomistic models undergoing large conformational changes without knowledge of a target structure. The overall transition process involving nonlinear conformational changes is simulated through iterative cycles consisting of a biased MD simulation with an updated linear response force and a following unbiased MD simulation for relaxation. We applied the method to the simulation of global conformational changes of the yeast calmodulin N-terminal domain and successfully searched out the end conformation. The atomistically detailed trajectories revealed a sequence of molecular events that properly lead to the global conformational changes and identified key steps of local-global coupling that induce the conformational transitions. The LRPF method provides one with a powerful means to model conformational changes of proteins such as motors and transporters where local-global coupling plays a pivotal role in their functional processes.

Relating conformation to function in integrin α5β1.

PubMed

Su, Yang; Xia, Wei; Li, Jing; Walz, Thomas; Humphries, Martin J; Vestweber, Dietmar; Cabañas, Carlos; Lu, Chafen; Springer, Timothy A

2016-07-05

Whether β1 integrin ectodomains visit conformational states similarly to β2 and β3 integrins has not been characterized. Furthermore, despite a wealth of activating and inhibitory antibodies to β1 integrins, the conformational states that these antibodies stabilize, and the relation of these conformations to function, remain incompletely characterized. Using negative-stain electron microscopy, we show that the integrin α5β1 ectodomain adopts extended-closed and extended-open conformations as well as a bent conformation. Antibodies SNAKA51, 8E3, N29, and 9EG7 bind to different domains in the α5 or β1 legs, activate, and stabilize extended ectodomain conformations. Antibodies 12G10 and HUTS-4 bind to the β1 βI domain and hybrid domains, respectively, activate, and stabilize the open headpiece conformation. Antibody TS2/16 binds a similar epitope as 12G10, activates, and appears to stabilize an open βI domain conformation without requiring extension or hybrid domain swing-out. mAb13 and SG/19 bind to the βI domain and βI-hybrid domain interface, respectively, inhibit, and stabilize the closed conformation of the headpiece. The effects of the antibodies on cell adhesion to fibronectin substrates suggest that the extended-open conformation of α5β1 is adhesive and that the extended-closed and bent-closed conformations are nonadhesive. The functional effects and binding sites of antibodies and fibronectin were consistent with their ability in binding to α5β1 on cell surfaces to cross-enhance or inhibit one another by competitive or noncompetitive (allosteric) mechanisms.

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

DOE PAGES

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew; ...

2015-09-30

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Altogether, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Altogether, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Conformation-dependent chemical reaction of formic acid with an oxygen atom.

PubMed

Khriachtchev, Leonid; Domanskaya, Alexandra; Marushkevich, Kseniya; Räsänen, Markku; Grigorenko, Bella; Ermilov, Alexander; Andrijchenko, Natalya; Nemukhin, Alexander

2009-07-23

Conformation dictates many physical and chemical properties of molecules. The importance of conformation in the selectivity and function of biologically active molecules is widely accepted. However, clear examples of conformation-dependent bimolecular chemical reactions are lacking. Here we consider a case of formic acid (HCOOH) that is a valuable model system containing the -COOH carboxyl functional group, similar to many biomolecules including the standard amino acids. We have found a strong case of conformation-dependent reaction between formic acid and atomic oxygen obtained in cryogenic matrices. The reaction surprisingly leads to peroxyformic acid only from the ground-state trans conformer of formic acid, and it results in the hydrogen-bonded complex for the higher-energy cis conformer.

Conformal geodesics in spherically symmetric vacuum spacetimes with cosmological constant

NASA Astrophysics Data System (ADS)

García-Parrado Gómez-Lobo, A.; Gasperín, E.; Valiente Kroon, J. A.

2018-02-01

An analysis of conformal geodesics in the Schwarzschild–de Sitter and Schwarzschild–anti-de Sitter families of spacetimes is given. For both families of spacetimes we show that initial data on a spacelike hypersurface can be given such that the congruence of conformal geodesics arising from this data cover the whole maximal extension of canonical conformal representations of the spacetimes without forming caustic points. For the Schwarzschild–de Sitter family, the resulting congruence can be used to obtain global conformal Gaussian systems of coordinates of the conformal representation. In the case of the Schwarzschild–anti-de Sitter family, the natural parameter of the curves only covers a restricted time span so that these global conformal Gaussian systems do not exist.

78 FR 29027 - Approval and Promulgation of Implementation Plans; Tennessee; Transportation Conformity Revisions

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-17

... revision includes the transportation conformity consultation, conflict resolution and public participation... conformity consultation, conflict resolution and public participation procedures for Montgomery County... revision updates the transportation conformity consultation, conflict resolution and public participation...

Complexin induces a conformational change at the membrane-proximal C-terminal end of the SNARE complex

PubMed Central

Choi, Ucheor B; Zhao, Minglei; Zhang, Yunxiang; Lai, Ying; Brunger, Axel T

2016-01-01

Complexin regulates spontaneous and activates Ca2+-triggered neurotransmitter release, yet the molecular mechanisms are still unclear. Here we performed single molecule fluorescence resonance energy transfer experiments and uncovered two conformations of complexin-1 bound to the ternary SNARE complex. In the cis conformation, complexin-1 induces a conformational change at the membrane-proximal C-terminal end of the ternary SNARE complex that specifically depends on the N-terminal, accessory, and central domains of complexin-1. The complexin-1 induced conformation of the ternary SNARE complex may be related to a conformation that is juxtaposing the synaptic vesicle and plasma membranes. In the trans conformation, complexin-1 can simultaneously interact with a ternary SNARE complex via the central domain and a binary SNARE complex consisting of syntaxin-1A and SNAP-25A via the accessory domain. The cis conformation may be involved in activation of synchronous neurotransmitter release, whereas both conformations may be involved in regulating spontaneous release. DOI: http://dx.doi.org/10.7554/eLife.16886.001 PMID:27253060

Two intermediate states of the conformational switch in dual specificity phosphatase 13a.

PubMed

Wei, Chun Hwa; Min, Hee Gyeong; Kim, Myeongbin; Kim, Gwan Hee; Chun, Ha-Jung; Ryu, Seong Eon

2018-02-01

Dual specificity phosphatases (DUSPs) include MAP kinase phosphatases and atypical dual specificity phosphatases and mediate cell growth and differentiation, brain function, and immune responses. They serve as targets for drug development against cancers, diabetes and depression. Several DUSPs have non-canonical conformation of the central β-sheet and active site loops, suggesting that they may have conformational switch that is related to the regulation of enzyme activity. Here, we determined the crystal structure of DUSP13a, and identified two different structures that represent intermediates of the postulated conformational switch. Amino acid sequence of DUSP13a is not significantly homologous to DUSPs with conformational switch, indicating that the conformational switch is not sequence-dependent, but rather determined by ligand interaction. The sequence-independency suggests that other DUSPs with canonical conformation may have the conformational switch during specific cellular regulation. The conformational switch leads to significant changes in the protein surface, including a hydrophobic surface and pockets, which can be exploited for development of allosteric modulators of drug target DUSPs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rotational Spectroscopy and Conformational Studies of 4-PENTYNENITRILE, 4-PENTENENITRILE, and Glutaronitrile

NASA Astrophysics Data System (ADS)

Hays, Brian M.; Mehta-Hurt, Deepali; Jawad, Khadija M.; Hernandez-Castillo, Alicia O.; Abeysekera, Chamara; Zhang, Di; Zwier, Timothy S.

2017-06-01

The pure rotational spectra of 4-pentynenitrile, 4-pentenenitrile, and glutaronitrile were acquired using chirped pulse Fouirer transform microwave spectroscopy. 4-pentynenitrile and 4-pentenenitrile are the recombination products of two resonance stabilized radicals, propargyl + cyanomethyl or allyl + cyanomethyl, respectively, and are thus anticipated to be significant among the more complex nitriles in Titan's atmosphere. Indeed, these partially unsaturated alkyl cyanides have been found in laboratory analogs of tholins and are also expected to have interesting photochemistry. The optimized structures of all conformers below predicted energies of 500 \\wn were calculated for each molecule. Both of the conformers, trans and gauche, for 4-pentynenitrile have been identified and assigned. Five conformers were assigned in 4-pentenenitrile. The eclipsed conformers, with respect to the vinyl group, dominate the spectrum but some population was found in the syn conformers including the syn-gauche conformer, calculated to be 324 \\wn above the global minimum. The glutaronitrile spectrum contained only the two conformers below 500 \\wn, with reduced amount of the gauche trans conformer. The assigned spectra and structural assignments will be presented.

Sialyldisaccharide conformations: a molecular dynamics perspective

NASA Astrophysics Data System (ADS)

Selvin, Jeyasigamani F. A.; Priyadarzini, Thanu R. K.; Veluraja, Kasinadar

2012-04-01

Sialyldisaccharides are significant terminal components of glycoconjugates and their negative charge and conformation are extensively utilized in molecular recognition processes. The conformation and flexibility of four biologically important sialyldisaccharides [Neu5Acα(2-3)Gal, Neu5Acα(2-6)Gal, Neu5Acα(2-8)Neu5Ac and Neu5Acα(2-9)Neu5Ac] are studied using Molecular Dynamics simulations of 20 ns duration to deduce the conformational preferences of the sialyldisaccharides and the interactions which stabilize the conformations. This study clearly describes the possible conformational models of sialyldisaccharides deduced from 20 ns Molecular Dynamics simulations and our results confirm the role of water in the structural stabilization of sialyldisaccharides. An extensive analysis on the sialyldisaccharide structures available in PDB also confirms the conformational regions found by experiments are detected in MD simulations of 20 ns duration. The three dimensional structural coordinates for all the MD derived sialyldisaccharide conformations are deposited in the 3DSDSCAR database and these conformational models will be useful for glycobiologists and biotechnologists to understand the biological functions of sialic acid containing glycoconjugates.

REVIEW: High pressure NMR study of proteins - seeking roots for function, evolution, disease and food applications

NASA Astrophysics Data System (ADS)

Akasaka, Kazuyuki

2010-12-01

NMR experiments at variable pressure reveal a wide range of conformation of a globular protein spanning from within the folded ensemble to the fully unfolded ensemble, herewith collectively called "high-energy conformers". The observation of "high-energy conformers" in a wide variety of globular proteins has led to the "volume theorem": the partial molar volume of a protein decreases with the decrease in its conformational order. Since "high-energy conformers" are intrinsically more reactive than the basic folded conformer, they could play decisive roles in all phenomena of proteins, namely function, environmental adaptation and misfolding. Based on the information on high-energy conformers and the rules on their partial volume in its monomeric state and amyloidosis, one may have a general view on what is happening on proteins under pressure. Moreover, one may even choose a high-energy conformer of a protein with pressure as variable for a particular purpose. Bridging "high-energy conformers" to macroscopic pressure effects could be a key to success in pressure application to biology, medicine, food technology and industry in the near future.

PubChem3D: conformer ensemble accuracy

PubMed Central

2013-01-01

Background PubChem is a free and publicly available resource containing substance descriptions and their associated biological activity information. PubChem3D is an extension to PubChem containing computationally-derived three-dimensional (3-D) structures of small molecules. All the tools and services that are a part of PubChem3D rely upon the quality of the 3-D conformer models. Construction of the conformer models currently available in PubChem3D involves a clustering stage to sample the conformational space spanned by the molecule. While this stage allows one to downsize the conformer models to more manageable size, it may result in a loss of the ability to reproduce experimentally determined “bioactive” conformations, for example, found for PDB ligands. This study examines the extent of this accuracy loss and considers its effect on the 3-D similarity analysis of molecules. Results The conformer models consisting of up to 100,000 conformers per compound were generated for 47,123 small molecules whose structures were experimentally determined, and the conformers in each conformer model were clustered to reduce the size of the conformer model to a maximum of 500 conformers per molecule. The accuracy of the conformer models before and after clustering was evaluated using five different measures: root-mean-square distance (RMSD), shape-optimized shape-Tanimoto (STST-opt) and combo-Tanimoto (ComboTST-opt), and color-optimized color-Tanimoto (CTCT-opt) and combo-Tanimoto (ComboTCT-opt). On average, the effect of clustering decreased the conformer model accuracy, increasing the conformer ensemble’s RMSD to the bioactive conformer (by 0.18 ± 0.12 Å), and decreasing the STST-opt, ComboTST-opt, CTCT-opt, and ComboTCT-opt scores (by 0.04 ± 0.03, 0.16 ± 0.09, 0.09 ± 0.05, and 0.15 ± 0.09, respectively). Conclusion This study shows the RMSD accuracy performance of the PubChem3D conformer models is operating as designed. In addition, the effect of PubChem3D sampling on 3-D similarity measures shows that there is a linear degradation of average accuracy with respect to molecular size and flexibility. Generally speaking, one can likely expect the worst-case minimum accuracy of 90% or more of the PubChem3D ensembles to be 0.75, 1.09, 0.43, and 1.13, in terms of STST-opt, ComboTST-opt, CTCT-opt, and ComboTCT-opt, respectively. This expected accuracy improves linearly as the molecule becomes smaller or less flexible. PMID:23289532

Predicting heterocyclic ring coupling constants through a conformational search of tetra-O-methyl-(+)-catechin

Treesearch

Fred L. Tobiason; Richard W. Hemingway

1994-01-01

A GMMX conformational search routine gives a family of conformations that reflects the Boltzmann-averaged heterocyclic ring conformation as evidenced by accurate prediction of all three coupling constants observed for tetra-O-methyl-(+)-catechin.

Predicting heterocyclic ring coupling constants through a conformational search of tetra-o-methyl-(+)-catechin

Treesearch

Fred L. Tobiason; Richard w. Hemingway

1994-01-01

A GMMXe conformational search routine gives a family a conformations that reflects the boltzmann-averaged heterocyclic ring conformation as evidence by accurate prediction of all three coupling constants observed for tetra-O-methyl-(+)-catechin.

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 of...

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 of...

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 of...

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 of...

Supersymmetric Yang-Mills theory on conformal supergravity backgrounds in ten dimensions

NASA Astrophysics Data System (ADS)

de Medeiros, Paul; Figueroa-O'Farrill, José

2016-03-01

We consider bosonic supersymmetric backgrounds of ten-dimensional conformal supergravity. Up to local conformal isometry, we classify the maximally supersymmetric backgrounds, determine their conformal symmetry superalgebras and show how they arise as near-horizon geometries of certain half-BPS backgrounds or as a plane-wave limit thereof. We then show how to define Yang-Mills theory with rigid supersymmetry on any supersymmetric conformal supergravity background and, in particular, on the maximally supersymmetric backgrounds. We conclude by commenting on a striking resemblance between the supersymmetric backgrounds of ten-dimensional conformal supergravity and those of eleven-dimensional Poincaré supergravity.

Conformational properties of chiral tobacco alkaloids by DFT calculations and vibrational circular dichroism: (-)-S-anabasine.

PubMed

Rodríguez Ortega, P G; Montejo, M; Márquez, F; López González, J J

2015-07-01

A thorough DFT and MM study of the conformational landscape, molecular and electronic structures of (-)-S-anabasine is reported aimed to reveal the mechanism controlling its conformational preference. Although the conformational flexibility and diversity of this system is quite extensive, only two structures are populated both in gas-phase and solution (CCl4 and DMSO). NBO-aided electronic structure analyses performed for the eight conformers representing minima in the potential energy surface of (-)-S-anabasine indicate that both steric and electrostatic factors are determinant in the conformational distribution of the sample in gas phase. Nonetheless, hyperconjugative effects are the key force tipping the balance in the conformational equilibrium between the two main rotamers. Increasing the polarity of the medium (using the IEF-PCM formalism) barely affect the conformational energy profile, although a slight increase in the theoretical population of those structures more affected by electrostatic interactions is predicted. The validity of the theoretical models and calculated conformers populations are endorsed by the accurate reproduction of the IR and VCD spectra (recorded in pure liquid and in CCl4 solution) of the sample (that have been firstly recorded and assigned in the present work) which are consistent with the occurrence of a 2:1 conformational ratio. Copyright © 2015 Elsevier Inc. All rights reserved.

Is non-conformity WEIRD? Cultural variation in adults' beliefs about children's competency and conformity.

PubMed

Clegg, Jennifer M; Wen, Nicole J; Legare, Cristine H

2017-03-01

Cross-cultural comparisons provide critical insight into variation in reasoning about intelligence. In two studies, the authors used a novel methodology based on multivocal ethnography to assess the role of conformity in U.S. and Ni-Vanuatu adults' judgments of children's intelligence and, as a comparison trait, good behavior. In Study 1, there were cultural differences in the impact of conformity on U.S. and Ni-Vanuatu adults' judgments of children's intelligence and good behavior. When evaluating U.S. children only, U.S. adults were less likely to endorse high conformity children as intelligent, often citing creativity as a justification for their judgments. In contrast, Ni-Vanuatu adults were more likely to endorse Ni-Vanuatu high conformity children as intelligent. Ni-Vanuatu adults were also more likely to endorse high conformity children as well-behaved than U.S. adults. In Study 2, there were no effects of socioeconomic status on U.S. adults' evaluations of conformity. U.S. adults were less likely to endorse high conformity children as intelligent than Ni-Vanuatu adults. Taken together, the data demonstrate that beliefs about the relations between intelligence, conformity, and creativity vary within and across cultures. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Single-Molecule Spectroscopy and Imaging Studies of Protein Dynamics

NASA Astrophysics Data System (ADS)

Lu, H. Peter

2012-04-01

Enzymatic reactions and protein-protein interactions are traditionally studied at the ensemble level, despite significant static and dynamic inhomogeneities. Subtle conformational changes play a crucial role in protein functions, and these protein conformations are highly dynamic rather than being static. We applied AFM-enhanced single-molecule spectroscopy to study the mechanisms and dynamics of enzymatic reactions involved with kinase and lysozyme proteins. Enzymatic reaction turnovers and the associated structure changes of individual protein molecules were observed simultaneously in real-time by single-molecule FRET detections. Our single-molecule spectroscopy measurements of T4 lysozyme and HPPK enzymatic conformational dynamics have revealed time bunching effect and intermittent coherence in conformational state change dynamics involving in enzymatic reaction cycles. The coherent conformational state dynamics suggests that the enzymatic catalysis involves a multi-step conformational motion along the coordinates of substrate-enzyme complex formation and product releasing, presenting as an extreme dynamic behavior intrinsically related to the time bunching effect that we have reported previously. Our results of HPPK interaction with substrate support a multiple-conformational state model, being consistent with a complementary conformation selection and induced-fit enzymatic loop-gated conformational change mechanism in substrate-enzyme active complex formation. Our new approach is applicable to a wide range of single-molecule FRET measurements for protein conformational changes under enzymatic reactions.

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

Cyclo-biphenalenyl biradicaloid molecular materials: conformation, tautomerization, magnetism, and thermochromism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Jingsong; Sumpter, Bobby G; Meunier, Vincent

2011-01-01

Phenalenyl and its derivatives have recently attracted a great deal of interest as a result of a 2-electron multicenter (2e/mc) covalent pi-pi bonding between two pi-stacked phenalenyl units. The 2e/mc bonded pi-dimers are close in energy to the sigma-dimers of phenalenyl and therefore fickle properties may emerge from bond fluctuation, yielding smart pi-functional materials. Here we examine the valence tautomerization of two cyclo-biphenalenyl biradicaloid molecular materials with chair- and boat-conformations by spin-restricted (R) and unrestricted (U) DFT using the M06 and B3LYP functionals. We found that the chair-conformation involves a 2e/4c pi-pi bonded structure while the boat-conformation involves a 2e/12cmore » pi-pi bonded structure on their potential energy surfaces. The global minimum for the chair-conformation is the sigma-bonded structure while it is the pi-pi bonded structure for the boat-conformation. The chair-conformation exhibits a stepwise [3,3]-sigmatropic rearrangement, and calculations predict a negligible paramagnetic susceptibility near room temperature. In comparison, the paramagnetism of the boat-conformation should be observable by SQUID and/or ESR. According to the difference of the global minima of the two conformations and the parameterized UV-Vis calculations, the color of the chair-conformation is expected to become darker while that of the boat-conformation become lighter with increasing temperature.« less

Conformity and Psychopathology: A Comparative Study of Conformity Behaviors in Manic-depressive, Paranoid Schizophrenic and Normal Populations

ERIC Educational Resources Information Center

Marsella, Anthony J.

1975-01-01

The present study investigated the relationship between conformity and psychopathology in male and female manic-depressive (MD), paranoid schizophrenics (PS), and normals (N) on two conformity tasks under conditions of live social pressure. (Author)

14 CFR 21.53 - Statement of conformity.

Code of Federal Regulations, 2011 CFR

2011-01-01

... each aircraft engine and propeller presented to the Administrator for type certification. This statement of conformity must include a statement that the aircraft engine or propeller conforms to the type... aircraft engine or propeller presented for type certification conforms to its type design. ...

Conformable derivative approach to anomalous diffusion

NASA Astrophysics Data System (ADS)

Zhou, H. W.; Yang, S.; Zhang, S. Q.

2018-02-01

By using a new derivative with fractional order, referred to conformable derivative, an alternative representation of the diffusion equation is proposed to improve the modeling of anomalous diffusion. The analytical solutions of the conformable derivative model in terms of Gauss kernel and Error function are presented. The power law of the mean square displacement for the conformable diffusion model is studied invoking the time-dependent Gauss kernel. The parameters related to the conformable derivative model are determined by Levenberg-Marquardt method on the basis of the experimental data of chloride ions transportation in reinforced concrete. The data fitting results showed that the conformable derivative model agrees better with the experimental data than the normal diffusion equation. Furthermore, the potential application of the proposed conformable derivative model of water flow in low-permeability media is discussed.

Conformational and stereoelectronic investigation in 1,2-difluoropropane: The gauche effect

NASA Astrophysics Data System (ADS)

Bitencourt, Michelle; Freitas, Matheus P.; Rittner, Roberto

2007-09-01

The effect of attaching an additional fluorine atom at C-2 in 1-fluoropropane (FP), giving 1,2-difluoropropane (DFP), on its conformational equilibrium, is theoretically evaluated. This substitution causes critical implications on the conformer stabilities of DFP (TG, GT and GG conformations) and the steric and electrostatic interactions should favor the conformer with fluorine atoms trans. However, the gauche effect plays a major role in describing the energies balance in DFP, shifting the equilibrium towards the conformation in which the two fluorine atoms are gauche. The origin of this effect is discussed through an NBO analysis, which allows the evaluation of both classical and non-classical (hyperconjugation and bent bonds) interactions as the prevailing factors governing the conformational equilibrium of molecules containing the 1,2-difluoroethane fragment.

Weight shifting operators and conformal blocks

NASA Astrophysics Data System (ADS)

Karateev, Denis; Kravchuk, Petr; Simmons-Duffin, David

2018-02-01

We introduce a large class of conformally-covariant differential operators and a crossing equation that they obey. Together, these tools dramatically simplify calculations involving operators with spin in conformal field theories. As an application, we derive a formula for a general conformal block (with arbitrary internal and external representations) in terms of derivatives of blocks for external scalars. In particular, our formula gives new expressions for "seed conformal blocks" in 3d and 4d CFTs. We also find simple derivations of identities between external-scalar blocks with different dimensions and internal spins. We comment on additional applications, including deriving recursion relations for general conformal blocks, reducing inversion formulae for spinning operators to inversion formulae for scalars, and deriving identities between general 6 j symbols (Racah-Wigner coefficients/"crossing kernels") of the conformal group.

An ab-initio study of the relative stability of the ggg and the gtg conformer in hexane

NASA Astrophysics Data System (ADS)

Koglin, Eckhard; Meier, Robert J.

1999-10-01

Earlier ab-initio work suggested, on the basis of MP2 level calculations, that the hexane ggg conformer is more stable than the gtg conformer. Because this is unexpected and if true might have a significant impact on force field parametrisations, we have applied Hartree-Fock and post-HF methods to evaluate the relative stability of these conformers. We find that at levels higher than MP2 the gtg conformer is more stable than the ggg conformer, in agreement with the conventional idea that each additional gauche bond causes a further decrease in stability of the conformer. DFT methods were also applied, but although DFT methods including gradient corrections show correct qualitative behaviour, quantitatively the relative energies are far off compared to the post-HF results.

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

PubMed Central

Keedy, Daniel A; Kenner, Lillian R; Warkentin, Matthew; Woldeyes, Rahel A; Hopkins, Jesse B; Thompson, Michael C; Brewster, Aaron S; Van Benschoten, Andrew H; Baxter, Elizabeth L; Uervirojnangkoorn, Monarin; McPhillips, Scott E; Song, Jinhu; Alonso-Mori, Roberto; Holton, James M; Weis, William I; Brunger, Axel T; Soltis, S Michael; Lemke, Henrik; Gonzalez, Ana; Sauter, Nicholas K; Cohen, Aina E; van den Bedem, Henry; Thorne, Robert E; Fraser, James S

2015-01-01

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences of these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function. DOI: http://dx.doi.org/10.7554/eLife.07574.001 PMID:26422513

A conformational study of protonated noradrenaline by UV-UV and IR dip double resonance laser spectroscopy combined with an electrospray and a cold ion trap method.

PubMed

Wako, Hiromichi; Ishiuchi, Shun-Ichi; Kato, Daichi; Féraud, Géraldine; Dedonder-Lardeux, Claude; Jouvet, Christophe; Fujii, Masaaki

2017-05-03

The conformer-selected ultraviolet (UV) and infrared (IR) spectra of protonated noradrenaline were measured using an electrospray/cryogenic ion trap technique combined with photo-dissociation spectroscopy. By comparing the UV photo dissociation (UVPD) spectra with the UV-UV hole burning (HB) spectra, it was found that five conformers coexist under ultra-cold conditions. Based on the spectral features of the IR dip spectra of each conformer, two different conformations on the amine side chain were identified. Three conformers (group I) were assigned to folded and others (group II) to extended structures by comparing the observed IR spectra with the calculated ones. Observation of the significantly less-stable extended conformers strongly suggests that the extended structures are dominant in solution and are detected in the gas phase by kinetic trapping. The conformers in each group are assignable to rotamers of OH orientations in the catechol ring. By comparing the UV-UV HB spectra and the calculated Franck-Condon spectra obtained by harmonic vibrational analysis of the S 1 state, with the aid of relative stabilization energies of each conformer in the S 0 state, the absolute orientations of catechol OHs of the observed five conformers were successfully determined. It was found that the 0-0 transition of one folded conformer is red-shifted by about 1000 cm -1 from the others. The significant red-shift was explained by a large contribution of the πσ* state to S 1 in the conformer in which an oxygen atom of the meta-OH group is close to the ammonium group.

MUFASA: the strength and evolution of galaxy conformity in various tracers

NASA Astrophysics Data System (ADS)

Rafieferantsoa, Mika; Davé, Romeel

2018-03-01

We investigate galaxy conformity using the MUFASA cosmological hydrodynamical simulation. We show a bimodal distribution in galaxy colour with radius, albeit with too many low-mass quenched satellite galaxies compared to observations. MUFASA produces conformity in observed properties such as colour, specific star formation rate (sSFR), and H I content, i.e. neighbouring galaxies have similar properties. We see analogous trends in other properties such as in environment, stellar age, H2 content, and metallicity. We introduce quantifying conformity using S(R), measuring the relative difference in upper and lower quartile properties of the neighbours. We show that low-mass and non-quenched haloes have weak conformity (S(R)≲ 0.5) extending to large projected radii R in all properties, while high-mass and quenched haloes have strong conformity (S(R)˜ 1) that diminishes rapidly with R and disappears at R ≳ 1 Mpc. S(R) is strongest for environment in low-mass haloes, and sSFR (or colour) in high-mass haloes, and is dominated by one-halo conformity with the exception of H I in small haloes. Metallicity shows a curious anticonformity in massive haloes. Tracking the evolution of conformity for z = 0 galaxies back in time shows that conformity broadly emerges as a late-time (z ≲ 1) phenomenon. However, for fixed halo mass bins, conformity is fairly constant with redshift out to z ≳ 2. These trends are consistent with the idea that strong conformity only emerges once haloes grow above MUFASA's quenching mass scale of ˜1012 M⊙. A quantitative measure of conformity in various properties, along with its evolution, thus represents a new and stringent test of the impact of quenching on environment within current galaxy formation models.

Vapor deposition routes to conformal polymer thin films

PubMed Central

Moni, Priya; Al-Obeidi, Ahmed

2017-01-01

Vapor phase syntheses, including parylene chemical vapor deposition (CVD) and initiated CVD, enable the deposition of conformal polymer thin films to benefit a diverse array of applications. This short review for nanotechnologists, including those new to vapor deposition methods, covers the basic theory in designing a conformal polymer film vapor deposition, sample preparation and imaging techniques to assess film conformality, and several applications that have benefited from vapor deposited, conformal polymer thin films. PMID:28487816

Stabilizing the boat conformation of cyclohexane rings

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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.

Essential role of conformational selection in ligand binding.

PubMed

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

2014-02-01

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 are 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] has been seen as diagnostic of conformational selection, while a value of kobs increasing hyperbolically with [L] has been considered diagnostic of induced fit. However, this simple conclusion is only valid under 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 with, 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 few cases. Therefore, the long assumed importance and preponderance of induced fit as a mechanism of ligand binding should be reconsidered. © 2013 Elsevier B.V. All rights reserved.

A Novel Method Using Abstract Convex Underestimation in Ab-Initio Protein Structure Prediction for Guiding Search in Conformational Feature Space.

PubMed

Hao, Xiao-Hu; Zhang, Gui-Jun; Zhou, Xiao-Gen; Yu, Xu-Feng

2016-01-01

To address the searching problem of protein conformational space in ab-initio protein structure prediction, a novel method using abstract convex underestimation (ACUE) based on the framework of evolutionary algorithm was proposed. Computing such conformations, essential to associate structural and functional information with gene sequences, is challenging due to the high-dimensionality and rugged energy surface of the protein conformational space. As a consequence, the dimension of protein conformational space should be reduced to a proper level. In this paper, the high-dimensionality original conformational space was converted into feature space whose dimension is considerably reduced by feature extraction technique. And, the underestimate space could be constructed according to abstract convex theory. Thus, the entropy effect caused by searching in the high-dimensionality conformational space could be avoided through such conversion. The tight lower bound estimate information was obtained to guide the searching direction, and the invalid searching area in which the global optimal solution is not located could be eliminated in advance. Moreover, instead of expensively calculating the energy of conformations in the original conformational space, the estimate value is employed to judge if the conformation is worth exploring to reduce the evaluation time, thereby making computational cost lower and the searching process more efficient. Additionally, fragment assembly and the Monte Carlo method are combined to generate a series of metastable conformations by sampling in the conformational space. The proposed method provides a novel technique to solve the searching problem of protein conformational space. Twenty small-to-medium structurally diverse proteins were tested, and the proposed ACUE method was compared with It Fix, HEA, Rosetta and the developed method LEDE without underestimate information. Test results show that the ACUE method can more rapidly and more efficiently obtain the near-native protein structure.

Toward Consistent Terminology for Cyclohexane Conformers in Introductory Organic Chemistry

ERIC Educational Resources Information Center

Nelson, Donna J.; Brammer, Christopher N.

2011-01-01

Recommended changes in use of cyclohexane conformers and their nomenclature will remedy inconsistencies in cyclohexane conformers and their nomenclature that exist across currently used organic chemistry textbooks. These inconsistencies prompted this logical analysis and the resulting recommendations. Recommended conformer names are "chair",…

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

PubMed Central

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

2013-01-01

The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning “induced fit” versus “conformational selection” has, however, ignored detoxication enzymes, which exhibit catalytic promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1–1 (GSTA1–1), exploits a molten globule-like active site to achieve remarkable catalytic promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic promiscuity is used to compare engineered variants of GSTA1–1 and the catalytic promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that “local” molten globule behavior optimizes detoxication enzymes. PMID:23649628

An Accurate Method for Measuring Airplane-Borne Conformal Antenna's Radar Cross Section

NASA Astrophysics Data System (ADS)

Guo, Shuxia; Zhang, Lei; Wang, Yafeng; Hu, Chufeng

2016-09-01

The airplane-borne conformal antenna attaches itself tightly with the airplane skin, so the conventional measurement method cannot determine the contribution of the airplane-borne conformal antenna to its radar cross section (RCS). This paper uses the 2D microwave imaging to isolate and extract the distribution of the reflectivity of the airplane-borne conformal antenna. It obtains the 2D spatial spectra of the conformal antenna through the wave spectral transform between the 2D spatial image and the 2D spatial spectrum. After the interpolation from the rectangular coordinate domain to the polar coordinate domain, the spectral domain data for the variation of the scatter of the conformal antenna with frequency and angle is obtained. The experimental results show that the measurement method proposed in this paper greatly enhances the airplane-borne conformal antenna's RCS measurement accuracy, essentially eliminates the influences caused by the airplane skin and more accurately reveals the airplane-borne conformal antenna's RCS scatter properties.

Molecular Simulation Uncovers the Conformational Space of the λ Cro Dimer in Solution

PubMed Central

Ahlstrom, Logan S.; Miyashita, Osamu

2011-01-01

The significant variation among solved structures of the λ Cro dimer suggests its flexibility. However, contacts in the crystal lattice could have stabilized a conformation which is unrepresentative of its dominant solution form. Here we report on the conformational space of the Cro dimer in solution using replica exchange molecular dynamics in explicit solvent. The simulated ensemble shows remarkable correlation with available x-ray structures. Network analysis and a free energy surface reveal the predominance of closed and semi-open dimers, with a modest barrier separating these two states. The fully open conformation lies higher in free energy, indicating that it requires stabilization by DNA or crystal contacts. Most NMR models are found to be unstable conformations in solution. Intersubunit salt bridging between Arg4 and Glu53 during simulation stabilizes closed conformations. Because a semi-open state is among the low-energy conformations sampled in simulation, we propose that Cro-DNA binding may not entail a large conformational change relative to the dominant dimer forms in solution. PMID:22098751

Bioactive focus in conformational ensembles: a pluralistic approach

NASA Astrophysics Data System (ADS)

Habgood, Matthew

2017-12-01

Computational generation of conformational ensembles is key to contemporary drug design. Selecting the members of the ensemble that will approximate the conformation most likely to bind to a desired target (the bioactive conformation) is difficult, given that the potential energy usually used to generate and rank the ensemble is a notoriously poor discriminator between bioactive and non-bioactive conformations. In this study an approach to generating a focused ensemble is proposed in which each conformation is assigned multiple rankings based not just on potential energy but also on solvation energy, hydrophobic or hydrophilic interaction energy, radius of gyration, and on a statistical potential derived from Cambridge Structural Database data. The best ranked structures derived from each system are then assembled into a new ensemble that is shown to be better focused on bioactive conformations. This pluralistic approach is tested on ensembles generated by the Molecular Operating Environment's Low Mode Molecular Dynamics module, and by the Cambridge Crystallographic Data Centre's conformation generator software.

Probing RNA Native Conformational Ensembles with Structural Constraints.

PubMed

Fonseca, Rasmus; van den Bedem, Henry; Bernauer, Julie

2016-05-01

Noncoding ribonucleic acids (RNA) play a critical role in a wide variety of cellular processes, ranging from regulating gene expression to post-translational modification and protein synthesis. Their activity is modulated by highly dynamic exchanges between three-dimensional conformational substates, which are difficult to characterize experimentally and computationally. Here, we present an innovative, entirely kinematic computational procedure to efficiently explore the native ensemble of RNA molecules. Our procedure projects degrees of freedom onto a subspace of conformation space defined by distance constraints in the tertiary structure. The dimensionality reduction enables efficient exploration of conformational space. We show that the conformational distributions obtained with our method broadly sample the conformational landscape observed in NMR experiments. Compared to normal mode analysis-based exploration, our procedure diffuses faster through the experimental ensemble while also accessing conformational substates to greater precision. Our results suggest that conformational sampling with a highly reduced but fully atomistic representation of noncoding RNA expresses key features of their dynamic nature.

5-Ethynyl-2'-deoxycytidine: a DNA building block with a 'clickable' side chain.

PubMed

Seela, Frank; Mei, Hui; Xiong, Hai; Budow, Simone; Eickmeier, Henning; Reuter, Hans

2012-10-01

The title compound [systematic name: 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-ethynylpyrimidin-2(1H)-one], C(11)H(13)N(3)O(4), shows two conformations in the crystalline state. The N-glycosylic bonds of both conformers adopt similar conformations, with χ = -149.2 (1)° for conformer (I-1) and -151.4 (1)° for conformer (I-2), both in the anti range. The sugar residue of (I-1) shows a C2'-endo envelope conformation ((2)E, S-type), with P = 164.7 (1)° and τ(m) = 36.9 (1)°, while (I-2) shows a major C3'-exo sugar pucker (C3'-exo-C2'-endo, (3)T(2), S-type), with P = 189.2 (1)° and τ(m) = 33.3 (1)°. Both conformers participate in the formation of a layered three-dimensional crystal structure with a chain-like arrangement of the conformers. The ethynyl groups do not participate in hydrogen bonding, but are arranged in proximal positions.

Entanglement evolution across a conformal interface

NASA Astrophysics Data System (ADS)

Wen, Xueda; Wang, Yuxuan; Ryu, Shinsei

2018-05-01

For two-dimensional conformal field theories (CFTs) in the ground state, it is known that a conformal interface along the entanglement cut can suppress the entanglement entropy from to , where L is the length of the subsystem A, and is the effective central charge which depends on the transmission property of the conformal interface. In this work, by making use of conformal mappings, we show that a conformal interface has the same effect on entanglement evolution in non-equilibrium cases, including global, local and certain inhomogeneous quantum quenches. I.e. a conformal interface suppresses the time evolution of entanglement entropy by effectively replacing the central charge c with , where is exactly the same as that in the ground state case. We confirm this conclusion by a numerical study on a critical fermion chain. Furthermore, based on the quasi-particle picture, we conjecture that this conclusion holds for an arbitrary quantum quench in CFTs, as long as the initial state can be described by a regularized conformal boundary state.

Dynamic clustering threshold reduces conformer ensemble size while maintaining a biologically relevant ensemble

PubMed Central

Yongye, Austin B.; Bender, Andreas

2010-01-01

Representing the 3D structures of ligands in virtual screenings via multi-conformer ensembles can be computationally intensive, especially for compounds with a large number of rotatable bonds. Thus, reducing the size of multi-conformer databases and the number of query conformers, while simultaneously reproducing the bioactive conformer with good accuracy, is of crucial interest. While clustering and RMSD filtering methods are employed in existing conformer generators, the novelty of this work is the inclusion of a clustering scheme (NMRCLUST) that does not require a user-defined cut-off value. This algorithm simultaneously optimizes the number and the average spread of the clusters. Here we describe and test four inter-dependent approaches for selecting computer-generated conformers, namely: OMEGA, NMRCLUST, RMS filtering and averaged-RMS filtering. The bioactive conformations of 65 selected ligands were extracted from the corresponding protein:ligand complexes from the Protein Data Bank, including eight ligands that adopted dissimilar bound conformations within different receptors. We show that NMRCLUST can be employed to further filter OMEGA-generated conformers while maintaining biological relevance of the ensemble. It was observed that NMRCLUST (containing on average 10 times fewer conformers per compound) performed nearly as well as OMEGA, and both outperformed RMS filtering and averaged-RMS filtering in terms of identifying the bioactive conformations with excellent and good matches (0.5 < RMSD < 1.0 Å). Furthermore, we propose thresholds for OMEGA root-mean square filtering depending on the number of rotors in a compound: 0.8, 1.0 and 1.4 for structures with low (1–4), medium (5–9) and high (10–15) numbers of rotatable bonds, respectively. The protocol employed is general and can be applied to reduce the number of conformers in multi-conformer compound collections and alleviate the complexity of downstream data processing in virtual screening experiments. Electronic supplementary material The online version of this article (doi:10.1007/s10822-010-9365-1) contains supplementary material, which is available to authorized users. PMID:20499135

Structure-activity relationships of pyrethroid insecticides. Part 2. The use of molecular dynamics for conformation searching and average parameter calculation

NASA Astrophysics Data System (ADS)

Hudson, Brian D.; George, Ashley R.; Ford, Martyn G.; Livingstone, David J.

1992-04-01

Molecular dynamics simulations have been performed on a number of conformationally flexible pyrethroid insecticides. The results indicate that molecular dynamics is a suitable tool for conformational searching of small molecules given suitable simulation parameters. The structures derived from the simulations are compared with the static conformation used in a previous study. Various physicochemical parameters have been calculated for a set of conformations selected from the simulations using multivariate analysis. The averaged values of the parameters over the selected set (and the factors derived from them) are compared with the single conformation values used in the previous study.

Conformers of CL-20 explosive and ab initio refinement using perturbation theory: implications to detonation mechanisms.

PubMed

Molt, Robert W; Bartlett, Rodney J; Watson, Thomas; Bazanté, Alexandre P

2012-12-13

We have identified the major conformers of CL-20 explosive, otherwise known as 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane, more formally known as 2,4,6,8,10,12-hexanitrohexaazatetracyclo[5.5.0.0]-dodecane, via Monte Carlo search in conformational space through molecular mechanics and subsequent quantum mechanical refinement using perturbation theory. Our search produced enough conformers to account for all of the various forms of CL-20 found in crystals. This suggests that our methodology will be useful in studying the conformational landscape of other nitramines. The energy levels of the conformers found are all within 0.25 eV of one another based on MBPT(2)/6-311G(d,p); consequently, without further refinement from a method such as coupled cluster theory, all conformers may reasonably be populated at STP in the gas phase. We also report the harmonic vibrational frequencies of conformers, including the implications on the mechanism of detonation. In particular, we establish that the weakest N-N nitramine of CL-20 is the cyclohexane equatorial nitramine. This preliminary mapping of the conformers of CL-20 makes it possible to study the mechanism of detonation of this explosive rigorously in future work.

Side-chain conformational space analysis (SCSA): A multi conformation-based QSAR approach for modeling and prediction of protein-peptide binding affinities

NASA Astrophysics Data System (ADS)

Zhou, Peng; Chen, Xiang; Shang, Zhicai

2009-03-01

In this article, the concept of multi conformation-based quantitative structure-activity relationship (MCB-QSAR) is proposed, and based upon that, we describe a new approach called the side-chain conformational space analysis (SCSA) to model and predict protein-peptide binding affinities. In SCSA, multi-conformations (rather than traditional single-conformation) have received much attention, and the statistical average information on multi-conformations of side chains is determined using self-consistent mean field theory based upon side chain rotamer library. Thereby, enthalpy contributions (including electrostatic, steric, hydrophobic interaction and hydrogen bond) and conformational entropy effects to the binding are investigated in terms of occurrence probability of residue rotamers. Then, SCSA was applied into the dataset of 419 HLA-A*0201 binding peptides, and nonbonding contributions of each position in peptide ligands are well determined. For the peptides, the hydrogen bond and electrostatic interactions of the two ends are essential to the binding specificity, van der Waals and hydrophobic interactions of all the positions ensure strong binding affinity, and the loss of conformational entropy at anchor positions partially counteracts other favorable nonbonding effects.

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

Dissecting the conformational determinants of chitosan and chitlac oligomers.

PubMed

Esteban, Carmen; Donati, Ivan; Pantano, Sergio; Villegas, Myriam; Benegas, Julio; Paoletti, Sergio

2018-06-01

Chitosan and its highly hydrophilic 1-deoxy-lactit-1-yl derivative (Chitlac) are polysaccharides with increasing biomedical applications. Aimed to unravel their conformational properties we have performed a series of molecular dynamics simulations of Chitosan/Chitlac decamers, exploring different degrees of substitution (DS) of lactitol side chains. At low DS, two conformational regions with different populations are visited, while for DS ≥ 20% the oligomers remain mostly linear and only one main region of the glycosidic angles is sampled. These conformers are (locally) characterized by extended helical "propensities". Helical conformations 3 2 and 2 1, by far the most abundant, only develop in the main region. The accessible conformational space is clearly enlarged at high ionic strength, evidencing also a new region accessible to the glycosidic angles, with short and frequent interchange between regions. Simulations of neutral decamers share these features, pointing to a central role of electrostatic repulsion between charged moieties. These interactions seem to determine the conformational behavior of the chitosan backbone, with no evident influence of H-bond interactions. Finally, it is also shown that increasing temperature only slightly enlarges the available conformational space, but certainly without signs of a temperature-induced conformational transition. © 2018 Wiley Periodicals, Inc.

Hairpin Folding of HIV gp41 Abrogates Lipid Mixing Function at Physiologic pH and Inhibits Lipid Mixing by Exposed gp41 Constructs†

PubMed Central

Sackett, Kelly; Nethercott, Matthew J.; Shai, Yechiel; Weliky, David P.

2009-01-01

Conformational changes in the HIV gp41 protein are directly correlated with fusion between the HIV and target cell plasma membranes which is the initial step of infection. Key gp41 fusion conformations include an early extended conformation termed pre-hairpin which contains exposed regions and a final low energy conformation termed hairpin which has compact six-helix bundle structure. Current fusion models debate the roles of hairpin and pre-hairpin conformations in the process of membrane merger. In the present work, gp41 constructs have been engineered which correspond to fusion relevant parts of both pre-hairpin and hairpin conformations, and have been analyzed for their ability to induce lipid mixing between membrane vesicles. The data correlate membrane fusion function with the pre-hairpin conformation and suggest that one of the roles of the final hairpin conformation is sequestration of membrane perturbing gp41 regions with consequent loss of the membrane disruption induced earlier by the pre-hairpin structure. To our knowledge, this is the first biophysical study to delineate the membrane fusion potential of gp41 constructs modeling key fusion conformations. PMID:19222185

Backbone conformational preferences of an intrinsically disordered protein in solution.

PubMed

Espinoza-Fonseca, L Michel; Ilizaliturri-Flores, Ian; Correa-Basurto, José

2012-06-01

We have performed a 4-μs molecular dynamics simulation to investigate the native conformational preferences of the intrinsically disordered kinase-inducible domain (KID) of the transcription factor CREB in solution. There is solid experimental evidence showing that KID does not possess a bound-like structure in solution; however, it has been proposed that coil-to-helix transitions upon binding to its binding partner (CBP) are template-driven. While these studies indicate that IDPs possess a bias towards the bound structure, they do not provide direct evidence on the time-dependent conformational preferences of IDPs in atomic detail. Our simulation captured intrinsic conformational characteristics of KID that are in good agreement with experimental data such as a very small percentage of helical structure in its segment α(B) and structural disorder in solution. We used dihedral principal component analysis dPCA to map the conformations of KID in the microsecond timescale. By using principal components as reaction coordinates, we further constructed dPCA-based free energy landscapes of KID. Analysis of the free energy landscapes showed that KID is best characterized as a conformational ensemble of rapidly interconverting conformations. Interestingly, we found that despite the conformational heterogeneity of the backbone and the absence of substantial secondary structure, KID does not randomly sample the conformational space in solution: analysis of the (Φ, Ψ) dihedral angles showed that several individual residues of KID possess a strong bias toward the helical region of the Ramachandran plot. We suggest that the intrinsic conformational preferences of KID provide a bias toward the folded state without having to populate bound-like conformations before binding. Furthermore, we argue that these conformational preferences do not represent actual structural constraints which drive binding through a single pathway, which allows for specific interactions with multiple binding partners. Based on this evidence, we propose that the backbone conformational preferences of KID provide a thermodynamic advantage for folding and binding without negatively affecting the kinetics of binding. We further discuss the relation of our results to previous studies to rationalize the functional implications of the conformational preferences of IDPs, such as the optimization of structural disorder in protein-protein interactions. This study illustrates the importance in obtaining atomistic information of intrinsically disordered proteins in real time to reveal functional features arising from their complex conformational space.

Potential Energy Surface-Based Automatic Deduction of Conformational Transition Networks and Its Application on Quantum Mechanical Landscapes of d-Glucose Conformers.

PubMed

Satoh, Hiroko; Oda, Tomohiro; Nakakoji, Kumiyo; Uno, Takeaki; Tanaka, Hiroaki; Iwata, Satoru; Ohno, Koichi

2016-11-08

This paper describes our approach that is built upon the potential energy surface (PES)-based conformational analysis. This approach automatically deduces a conformational transition network, called a conformational reaction route map (r-map), by using the Scaled Hypersphere Search of the Anharmonic Downward Distortion Following method (SHS-ADDF). The PES-based conformational search has been achieved by using large ADDF, which makes it possible to trace only low transition state (TS) barriers while restraining bond lengths and structures with high free energy. It automatically performs sampling the minima and TS structures by simply taking into account the mathematical feature of PES without requiring any a priori specification of variable internal coordinates. An obtained r-map is composed of equilibrium (EQ) conformers connected by reaction routes via TS conformers, where all of the reaction routes are already confirmed during the process of the deduction using the intrinsic reaction coordinate (IRC) method. The postcalculation analysis of the deduced r-map is interactively carried out using the RMapViewer software we have developed. This paper presents computational details of the PES-based conformational analysis and its application to d-glucose. The calculations have been performed for an isolated glucose molecule in the gas phase at the RHF/6-31G level. The obtained conformational r-map for α-d-glucose is composed of 201 EQ and 435 TS conformers and that for β-d-glucose is composed of 202 EQ and 371 TS conformers. For the postcalculation analysis of the conformational r-maps by using the RMapViewer software program we have found multiple minimum energy paths (MEPs) between global minima of 1 C 4 and 4 C 1 chair conformations. The analysis using RMapViewer allows us to confirm the thermodynamic and kinetic predominance of 4 C 1 conformations; that is, the potential energy of the global minimum of 4 C 1 is lower than that of 1 C 4 (thermodynamic predominance) and that the highest energy of those of all the TS structures along a route from 4 C 1 to 1 C 4 is lower than that of 1 C 4 to 4 C 1 (kinetic predominance).

16 CFR 1112.25 - What are a third party conformity assessment body's recordkeeping responsibilities?

Code of Federal Regulations, 2014 CFR

2014-01-01

... conformity assessment body must make copies of the original (non-English language) available to the CPSC... body's recordkeeping responsibilities? 1112.25 Section 1112.25 Commercial Practices CONSUMER PRODUCT... CONFORMITY ASSESSMENT BODIES General Requirements Pertaining to Third Party Conformity Assessment Bodies...

14 CFR 21.53 - Statement of conformity.

Code of Federal Regulations, 2010 CFR

2010-01-01

... conformity (FAA Form 317) to the Administrator for each aircraft engine and propeller presented to the... engine or propeller conforms to the type design therefor. (b) Each applicant must submit a statement of... statement that each aircraft engine or propeller presented for type certification conforms to its type...

Gluon amplitudes as 2 d conformal correlators

NASA Astrophysics Data System (ADS)

Pasterski, Sabrina; Shao, Shu-Heng; Strominger, Andrew

2017-10-01

Recently, spin-one wave functions in four dimensions that are conformal primaries of the Lorentz group S L (2 ,C ) were constructed. We compute low-point, tree-level gluon scattering amplitudes in the space of these conformal primary wave functions. The answers have the same conformal covariance as correlators of spin-one primaries in a 2 d CFT. The Britto-Cachazo-Feng-Witten (BCFW) recursion relation between three- and four-point gluon amplitudes is recast into this conformal basis.

Citronellal assumes a folded conformation in solution due to dispersion interactions: A joint NMR-DFT analysis

NASA Astrophysics Data System (ADS)

Nardini, Viviani; Dias, Luis Gustavo; Palaretti, Vinicius; da Silva, Gil Valdo José

2018-04-01

Citronellal, an acyclic monoterpenoid, is a small molecule suitable for systematic scanning of its conformational geometric parameters in solution or in the gas phase. We have studied the conformational distribution of citronellal by correlating its structure and theoretical chemical shifts with nuclear magnetic resonance data. Interestingly, folded conformations were the most relevant, as confirmed by NOE experiments. We concluded that the conformational distribution is due to intramolecular dispersion interactions.

Conformal invariance and conserved quantities of mechanical system with unilateral constraints

NASA Astrophysics Data System (ADS)

Wang, Peng

2018-06-01

By distinguishing the different constraint cases, the whole course and piecewise conserved quantities, which deduced from conformal invariance of mechanical systems with unilateral constraints, are given. The determining equation of conformal invariance of the system is obtained. The sufficient and necessary conditions for the conformal invariance must be Lie symmetry of the system are given. The forms of conformal factors are obtained. An example is given to illustrate the results in this paper.

Anomalous conformer dependent S 1 lifetime of L-phenylalanine

NASA Astrophysics Data System (ADS)

Hashimoto, Takayo; Takasu, Yuichi; Yamada, Yuji; Ebata, Takayuki

2006-04-01

The fluorescence lifetimes were measured for six conformers of L-phenylalanine cooled in a supersonic jet. It was found that the S 1 state lifetimes differ by a factor of three among the conformers. Especially, the most stable conformer (intramolecular hydrogen-bonded form) in S 0 had the shortest lifetime. Time-dependent DFT calculation suggested an importance of the mixing of the nπ ∗ character to S 1(ππ ∗) in this conformer dependent dynamics.

Substrate binding interferes with active site conformational dynamics in endoglucanase Cel5A from Thermobifida fusca.

PubMed

Jiang, Xukai; Wang, Yuying; Xu, Limei; Chen, Guanjun; Wang, Lushan

2017-09-09

The role of protein dynamics in enzyme catalysis is one of the most active areas in current enzymological research. Here, using endoglucanase Cel5A from Thermobifida fusca (TfCel5A) as a model, we applied molecular dynamics simulations to explore the dynamic behavior of the enzyme upon substrate binding. The collective motions of the active site revealed that the mechanism of TfCel5A substrate binding can likely be described by the conformational-selection model; however, we observed that the conformations of active site residues changed differently along with substrate binding. Although most active site residues retained their native conformational ensemble, some (Tyr163 and Glu355) generated newly induced conformations, whereas others (Phe162 and Tyr189) exhibited shifts in the equilibration of their conformational distributions. These results showed that TfCel5A substrate binding relied on a hybrid mechanism involving induced fit and conformational selection. Interestingly, we found that TfCel5A active site could only partly rebalance its conformational dynamics upon substrate dissociation within the same simulation time, which implies that the conformational rebalance upon substrate dissociation is likely more difficult than the conformational selection upon substrate binding at least in the view of the time required. Our findings offer new insight into enzyme catalysis and potential applications for future protein engineering. Copyright © 2017 Elsevier Inc. All rights reserved.

Adsorption and conformational modification of fibronectin and fibrinogen adsorbed on hydroxyapatite. A QCM-D study.

PubMed

Fernández-Montes Moraleda, Belén; San Román, Julio; Rodríguez-Lorenzo, Luís M

2016-10-01

Hydroxyapatite is a bioactive ceramic frequently used for bone engineering/replacement. One of the parameters that influence the biological response to implanted materials is the conformation of the first adsorbed protein layer. In this work, the adsorption and conformational changes of two fibroid serum proteins; fibronectin and fibrinogen adsorbed onto four different hydroxyapatite powders are studied with a Quartz Crystal Microbalance with Dissipation (QCM-D). Each of the calcined apatites adsorbs less protein than their corresponding synthesized samples. Adsorption on synthesized samples yields always an extended conformation whereas a reorganization of the layer is observed for the calcined samples. Fg acquires a "Side on" conformation in all the samples at the beginning of the experiment except for one of the synthesized samples where an "End-on" conformation is obtained during the whole experiment. The Extended conformation is the active conformation for Fn. This conformation is favored by apatites with large specific surface area (SSA) and on highly concentrated media. Apatite surface features should be considered in the selection or design of materials for bone regeneration, since it is possible to control the conformation mode of attachment of Fn and Fg by an appropriate selection of them. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2585-2594, 2016. © 2016 Wiley Periodicals, Inc.

C dbnd N sbnd N dbnd C conformational isomers of 2'-hydroxyacetophenone azine: FTIR matrix isolation and DFT study

NASA Astrophysics Data System (ADS)

Grzegorzek, Joanna; Mielke, Zofia; Filarowski, Aleksander

2010-07-01

2'-hydroxyacetophenone azine (APA) has been studied by matrix isolation infrared spectroscopy and quantum chemical calculations. The DFT/B3LYP/6-311++G(2d,2p) calculations demonstrated the existence of two conformers for the lowest energy E/ E configuration of APA, a s- trans and a gauche ones. The conformers are characterized by similar energies and differ in the value of a C dbnd N sbnd N dbnd C angle, that was calculated to be 180° for a planar s-trans conformer and 155° for a non-planar gauche one . The calculated barrier for conformational interconversion is also very low, ca. 1 kJ mol -1 for the conversion from a gauche conformer to a trans one. The FTIR spectra of an argon matrix doped with APA from a vapour above solid sample evidence the presence of both conformers that exhibit reversible interconversion at matrix temperatures. The comparison of the theoretical spectra with the experimental ones and reversible temperature dependence of the experimental spectra allowed for unambiguous spectroscopic characterization of the trans and gauche conformers. The experiment also demonstrated that a gauche conformer is more stable than a trans one. The spectra analysis indicates that transformation from a trans conformer to a gauche one weakens the intramolecular O sbnd H⋯N bonds in the molecule.

Discovering Conformational Sub-States Relevant to Protein Function

PubMed Central

Ramanathan, Arvind; Savol, Andrej J.; Langmead, Christopher J.; Agarwal, Pratul K.; Chennubhotla, Chakra S.

2011-01-01

Background 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. Methods and Findings 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. Conclusions Overall, QAA provides a novel framework to intuitively understand the biophysical basis of conformational diversity and its relevance to protein function. PMID:21297978

Evidence that Membrane Insertion of the Cytosolic Domain of Bcl-xL is Governed by an Electrostatic Mechanism

PubMed Central

Thuduppathy, Guruvasuthevan R.; Craig, Jeffrey W.; Schon, Victoria Kholodenko Arne; Hill, R. Blake

2006-01-01

Signals from different cellular networks are integrated at the mitochondria in the regulation of apoptosis. This integration is controlled by the Bcl-2 proteins, many of which change localization fromthe cytosol to the mitochondrial outer membrane in this regulation. For Bcl-xL, this change in localization reflects the ability to undergo a conformational change from a solution to integral membrane conformation. To characterize this conformational change, structural and thermodynamic measurements were performed in the absence and presence of lipid vesicles with Bcl-xL. A pH-dependent model is proposed for the solution to membrane conformational change that consists of three stable conformations: a solution conformation, a conformation similar to the solution conformation but anchored to the membrane by its C-terminal transmembrane domain, and a membrane conformation that is fully associated with the membrane. This model predicts that the solution to membrane conformational change is independent of the C-terminal trans-membrane domain, which is experimentally demonstrated. The conformational change is associated with changes in secondary and, especially, tertiary structure of the protein, as measured by far and near-UV circular dichroism spectroscopy, respectively. Membrane insertion was distinguished from peripheral association with the membrane by quenching of intrinsic tryptophan fluorescence by acrylamide and brominated lipids. For the cytosolic domain, the free energy of insertion ( ΔGox) into lipid vesicles was determined to be −6.5 k cal mol−1 at pH4.9 by vesicle binding experiments. To test whether electrostatic interactions were significant to this process, the salt dependence of this conformational change was measured and analyzed in terms of Gouy–Chapman theory to estimate an electrostatic contribution of ΔGoel ~−2.5 kcal mol−1 and a non-electrostatic contribution of ΔGonel ~−4.0 kcal mol−1 to the free energy of insertion, ΔGox. Calcium, which blocks ion channel activity of Bcl-xL, did not affect the solution to membrane conformational change more than predicted by these electrostatic considerations. The lipid cardiolipin, that is enriched at mitochondrial contact sites and reported to be important for the localization of Bcl-2 proteins, did not affect the solution to membrane conformational change of the cytosolic domain, suggesting that this lipid is not involved in the localization of Bcl-xL in vivo. Collectively, these data suggest the solution to membrane conformational change is controlled by an electrostatic mechanism. Given the distinct biological activities of these conformations, the possibility that this conformational change might be a regulatory checkpoint for apoptosis is discussed. PMID:16650855

Electromagnetic fields of slowly rotating magnetized compact stars in conformal gravity

NASA Astrophysics Data System (ADS)

Turimov, Bobur; Ahmedov, Bobomurat; Abdujabbarov, Ahmadjon; Bambi, Cosimo

2018-06-01

In this paper we investigate the exterior vacuum electromagnetic fields of slow-rotating magnetized compact stars in conformal gravity. Assuming the dipolar magnetic field configuration, we obtain an analytical solution of the Maxwell equations for the magnetic and the electric fields outside a slowly rotating magnetized star in conformal gravity. Furthermore, we study the dipolar electromagnetic radiation and energy losses from a rotating magnetized star in conformal gravity. In order to get constraints on the L parameter of conformal gravity, the theoretical results for the magnetic field of a magnetized star in conformal gravity are combined with the precise observational data of radio pulsar period slowdown, and it is found that the maximum value of the parameter of conformal gravity is less than L ≲9.5 ×105 cm (L /M ≲5 ).

Network visualization of conformational sampling during molecular dynamics simulation.

PubMed

Ahlstrom, Logan S; Baker, Joseph Lee; Ehrlich, Kent; Campbell, Zachary T; Patel, Sunita; Vorontsov, Ivan I; Tama, Florence; Miyashita, Osamu

2013-11-01

Effective data reduction methods are necessary for uncovering the inherent conformational relationships present in large molecular dynamics (MD) trajectories. Clustering algorithms provide a means to interpret the conformational sampling of molecules during simulation by grouping trajectory snapshots into a few subgroups, or clusters, but the relationships between the individual clusters may not be readily understood. Here we show that network analysis can be used to visualize the dominant conformational states explored during simulation as well as the connectivity between them, providing a more coherent description of conformational space than traditional clustering techniques alone. We compare the results of network visualization against 11 clustering algorithms and principal component conformer plots. Several MD simulations of proteins undergoing different conformational changes demonstrate the effectiveness of networks in reaching functional conclusions. Copyright © 2013 Elsevier Inc. All rights reserved.

A Projective-to-Conformal Fefferman-Type Construction

NASA Astrophysics Data System (ADS)

Hammerl, Matthias; Sagerschnig, Katja; Šilhan, Josef; Taghavi-Chabert, Arman; Zádník, Vojtĕch

2017-10-01

We study a Fefferman-type construction based on the inclusion of Lie groups SL(n+1) into Spin(n+1,n+1). The construction associates a split-signature (n,n)-conformal spin structure to a projective structure of dimension n. We prove the existence of a canonical pure twistor spinor and a light-like conformal Killing field on the constructed conformal space. We obtain a complete characterisation of the constructed conformal spaces in terms of these solutions to overdetermined equations and an integrability condition on the Weyl curvature. The Fefferman-type construction presented here can be understood as an alternative approach to study a conformal version of classical Patterson-Walker metrics as discussed in recent works by Dunajski-Tod and by the authors. The present work therefore gives a complete exposition of conformal Patterson-Walker metrics from the viewpoint of parabolic geometry.

Analysis of Cytochrome P450 CYP119 Ligand-dependent Conformational Dynamics by Two-dimensional NMR and X-ray Crystallography*

PubMed Central

Basudhar, Debashree; Madrona, Yarrow; Kandel, Sylvie; Lampe, Jed N.; Nishida, Clinton R.; de Montellano, Paul R. Ortiz

2015-01-01

Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. We used two-dimensional 1H,15N HSQC chemical shift perturbation mapping of 15N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop with various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. The results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states. PMID:25670859

A normal mode-based geometric simulation approach for exploring biologically relevant conformational transitions in proteins.

PubMed

Ahmed, Aqeel; Rippmann, Friedrich; Barnickel, Gerhard; Gohlke, Holger

2011-07-25

A three-step approach for multiscale modeling of protein conformational changes is presented that incorporates information about preferred directions of protein motions into a geometric simulation algorithm. The first two steps are based on a rigid cluster normal-mode analysis (RCNMA). Low-frequency normal modes are used in the third step (NMSim) to extend the recently introduced idea of constrained geometric simulations of diffusive motions in proteins by biasing backbone motions of the protein, whereas side-chain motions are biased toward favorable rotamer states. The generated structures are iteratively corrected regarding steric clashes and stereochemical constraint violations. The approach allows performing three simulation types: unbiased exploration of conformational space; pathway generation by a targeted simulation; and radius of gyration-guided simulation. When applied to a data set of proteins with experimentally observed conformational changes, conformational variabilities are reproduced very well for 4 out of 5 proteins that show domain motions, with correlation coefficients r > 0.70 and as high as r = 0.92 in the case of adenylate kinase. In 7 out of 8 cases, NMSim simulations starting from unbound structures are able to sample conformations that are similar (root-mean-square deviation = 1.0-3.1 Å) to ligand bound conformations. An NMSim generated pathway of conformational change of adenylate kinase correctly describes the sequence of domain closing. The NMSim approach is a computationally efficient alternative to molecular dynamics simulations for conformational sampling of proteins. The generated conformations and pathways of conformational transitions can serve as input to docking approaches or as starting points for more sophisticated sampling techniques.

A Mediated Moderation Model of Conformative Peer Bullying

ERIC Educational Resources Information Center

Cho, Yoonju; Chung, Ock-Boon

2012-01-01

We investigated the relationship between conformative peer bullying and issues of peer conformity among adolescents. This relationship is examined through the establishment of a mediated moderation model for conformative peer bullying using structural equation modeling in a sample of 391 second-year middle school students in Seoul, South Korea. We…

40 CFR 91.122 - Amending the application and certificate of conformity.

Code of Federal Regulations, 2010 CFR

2010-07-01

... certificate of conformity. 91.122 Section 91.122 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Standards and Certification Provisions § 91.122 Amending the application and certificate of conformity. (a... to a certificate of conformity or changes are to be made to a product line covered by a certificate...

40 CFR 91.122 - Amending the application and certificate of conformity.

Code of Federal Regulations, 2011 CFR

2011-07-01

... certificate of conformity. 91.122 Section 91.122 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Standards and Certification Provisions § 91.122 Amending the application and certificate of conformity. (a... to a certificate of conformity or changes are to be made to a product line covered by a certificate...

75 FR 45057 - Adequacy Status of Motor Vehicle Emissions Budgets in Submitted Reasonable Further Progress and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-02

... determining whether they conform. Conformity to a SIP means that transportation activities will not produce... Nonattainment areas for Transportation Conformity Purposes; NY AGENCY: Environmental Protection Agency (EPA... Poughkeepsie, New York 8-hour ozone nonattainment area, to be adequate for transportation conformity purposes...

21 CFR 26.70 - Conformity assessment bodies.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Conformity assessment bodies. 26.70 Section 26.70...Frameworkâ Provisions § 26.70 Conformity assessment bodies. Each party recognizes that the conformity assessment bodies (CAB's) listed in subpart B of this part fulfill the conditions of eligibility to assess...

Conformational Contribution to Thermodynamics of Binding in Protein-Peptide Complexes through Microscopic Simulation

PubMed Central

Das, Amit; Chakrabarti, J.; Ghosh, Mahua

2013-01-01

We extract the thermodynamics of conformational changes in biomacromolecular complexes from the distributions of the dihedral angles of the macromolecules. These distributions are obtained from the equilibrium configurations generated via all-atom molecular dynamics simulations. The conformational thermodynamics data we obtained for calmodulin-peptide complexes using our methodology corroborate well with the experimentally observed conformational and binding entropies. The conformational free-energy changes and their contributions for different peptide-binding regions of calmodulin are evaluated microscopically. PMID:23528087

Laboratory evolution of protein conformational dynamics.

PubMed

Campbell, Eleanor C; Correy, Galen J; Mabbitt, Peter D; Buckle, Ashley M; Tokuriki, Nobuhiko; Jackson, Colin J

2017-11-08

This review focuses on recent work that has begun to establish specific functional roles for protein conformational dynamics, specifically how the conformational landscapes that proteins can sample can evolve under laboratory based evolutionary selection. We discuss recent technical advances in computational and biophysical chemistry, which have provided us with new ways to dissect evolutionary processes. Finally, we offer some perspectives on the emerging view of conformational dynamics and evolution, and the challenges that we face in rationally engineering conformational dynamics. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modeling the effect of pathogenic mutations on the conformational landscape of protein kinases.

PubMed

Saladino, Giorgio; Gervasio, Francesco Luigi

2016-04-01

Most proteins assume different conformations to perform their cellular functions. This conformational dynamics is physiologically regulated by binding events and post-translational modifications, but can also be affected by pathogenic mutations. Atomistic molecular dynamics simulations complemented by enhanced sampling approaches are increasingly used to probe the effect of mutations on the conformational dynamics and on the underlying conformational free energy landscape of proteins. In this short review we discuss recent successful examples of simulations used to understand the molecular mechanism underlying the deregulation of physiological conformational dynamics due to non-synonymous single point mutations. Our examples are mostly drawn from the protein kinase family. Copyright © 2016 Elsevier Ltd. All rights reserved.

Conformational effects on circular dichroism in the photoelectron angular distribution.

PubMed

Di Tommaso, Devis; Stener, Mauro; Fronzoni, Giovanna; Decleva, Piero

2006-04-10

The B-spline density-functional method has been applied to the conformers of the (1R, 2R)-1,2-dibromo-1,2-dichloro-1,2-difluoroethane molecule. The cross section, asymmetry, and dichroic parameters relative to core and valence orbitals, which do not change their nature along the conformational curve, have been systematically studied. While the cross section and the asymmetry parameter are weakly affected, the dichroic parameter appears to be rather sensitive to the particular conformer of the molecule, suggesting that this dynamical property could be a useful tool for conformational analysis. The computational method has also been applied to methyl rotation in methyloxirane. Unexpected and dramatic sensitivity of the dichroic-parameter profile to the methyl rotation, both in the core and valence states, has been found. Boltzmann averaging over the conformers reproduces quite closely the profiles previously obtained for the minimum-energy conformation, which is in good agreement with the experimental results.

Research on conformal dome of Karman-curve shape

NASA Astrophysics Data System (ADS)

Zhang, Yunqiang; Chang, Jun; Niu, Yajun

2018-01-01

Because the conformal optical technology can obviously improve the aerodynamic performance of the infrared guidance missile, it has been studied deeply in recent years. By comparing the performance of the missiles with conformal dome and conventional missiles, the advantages of the conformal optical technology are demonstrated in the maneuverability and stealth of the missile. At present, the study of conformal optical systems focuses on ellipsoid or quadratic curve types. But in actual use, the dome using these curves is not the best choice. In this paper, the influence of different shape of the dome on aerodynamic performance, aerodynamic heating, internal space volume and other properties is discussed. The result shows infrared optical system with conformal dome of Karman-curve shape has a good application prospect, is the future direction of development. Finally, the difficult problems of conformal dome of Karman-curve shape are discussed.

Estimation of the rotamerization constants of different conformations of N-acetylalanine: a theoretical and matrix-isolation FT-IR study.

PubMed

Boeckx, Bram; Maes, Guido

2012-02-01

The conformational landscape of N-acetylalanine has been investigated by a theoretical and matrix-isolation FT-IR study. Optimizations of N-acetylalanine structures has been conducted at successive higher levels of theory HF/3-21G, DFT(B3LYP)/6-31++G** and MP2/6-31++G**. This resulted in three stable conformations. Among these, one conformation contains an intramolecular H-bond. The vibrational properties of these conformations were calculated and used to identify the conformations in a cryogenic argon matrix. The intensities of some bands assigned to a particular conformation were used to estimate the rotamerization constants K(r12) and K(r13) for the equilibria NAA1 NAA2 and NAA1 NAA3, respectively. The obtained experimental values were in agreement with the theoretical predictions. Copyright © 2011 Elsevier B.V. All rights reserved.

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.

Toward canonical ensemble distribution from self-guided Langevin dynamics simulation

NASA Astrophysics Data System (ADS)

Wu, Xiongwu; Brooks, Bernard R.

2011-04-01

This work derives a quantitative description of the conformational distribution in self-guided Langevin dynamics (SGLD) simulations. SGLD simulations employ guiding forces calculated from local average momentums to enhance low-frequency motion. This enhancement in low-frequency motion dramatically accelerates conformational search efficiency, but also induces certain perturbations in conformational distribution. Through the local averaging, we separate properties of molecular systems into low-frequency and high-frequency portions. The guiding force effect on the conformational distribution is quantitatively described using these low-frequency and high-frequency properties. This quantitative relation provides a way to convert between a canonical ensemble and a self-guided ensemble. Using example systems, we demonstrated how to utilize the relation to obtain canonical ensemble properties and conformational distributions from SGLD simulations. This development makes SGLD not only an efficient approach for conformational searching, but also an accurate means for conformational sampling.

Photooxidation of Trimethyl Phosphite in Nitrogen, Oxygen, and para-Hydrogen Matrixes at Low Temperatures.

PubMed

Ramanathan, N; Sundararajan, K; Gopi, R; Sankaran, K

2017-03-16

Trimethyl phosphite (TMPhite) was photooxidized to trimethyl phosphate (TMP) in N 2 , O 2 , and para-H 2 matrixes at low temperatures to correlate the conformational landscape of these two molecules. The photooxidation produced the trans (TGG)-rich conformer with respect to the ground state gauche (GGG) conformer of TMP in N 2 and O 2 matrixes, which has diverged from the conformational composition of freshly deposited pure TMP in the low-temperature matrixes. The enrichment of the trans conformer in preference to the gauche conformer of TMP during photooxidation is due to the TMPhite precursor, which exists exclusively in the trans conformer. Interestingly, whereas the photooxidized TMP molecule suffers site effects possibly due to the local asymmetry in N 2 and O 2 matrixes, in the para-H 2 matrix owing to the quantum crystal nature the site effects were observed to be self-repaired.

Chain Assembly and Disassembly Processes Differently Affect the Conformational Space of Ubiquitin Chains.

PubMed

Kniss, Andreas; Schuetz, Denise; Kazemi, Sina; Pluska, Lukas; Spindler, Philipp E; Rogov, Vladimir V; Husnjak, Koraljka; Dikic, Ivan; Güntert, Peter; Sommer, Thomas; Prisner, Thomas F; Dötsch, Volker

2018-02-06

Ubiquitination is the most versatile posttranslational modification. The information is encoded by linkage type as well as chain length, which are translated by ubiquitin binding domains into specific signaling events. Chain topology determines the conformational space of a ubiquitin chain and adds an additional regulatory layer to this ubiquitin code. In particular, processes that modify chain length will be affected by chain conformations as they require access to the elongation or cleavage sites. We investigated conformational distributions in the context of chain elongation and disassembly using pulsed electron-electron double resonance spectroscopy in combination with molecular modeling. Analysis of the conformational space of diubiquitin revealed conformational selection or remodeling as mechanisms for chain recognition during elongation or hydrolysis, respectively. Chain elongation to tetraubiquitin increases the sampled conformational space, suggesting that a high intrinsic flexibility of K48-linked chains may contribute to efficient proteasomal degradation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Conformational free energy modeling of druglike molecules by metadynamics in the WHIM space.

PubMed

Spiwok, Vojtěch; Hlat-Glembová, Katarína; Tvaroška, Igor; Králová, Blanka

2012-03-26

Protein-ligand affinities can be significantly influenced not only by the interaction itself but also by conformational equilibrium of both binding partners, free ligand and free protein. Identification of important conformational families of a ligand and prediction of their thermodynamics is important for efficient ligand design. Here we report conformational free energy modeling of nine small-molecule drugs in explicitly modeled water by metadynamics with a bias potential applied in the space of weighted holistic invariant molecular (WHIM) descriptors. Application of metadynamics enhances conformational sampling compared to unbiased molecular dynamics simulation and allows to predict relative free energies of key conformations. Selected free energy minima and one example of transition state were tested by a series of unbiased molecular dynamics simulation. Comparison of free energy surfaces of free and target-bound Imatinib provides an estimate of free energy penalty of conformational change induced by its binding to the target. © 2012 American Chemical Society

Theoretical study of γ-aminobutyric acid conformers: Intramolecular interactions and ionization energies

NASA Astrophysics Data System (ADS)

Wang, Ke-Dong; Wang, Mei-Ting; Meng, Ju

2014-10-01

Allowing for all combinations of internal single-bond rotamers, 1,296 unique trial structures of γ-Aminobutyric acid (GABA) are obtained. All of these structures are optimized at the M06-2X level of theory and a total of 68 local minimal conformers are found. The nine low-lying conformers are used for further studies. According to the calculated relative Gibbs free energies at M06-2X level of theory, we find that the dispersion is important for the relative energy of GABA. The intramolecular hydrogen bonds and hyperconjugative interaction and their effects on the conformational stability are studied. The results show that both of them have great influence on the conformers. The vertical ionization energies (VIE) are calculated and match the experimental data well. The results show that the neutral GABA in the gas phase is a multi-conformer system and at least four conformations exist.

75 FR 66245 - HUD Programs: Violence Against Women Act Conforming Amendments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-27

...: Violence Against Women Act Conforming Amendments; Final Rule #0;#0;Federal Register / Vol. 75 , No. 207...-F-02] RIN 2577-AC65 HUD Programs: Violence Against Women Act Conforming Amendments AGENCY: Office of... rule that conformed HUD's regulations to those provisions of the Violence Against Women Act (VAWA), as...

21 CFR 26.67 - Suspension of listed conformity assessment bodies.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Suspension of listed conformity assessment bodies... EUROPEAN COMMUNITY âFrameworkâ Provisions § 26.67 Suspension of listed conformity assessment bodies. The following procedures shall apply with regard to the suspension of a conformity assessment body (CAB) listed...

21 CFR 26.69 - Monitoring of conformity assessment bodies.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Monitoring of conformity assessment bodies. 26.69... COMMUNITY âFrameworkâ Provisions § 26.69 Monitoring of conformity assessment bodies. The following shall apply with regard to the monitoring of conformity assessment bodies (CAB's) listed in subpart B of this...

Latent Class Analysis of Peer Conformity: Who Is Yielding to Pressure and Why?

ERIC Educational Resources Information Center

Kosten, Paul A.; Scheier, Lawrence M.; Grenard, Jerry L.

2013-01-01

This study used latent class analysis to examine typologies of peer conformity in a community sample of middle school students. Students responded to 31 items assessing diverse facets of conformity dispositions. The most parsimonious model produced three qualitatively distinct classes that differed on the basis of conformity to recreational…

Standing in the Hallway Improves Students' Understanding of Conformity

ERIC Educational Resources Information Center

Lawson, Timothy J.; Haubner, Richard R.; Bodle, James H.

2013-01-01

To help beginning psychology students understand how they are influenced by social pressures to conform, we developed a demonstration designed to elicit their conformity to a small group of students standing in the hallway before class. Results showed the demonstration increased students' recognition of their own tendency to conform, knowledge of…

Basic Theory of Fractional Conformal Invariance of Mei Symmetry and its Applications to Physics

NASA Astrophysics Data System (ADS)

Luo, Shao-Kai; Dai, Yun; Yang, Ming-Jing; Zhang, Xiao-Tian

2018-04-01

In this paper, we present a basic theory of fractional dynamics, i.e., the fractional conformal invariance of Mei symmetry, and find a new kind of conserved quantity led by fractional conformal invariance. For a dynamical system that can be transformed into fractional generalized Hamiltonian representation, we introduce a more general kind of single-parameter fractional infinitesimal transformation of Lie group, the definition and determining equation of fractional conformal invariance are given. And then, we reveal the fractional conformal invariance of Mei symmetry, and the necessary and sufficient condition whether the fractional conformal invariance would be the fractional Mei symmetry is found. In particular, we present the basic theory of fractional conformal invariance of Mei symmetry and it is found that, using the new approach, we can find a new kind of conserved quantity; as a special case, we find that an autonomous fractional generalized Hamiltonian system possesses more conserved quantities. Also, as the new method's applications, we, respectively, find the conserved quantities of a fractional general relativistic Buchduhl model and a fractional Duffing oscillator led by fractional conformal invariance of Mei symmetry.

Solid-state and solution /sup 13/C NMR in the conformational analysis of methadone-hydrochloride and related narcotic analgesics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sumner, S.C.J.

1986-01-01

Solid state and solution /sup 13/C NMR have been used to study the conformations of the racemic mixtures and single enantiomers of methadone hydrochloride, alpha and beta methadol hydrochloride, and alpha and beta acetylmethadol hydrochloride. The NMR spectra acquired for the compounds as solids, and in polar and nonpolar solvents are compared, in order to determine the conformation of the molecules in solution. To determine the reliability of assigning solution conformations by comparing solution and solid state chemical shift data, three bond coupling constants measured in solution are compared with those calculated from X-ray data. The conformations of the racemicmore » mixture and plus enantiomer of methadone hydrochloride have been shown to be very similar in the solid state, where minor differences in conformation can be seen by comparing NMR spectra obtained for the solids. Also shown is that the molecules of methadone hydrochloride have conformations in polar and in nonpolar solvents which are very similar to the conformation of the molecules in the solid state.« less

Light cone thermodynamics

NASA Astrophysics Data System (ADS)

De Lorenzo, Tommaso; Perez, Alejandro

2018-02-01

We show that null surfaces defined by the outgoing and infalling wave fronts emanating from and arriving at a sphere in Minkowski spacetime have thermodynamical properties that are in strict formal correspondence with those of black hole horizons in curved spacetimes. Such null surfaces, made of pieces of light cones, are bifurcate conformal Killing horizons for suitable conformally stationary observers. They can be extremal and nonextremal depending on the radius of the shining sphere. Such conformal Killing horizons have a constant light cone (conformal) temperature, given by the standard expression in terms of the generalization of surface gravity for conformal Killing horizons. Exchanges of conformally invariant energy across the horizon are described by a first law where entropy changes are given by 1 /(4 ℓp2) of the changes of a geometric quantity with the meaning of horizon area in a suitable conformal frame. These conformal horizons satisfy the zeroth to the third laws of thermodynamics in an appropriate way. In the extremal case they become light cones associated with a single event; these have vanishing temperature as well as vanishing entropy.

Monte Carlo replica-exchange based ensemble docking of protein conformations.

PubMed

Zhang, Zhe; Ehmann, Uwe; Zacharias, Martin

2017-05-01

A replica-exchange Monte Carlo (REMC) ensemble docking approach has been developed that allows efficient exploration of protein-protein docking geometries. In addition to Monte Carlo steps in translation and orientation of binding partners, possible conformational changes upon binding are included based on Monte Carlo selection of protein conformations stored as ordered pregenerated conformational ensembles. The conformational ensembles of each binding partner protein were generated by three different approaches starting from the unbound partner protein structure with a range spanning a root mean square deviation of 1-2.5 Å with respect to the unbound structure. Because MC sampling is performed to select appropriate partner conformations on the fly the approach is not limited by the number of conformations in the ensemble compared to ensemble docking of each conformer pair in ensemble cross docking. Although only a fraction of generated conformers was in closer agreement with the bound structure the REMC ensemble docking approach achieved improved docking results compared to REMC docking with only the unbound partner structures or using docking energy minimization methods. The approach has significant potential for further improvement in combination with more realistic structural ensembles and better docking scoring functions. Proteins 2017; 85:924-937. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Dissecting the large-scale galactic conformity

NASA Astrophysics Data System (ADS)

Seo, Seongu

2018-01-01

Galactic conformity is an observed phenomenon that galaxies located in the same region have similar properties such as star formation rate, color, gas fraction, and so on. The conformity was first observed among galaxies within in the same halos (“one-halo conformity”). The one-halo conformity can be readily explained by mutual interactions among galaxies within a halo. Recent observations however further witnessed a puzzling connection among galaxies with no direct interaction. In particular, galaxies located within a sphere of ~5 Mpc radius tend to show similarities, even though the galaxies do not share common halos with each other ("two-halo conformity" or “large-scale conformity”). Using a cosmological hydrodynamic simulation, Illustris, we investigate the physical origin of the two-halo conformity and put forward two scenarios. First, back-splash galaxies are likely responsible for the large-scale conformity. They have evolved into red galaxies due to ram-pressure stripping in a given galaxy cluster and happen to reside now within a ~5 Mpc sphere. Second, galaxies in strong tidal field induced by large-scale structure also seem to give rise to the large-scale conformity. The strong tides suppress star formation in the galaxies. We discuss the importance of the large-scale conformity in the context of galaxy evolution.

Analysis of B3LYP and MP2 conformational population distributions in trans-nicotine, acetylcholine, and ABT-594

NASA Astrophysics Data System (ADS)

Mora, M.; Castro, M. E.; Niño, A.; Melendez, F. J.; Muñoz-Caro, C.

This work presents an analysis of the equivalence of MP2 and DFT (B3LYP functional) conformational populations. As a test case, we select three cholinergic agents (trans-nicotine, acetylcholine, and the nicotinic analgesic ABT-594), where the minima on the conformational energy hypersurfaces expand a large range of energies (˜0-30 kJ mol-1). From energetic and structural data obtained in vacuo at the MP2 and B3LYP/cc-pVDZ levels, we build conformational partition functions, including the effect of the conformational kinetic energy and the rotovibrational coupling. Our results at a physiological temperature (37°C) show qualitative agreement in all cases. Quantitative agreement, however, is only found for trans-nicotine and ABT-594. In the first case, energy minima differ by <0.2 kJ mol-1. Therefore, the equivalence of structural results translates in the equivalence of the conformational distribution. For ABT-594, the minima are separated by as much as 8.0 kJ mol-1, and the conformational energy determines the conformational distribution. In this case, the slight relative variation of conformational energy, between B3LYP and MP2, does not affect the population, since the secondary minima are high in energy and very low in population.

Conformational landscape of an amyloid intra-cellular domain and Landau-Ginzburg-Wilson paradigm in protein dynamics

NASA Astrophysics Data System (ADS)

Dai, Jin; Niemi, Antti J.; He, Jianfeng

2016-07-01

The Landau-Ginzburg-Wilson paradigm is proposed as a framework, to investigate the conformational landscape of intrinsically unstructured proteins. A universal Cα-trace Landau free energy is deduced from general symmetry considerations, with the ensuing all-atom structure modeled using publicly available reconstruction programs Pulchra and Scwrl. As an example, the conformational stability of an amyloid precursor protein intra-cellular domain (AICD) is inspected; the reference conformation is the crystallographic structure with code 3DXC in Protein Data Bank (PDB) that describes a heterodimer of AICD and a nuclear multi-domain adaptor protein Fe65. Those conformations of AICD that correspond to local or near-local minima of the Landau free energy are identified. For this, the response of the original 3DXC conformation to variations in the ambient temperature is investigated, using the Glauber algorithm. The conclusion is that in isolation the AICD conformation in 3DXC must be unstable. A family of degenerate conformations that minimise the Landau free energy is identified, and it is proposed that the native state of an isolated AICD is a superposition of these conformations. The results are fully in line with the presumed intrinsically unstructured character of isolated AICD and should provide a basis for a systematic analysis of AICD structure in future NMR experiments.

Populations of the Minor α-Conformation in AcGXGNH2 and the α-Helical Nucleation Propensities

NASA Astrophysics Data System (ADS)

Zhou, Yanjun; He, Liu; Zhang, Wenwen; Hu, Jingjing; Shi, Zhengshuang

2016-06-01

Intrinsic backbone conformational preferences of different amino acids are important for understanding the local structure of unfolded protein chains. Recent evidence suggests α-structure is relatively minor among three major backbone conformations for unfolded proteins. The α-helices are the dominant structures in many proteins. For these proteins, how could the α-structures occur from the least in unfolded to the most in folded states? Populations of the minor α-conformation in model peptides provide vital information. Reliable determination of populations of the α-conformers in these peptides that exist in multiple equilibriums of different conformations remains a challenge. Combined analyses on data from AcGXPNH2 and AcGXGNH2 peptides allow us to derive the populations of PII, β and α in AcGXGNH2. Our results show that on average residue X in AcGXGNH2 adopt PII, β, and α 44.7%, 44.5% and 10.8% of time, respectively. The contents of α-conformations for different amino acids define an α-helix nucleation propensity scale. With derived PII, β and α-contents, we can construct a free energy-conformation diagram on each AcGXGNH2 in aqueous solution for the three major backbone conformations. Our results would have broad implications on early-stage events of protein folding.

Conformations of cationized linear oligosaccharides revealed by FTMS combined with in-ESI H/D exchange.

PubMed

Kostyukevich, Yury; Kononikhin, Alexey; Popov, Igor; Nikolaev, Eugene

2015-10-01

Previously (Kostyukevich et al. Anal Chem 2014, 86, 2595), we have reported that oligosaccharides anions are produced in the electrospray in two different conformations, which differ by the rate of gas phase hydrogen/deuterium (H/D) exchange reaction. In the present paper, we apply the in-electrospray ionization (ESI) source H/D exchange approach for the investigation of the oligosaccharides cations formed by attaching of metal ions (Na, K) to the molecule. It was observed that the formation of different conformers can be manipulated by varying the temperature of the desolvating capillary of the ESI interphase. Separation of the conformers was performed using gas phase H/D approach. Because the conformers have different rates of the H/D exchange reaction, the deuterium distribution spectrum becomes bimodal. It was found that the conformation corresponding to the slow H/D exchange rate dominates in the spectrum when the capillary temperature is low (~200 °C), and the conformation corresponding to the fast H/D exchange rate dominates at high (~400 °C) temperatures. In the intermediate temperature region, two conformers are present simultaneously. It was also observed that large oligosaccharide requires higher temperature for the formation of another conformer. It was found that the presence of the conformers considerably depends on the solvent used for ESI and the pH. We have compared these results with the previously performed in-ESI source H/D exchange experiments with peptides and proteins. Copyright © 2015 John Wiley & Sons, Ltd.

Ligand Induced Conformational Changes of the Human Serotonin Transporter Revealed by Molecular Dynamics Simulations

PubMed Central

Grouleff, Julie; Schiøtt, Birgit

2013-01-01

The competitive inhibitor cocaine and the non-competitive inhibitor ibogaine induce different conformational states of the human serotonin transporter. It has been shown from accessibility experiments that cocaine mainly induces an outward-facing conformation, while the non-competitive inhibitor ibogaine, and its active metabolite noribogaine, have been proposed to induce an inward-facing conformation of the human serotonin transporter similar to what has been observed for the endogenous substrate, serotonin. The ligand induced conformational changes within the human serotonin transporter caused by these three different types of ligands, substrate, non-competitive and competitive inhibitors, are studied from multiple atomistic molecular dynamics simulations initiated from a homology model of the human serotonin transporter. The results reveal that diverse conformations of the human serotonin transporter are captured from the molecular dynamics simulations depending on the type of the ligand bound. The inward-facing conformation of the human serotonin transporter is reached with noribogaine bound, and this state resembles a previously identified inward-facing conformation of the human serotonin transporter obtained from molecular dynamics simulation with bound substrate, but also a recently published inward-facing conformation of a bacterial homolog, the leucine transporter from Aquifex Aoelicus. The differences observed in ligand induced behavior are found to originate from different interaction patterns between the ligands and the protein. Such atomic-level understanding of how an inhibitor can dictate the conformational response of a transporter by ligand binding may be of great importance for future drug design. PMID:23776432

DockRank: Ranking docked conformations using partner-specific sequence homology-based protein interface prediction

PubMed Central

Xue, Li C.; Jordan, Rafael A.; EL-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

2015-01-01

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. Dock-Rank uses interface residues predicted by partner-specific sequence homology-based protein–protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. PMID:23873600

DockRank: ranking docked conformations using partner-specific sequence homology-based protein interface prediction.

PubMed

Xue, Li C; Jordan, Rafael A; El-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

2014-02-01

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. DockRank uses interface residues predicted by partner-specific sequence homology-based protein-protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. Copyright © 2013 Wiley Periodicals, Inc.

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

PubMed

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

2014-01-09

Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38α leads to a large change in free-energy barrier (ΔΔG ≈ 7 kcal/mol), promoting the transition from DFG-in to DFG-out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38α is also studied, which reduces the free-energy difference between the two functional states of p38α and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions.

Analysis of cytochrome P450 CYP119 ligand-dependent conformational dynamics by two-dimensional NMR and X-ray crystallography.

PubMed

Basudhar, Debashree; Madrona, Yarrow; Kandel, Sylvie; Lampe, Jed N; Nishida, Clinton R; de Montellano, Paul R Ortiz

2015-04-17

Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. We used two-dimensional (1)H,(15)N HSQC chemical shift perturbation mapping of (15)N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop with various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. The results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Analysis of Cytochrome P450 CYP119 Ligand-dependent Conformational Dynamics by Two-dimensional NMR and X-ray Crystallography

DOE PAGES

Basudhar, Debashree; Madrona, Yarrow; Kandel, Sylvie; ...

2015-02-10

Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. In this paper, we used two-dimensional 1H,15N HSQC chemical shift perturbation mapping of 15N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop withmore » various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. Finally, the results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states.« less

Analysis of Cytochrome P450 CYP119 Ligand-dependent Conformational Dynamics by Two-dimensional NMR and X-ray Crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basudhar, Debashree; Madrona, Yarrow; Kandel, Sylvie

Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. In this paper, we used two-dimensional 1H,15N HSQC chemical shift perturbation mapping of 15N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop withmore » various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. Finally, the results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states.« less

NMR investigation and theoretical calculations of the solvent effect on the conformation of valsartan

NASA Astrophysics Data System (ADS)

Chashmniam, Saeed; Tafazzoli, Mohsen

2017-11-01

Structure and conformational properties of valsartan were studied by advanced NMR techniques and quantum calculation methods. Potential energy scanning using B3LYP/6-311++g** and B3LYP-D3/6-311++g** methods were performed and four conformers (V1-V4) at minimum points of PES diagram were observed. According to the NMR spectra in acetone-d6, there are two conformers (M and m) with m/M = 0.52 ratio simultaneously and energy barriers of the two conformers were predicted from chemical shifts and multiplicities. While, intramolecular hydrogen bond at tetrazole ring and carboxylic groups prevent the free rotation on N6sbnd C11 bond in M-conformer, this bond rotates freely in m-conformer. On the other hand, intramolecular hydrogen bond at carbonyl and carboxylic acid can be observed at m-conformer. So, different intramolecular hydrogen bond is the reason for the stability of both M and m structures. Quite interestingly, 1H NMR spectra in CDCl3 show two distinct conformers (N and n) with unequal ratio which are differ from M-m conformers. Also, intramolecular hydrogen bond seven-member ring involving five-membered tetrazole ring and carboxylic acid group observed in both N and n-conformers Solvent effect, by using a set of polar and non-polar solvents including DMSO-d6, methanol-d4, benzene-d6, THF-d8, nitromethane-d3, methylene chloride-d2 and acetonitrile-d3 were investigated. NMR parameters include chemical shifts and spin-spin coupling constants were obtained from a set of 2D NMR spectra (H-H COSY, HMQC and HMBC). For this purpose, several DFT functionals from LDA, GGA and hybrid categories were used which the hybrid method showed better agreement with experiment values.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, G.D.; Bharadwaj, R.K.

The molecular geometries and conformational energies of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) and 1,3-dimethyl-1,3-dinitro methyldiamine (DDMD) and have been determined from high-level quantum chemistry calculations and have been used in parametrizing a classical potential function for simulations of HMX. Geometry optimizations for HMX and DDMD and rotational energy barrier searches for DDMD were performed at the B3LYP/6-311G** level, with subsequent single-point energy calculations at the MP2/6-311G** level. Four unique low-energy conformers were found for HMX, two whose conformational geometries correspond closely to those found in HMX polymorphs from crystallographic studies and two additional, lower energy conformers that are not seen in the crystallinemore » phases. For DDMD, three unique low-energy conformers, and the rotational energy barriers between them, were located. In parametrizing the classical potential function for HMX, nonbonded repulsion/dispersion parameters, valence parameters, and parameters describing nitro group rotation and out-of-plane distortion at the amine nitrogen were taken from the previous studies of dimethylnitramine. Polar effects in HMX and DDMD were represented by sets of partial atomic charges that reproduce the electrostatic potential and dipole moments for the low-energy conformers of these molecules as determined from the quantum chemistry wave functions. Parameters describing conformational energetics for the C-N-C-N dihedrals were determined by fitting the classical potential function to reproduce relative conformational energies in HMX as found from quantum chemistry. The resulting potential was found to give a good representation of the conformer geometries and relative conformer energies in HMX and a reasonable description of the low-energy conformers and rotational energy barriers in DDMD.« less

Molecular mechanisms of conformational specificity: A study of Hox in vivo target DNA binding specificities and the structure of a Ure2p mutation that affects fibril formation rates

NASA Astrophysics Data System (ADS)

Bauer, William Joseph, Jr.

The fate of an individual cell, or even an entire organism, is often determined by minute, yet very specific differences in the conformation of a single protein species. Very often, proteins take on alternate folds or even side chain conformations to deal with different situations present within the cell. These differences can be as large as a whole domain or as subtle as the alteration of a single amino acid side chain. Yet, even these seemingly minor side chain conformational differences can determine the development of a cell type during differentiation or even dictate whether a cell will live or die. Two examples of situations where minor conformational differences within a specific protein could lead to major differences in the life cycle of a cell are described herein. The first example describes the variations seen in DNA conformations which can lead to slightly different Hox protein binding conformations responsible for recognizing biologically relevant regulatory sites. These specific differences occur in the minor groove of the bound DNA and are limited to the conformation of only two side chains. The conformation of the bound DNA, however, is not solely determined by the sequence of the DNA, as multiple sequences can result in the same DNA conformation. The second example takes place in the context of a yeast prion protein which contains a mutation that decreases the frequency at which fibrils form. While the specific interactions leading to this physiological change were not directly detected, it can be ascertained from the crystal structure that the structural changes are subtle and most likely involve another binding partner. In both cases, these conformational changes are very slight but have a profound effect on the downstream processes.

Dynamics of the His79-heme alkaline transition of yeast iso-1-cytochrome c probed by conformationally gated electron transfer with Co(II)bis(terpyridine).

PubMed

Cherney, Melisa M; Junior, Carolyn C; Bergquist, Bryan B; Bowler, Bruce E

2013-08-28

Alkaline conformers of cytochrome c may be involved in both its electron transport and apoptotic functions. We use cobalt(II)bis(terpyridine), Co(terpy)2(2+), as a reagent for conformationally gated electron-transfer (gated ET) experiments to study the alkaline conformational transition of K79H variants of yeast iso-1-cytochrome c expressed in Escherichia coli , WT*K79H, with alanine at position 72 and Saccharomyces cerevisiae , yK79H, with trimethyllysine (Tml) at position 72. Co(terpy)2(2+) is well-suited to the 100 ms to 1 s time scale of the His79-mediated alkaline conformational transition of these variants. Reduction of the His79-heme alkaline conformer by Co(terpy)2(2+) occurs primarily by gated ET, which involves conversion to the native state followed by reduction, with a small fraction of the His79-heme alkaline conformer directly reduced by Co(terpy)2(2+). The gated ET experiments show that the mechanism of formation of the His79-heme alkaline conformer involves only two ionizable groups. In previous work, we showed that the mechanism of the His73-mediated alkaline conformational transition requires three ionizable groups. Thus, the mechanism of heme crevice opening depends upon the position of the ligand mediating the process. The microscopic rate constants provided by gated ET studies show that mutation of Tml72 (yK79H variant) in the heme crevice loop to Ala72 (WT*K79H variant) affects the dynamics of heme crevice opening through a small destabilization of both the native conformer and the transition state relative to the His79-heme alkaline conformer. Previous pH jump data had indicated that the Tml72→Ala mutation primarily stabilized the transition state for the His79-mediated alkaline conformational transition.

Characterizing Peptide β-HAIRPIN Loops via Cold Ion Spectroscopy of Model Compounds

NASA Astrophysics Data System (ADS)

Lawler, John T.; DeBlase, Andrew F.; Harrilal, Christopher P.; Fischer, Joshua L.; McLuckey, Scott A.; Zwier, Timothy S.

2017-06-01

The introduction of non-native D-amino acids into peptides is known to reduce conformational entropy in peptides. D-proline has been shown to promote the formation of β-hairpin loops when paired with Gly, providing a framework for building these loops with different lengths of anti-parallel beta-sheet. This study seeks to characterize and compare the conformational preferences of a model protonated pentapeptide containing DPG, [YAP^{D}GA+H]^{+}, with its L-Pro counterpart via conformation specific cold ion spectroscopy as a foundation for future consideration of larger beta-hairpin models. The UV spectrum of YAP^{D}GA of the Tyr chromophore is beautifully sharp, but contains a complicated set of transitions that could arise from the presence of more than one conformer. To assess this possibility, we recorded non-conformation specific IR "gain" spectra in the hydride stretch region. The IR spectrum so obtained displays a set of five strong IR transitions that bear a close resemblance to those found in one of the conformers of its close analog, [YAP^{D}AA+H]^{+}, signaling that a single conformer dominates the population. Two transitions at 3392 and 3464 cm-1 are slightly shifted versions of the C10 and C14 hydrogen bonds found in one of the conformers of [YAP^{D}AA+H]^{+}, and are characteristic of formation of a β-hairpin loop. Notably, in [YAP^{D}GA+H]^{+}, there is at most a minor second conformer with a free carboxylic acid OH, appearing weakly in the IR "gain" spectrum. As expected, the UV spectrum of YAP^{L}GA is more congested, which suggests the presence of multiple conformers. Further investigation into this peptide will reveal the conformational preferences of the L-pro containing molecule. Preliminary data affirms that D-proline containing peptides show reduced conformational states when compared to their natural counterparts.

Dynamics of the His79-heme Alkaline Transition of Yeast Iso-1-cytochrome c Probed by Conformationally-gated Electron Transfer with Co(II)bis(terpyridine)†

PubMed Central

Cherney, Melisa M.; Junior, Carolyn C.; Bergquist, Bryan B.; Bowler, Bruce E.

2013-01-01

Alkaline conformers of cytochrome c may be involved in both its electron transport and apoptotic functions. We use cobalt(II)bis(terpyridine), Co(terpy)22+, as a reagent for conformationally-gated electron transfer (gated ET) experiments to study the alkaline conformational transition of K79H variants of yeast iso-1-cytochrome c expressed in Escherichia coli, WT*K79H, with alanine at position 72, and Saccharomyces cerevisiae, yK79H, with trimethyllysine (Tml) at position 72. Co(terpy)22+ is well-suited to the 100 ms to 1 s time scale of the His79-mediated alkaline conformational transition of these variants. Reduction of the His79-heme alkaline conformer by Co(terpy)22+ occurs primarily by gated ET, which involves conversion to the native state followed by reduction, with a small fraction of the His79- heme alkaline conformer directly reduced by Co(terpy)22+. The gated ET experiments show that the mechanism of formation of the His79-heme alkaline conformer involves only two ionizable groups. In previous work, we showed that the mechanism of the His73-mediated alkaline conformational transition requires three ionizable groups. Thus, the mechanism of heme crevice opening depends upon the position of the ligand mediating the process. The microscopic rate constants provided by gated ET studies show that mutation of Tml72 (yK79H variant) in the heme crevice loop to Ala72 (WT*K79H variant) affects the dynamics of heme crevice opening through a small destabilization of both the native conformer and the transition state relative to the His79-heme alkaline conformer. Previous pH jump data had indicated that the Tml72→Ala mutation primarily stabilized the transition state for the His79-mediated alkaline conformational transition. PMID:23899348

Conformational preferences of γ-aminobutyric acid in the gas phase and in water

NASA Astrophysics Data System (ADS)

Song, Il Keun; Kang, Young Kee

2012-09-01

The conformational study of γ-aminobutyric acid (GABA) has been carried out at the M06-2X/cc-pVTZ level of theory in the gas phase and the SMD M06-2X/cc-pVTZ level of theory in water. In the gas phase, the folded conformation gG1 with gauche- and gauche+ conformations for the Cβsbnd Cα and Cγsbnd Cβ bonds, respectively, is found to be lowest in energy and enthalpy, which can be ascribed to the favored hyperconjugative n → π* interaction between the lone electron pair of the amine nitrogen atom and the Cdbnd O bond of the carboxylic group and the favored antiparallel dipole-dipole interaction between the Nsbnd H bond and the Cdbnd O bond. In addition, the intramolecular hydrogen bonds between the carboxylic group and the amine Nsbnd H group have contributed to stabilize some low-energy conformers. However, the most preferred conformation is found to be tG1 and more stable by 0.4 kcal/mol in ΔG than the conformer gG1, in which the favored entropic term due to the conformational flexibility and the other favored n → σ*, σ → σ*, and π → σ* interactions seem to play a role. The conformational preferences of the neutral GABA calculated by ΔG's are reasonably consistent with the populations deduced from FT microwave spectroscopy in supersonic jets combined with laser ablation. In water, the two folded conformers Gg and gG of the zwitterionic GABA are dominantly populated, each of which has the population of 47%, and the hydrogen bond between the ammonium Nsbnd H group and the lone electron pair of the Csbnd O- group seems to be crucial in stabilizing these conformers. Our calculated result that the folded conformers preferentially exist in water is consistent with the 1H NMR experiments in D2O.

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

PubMed Central

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

2011-01-01

Characterizing the conformations of protein in the transition state ensemble (TSE) is important for studying protein folding. A promising approach pioneered by Vendruscolo [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 [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 , J. Chem. Phys. 129, 094101 (2008); Zhang 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 studies, our results show that transition state conformations are very diverse and are far from nativelike when measured in cartesian root-mean-square deviation (cRMSD): the average cRMSD between TSE conformations and the native structure is 9.4 Å  for this short protein, instead of 6 Å reported in previous studies. In addition, we found that the average fraction of native contacts in the TSE is 0.37, with enrichment in native-like β-sheets and a shortage of long range contacts, suggesting such contacts form at a later stage of folding. We further calculate the first passage time of folding of TSE conformations through calculation of physical time associated with the regrowth moves in MCMC simulation through mapping such moves to a Markovian state model, whose transition time was obtained by Langevin dynamics simulations. Our results indicate that despite the large structural diversity of the TSE, they are characterized by similar folding time. Our approach is general and can be used to study TSE in other macromolecules. PMID:21341875

Conformational study of the proline rich peptide from bovine neurohypophysis secretory granules

NASA Astrophysics Data System (ADS)

Alieva, Irada; Velieva, Lala; Aliev, Dshavanchir; Gojayev, Niftali; Demukhamedova, Svetlana

2004-01-01

The spatial organization and conformational properties of the Proline Rich Peptide (PRP) from bovine neurohypophysis secretory granules have been established by the methods of molecular mechanics and molecular dynamics simulations in water solution. Conformational studies showed the peptide with limited conformational flexibility. Two β-type III turns are observed in PRP spatial organization.

Free volume distribution of branched poly(methyl methacrylates): Conformational probes study

NASA Astrophysics Data System (ADS)

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

2016-12-01

In this work we studied the free volume distribution of the branched poly (methylmethacrylates) by the method of conformational probes. The freezing temperatures of the conformational transitions of the probes introduced into branched polymers were determined by FTIR spectra. The influence of covalently connected fullerene С60 on the freezing temperatures of conformational transitions was shown.

Conformal array design on arbitrary polygon surface with transformation optics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng, Li, E-mail: dengl@bupt.edu.cn; Hong, Weijun, E-mail: hongwj@bupt.edu.cn; Zhu, Jianfeng

2016-06-15

A transformation-optics based method to design a conformal antenna array on an arbitrary polygon surface is proposed and demonstrated in this paper. This conformal antenna array can be adjusted to behave equivalently as a uniformly spaced linear array by applying an appropriate transformation medium. An typical example of general arbitrary polygon conformal arrays, not limited to circular array, is presented, verifying the proposed approach. In summary, the novel arbitrary polygon surface conformal array can be utilized in array synthesis and beam-forming, maintaining all benefits of linear array.

Method and apparatus for enhancing vortex pinning by conformal crystal arrays

DOEpatents

Janko, Boldizsar; Reichhardt, Cynthia; Reichhardt, Charles; Ray, Dipanjan

2015-07-14

Disclosed is a method and apparatus for strongly enhancing vortex pinning by conformal crystal arrays. The conformal crystal array is constructed by a conformal transformation of a hexagonal lattice, producing a non-uniform structure with a gradient where the local six-fold coordination of the pinning sites is preserved, and with an arching effect. The conformal pinning arrays produce significantly enhanced vortex pinning over a much wider range of field than that found for other vortex pinning geometries with an equivalent number of vortex pinning sites, such as random, square, and triangular.

An automated and efficient conformation search of L-cysteine and L,L-cystine using the scaled hypersphere search method

NASA Astrophysics Data System (ADS)

Kishimoto, Naoki; Waizumi, Hiroki

2017-10-01

Stable conformers of L-cysteine and L,L-cystine were explored using an automated and efficient conformational searching method. The Gibbs energies of the stable conformers of L-cysteine and L,L-cystine were calculated with G4 and MP2 methods, respectively, at 450, 298.15, and 150 K. By assuming thermodynamic equilibrium and the barrier energies for the conformational isomerization pathways, the estimated ratios of the stable conformers of L-cysteine were compared with those determined by microwave spectroscopy in a previous study. Equilibrium structures of 1:1 and 2:1 cystine-Fe complexes were also calculated, and the energy of insertion of Fe into the disulfide bond was obtained.

Development of a conformational search strategy for flexible ligands: A study of the potent μ-selective opioid analgesic fentanyl

NASA Astrophysics Data System (ADS)

Cometta-Morini, Chiara; Loew, Gilda H.

1991-08-01

An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations. The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.

Rotationally resolved electronic spectroscopy study of the conformational space of 3-methoxyphenol

NASA Astrophysics Data System (ADS)

Wilke, Martin; Schneider, Michael; Wilke, Josefin; Ruiz-Santoyo, José Arturo; Campos-Amador, Jorge J.; González-Medina, M. Elena; Álvarez-Valtierra, Leonardo; Schmitt, Michael

2017-07-01

Conformational preferences are determined by (de-)stabilization effects like intramolecular hydrogen bonds or steric hindrance of adjacent substituents and thus, influence the stability and reactivity of the conformers. In the present contribution, we investigate the conformational landscape of 3-methoxyphenol using a combination of high resolution electronic spectroscopy and ab initio calculations. Three of the four possible conformational isomers were characterized in their electronic ground and lowest excited singlet states on the basis of their rotational constants and other molecular parameters. The absence of one conformer in molecular beam studies can be explained by its non-planar structure in the excited state, which leads to a vanishingly small Franck-Condon factor of the respective origin excitation.

Memory, metamemory, and social cues: Between conformity and resistance.

PubMed

Zawadzka, Katarzyna; Krogulska, Aleksandra; Button, Roberta; Higham, Philip A; Hanczakowski, Maciej

2016-02-01

When presented with responses of another person, people incorporate these responses into memory reports: a finding termed memory conformity. Research on memory conformity in recognition reveals that people rely on external social cues to guide their memory responses when their own ability to respond is at chance. In this way, conforming to a reliable source boosts recognition performance but conforming to a random source does not impair it. In the present study we assessed whether people would conform indiscriminately to reliable and unreliable (random) sources when they are given the opportunity to exercise metamemory control over their responding by withholding answers in a recognition test. In Experiments 1 and 2, we found the pattern of memory conformity to reliable and unreliable sources in 2 variants of a free-report recognition test, yet at the same time the provision of external cues did not affect the rate of response withholding. In Experiment 3, we provided participants with initial feedback on their recognition decisions, facilitating the discrimination between the reliable and unreliable source. This led to the reduction of memory conformity to the unreliable source, and at the same time modulated metamemory decisions concerning response withholding: participants displayed metamemory conformity to the reliable source, volunteering more responses in their memory report, and metamemory resistance to the random source, withholding more responses from the memory report. Together, the results show how metamemory decisions dissociate various types of memory conformity and that memory and metamemory decisions can be independent of each other. PsycINFO Database Record (c) 2016 APA, all rights reserved.

Enhanced conformational sampling technique provides an energy landscape view of large-scale protein conformational transitions.

PubMed

Shao, Qiang

2016-10-26

Large-scale conformational changes in proteins are important for their functions. Tracking the conformational change in real time at the level of a single protein molecule, however, remains a great challenge. In this article, we present a novel in silico approach with the combination of normal mode analysis and integrated-tempering-sampling molecular simulation (NMA-ITS) to give quantitative data for exploring the conformational transition pathway in multi-dimensional energy landscapes starting only from the knowledge of the two endpoint structures of the protein. The open-to-closed transitions of three proteins, including nCaM, AdK, and HIV-1 PR, were investigated using NMA-ITS simulations. The three proteins have varied structural flexibilities and domain communications in their respective conformational changes. The transition state structure in the conformational change of nCaM and the associated free-energy barrier are in agreement with those measured in a standard explicit-solvent REMD simulation. The experimentally measured transition intermediate structures of the intrinsically flexible AdK are captured by the conformational transition pathway measured here. The dominant transition pathways between the closed and fully open states of HIV-1 PR are very similar to those observed in recent REMD simulations. Finally, the evaluated relaxation times of the conformational transitions of three proteins are roughly at the same level as reported experimental data. Therefore, the NMA-ITS method is applicable for a variety of cases, providing both qualitative and quantitative insights into the conformational changes associated with the real functions of proteins.

Rates and equilibrium constants of the ligand-induced conformational transition of an HCN ion channel protein domain determined by DEER spectroscopy.

PubMed

Collauto, Alberto; DeBerg, Hannah A; Kaufmann, Royi; Zagotta, William N; Stoll, Stefan; Goldfarb, Daniella

2017-06-14

Ligand binding can induce significant conformational changes in proteins. The mechanism of this process couples equilibria associated with the ligand binding event and the conformational change. Here we show that by combining the application of W-band double electron-electron resonance (DEER) spectroscopy with microfluidic rapid freeze quench (μRFQ) it is possible to resolve these processes and obtain both equilibrium constants and reaction rates. We studied the conformational transition of the nitroxide labeled, isolated carboxy-terminal cyclic-nucleotide binding domain (CNBD) of the HCN2 ion channel upon binding of the ligand 3',5'-cyclic adenosine monophosphate (cAMP). Using model-based global analysis, the time-resolved data of the μRFQ DEER experiments directly provide fractional populations of the open and closed conformations as a function of time. We modeled the ligand-induced conformational change in the protein using a four-state model: apo/open (AO), apo/closed (AC), bound/open (BO), bound/closed (BC). These species interconvert according to AC + L ⇌ AO + L ⇌ BO ⇌ BC. By analyzing the concentration dependence of the relative contributions of the closed and open conformations at equilibrium, we estimated the equilibrium constants for the two conformational equilibria and the open-state ligand dissociation constant. Analysis of the time-resolved μRFQ DEER data gave estimates for the intrinsic rates of ligand binding and unbinding as well as the rates of the conformational change. This demonstrates that DEER can quantitatively resolve both the thermodynamics and the kinetics of ligand binding and the associated conformational change.

A Dualistic Conformational Response to Substrate Binding in the Human Serotonin Transporter Reveals a High Affinity State for Serotonin*

PubMed Central

Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida; Wiborg, Ove; Sinning, Steffen

2015-01-01

Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT. PMID:25614630

Direct Determination of Site-Specific Noncovalent Interaction Strengths of Proteins from NMR-Derived Fast Side Chain Motional Parameters.

PubMed

Rajeshwar T, Rajitha; Krishnan, Marimuthu

2017-05-25

A novel approach to accurately determine residue-specific noncovalent interaction strengths (ξ) of proteins from NMR-measured fast side chain motional parameters (O axis 2 ) is presented. By probing the environmental sensitivity of side chain conformational energy surfaces of individual residues of a diverse set of proteins, the microscopic connections between ξ, O axis 2 , conformational entropy (S conf ), conformational barriers, and rotamer stabilities established here are found to be universal among proteins. The results reveal that side chain flexibility and conformational entropy of each residue decrease with increasing ξ and that for each residue type there exists a critical range of ξ, determined primarily by the mean side chain conformational barriers, within which flexibility of any residue can be reversibly tuned from highly flexible (with O axis 2 ∼ 0) to highly restricted (with O axis 2 ∼ 1) by increasing ξ by ∼3 kcal/mol. Beyond this critical range of ξ, both side chain flexibility and conformational entropy are insensitive to ξ. The interrelationships between conformational dynamics, conformational entropy, and noncovalent interactions of protein side chains established here open up new avenues to probe perturbation-induced (for example, ligand-binding, temperature, pressure) changes in fast side chain dynamics and thermodynamics of proteins by comparing their conformational energy surfaces in the native and perturbed states.

Investigating ion channel conformational changes using voltage clamp fluorometry.

PubMed

Talwar, Sahil; Lynch, Joseph W

2015-11-01

Ion channels are membrane proteins whose functions are governed by conformational changes. The widespread distribution of ion channels, coupled with their involvement in most physiological and pathological processes and their importance as therapeutic targets, renders the elucidation of these conformational mechanisms highly compelling from a drug discovery perspective. Thanks to recent advances in structural biology techniques, we now have high-resolution static molecular structures for members of the major ion channel families. However, major questions remain to be resolved about the conformational states that ion channels adopt during activation, drug modulation and desensitization. Patch-clamp electrophysiology has long been used to define ion channel conformational states based on functional criteria. It achieves this by monitoring conformational changes at the channel gate and cannot detect conformational changes occurring in regions distant from the gate. Voltage clamp fluorometry involves labelling cysteines introduced into domains of interest with environmentally sensitive fluorophores and inferring structural rearrangements from voltage or ligand-induced fluorescence changes. Ion channel currents are monitored simultaneously to verify the conformational status. By defining real time conformational changes in domains distant from the gate, this technique provides unexpected new insights into ion channel structure and function. This review aims to summarise the methodology and highlight recent innovative applications of this powerful technique. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 Elsevier Ltd. All rights reserved.

How Diverse are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

NASA Astrophysics Data System (ADS)

Friedrich, Nils-Ole; Simsir, Méliné; Kirchmair, Johannes

2018-03-01

Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set (“Sperrylite Dataset”) of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules—each represented by a minimum of ten structures—and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from http://www.zbh.uni-hamburg.de/sperrylite_dataset.

The Dynameomics Entropy Dictionary: A Large-Scale Assessment of Conformational Entropy across Protein Fold Space.

PubMed

Towse, Clare-Louise; Akke, Mikael; Daggett, Valerie

2017-04-27

Molecular dynamics (MD) simulations contain considerable information with regard to the motions and fluctuations of a protein, the magnitude of which can be used to estimate conformational entropy. Here we survey conformational entropy across protein fold space using the Dynameomics database, which represents the largest existing data set of protein MD simulations for representatives of essentially all known protein folds. We provide an overview of MD-derived entropies accounting for all possible degrees of dihedral freedom on an unprecedented scale. Although different side chains might be expected to impose varying restrictions on the conformational space that the backbone can sample, we found that the backbone entropy and side chain size are not strictly coupled. An outcome of these analyses is the Dynameomics Entropy Dictionary, the contents of which have been compared with entropies derived by other theoretical approaches and experiment. As might be expected, the conformational entropies scale linearly with the number of residues, demonstrating that conformational entropy is an extensive property of proteins. The calculated conformational entropies of folding agree well with previous estimates. Detailed analysis of specific cases identifies deviations in conformational entropy from the average values that highlight how conformational entropy varies with sequence, secondary structure, and tertiary fold. Notably, α-helices have lower entropy on average than do β-sheets, and both are lower than coil regions.

Theoretical study on the adsorption and relative stability of conformers of L-ascorbic acid on γ - alumina (100) surface

NASA Astrophysics Data System (ADS)

Mozaffari Majd, M.; Dabbagh, H. A.; Farrokhpour, H.; Najafi Chermahini, A.

2017-11-01

The adsorption energies (Eads) and relative stabilities of selected conformers of the most stable tautomer of L-ascorbic acid (vitamin C) on the dehydroxylated γ-alumina (100) surface were calculated in both gas phase and solvent (water) using the density functional theory (DFT) method. The selected conformers were related to the different rotational angles of OH groups of L-ascorbic acid. The conformational analysis of bare tautomer in both gas and water showed that the conformer No.20 (conf. 20) and 13 (conf. 13) with the dihedral angles of H15sbnd O10sbnd C11sbnd C9 (-73°) and H20sbnd O19sbnd C9sbnd C11 (-135°) were the most stable and unstable conformers, respectively. The performed calculations in the presence of surface showed that the interaction of the conformers with the surface changes their relative stabilities and structures in both gas phase and water. The Ead of each conformer was calculated and it was determined that conf. 8 and conf. 16 have the highest value of Ead in the gas phase (-62.56 kcal/mol) and water (-54.44 kcal/mol), respectively. The optimized structure of each conformer on the surface and the number of hydrogen bonds between it and surface along with their bond lengths were determined.

Conformational Transition of Key Structural Features Involved in Activation of ALK Induced by Two Neuroblastoma Mutations and ATP Binding: Insight from Accelerated Molecular Dynamics Simulations.

PubMed

He, Mu-Yang; Li, Wei-Kang; Zheng, Qing-Chuan; Zhang, Hong-Xing

2018-04-17

Deregulated kinase activity of anaplastic lymphoma kinase (ALK) has been observed to be implicated in the development of tumor progression. The activation mechanism of ALK is proposed to be similar to other receptor tyrosine kinases (RTKs), but the distinct static X-ray crystal conformation of ALK suggests its unique conformational transition. Herein, we have illustrated the dynamic conformational property of wild-type ALK as well as the kinase activation equilibrium variation induced by two neuroblastoma mutations (R1275Q and Y1278S) and ATP binding by performing enhanced sampling accelerated Molecular Dynamics (aMD) simulations. The results suggest that the wild-type ALK is mostly favored in the inactive state, whereas the mutations and ATP binding promote a clear shift toward the active-like conformation. The R1275Q mutant stabilizes the active conformation by rigidifying the αC-in conformation. The Y1278S mutant promotes activation at the expense of a π-stacking hydrophobic cluster, which plays a critical role in the stabilization of the inactive conformation of native ALK. ATP produces a more compact active site and thereby facilitates the activation of ALK. Taken together, these findings not only elucidate the diverse conformations in different ALKs but can also shed light on new strategies for protein engineering and structural-based drug design for ALK.

Vibrational spectrum, ab initio calculations, conformational stabilities and assignment of fundamentals of 1,2-dibromopropane

NASA Astrophysics Data System (ADS)

LaPlante, Arthur J.; Stidham, Howard D.

2009-10-01

The mid and far infrared and the Raman spectrum of 1,2-dibromopropane is reported in solid, liquid and gas. Several bands reported by earlier workers are not present in the spectrum of the purified material. Ab initio calculations of optimized geometry, energy, dipole moment, molar volume, vibrational spectrum and normal coordinate calculation were performed using the density functional B3LYP/6-311++g(3df,2pd), and the results used to assist a complete assignment of the 81 fundamental modes of vibrations of the three conformers of 1,2-dibromopropane. Relative energies found conformer A the lowest with G and G' at 815.6 and 871.4 cm -1 higher. The temperature dependence of the Raman spectrum of the liquid was investigated in the CCC bending region and the relative energies determined. It was found that the G' and G conformers lie 236 ± 11 and 327 ±11 cm -1, respectively above the A conformer, leading to the room temperature composition of the liquid as A, 65 ± 1; G', 21 ± 1; G, 14 ± 1%. It is apparent that the calculated highest energy conformer G' is stabilized more than the G conformer in the liquid. The G' conformer has the lowest molar volume effectively changing the interaction distance between conformers in the liquid, and enhancing the effect of its dipole moment.

Vibrational spectrum, ab initio calculations, conformational stabilities and assignment of fundamentals of 1,2-dibromopropane.

PubMed

LaPlante, Arthur J; Stidham, Howard D

2009-10-15

The mid and far infrared and the Raman spectrum of 1,2-dibromopropane is reported in solid, liquid and gas. Several bands reported by earlier workers are not present in the spectrum of the purified material. Ab initio calculations of optimized geometry, energy, dipole moment, molar volume, vibrational spectrum and normal coordinate calculation were performed using the density functional B3LYP/6-311++g(3df,2pd), and the results used to assist a complete assignment of the 81 fundamental modes of vibrations of the three conformers of 1,2-dibromopropane. Relative energies found conformer A the lowest with G and G' at 815.6 and 871.4 cm(-1) higher. The temperature dependence of the Raman spectrum of the liquid was investigated in the CCC bending region and the relative energies determined. It was found that the G' and G conformers lie 236+/-11 and 327+/-11 cm(-1), respectively above the A conformer, leading to the room temperature composition of the liquid as A, 65+/-1; G', 21+/-1; G, 14+/-1%. It is apparent that the calculated highest energy conformer G' is stabilized more than the G conformer in the liquid. The G' conformer has the lowest molar volume effectively changing the interaction distance between conformers in the liquid, and enhancing the effect of its dipole moment.

Meta-analyses of the relationship between conformity to masculine norms and mental health-related outcomes.

PubMed

Wong, Y Joel; Ho, Moon-Ho Ringo; Wang, Shu-Yi; Miller, I S Keino

2017-01-01

Despite theoretical postulations that individuals' conformity to masculine norms is differentially related to mental health-related outcomes depending on a variety of contexts, there has not been any systematic synthesis of the empirical research on this topic. Therefore, the authors of this study conducted meta-analyses of the relationships between conformity to masculine norms (as measured by the Conformity to Masculine Norms Inventory-94 and other versions of this scale) and mental health-related outcomes using 78 samples and 19,453 participants. Conformity to masculine norms was modestly and unfavorably associated with mental health as well as moderately and unfavorably related to psychological help seeking. The authors also identified several moderation effects. Conformity to masculine norms was more strongly correlated with negative social functioning than with psychological indicators of negative mental health. Conformity to the specific masculine norms of self-reliance, power over women, and playboy were unfavorably, robustly, and consistently related to mental health-related outcomes, whereas conformity to the masculine norm of primacy of work was not significantly related to any mental health-related outcome. These findings highlight the need for researchers to disaggregate the generic construct of conformity to masculine norms and to focus instead on specific dimensions of masculine norms and their differential associations with other outcomes. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Conformational study of glyoxal bis(amidinohydrazone) by ab initio methods

NASA Astrophysics Data System (ADS)

Mannfors, B.; Koskinen, J. T.; Pietilä, L.-O.

1997-08-01

We report the first ab initio molecular orbital study on the ground state of the endiamine tautomer of glyoxal bis(amidinohydrazone) (or glyoxal bis(guanylhydrazone), GBG) free base. The calculations were performed at the following levels of theory: Hartree-Fock, second-order Møller-Plesset perturbation theory and density functional theory (B-LYP and B3-LYP) as implemented in the Gaussian 94 software. The standard basis set 6-31G(d) was found to be sufficient. The default fine grid of Gaussian 94 was used in the density functional calculations. Molecular properties, such as optimized structures, total energies and the electrostatic potential derived (CHELPG) atomic charges, were studied as functions of C-C and N-N conformations. The lowest energy conformation was found to be all- trans, in agreement with the experimental solid-state structure. The second conformer with respect to rotation around the central C-C bond was found to be the cis conformer with an MP2//HF energy of 4.67 kcal mol -1. For rotation around the N-N bond the energy increased monotonically from the trans conformation to the cis conformation, the cis energy being very high, 22.01 kcal mol -1 (MP2//HF). The atomic charges were shown to be conformation dependent, and the bond charge increments and especially the conformational changes of the bond charge increments were found to be easily transferable between structurally related systems.

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.

An Abbreviated Tool for Assessing Feminine Norm Conformity: Psychometric Properties of the Conformity to Feminine Norms Inventory-45

ERIC Educational Resources Information Center

Parent, Mike C.; Moradi, Bonnie

2011-01-01

The Conformity to Feminine Norms Inventory-45 (CFNI-45; Parent & Moradi, 2010) is an important tool for assessing level of conformity to feminine gender norms and for investigating the implications of such norms for women's functioning. The authors of the present study assessed the factor structure, measurement invariance, reliability, and…

Isomers and conformational barriers of gas phase nicotine, nornicotine and their protonated forms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoshida, Tomoki; Farone, William A.; Xantheas, Sotiris S.

We report extensive conformational searches of the neutral nicotine, nornicotine and their protonated analogs that are based on ab-initio second order Møller-Plesset perturbation (MP2) electronic structure calculations. Initial searches were performed with the 6-31G(d,p) and the energetics of the most important structures were further refined from geometry optimizations with the aug-cc-pVTZ basis set. Based on the calculated free energies at T=298 K for the gas phase molecules, neutral nicotine has two dominant trans conformers, whereas neutral nornicotine is a mixture of several conformers. For nicotine, the protonation on both the pyridine and the pyrrolidine sites is energetically competitive, whereas nornicotinemore » prefers protonation on the pyridine nitrogen. The protonated form of nicotine is mainly a mixture of two pyridine-protonated trans conformers and two pyrrolidine-protonated trans conformers, whereas the protonated form of nornicotine is a mixture of four pyridine-protonated trans conformers. Nornicotine is conformationally more flexible than nicotine, however it is less protonated at the biologically important pyrrolidine nitrogen site. The lowest energy isomers for each case were found to interconvert via low (< 6 kcal/mol) rotational barriers around the pyridine-pyrrolidine bond.« less

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

DFT calculations and NMR measurements applied to the conformational analysis of cis and trans-3-phenylaminocyclohexyl N,N-dimethylcarbamates

NASA Astrophysics Data System (ADS)

Melo, Ulisses Zonta de; Yamazaki, Diego Alberto dos Santos; Cândido, Augusto de Araújo; Basso, Ernani Abicht; Gauze, Gisele de Freitas

2018-07-01

The three-dimensional structure of a potential drug molecule is of critical importance. Factors that determine its conformational stability and, consequently, corresponding biological/physicochemical properties of interest must therefore be carefully analyzed. Conformational properties and molecular structures of cis and trans-3-phenylaminocyclohexyl N,N-dimethylcarbamates were studied by low temperature 1H and 13C NMR spectroscopy and electronic structure calculations. B3LYP and M06-2X methods associated with the 6-311++G(2df,2p) basis set, and the integral-equation-formalism polarizable continuum model were used to study the conformational preferences in dichloromethane, acetone and methanol. NMR measurements indicated that for the cis isomer, the conformer with both substituents in equatorial position is the most stable, while for the trans isomer, the conformer with the carbamate group in the axial position and the arylamine in the equatorial position is favored in all solvents. B3LYP/6-311++G(2df,2p) theory level associated with IEF-PCM described properly the conformational preference in solution. NBO analyses were applied to determine the importance of hyperconjugative interactions in the conformational equilibrium.

Conformational transition of κ-casein in micellar environment: Insight from the tryptophan fluorescence

NASA Astrophysics Data System (ADS)

Mishra, Smruti; Meher, Geetanjali; Chakraborty, Hirak

2017-11-01

Intrinsically disordered proteins (IDPs) are under intense analysis due to their structural flexibility and importance in biological functions. Minuscule modulation in the microenvironment induces significant conformational changes in IDPs, and these non-native conformations of the IDPs often induce aggregation and cause cell death. Changes in the membrane composition often change the microenvironment, which promote conformational change and aggregation of IDPs. κ-Casein, an important milk protein, belongs to the class of IDPs containing net negative charges. In this present work, we have studied the interaction of κ-casein with cetyltrimethyl ammonium bromide (CTAB), a positively charged surfactant, utilizing various steady state fluorescence, time-resolved fluorescence and circular dichroism spectroscopy. Our results clearly indicate that κ-casein undergoes at least two conformational transitions in presence of various concentrations of CTAB. The intrinsically disordered κ-casein assumes a partially folded conformation at lower concentration of CTAB, which adopts an unstructured conformation at higher concentration of CTAB. The partially folded conformation of κ-casein at a lower CTAB concentration might be induced by the favorable electrostatic interaction between the positively charged surfactant headgroup and net negative charges of the protein, whereas surfactant nature of CTAB is being pronounced at higher concentration of CTAB.

RDX geometries, excited states, and revised energy ordering of conformers via MP2 and CCSD(T) methodologies: insights into decomposition mechanism.

PubMed

Molt, Robert W; Watson, Thomas; Lotrich, Victor F; Bartlett, Rodney J

2011-02-10

The geometries, harmonic frequencies, elec-tronic excitation levels, and energetic orderings of various conformers of RDX have been computed at the ab initio MP2 and CCSD(T) levels, providing more reliable results than have been previously obtained. We observe that the various local minimum-energy conformers are all competitive for being the absolute minimum and that, at reasonable temperatures, several conformers will appreciably contribute to the population of RDX. As a result, we have concluded that any mechanistic study to investigate thermal decomposition can reasonably begin from any one of the cyclohexane conformers of RDX. As such, it is necessary to consider the transition states for each RDX conformer to gauge what the activation energy is. Homolytic bond dissociation has long been speculated to be critical to detonation; we report here the most accurate estimates of homolytic BDEs yet calculated, likely to be accurate within 3 kcal mol(-1). The differences in energy for homolytic BDEs among all the possible RDR conformers are again small, such that most all of the conformers can reasonably be speculated as the next step in the mechanism starting from the RDR radical.

Reactions driving conformational movements (molecular motors) in gels: conformational and structural chemical kinetics.

PubMed

Otero, Toribio F

2017-01-18

In this perspective the empirical kinetics of conducting polymers exchanging anions and solvent during electrochemical reactions to get dense reactive gels is reviewed. The reaction drives conformational movements of the chains (molecular motors), exchange of ions and solvent with the electrolyte and structural (relaxation, swelling, shrinking and compaction) gel changes. Reaction-driven structural changes are identified and quantified from electrochemical responses. The empirical reaction activation energy (E a ), the reaction coefficient (k) and the reaction orders (α and β) change as a function of the conformational energy variation during the reaction. This conformational energy becomes an empirical magnitude. E a , k, α and β include and provide quantitative conformational and structural information. The chemical kinetics becomes structural chemical kinetics (SCK) for reactions driving conformational movements of the reactants. The electrochemically stimulated conformational relaxation model describes empirical results and some results from the literature for biochemical reactions. In parallel the development of an emerging technological world of soft, wet, multifunctional and biomimetic tools and anthropomorphic robots driven by reactions of the constitutive material, as in biological organs, can be now envisaged being theoretically supported by the kinetic model.

Conformal expansions and renormalons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rathsman, J.

2000-02-07

The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients.more » As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.« less

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

PubMed

Sutto, Ludovico; Gervasio, Francesco Luigi

2013-06-25

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.

Interpreting medium ring canonical conformers by a triangular plane tessellation of the macrocycle

NASA Astrophysics Data System (ADS)

Khalili, Pegah; Barnett, Christopher B.; Naidoo, Kevin J.

2013-05-01

Cyclic conformational coordinates are essential for the distinction of molecular ring conformers as the use of Cremer-Pople coordinates have illustrated for five- and six-membered rings. Here, by tessellating medium rings into triangular planes and using the relative angles made between triangular planes we are able to assign macrocyclic pucker conformations into canonical pucker conformers such as chairs, boats, etc. We show that the definition is straightforward compared with other methods popularly used for small rings and that it is computationally simple to implement for complex macrocyclic rings. These cyclic conformational coordinates directly couple to the motion of individual nodes of a ring. Therefore, they are useful for correlating the physical properties of macrocycles with their ring pucker and measuring the dynamic ring conformational behavior. We illustrate the triangular tessellation, assignment, and pucker analysis on 7- and 8-membered rings. Sets of canonical states are given for cycloheptane and cyclooctane that have been previously experimentally analysed.

LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis.

PubMed

Thomas, James R; Gedeon, Patrick C; Grant, Barry J; Madura, Jeffry D

2012-07-03

Monoamine transporters (MATs) function by coupling ion gradients to the transport of dopamine, norepinephrine, or serotonin. Despite their importance in regulating neurotransmission, the exact conformational mechanism by which MATs function remains elusive. To this end, we have performed seven 250 ns accelerated molecular dynamics simulations of the leucine transporter, a model for neurotransmitter MATs. By varying the presence of binding-pocket leucine substrate and sodium ions, we have sampled plausible conformational states representative of the substrate transport cycle. The resulting trajectories were analyzed using principal component analysis of transmembrane helices 1b and 6a. This analysis revealed seven unique structures: two of the obtained conformations are similar to the currently published crystallographic structures, one conformation is similar to a proposed open inward structure, and four conformations represent novel structures of potential importance to the transport cycle. Further analysis reveals that the presence of binding-pocket sodium ions is necessary to stabilize the locked-occluded and open-inward conformations. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

A Peptide/MHCII conformer generated in the presence of exchange peptide is substrate for HLA-DM editing

PubMed Central

Ferrante, Andrea; Gorski, Jack

2012-01-01

The mechanism of HLA-DM (DM) activity is still unclear. We have shown that DM-mediated peptide release from HLA-DR (DR) is dependent on the presence of exchange peptide. However, DM also promotes a small amount of peptide release in the absence of exchange peptide. Here we show that SDS-PAGE separates purified peptide/DR1 complexes (pDR1) into two conformers whose ratio is peptide Kd-dependent. In the absence of exchange peptide, DM only releases peptide from the slower migrating conformer. Addition of exchange peptide converts the DM-resistant conformer to the slower migrating conformer, which is DM labile. Thus, exchange peptide generates a conformer of pDR1 which constitutes the intermediate for peptide exchange and the substrate for DM activity. The resolution of the intermediate favors the highest affinity peptide. However, once folded into the DM-resistant conformer, even low affinity peptides can be presented in the absence of free peptide, broadening the repertoire available for presentation. PMID:22545194

Cross-protection in Neisseria meningitidis serogroups Y and W polysaccharides: A comparative conformational analysis.

PubMed

Kuttel, Michelle M; Timol, Zaheer; Ravenscroft, Neil

2017-06-29

The capsular polysaccharide is the main virulence factor in meningococcus. The capsular polysaccharides for meningococcal serogroups Y and W are almost identical polymers of hexose-sialic acid, suggesting the possibility of cross-protection between group Y and W vaccines. However, early studies indicated that they elicit different levels of cross-protection. Here we explore the conformations of the meningococcal Y and W polysaccharides with molecular dynamics simulations of three repeating unit oligosaccharide strands. We find differences in Y and W antigen conformation: the Y polysaccharide has a single dominant conformation, whereas W exhibits a family of conformations including the Y conformation. This result is supported by our NMR NOESY analysis, which indicates key close contacts for W that are not present in Y. These conformational differences provide an explanation for the different levels of cross-protection measured for the Y and W monovalent vaccines and the high group W responses observed in HibMenCY-TT vaccinees. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of the position of the methoxy group on the stabilities of the syn and anti conformers of 4-, 5-, and 6-methoxyindole

NASA Astrophysics Data System (ADS)

Wilke, Martin; Brand, Christian; Wilke, Josefin; Schmitt, Michael

2017-07-01

Even though the two possible rotamers of methoxy-substituted indoles only differ in the orientation of a methoxy group, this slight geometry change can have a strong influence on the stabilities and further molecular properties of the conformers. In the present study, we evaluate the effect of the methyl group position on the presence of different conformers in molecular beam studies for the systems 4-, 5-, and 6-methoxyindole. By using rotationally resolved electronic Stark spectroscopy in combination with high level ab initio calculations the structures of the observable conformers have been assigned and reasons for the absence of the missing conformers discussed. Thereby, we could show that the relative ground state energies and isomerization barriers for both conformers strongly depend on the position of the methoxy group and are the main explanation for the absence of the syn conformers of 4-, and 5-methoxyindole.

On-the-Fly ab Initio Semiclassical Calculation of Glycine Vibrational Spectrum

PubMed Central

2017-01-01

We present an on-the-fly ab initio semiclassical study of vibrational energy levels of glycine, calculated by Fourier transform of the wavepacket correlation function. It is based on a multiple coherent states approach integrated with monodromy matrix regularization for chaotic dynamics. All four lowest-energy glycine conformers are investigated by means of single-trajectory semiclassical spectra obtained upon classical evolution of on-the-fly trajectories with harmonic zero-point energy. For the most stable conformer I, direct dynamics trajectories are also run for each vibrational mode with energy equal to the first harmonic excitation. An analysis of trajectories evolved up to 50 000 atomic time units demonstrates that, in this time span, conformers II and III can be considered as isolated species, while conformers I and IV show a pretty facile interconversion. Therefore, previous perturbative studies based on the assumption of isolated conformers are often reliable but might be not completely appropriate in the case of conformer IV and conformer I for which interconversion occurs promptly. PMID:28489368

Opening mechanism of adenylate kinase can vary according to selected molecular dynamics force field

NASA Astrophysics Data System (ADS)

Unan, Hulya; Yildirim, Ahmet; Tekpinar, Mustafa

2015-07-01

Adenylate kinase is a widely used test case for many conformational transition studies. It performs a large conformational transition between closed and open conformations while performing its catalytic function. To understand conformational transition mechanism and impact of force field choice on E. Coli adenylate kinase, we performed all-atom explicit solvent classical molecular dynamics simulations starting from the closed conformation with four commonly used force fields, namely, Amber99, Charmm27, Gromos53a6, Opls-aa. We carried out 40 simulations, each one 200 ns. We analyzed completely 12 of them that show full conformational transition from the closed state to the open one. Our study shows that different force fields can have a bias toward different transition pathways. Transition time scales, frequency of conformational transitions, order of domain motions and free energy landscapes of each force field may also vary. In general, Amber99 and Charmm27 behave similarly while Gromos53a6 results have a resemblance to the Opls-aa force field results.

Galilean field theories and conformal structure

NASA Astrophysics Data System (ADS)

Bagchi, Arjun; Chakrabortty, Joydeep; Mehra, Aditya

2018-04-01

We perform a detailed analysis of Galilean field theories, starting with free theories and then interacting theories. We consider non-relativistic versions of massless scalar and Dirac field theories before we go on to review our previous construction of Galilean Electrodynamics and Galilean Yang-Mills theory. We show that in all these cases, the field theories exhibit non-relativistic conformal structure (in appropriate dimensions). The surprising aspect of the analysis is that the non-relativistic conformal structure exhibited by these theories, unlike relativistic conformal invariance, becomes infinite dimensional even in spacetime dimensions greater than two. We then couple matter with Galilean gauge theories and show that there is a myriad of different sectors that arise in the non-relativistic limit from the parent relativistic theories. In every case, if the parent relativistic theory exhibited conformal invariance, we find an infinitely enhanced Galilean conformal invariance in the non-relativistic case. This leads us to suggest that infinite enhancement of symmetries in the non-relativistic limit is a generic feature of conformal field theories in any dimension.

Conformational Aspects of the O-acetylation of C-tetra(phenyl)calixpyrogallol[4]arene.

PubMed

Casas-Hinestroza, José Luis; Maldonado, Mauricio

2018-05-20

Reaction between pyrogallol and benzaldehyde results in a conformational mixture of C- tetra(phenyl)pyrogallol[4]arene (crown and chair). The conformer mixture was separated using crystallization procedures and the structures were determined using FTIR, ¹H-NMR, and 13 C-NMR. O -acetylation of C- tetra(phenyl)pyrogallol[4]arene (chair) with acetic anhydride, in pyridine results in the formation of dodecaacetyl-tetra(phenyl)pyrogallol[4]arene. The structure was determined using ¹H-NMR and 13 C-NMR finding that the product maintains the conformation of the starting conformer. On the other hand, the O -acetylation reaction of C- tetra(phenyl)pirogallol[4]arene (crown) under same conditions proceeded efficiently, and its structure was determined using ¹H-NMR and 13 C-NMR. Dynamic ¹H-NMR of acetylated pyrogallolarene was studied by means of variable temperature in DMSO- d ₆ solution, and it revealed that two conformers are formed in the solution. Boat conformations for acetylated pyrogallolarene showed a slow interconversion at room temperature.

Dynamic NMR study of trans-cyclodecene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pawar, D.M.; Noe, E.A.

1996-12-18

The slow-exchange {sup 13}C spectrum of trans-cyclodecene at -154.9{degree}C shows eight peaks of the olefinic carbons, and these are interpreted in terms of five conformations. Three of the conformations are of C{sub 1} symmetry, and two are of C{sub 2} symmetry. Further evidence for the number of conformations and their symmetries came from a proton NMR spectrum of the olefinic hydrogens taken at -154.9{degree}C with decoupling the allylic hydrogens. Populations ranged from 3.0% to 37.6% with the least-populated conformation having a free energy of 0.59 kcal/mol, relative to the most stable conformer. The conformations studied by Saunders and Jimenez-Vazquez usingmore » Allinger`s MM3 force field are described, and the calculated strain energies and populations are discussed. Energies for six conformations were also obtained from ab initio calculations at the HF/6-311G{sup *} level. 22 refs., 4 figs., 3 tabs.« less

Molecular modelling indicates that the pathological conformations of prion proteins might be beta-helical.

PubMed Central

Downing, D T; Lazo, N D

1999-01-01

Creutzfeldt-Jakob disease, kuru, scrapie and bovine spongiform encephalopathy are diseases of the mammalian central nervous system that involve the conversion of a cellular protein into an insoluble extracellular isoform. Spectroscopic studies have shown that the precursor protein contains mainly alpha-helical and random-coil conformations, whereas the prion isoform is largely in the beta conformation. The pathogenic prion is resistant to denaturation and protease digestion and can promote the conversion of the precursor protein to the pathogenic form. These properties have yet to be explained in terms of the structural conformations of the proteins. In the present study, molecular modelling showed that prion proteins could adopt the beta-helical conformation, which has been established for a number of fibrous proteins and has been suggested previously as the basis of amyloid fibrils. The beta-helical conformation provides explanations for the biophysical and biochemical stability of prions, their ability to form templates for the transmission of pathological conformation, and the existence of phenotypical strains of the prion diseases. PMID:10510313

A mutation uncouples the tubulin conformational and GTPase cycles, revealing allosteric control of microtubule dynamics

PubMed Central

Geyer, Elisabeth A; Burns, Alexander; Lalonde, Beth A; Ye, Xuecheng; Piedra, Felipe-Andres; Huffaker, Tim C; Rice, Luke M

2015-01-01

Microtubule dynamic instability depends on the GTPase activity of the polymerizing αβ-tubulin subunits, which cycle through at least three distinct conformations as they move into and out of microtubules. How this conformational cycle contributes to microtubule growing, shrinking, and switching remains unknown. Here, we report that a buried mutation in αβ-tubulin yields microtubules with dramatically reduced shrinking rate and catastrophe frequency. The mutation causes these effects by suppressing a conformational change that normally occurs in response to GTP hydrolysis in the lattice, without detectably changing the conformation of unpolymerized αβ-tubulin. Thus, the mutation weakens the coupling between the conformational and GTPase cycles of αβ-tubulin. By showing that the mutation predominantly affects post-GTPase conformational and dynamic properties of microtubules, our data reveal that the strength of the allosteric response to GDP in the lattice dictates the frequency of catastrophe and the severity of rapid shrinking. DOI: http://dx.doi.org/10.7554/eLife.10113.001 PMID:26439009

Conformity, Anticonformity, andIndependence: Their Dimensionality and Generality

ERIC Educational Resources Information Center

Stricker, Lawrence J.; And Others

1970-01-01

Examines response to group pressure involving different judgments and social situations. One bipolar dimension included conformity and anticonformity, the other, conformity and independence. Tables, graphs, and bibliography. (RW)

Conformational Structure of Tyrosine, Tyrosyl-Glycine, and Tyrosyl-Glycyl-Glycine by Double Resonance Spectroscopy

NASA Technical Reports Server (NTRS)

Abo-Riziq, Ali; Grace, Louis; Crews, Bridgit; Callahan, Michael P,; van Mourik, Tanja; de Vries, Mattanjah S,

2011-01-01

We investigated the variation in conformation for the amino acid tyrosine (Y), alone and in the small peptides tyrosine-glycine (YC) and tyrosine-glycine-glycine (YGG), in the gas phase by using UV-UV and IR-UV double resonance spectroscopy and density functional theory calculations. For tyrosine we found seven different conformations, for YG we found four different conformations, and for YGG we found three different conformations. As the peptides get larger, we observe fewer stable conformers, despite the increasing complexity and number of degrees of freedom. We find structural trends similar to those in phenylalanine-glycine glycine (FGG) and tryptophan-glycine-glycine (WGG)j however) the effect of dispersive forces in FGG for stabilizing a folded structure is replaced by that of hydrogen bonding in YGG.

Conformal collineations and anisotropic fluids in general relativity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duggal, K.L.; Sharma, R.

1986-10-01

Recently, Herrera et al. (L. Herrera, J. Jimenez, L. Leal, J. Ponce de Leon, M. Esculpi, and V. Galino, J. Math. Phys. 25, 3274 (1984)) studied the consequences of the existence of a one-parameter group of conformal motions for anisotropic matter. They concluded that for special conformal motions, the stiff equation of state (p = ..mu..) is singled out in a unique way, provided the generating conformal vector field is orthogonal to the four-velocity. In this paper, the same problem is studied by using conformal collineations (which include conformal motions as subgroups). It is shown that, for a special conformalmore » collineation, the stiff equation of state is not singled out. Non-Einstein Ricci-recurrent spaces are considered as physical models for the fluid matter.« less

Integrability conditions for Killing-Yano tensors and conformal Killing-Yano tensors

NASA Astrophysics Data System (ADS)

Batista, Carlos

2015-01-01

The integrability conditions for the existence of a conformal Killing-Yano tensor of arbitrary order are worked out in all dimensions and expressed in terms of the Weyl tensor. As a consequence, the integrability conditions for the existence of a Killing-Yano tensor are also obtained. By means of such conditions, it is shown that in certain Einstein spaces one can use a conformal Killing-Yano tensor of order p to generate a Killing-Yano tensor of order (p -1 ) . Finally, it is proved that in maximally symmetric spaces the covariant derivative of a Killing-Yano tensor is a closed conformal Killing-Yano tensor and that every conformal Killing-Yano tensor is uniquely decomposed as the sum of a Killing-Yano tensor and a closed conformal Killing-Yano tensor.

Interplay between intramolecular and intermolecular structures of 1,1,2,2-tetrachloro-1,2-difluoroethane

NASA Astrophysics Data System (ADS)

Rovira-Esteva, M.; Murugan, N. A.; Pardo, L. C.; Busch, S.; Tamarit, J. Ll.; Pothoczki, Sz.; Cuello, G. J.; Bermejo, F. J.

2011-08-01

We report on the interplay between the short-range order of molecules in the liquid phase of 1,1,2,2-tetrachloro-1,2-difluoroethane and the possible molecular conformations, trans and gauche. Two complementary approaches have been used to get a comprehensive picture: analysis of neutron-diffraction data by a Bayesian fit algorithm and a molecular dynamics simulation. The results of both show that the population of trans and gauche conformers in the liquid state can only correspond to the gauche conformer being more stable than the trans conformer. Distinct conformer geometries induce distinct molecular short-range orders around them, suggesting that a deep intra- and intermolecular interaction coupling is energetically favoring one of the conformers by reducing the total molecular free energy.

Static models with conformal symmetry

NASA Astrophysics Data System (ADS)

Manjonjo, A. M.; Maharaj, S. D.; Moopanar, S.

2018-02-01

We study static spherically symmetric spacetimes with a spherical conformal symmetry and a nonstatic conformal factor associated with the conformal Killing field. With these assumptions we find an explicit relationship relating two metric components of the metric tensor field. This leads to the general solution of the Einstein field equations with a conformal symmetry in a static spherically symmetric spacetime. For perfect fluids we can find all metrics explicitly and show that the models always admit a barotropic equation of state. Contained within this class of spacetimes are the well known metrics of (interior) Schwarzschild, Tolman, Kuchowicz, Korkina and Orlyanskii, Patwardhan and Vaidya, and Buchdahl and Land. The isothermal metric of Saslaw et al also admits a conformal symmetry. For imperfect fluids an infinite family of exact solutions to the field equations can be generated.

Requirements for conformal coating and staking of printed wiring boards and electronic assemblies

NASA Technical Reports Server (NTRS)

1985-01-01

In order to maintain the high standards of the NASA conformal coating and staking program, this publication: prescribes NASA's requirements for assuring reliable conformal coating and staking for printed wiring boards and electronic assemblies; describes and incorporates basic considerations necessary to assure reliable conformal coating and staking; establishes the supplier's responsibility to train and certify personnel; provides for supplier documentation of the fabrication and inspection procedures to be used for NASA work, including supplier innovations and changes in technology; and provides visual workmanship standards to aid those responsible for determining quality conformance to the established requirements.

Conformal Dimensions via Large Charge Expansion

NASA Astrophysics Data System (ADS)

Banerjee, Debasish; Chandrasekharan, Shailesh; Orlando, Domenico

2018-02-01

We construct an efficient Monte Carlo algorithm that overcomes the severe signal-to-noise ratio problems and helps us to accurately compute the conformal dimensions of large-Q fields at the Wilson-Fisher fixed point in the O (2 ) universality class. Using it, we verify a recent proposal that conformal dimensions of strongly coupled conformal field theories with a global U (1 ) charge can be obtained via a series expansion in the inverse charge 1 /Q . We find that the conformal dimensions of the lowest operator with a fixed charge Q are almost entirely determined by the first few terms in the series.

Pilot Non-Conformance to Alerting System Commands

NASA Technical Reports Server (NTRS)

Pritchett, Amy R.; Hansman, R. John

1997-01-01

Instances of pilot non-conformance to alerting system commands have been identified in previous studies. Pilot non-conformance changes the final behavior of the system, and therefore may reduce actual performance from that anticipated. A simulator study has examined pilot non-conformance, using the task of collision avoidance during closely spaced parallel approaches as a case study. Consonance between the display and the alerting system was found to significantly improve subject agreement with automatic alerts. Based on these results, a more general discussion of the factors involved in pilot conformance is given, and design guidelines for alerting systems are given.

Conformal and projective symmetries in Newtonian cosmology

NASA Astrophysics Data System (ADS)

Duval, C.; Gibbons, G. W.; Horváthy, P. A.

2017-02-01

Definitions of non-relativistic conformal transformations are considered both in the Newton-Cartan and in the Kaluza-Klein-type Eisenhart/Bargmann geometrical frameworks. The symmetry groups that come into play are exemplified by the cosmological, and also the Newton-Hooke solutions of Newton's gravitational field equations. It is shown, in particular, that the maximal symmetry group of the standard cosmological model is isomorphic to the 13-dimensional conformal-Newton-Cartan group whose conformal-Bargmann extension is explicitly worked out. Attention is drawn to the appearance of independent space and time dilations, in contrast with the Schrödinger group or the Conformal Galilei Algebra.

Conformal Dimensions via Large Charge Expansion.

PubMed

Banerjee, Debasish; Chandrasekharan, Shailesh; Orlando, Domenico

2018-02-09

We construct an efficient Monte Carlo algorithm that overcomes the severe signal-to-noise ratio problems and helps us to accurately compute the conformal dimensions of large-Q fields at the Wilson-Fisher fixed point in the O(2) universality class. Using it, we verify a recent proposal that conformal dimensions of strongly coupled conformal field theories with a global U(1) charge can be obtained via a series expansion in the inverse charge 1/Q. We find that the conformal dimensions of the lowest operator with a fixed charge Q are almost entirely determined by the first few terms in the series.

The two conformers of acetanilide unraveled using LA-MB-FTMW spectroscopy

NASA Astrophysics Data System (ADS)

Cabezas, C.; Varela, M.; Caminati, W.; Mata, S.; López, J. C.; Alonso, J. L.

2011-07-01

Acetanilide has been investigated by laser ablation molecular beam Fourier transform microwave LA-MB-FTMW spectroscopy. The rotational spectrum of both trans and cis conformers have been analyzed to determine the rotational and 14N quadrupole coupling the constants. The spectrum of the less abundant cis conformer has been assigned for the first time. The doublets observed for this conformer have been interpreted in terms of the tunneling motion between two equivalent non-planar conformations through a small barrier in which the acetamide group and phenyl ring plane are perpendicular. The results are compared with those of the related formanilide.

Structurally controlled deposition of silicon onto nanowires

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Weijie; Liu, Zuqin; Han, Song

Provided herein are nanostructures for lithium ion battery electrodes and methods of fabrication. In some embodiments, a nanostructure template coated with a silicon coating is provided. The silicon coating may include a non-conformal, more porous layer and a conformal, denser layer on the non-conformal, more porous layer. In some embodiments, two different deposition processes, e.g., a PECVD layer to deposit the non-conformal layer and a thermal CVD process to deposit the conformal layer, are used. Anodes including the nanostructures have longer cycle lifetimes than anodes made using either a PECVD or thermal CVD method alone.

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.

40 CFR 51.854 - Conformity analysis.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Federal Government taking an action subject to this subpart must make its own conformity determination... agency or develop its own analysis in order to make its conformity determination. Effective Date Note: At...

48 CFR 46.504 - Certificate of conformance.

Code of Federal Regulations, 2014 CFR

2014-10-01

... MANAGEMENT QUALITY ASSURANCE Acceptance 46.504 Certificate of conformance. A certificate of conformance (see... acceptable and any defective work would be replaced, corrected, or repaired without contest. In no case shall...

Fermion-scalar conformal blocks

DOE PAGES

Iliesiu, Luca; Kos, Filip; Poland, David; ...

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.

Study of polymer molecules and conformations with a nanopore

DOEpatents

Golovchenko, Jene A.; Li, Jiali; Stein, Derek; Gershow, Marc H.

2013-03-12

The invention features methods for evaluating the conformation of a polymer, for example, for determining the conformational distribution of a plurality of polymers and to detect binding or denaturation events. The methods employ a nanopore which the polymer, e.g., a nucleic acid, traverses. As the polymer traverses the nanopore, measurements of transport properties of the nanopore yield data on the conformation of the polymer.

Study of polymer molecules and conformations with a nanopore

DOEpatents

Golovchenko, Jene A.; Li, Jiali; Stein, Derek; Gershow, Marc H.

2010-12-07

The invention features methods for evaluating the conformation of a polymer, for example, for determining the conformational distribution of a plurality of polymers and to detect binding or denaturation events. The methods employ a nanopore which the polymer, e.g., a nucleic acid, traverses. As the polymer traverses the nanopore, measurements of transport properties of the nanopore yield data on the conformation of the polymer.

Study of polymer molecules and conformations with a nanopore

DOEpatents

Golovchenko, Jene A; Li, Jiali; Stein, Derek; Gershow, Marc H

2015-03-03

The invention features methods for evaluating the conformation of a polymer, for example, for determining the conformational distribution of a plurality of polymers and to detect binding or denaturation events. The methods employ a nanopore which the polymer, e.g., a nucleic acid, traverses. As the polymer traverses the nanopore, measurements of transport properties of the nanopore yield data on the conformation of the polymer.

Conformational analysis of a condensed macrocyclic β-lactam by NMR and molecular dynamics calculations

NASA Astrophysics Data System (ADS)

Keserű, György M.; Vásárhelyi, Helga; Makara, Gergely

1994-09-01

The conformation of the new macrocyclic β-lactam ( 1) was investigated by NMR and molecular dynamics (MD) calculations. Restraints obtained from NOESY and ROESY experiments were introduced into MD simulations which led to well-defined conformations. The preference for the calculated minimum energy conformation was confirmed by the analysis of vicinal coupling constants. Experimental coupling constants agreed with computed values.

Binding Site and Potency Prediction of Teixobactin and other Lipid II Ligands by Statistical Base Scoring of Conformational Space Maps.

PubMed

Lungu, Claudiu N; Diudea, Mircea V

2018-01-01

Lipid II, a peptidoglycan, is a precursor in bacterial cell synthesis. It has both hydrophilic and lipophilic properties. The molecule translocates a bacterial membrane to deliver and incorporate "building blocks" from disaccharide-pentapeptide into the peptidoglican wall. Lipid II is a valid antibiotic target. A receptor binding pocket may be occupied by a ligand in various plausible conformations, among which only few ones are energetically related to a biological activity in the physiological efficiency domain. This paper reports the mapping of the conformational space of Lipid II in its interaction with Teixobactin and other Lipid II ligands. In order to study computationally the complex between Lipid II and ligands, a docking study was first carried on. Docking site was retrieved form literature. After docking, 5 ligand conformations and further 5 complexes (denoted 00 to 04) for each molecule were taken into account. For each structure, conformational studies were performed. Statistical analysis, conformational analysis and molecular dynamics based clustering were used to predict the potency of these compounds. A score for potency prediction was developed. Appling lipid II classification according to Lipid II conformational energy, a conformation of Teixobactin proved to be energetically favorable, followed by Oritravicin, Dalbavycin, Telvanicin, Teicoplamin and Vancomycin, respectively. Scoring of molecules according to cluster band and PCA produced the same result. Molecules classified according to standard deviations showed Dalbavycin as the most favorable conformation, followed by Teicoplamin, Telvanicin, Teixobactin, Oritravicin and Vancomycin, respectively. Total score showing best energetic efficiency of complex formation shows Teixobactin to have the best conformation (a score of 15 points) followed by Dalbavycin (14 points), Oritravicin (12v points), Telvanicin (10 points), Teicoplamin (9 points), Vancomycin (3 points). Statistical analysis of conformations can be used to predict the efficiency of ligand - target interaction and consecutively to find insight regarding ligand potency and postulate about favorable conformation of ligand and binding site. In this study it was shown that Teixobactin is more efficient in binding with Lipid II compared to Vancomycin, results confirmed by experimental data reported in literature. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

IR low-temperature matrix, X-ray and ab initio study on L-isoserine conformations.

PubMed

Dobrowolski, Jan Cz; Jamróz, Michał H; Kołos, Robert; Rode, Joanna E; Cyrański, Michał K; Sadlej, Joanna

2010-09-28

The IR low-temperature Ar and Kr matrix spectra of l-isoserine were registered for the first time and interpreted by means of the anharmonic DFT frequencies calculated at the B3LYP/aug-cc-pVTZ and B3LYP/aug-cc-pVDZ levels. 54 l-isoserine conformers were predicted to be stable at the B3LYP/aug-cc-pVDZ level. Population of the 8 most stable conformers was based on the QCISD/aug-cc-pVDZ energies, corrected for thermal anharmonic factors obtained at the B3LYP/aug-cc-pVDZ level. We found several conformers to be present in the measured matrices and conformer 1 to be dominating. Presence of the conformer 2 is well confirmed by the nu(C=O) band at 1790 cm(-1) and two bands at 1380 and 1350 cm(-1). Presence of the conformer 4 is quite well confirmed by the nu(C-O) bands at 1120 and 1095 cm(-1). Slightly weaker arguments are found for the observation of conformers 6 and 3. Calculations on 54 neutral and 5 zwitterionic conformers in water at the IEF-PCM/B3LYP/aug-cc-pVDZ level suggest that one neutral and one zwitterionic conformer co-exist in the aqueous environment. The crystal structure of l-isoserine was solved by X-ray diffraction analysis. The compound crystallizes without solvent in the chiral P2(1)2(1)2 space group. The asymmetric unit contains a single molecule. The molecule is in its zwitterionic form with the CH(2)-NH(3) side chain in the gauche conformation with respect to the hydroxyl group and in the anti conformation with respect to the carboxylate group. The structure of l-isoserine is dominated by a set of intermolecular hydrogen bonds. The strongest one appears between the OH and COOH groups of two neighbouring molecules: the O...H contact is of 1.66(2) A, which is amongst the shortest H-bonds of this kind observed in amino acid crystal structures.

Spectra and structure of organophosphorus compounds. LI. IR and Raman spectra, conformational stability, barriers to internal rotation, vibrational assignment, and ab initio calculations of n-propylphosphine

NASA Astrophysics Data System (ADS)

Durig, J. R.; Gounev, T. K.; Lee, M. S.; Little, T. S.

1994-10-01

The Raman (3100 to 50 cm -1) and IR (3100 to 50 cm -1) spectra of gaseous and solid n-propylphosphine, C 3H 7PH 2, and the corresponding P- d2 isotopomer have been recorded. Additionally, the Raman spectra of the liquids have been obtained with qualitative depolarization ratios. From these data, all five possible conformers have been identified in the fluid states and the trans-trans conformer is shown to be the most stable rotamer in both the gaseous and liquid states and it is the only conformer present in the solid. The first trans refers to the orientation of the lone pair to the ethylene group (rotation around the PC bond) whereas the second trans refers to the orientation of the methyl group relative to the PC bond (rotation around the -CH 2CH 2 bond). The next most stable conformer is the gauche-trans rotamer where the enthalpy difference has been determined from variable-temperature Raman studies to be 140 ± 5 cm -1 (400 ± 14 cal mol -1) for the vapor and 351 ± 20 cm -1 (1004 ± 57 cal mol -1) for the liquid. The other three conformers have nearly the same stabilities but significantly higher energies than the two more stable rotamers. From the far-IR data and relative conformer stabilities, some of the coefficients of the potential function governing conformer interconversion are estimated. A complete vibrational assignment is proposed for the trans-trans conformer and for the fundamentals for most of the heavy atom motions for the other conformers. The conformational stabilities, barriers to internal rotation, and fundamental vibrational frequencies which have been determined experimentally are compared to those obtained from ab initio calculations employing the RHF/3-21G* and/or RHF/6-31G* basis sets. Additionally, the conformational stabilities and structural parameters have been determined with the 6-31G* basis set with electron correlation at the MP2 level. These results are compared with the corresponding quantities for some similar molecules.

X-ray crystallographic and MD simulation studies on the mechanism of interfacial activation of a family I.3 lipase with two lids.

PubMed

Angkawidjaja, Clement; Matsumura, Hiroyoshi; Koga, Yuichi; Takano, Kazufumi; Kanaya, Shigenori

2010-07-02

The interfacial activation mechanism of family I.3 lipase from Pseudomonas sp. MIS38 (PML), which has two alpha-helical lids (lid1 and lid2), was investigated using a combination of X-ray crystallography and molecular dynamics (MD) simulation. The crystal structure of PML in an open conformation was determined at 2.1 A resolution in the presence of Ca(2+) and Triton X-100. Comparison of this structure with that in the closed conformation indicates that both lids greatly change their positions and lid1 is anchored by the calcium ion (Ca1) in the open conformation. This structure was not seriously changed even when the protein was dialyzed extensively against the Ca(2+)-free buffer containing Triton X-100 before crystallization, indicating that the open conformation is fairly stable unless a micellar substance is removed. The crystal structure of the PML derivative, in which the active site serine residue (Ser207) is diethylphosphorylated by soaking the crystal of PML in the open conformation in a solution containing diethyl p-nitrophenyl phosphate, was also determined. This structure greatly resembles that in the open conformation, indicating that PML structure in the open conformation represents that in the active form. MD simulation of PML in the open conformation in the absence of micelles showed that lid2 closes first, while lid1 maintains its open conformation. Likewise, MD simulation of PML in the closed conformation in the absence of Ca(2+) and in the presence of octane or trilaurin micelles showed that lid1 opens, while lid2 remains closed. These results suggest that Ca1 functions as a hook for stabilization of a fully opened conformation of lid1 and for initiation of subsequent opening of lid2. Copyright 2010 Elsevier Ltd. All rights reserved.

Cinetica de oxidacion de polimeros conductores: poli-3,4- etilendioxitiofeno

NASA Astrophysics Data System (ADS)

Caballero Romero, Maria

Films of poly-3,4-ethylenedioxythiophene (PEDOT) perchlorate used as electrodes in liquid electrolytes incorporate anions and solvent during oxidation for charge and osmotic balance: the film swells. During reduction the film shrinks, closes its structure trapping counterions getting then rising conformational packed states by expulsion of counterions and solvent. Here by potential step from the same reduced initial state to the same oxidized final state the rate coefficient, the activation energy and reaction orders related to the counterion concentration in solution and to the concentration of active centers in the polymer film, were attained following the usual methodology used for chemical and electrochemical kinetics. Now the full methodology was repeated using different reduced-shrunk or reduced-conformational compacted initial states every time. Those initial states were attained by reduction of the oxidized film at rising cathodic potentials for the same reduction time each. Rising reduced and conformational compacted states give slower subsequent oxidation rates by potential step to the same anodic potential every time. The activation energy, the reaction coefficient and reaction orders change for rising conformational compacted initial states. Decreasing rate constants and increasing activation energies are obtained for the PEDOT oxidation from increasing conformational compacted initial states. The experimental activation energy presents two linear ranges as a function of the initial reduced-compacted state. Using as initial states for the oxidation open structures attained by reduction at low cathodic potentials, activation energies attained were constant: namely the chemical activation energy. Using as initial states for the oxidation deeper reduced, closed and packed conformational structures, the activation energy includes two components: the constant chemical energy plus the conformational energy required to relax the conformational structure generating free volume which allows the entrance of the balancing counterions required for the reaction. The conformational energy increases linearly as a function of the reduction-compaction potential. The kinetic magnitudes include conformational and structural information. The Chemical Kinetics becomes Structural (or conformational) Chemical Kinetics.

Conformational Equilibria in Monomeric α-Synuclein at the Single-Molecule Level

PubMed Central

Tessari, Isabella; Mammi, Stefano; Bergantino, Elisabetta; Musiani, Francesco; Brucale, Marco; Bubacco, Luigi; Samorì, Bruno

2008-01-01

Human α-Synuclein (αSyn) is a natively unfolded protein whose aggregation into amyloid fibrils is involved in the pathology of Parkinson disease. A full comprehension of the structure and dynamics of early intermediates leading to the aggregated states is an unsolved problem of essential importance to researchers attempting to decipher the molecular mechanisms of αSyn aggregation and formation of fibrils. Traditional bulk techniques used so far to solve this problem point to a direct correlation between αSyn's unique conformational properties and its propensity to aggregate, but these techniques can only provide ensemble-averaged information for monomers and oligomers alike. They therefore cannot characterize the full complexity of the conformational equilibria that trigger the aggregation process. We applied atomic force microscopy–based single-molecule mechanical unfolding methodology to study the conformational equilibrium of human wild-type and mutant αSyn. The conformational heterogeneity of monomeric αSyn was characterized at the single-molecule level. Three main classes of conformations, including disordered and “β-like” structures, were directly observed and quantified without any interference from oligomeric soluble forms. The relative abundance of the “β-like” structures significantly increased in different conditions promoting the aggregation of αSyn: the presence of Cu2+, the pathogenic A30P mutation, and high ionic strength. This methodology can explore the full conformational space of a protein at the single-molecule level, detecting even poorly populated conformers and measuring their distribution in a variety of biologically important conditions. To the best of our knowledge, we present for the first time evidence of a conformational equilibrium that controls the population of a specific class of monomeric αSyn conformers, positively correlated with conditions known to promote the formation of aggregates. A new tool is thus made available to test directly the influence of mutations and pharmacological strategies on the conformational equilibrium of monomeric αSyn. PMID:18198943

SU-E-T-211: Comparison of Seven New TrueBeam Linacs with Enhanced Beam Data Conformance Using a Beam Comparison Software Tool

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grzetic, S; Hessler, J; Gupta, N

2015-06-15

Purpose: To develop an independent software tool to assist in commissioning linacs with enhanced beam conformance, as well as perform ongoing QA for dosimetrically equivalent linacs. Methods: Linac manufacturers offer enhanced beam conformance as an option to allow for clinics to complete commissioning efficiently, as well as implement dosimetrically equivalent linacs. The specification for enhanced conformance includes PDD as well as profiles within 80% FWHM. Recently, we commissioned seven Varian TrueBeam linacs with enhanced beam conformance. We developed a software tool in Visual Basic to allow us to load the reference beam data and compare our beam data during commissioningmore » to evaluate enhanced beam conformance. This tool also allowed us to upload our beam data used for commissioning our dosimetrically equivalent beam models to compare and tweak each of our linac beams to match our modelled data in Varian’s Eclipse TPS. This tool will also be used during annual QA of the linacs to compare our beam data to our baseline data, as required by TG-142. Results: Our software tool was used to check beam conformance for seven TrueBeam linacs that we commissioned in the past six months. Using our tool we found that the factory conformed linacs showed up to 3.82% difference in their beam profile data upon installation. Using our beam comparison tool, we were able to adjust the energy and profiles of our beams to accomplish a better than 1.00% point by point data conformance. Conclusion: The availability of quantitative comparison tools is essential to accept and commission linacs with enhanced beam conformance, as well as to beam match multiple linacs. We further intend to use the same tool to ensure our beam data conforms to the commissioning beam data during our annual QA in keeping with the requirements of TG-142.« less

Molecular dynamics correctly models the unusual major conformation of the GAGU RNA internal loop and with NMR reveals an unusual minor conformation.

PubMed

Spasic, Aleksandar; Kennedy, Scott D; Needham, Laura; Manoharan, Muthiah; Kierzek, Ryszard; Turner, Douglas H; Mathews, David H

2018-05-01

The RNA "GAGU" duplex, (5'GAC GAGU GUCA) 2 , contains the internal loop (5'-GAGU-3') 2 , which has two conformations in solution as determined by NMR spectroscopy. The major conformation has a loop structure consisting of trans -Watson-Crick/Hoogsteen GG pairs, A residues stacked on each other, U residues bulged outside the helix, and all sugars with a C2'- endo conformation. This differs markedly from the internal loops, (5'-G AG C-3') 2 , (5'-A AG U-3') 2 , and (5'-UAGG-3') 2 , which all have cis -Watson-Crick/Watson-Crick AG "imino" pairs flanked by cis -Watson-Crick/Watson-Crick canonical pairs resulting in maximal hydrogen bonding. Here, molecular dynamics was used to test whether the Amber force field (ff99 + bsc0 + OL3) approximates molecular interactions well enough to keep stable the unexpected conformation of the GAGU major duplex structure and the NMR structures of the duplexes containing (5'-G AG C-3') 2 , (5'-A AG U-3') 2 , and (5'-U AG G-3') 2 internal loops. One-microsecond simulations were repeated four times for each of the duplexes starting in their NMR conformations. With the exception of (5'-UAGG-3') 2 , equivalent simulations were also run starting with alternative conformations. Results indicate that the Amber force field keeps the NMR conformations of the duplexes stable for at least 1 µsec. They also demonstrate an unexpected minor conformation for the (5'-GAGU-3') 2 loop that is consistent with newly measured NMR spectra of duplexes with natural and modified nucleotides. Thus, unrestrained simulations led to the determination of the previously unknown minor conformation. The stability of the native (5'-GAGU-3') 2 internal loop as compared to other loops can be explained by changes in hydrogen bonding and stacking as the flanking bases are changed. © 2018 Spasic et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Driving Calmodulin Protein towards Conformational Shift by Changing Ionization States of Select Residues

NASA Astrophysics Data System (ADS)

Negi, Sunita; Rana Atilgan, Ali; Atilgan, Canan

2012-12-01

Proteins are complex systems made up of many conformational sub-states which are mainly determined by the folded structure. External factors such as solvent type, temperature, pH and ionic strength play a very important role in the conformations sampled by proteins. Here we study the conformational multiplicity of calmodulin (CaM) which is a protein that plays an important role in calcium signaling pathways in the eukaryotic cells. CaM can bind to a variety of other proteins or small organic compounds, and mediates different physiological processes by activating various enzymes. Binding of calcium ions and proteins or small organic molecules to CaM induces large conformational changes that are distinct to each interacting partner. In particular, we discuss the effect of pH variation on the conformations of CaM. By using the pKa values of the charged residues as a basis to assign protonation states, the conformational changes induced in CaM by reducing the pH are studied by molecular dynamics simulations. Our current view suggests that at high pH, barrier crossing to the compact form is prevented by repulsive electrostatic interactions between the two lobes. At reduced pH, not only is barrier crossing facilitated by protonation of residues, but also conformations which are on average more compact are attained. The latter are in accordance with the fluorescence resonance energy transfer experiment results of other workers. The key events leading to the conformational change from the open to the compact conformation are (i) formation of a salt bridge between the N-lobe and the linker, stabilizing their relative motions, (ii) bending of the C-lobe towards the N-lobe, leading to a lowering of the interaction energy between the two-lobes, (iii) formation of a hydrophobic patch between the two lobes, further stabilizing the bent conformation by reducing the entropic cost of the compact form, (iv) sharing of a Ca+2 ion between the two lobes.

Transferred nuclear Overhauser enhancement experiments show that the monoclonal antibody strep 9 selects a local minimum conformation of a Streptococcus group A trisaccharide-hapten.

PubMed

Weimar, T; Harris, S L; Pitner, J B; Bock, K; Pinto, B M

1995-10-17

Transferred nuclear Overhauser enhancement (TRNOE) experiments have been performed to investigate the bound conformation of the trisaccharide repeating unit of the Streptococcus Group A cell-wall polysaccharide. Thus, the conformations of propyl 3-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-2-O-(alpha-L-rhamnopyran osyl)- alpha-L-rhamnopyranoside [C(A')B] (1) as a free ligand and when complexed to the monoclonal antibody Strep 9 were examined. Improved insights about the conformational preferences of the glycosidic linkages of the trisaccharide ligand showed that the free ligand populates various conformations in aqueous solution, thus displaying relatively flexible behavior. The NOE HNAc-H2A', which was not detected in previous work, accounts for a conformation at the beta-(1-->3) linkage with a phi angle of approximately 180 degrees. Observed TRNOEs for the complex are weak, and their analysis was further complicated by spin diffusion. With the use of transferred rotating-frame Overhauser enhancement (TRROE) experiments, the amount of spin diffusion was assessed experimentally, proving that all of the observed long-range TRNOEs arose through spin diffusion. Four interglycosidic distances, derived from the remaining TRNOEs and TRROEs, together with repulsive constraints, derived from the absence of TRROE effects, were used as input parameters in simulated annealing and molecular mechanics calculations to determine the bound conformation of the trisaccharide. Complexation by the antibody results in the selection of one defined conformation of the carbohydrate hapten. This bound conformation, which is a local energy minimum on the energy maps calculated for the trisaccharide ligand, shows only a change from a +gauche to a -gauche orientation at the psi angle of the alpha-(1-->2) linkage when compared to the global minimum conformation. The results infer that the bound conformation of the Streptococcus Group A cell-wall polysaccharide is different from its previously proposed solution structure (Kreis et al., 1995).

Minimal model for the secondary structures and conformational conversions in proteins

NASA Astrophysics Data System (ADS)

Imamura, Hideo

Better understanding of protein folding process can provide physical insights on the function of proteins and makes it possible to benefit from genetic information accumulated so far. Protein folding process normally takes place in less than seconds but even seconds are beyond reach of current computational power for simulations on a system of all-atom detail. Hence, to model and explore protein folding process it is crucial to construct a proper model that can adequately describe the physical process and mechanism for the relevant time scale. We discuss the reduced off-lattice model that can express _-helix and ?-hairpin conformations defined solely by a given sequence in order to investigate a protein folding mechanism of conformations such as a ?-hairpin and also to investigate conformational conversions in proteins. The first two chapters introduce and review essential concepts in protein folding modelling physical interaction in proteins, various simple models, and also review computational methods, in particular, the Metropolis Monte Carlo method, its dynamic interpretation and thermodynamic Monte Carlo algorithms. Chapter 3 describes the minimalist model that represents both _-helix and ?-sheet conformations using simple potentials. The native conformation can be specified by the sequence without particular conformational biases to a reference state. In Chapter 4, the model is used to investigate the folding mechanism of ?-hairpins exhaustively using the dynamic Monte Carlo and a thermodynamic Monte Carlo method an effcient combination of the multicanonical Monte Carlo and the weighted histogram analysis method. We show that the major folding pathways and folding rate depend on the location of a hydrophobic. The conformational conversions between _-helix and ?-sheet conformations are examined in Chapter 5 and 6. First, the conformational conversion due to mutation in a non-hydrophobic system and then the conformational conversion due to mutation with a hydrophobic pair at a different position at various temperatures are examined.

SU-E-T-278: Dose Conformity Index for the Target in a Multitarget Environment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harikrishnaperumal, Sudahar

2015-06-15

Purpose: The existing conformity index formulations are failing when multiple targets present outside the target of interest with same or different dose prescriptions. In the present study a novel methodology is introduced to solve this issue. Methods: The conformity index used by Nakamura et al (Int J Radiat Oncol Biol Phys 2001; 51(5):1313–1319) is taken as the base for this methodology. In this proposal, the prescription isodose volume (PIV) which normally includes the normal tissue and other target regions is restricted as PIV in annular regions of different thickness around the target of interest. The graphical line plotted between themore » thickness of annular region and the corresponding conformity index, will increase in the beginning and will reach a flat region, then it will increase again. The second increase in the conformity index depends basically on the distance between the targets, dose prescriptions, and size of the targets. The conformity index in the flat region should be the conformity index of the target of interest. This methodology was validated on dual target environment on a skull phantom in Multiplan planning system (Accuray Inc. Sunnyvale, USA) Results: When the surrounding target’s (sphere) size is changed from 1.5cm to 6cm diameter, the conformity index of the target of interest (3cm diameter) changed from 1.09 to 1.25. When the distance between the targets changed from 7.5cm to 2.5cm, the conformity index changed from 1.10 to 1.17. Similarly, when the prescribed dose changed from 25Gy to 50Gy the conformity index changed from 1.09 to 1.42. These values were above 2.0 when Nakamura et al formula was used. Conclusion: The proposed conformity index methodology eliminates the influence of surrounding targets to a greater extend. However, the limitations of this method should be studied further. Application of this method in clinical situations is the future scope.« less

Effects of Catalytic Action and Ligand Binding on Conformational Ensembles of Adenylate Kinase.

PubMed

Onuk, Emre; Badger, John; Wang, Yu Jing; Bardhan, Jaydeep; Chishti, Yasmin; Akcakaya, Murat; Brooks, Dana H; Erdogmus, Deniz; Minh, David D L; Makowski, Lee

2017-08-29

Crystal structures of adenylate kinase (AdK) from Escherichia coli capture two states: an "open" conformation (apo) obtained in the absence of ligands and a "closed" conformation in which ligands are bound. Other AdK crystal structures suggest intermediate conformations that may lie on the transition pathway between these two states. To characterize the transition from open to closed states in solution, X-ray solution scattering data were collected from AdK in the apo form and with progressively increasing concentrations of five different ligands. Scattering data from apo AdK are consistent with scattering predicted from the crystal structure of AdK in the open conformation. In contrast, data from AdK samples saturated with Ap5A do not agree with that calculated from AdK in the closed conformation. Using cluster analysis of available structures, we selected representative structures in five conformational states: open, partially open, intermediate, partially closed, and closed. We used these structures to estimate the relative abundances of these states for each experimental condition. X-ray solution scattering data obtained from AdK with AMP are dominated by scattering from AdK in the open conformation. For AdK in the presence of high concentrations of ATP and ADP, the conformational ensemble shifts to a mixture of partially open and closed states. Even when AdK is saturated with Ap5A, a significant proportion of AdK remains in a partially open conformation. These results are consistent with an induced-fit model in which the transition of AdK from an open state to a closed state is initiated by ATP binding.

Precursory signatures of protein folding/unfolding: From time series correlation analysis to atomistic mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, P. J.; Lai, S. K., E-mail: sklai@coll.phy.ncu.edu.tw; Molecular Science and Technology Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan

Folded conformations of proteins in thermodynamically stable states have long lifetimes. Before it folds into a stable conformation, or after unfolding from a stable conformation, the protein will generally stray from one random conformation to another leading thus to rapid fluctuations. Brief structural changes therefore occur before folding and unfolding events. These short-lived movements are easily overlooked in studies of folding/unfolding for they represent momentary excursions of the protein to explore conformations in the neighborhood of the stable conformation. The present study looks for precursory signatures of protein folding/unfolding within these rapid fluctuations through a combination of three techniques: (1)more » ultrafast shape recognition, (2) time series segmentation, and (3) time series correlation analysis. The first procedure measures the differences between statistical distance distributions of atoms in different conformations by calculating shape similarity indices from molecular dynamics simulation trajectories. The second procedure is used to discover the times at which the protein makes transitions from one conformation to another. Finally, we employ the third technique to exploit spatial fingerprints of the stable conformations; this procedure is to map out the sequences of changes preceding the actual folding and unfolding events, since strongly correlated atoms in different conformations are different due to bond and steric constraints. The aforementioned high-frequency fluctuations are therefore characterized by distinct correlational and structural changes that are associated with rate-limiting precursors that translate into brief segments. Guided by these technical procedures, we choose a model system, a fragment of the protein transthyretin, for identifying in this system not only the precursory signatures of transitions associated with α helix and β hairpin, but also the important role played by weaker correlations in such protein folding dynamics.« less

Localized conformational interrogation of antibody and antibody-drug conjugates by site-specific carboxyl group footprinting.

PubMed

Pan, Lucy Yan; Salas-Solano, Oscar; Valliere-Douglass, John F

Establishing and maintaining conformational integrity of monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) during development and manufacturing is critical for ensuring their clinical efficacy. As presented here, we applied site-specific carboxyl group footprinting (CGF) for localized conformational interrogation of mAbs. The approach relies on covalent labeling that introduces glycine ethyl ester tags onto solvent-accessible side chains of protein carboxylates. Peptide mapping is used to monitor the labeling kinetics of carboxyl residues and the labeling kinetics reflects the conformation or solvent-accessibility of side chains. Our results for two case studies are shown here. The first study was aimed at defining the conformational changes of mAbs induced by deglycosylation. We found that two residues in C H 2 domain (D268 and E297) show significantly enhanced side chain accessibility upon deglycosylation. This site-specific result highlighted the advantage of monitoring the labeling kinetics at the amino acid level as opposed to the peptide level, which would result in averaging out of highly localized conformational differences. The second study was designed to assess conformational effects brought on by conjugation of mAbs with drug-linkers. All 59 monitored carboxyl residues displayed similar solvent-accessibility between the ADC and mAb under native conditions, which suggests the ADC and mAb share similar side chain conformation. The findings are well correlated and complementary with results from other assays. This work illustrated that site-specific CGF is capable of pinpointing local conformational changes in mAbs or ADCs that might arise during development and manufacturing. The methodology can be readily implemented within the industry to provide comprehensive conformational assessment of these molecules.

Structural studies of Saccharomyces cerevesiae mitochondrial NADP-dependent isocitrate dehydrogenase in different enzymatic states reveal substantial conformational changes during the catalytic reaction.

PubMed

Peng, Yingjie; Zhong, Chen; Huang, Wei; Ding, Jianping

2008-09-01

Isocitrate dehydrogenases (IDHs) catalyze oxidative decarboxylation of isocitrate (ICT) into alpha-ketoglutarate (AKG). We report here the crystal structures of Saccharomyces cerevesiae mitochondrial NADP-IDH Idp1p in binary complexes with coenzyme NADP, or substrate ICT, or product AKG, and in a quaternary complex with NADPH, AKG, and Ca(2+), which represent different enzymatic states during the catalytic reaction. Analyses of these structures identify key residues involved in the binding of these ligands. Comparisons among these structures and with the previously reported structures of other NADP-IDHs reveal that eukaryotic NADP-IDHs undergo substantial conformational changes during the catalytic reaction. Binding or release of the ligands can cause significant conformational changes of the structural elements composing the active site, leading to rotation of the large domain relative to the small and clasp domains along two hinge regions (residues 118-124 and residues 284-287) while maintaining the integrity of its secondary structural elements, and thus, formation of at least three distinct overall conformations. Specifically, the enzyme adopts an open conformation when bound to NADP, a quasi-closed conformation when bound to ICT or AKG, and a fully closed conformation when bound to NADP, ICT, and Ca(2+) in the pseudo-Michaelis complex or with NADPH, AKG, and Ca(2+) in the product state. The conformational changes of eukaryotic NADP-IDHs are quite different from those of Escherichia coli NADP-IDH, for which significant conformational changes are observed only between two forms of the apo enzyme, suggesting that the catalytic mechanism of eukaryotic NADP-IDHs is more complex than that of EcIDH, and involves more fine-tuned conformational changes.

Conformational Complexity in the LH2 Antenna of the Purple Sulfur Bacterium Allochromatium vinosum Revealed by Hole-Burning Spectroscopy.

PubMed

Kell, Adam; Jassas, Mahboobe; Acharya, Khem; Hacking, Kirsty; Cogdell, Richard J; Jankowiak, Ryszard

2017-06-15

This work discusses the protein conformational complexity of the B800-850 LH2 complexes from the purple sulfur bacterium Allochromatium vinosum, focusing on the spectral characteristics of the B850 chromophores. Low-temperature B850 absorption and the split B800 band shift blue and red, respectively, at elevated temperatures, revealing isosbestic points. The latter indicates the presence of two (unresolved) conformations of B850 bacteriochlorophylls (BChls), referred to as conformations 1 and 2, and two conformations of B800 BChls, denoted as B800 R and B800 B . The energy differences between average site energies of conformations 1 and 2, and B800 R and B800 B are similar (∼200 cm -1 ), suggesting weak and strong hydrogen bonds linking two major subpopulations of BChls and the protein scaffolding. Although conformations 1 and 2 of the B850 chromophores, and B800 R and B800 B , exist in the ground state, selective excitation leads to 1 → 2 and B800 R → B800 B phototransformations. Different static inhomogeneous broadening is revealed for the lowest energy exciton states of B850 (fwhm ∼195 cm -1 ) and B800 R (fwhm ∼140 cm -1 ). To describe the 5 K absorption spectrum and the above-mentioned conformations, we employ an exciton model with dichotomous protein conformation disorder. We show that both experimental data and the modeling study support a two-site model with strongly and weakly hydrogen-bonded B850 and B800 BChls, which under illumination undergo conformational changes, most likely caused by proton dynamics.

Conformation transitions of a single polyelectrolyte chain in a poor solvent: a replica-exchange lattice Monte-Carlo study.

PubMed

Wang, Lang; Wang, Zheng; Jiang, Run; Yin, Yuhua; Li, Baohui

2017-03-15

The thermodynamic behaviors of a strongly charged polyelectrolyte chain in a poor solvent are studied using replica-exchange Monte-Carlo simulations on a lattice model, focusing on the effects of finite chain length and the solvent quality on the chain conformation and conformation transitions. The neutralizing counterions and solvent molecules are considered explicitly. The thermodynamic quantities that vary continuously with temperature over a wide range are computed using the multiple histogram reweighting method. Our results suggest that the strength of the short-range hydrophobic interaction, the chain length, and the temperature of the system, characterized by ε, N, and T, respectively, are important parameters that control the conformations of a charged chain. When ε is moderate, the competition between the electrostatic energy and the short-range hydrophobic interaction leads to rich conformations and conformation transitions for a longer chain with a fixed length. Our results have unambiguously demonstrated the stability of the n-pearl-necklace structures, where n has a maximum value and decreases with decreasing temperature. The maximum n value increases with increasing chain length. Our results have also demonstrated the first-order nature of the conformation transitions between the m-pearl and the (m-1)-pearl necklaces. With the increase of ε, the transition temperature increases and the first-order feature becomes more pronounced. It is deduced that at the thermodynamic limit of infinitely long chain length, the conformational transitions between the m-pearl and the (m-1)-pearl necklaces may remain first order when ε > 0 and m = 2 or 3. Pearl-necklace conformations cannot be observed when either ε is too large or N is too small. To observe a pearl-necklace conformation, the T value needs to be carefully chosen for simulations performed at only a single temperature.

Precursory signatures of protein folding/unfolding: From time series correlation analysis to atomistic mechanisms

NASA Astrophysics Data System (ADS)

Hsu, P. J.; Cheong, S. A.; Lai, S. K.

2014-05-01

Folded conformations of proteins in thermodynamically stable states have long lifetimes. Before it folds into a stable conformation, or after unfolding from a stable conformation, the protein will generally stray from one random conformation to another leading thus to rapid fluctuations. Brief structural changes therefore occur before folding and unfolding events. These short-lived movements are easily overlooked in studies of folding/unfolding for they represent momentary excursions of the protein to explore conformations in the neighborhood of the stable conformation. The present study looks for precursory signatures of protein folding/unfolding within these rapid fluctuations through a combination of three techniques: (1) ultrafast shape recognition, (2) time series segmentation, and (3) time series correlation analysis. The first procedure measures the differences between statistical distance distributions of atoms in different conformations by calculating shape similarity indices from molecular dynamics simulation trajectories. The second procedure is used to discover the times at which the protein makes transitions from one conformation to another. Finally, we employ the third technique to exploit spatial fingerprints of the stable conformations; this procedure is to map out the sequences of changes preceding the actual folding and unfolding events, since strongly correlated atoms in different conformations are different due to bond and steric constraints. The aforementioned high-frequency fluctuations are therefore characterized by distinct correlational and structural changes that are associated with rate-limiting precursors that translate into brief segments. Guided by these technical procedures, we choose a model system, a fragment of the protein transthyretin, for identifying in this system not only the precursory signatures of transitions associated with α helix and β hairpin, but also the important role played by weaker correlations in such protein folding dynamics.

Structural studies of Saccharomyces cerevesiae mitochondrial NADP-dependent isocitrate dehydrogenase in different enzymatic states reveal substantial conformational changes during the catalytic reaction

PubMed Central

Peng, Yingjie; Zhong, Chen; Huang, Wei; Ding, Jianping

2008-01-01

Isocitrate dehydrogenases (IDHs) catalyze oxidative decarboxylation of isocitrate (ICT) into α-ketoglutarate (AKG). We report here the crystal structures of Saccharomyces cerevesiae mitochondrial NADP-IDH Idp1p in binary complexes with coenzyme NADP, or substrate ICT, or product AKG, and in a quaternary complex with NADPH, AKG, and Ca2+, which represent different enzymatic states during the catalytic reaction. Analyses of these structures identify key residues involved in the binding of these ligands. Comparisons among these structures and with the previously reported structures of other NADP-IDHs reveal that eukaryotic NADP-IDHs undergo substantial conformational changes during the catalytic reaction. Binding or release of the ligands can cause significant conformational changes of the structural elements composing the active site, leading to rotation of the large domain relative to the small and clasp domains along two hinge regions (residues 118–124 and residues 284–287) while maintaining the integrity of its secondary structural elements, and thus, formation of at least three distinct overall conformations. Specifically, the enzyme adopts an open conformation when bound to NADP, a quasi-closed conformation when bound to ICT or AKG, and a fully closed conformation when bound to NADP, ICT, and Ca2+ in the pseudo-Michaelis complex or with NADPH, AKG, and Ca2+ in the product state. The conformational changes of eukaryotic NADP-IDHs are quite different from those of Escherichia coli NADP-IDH, for which significant conformational changes are observed only between two forms of the apo enzyme, suggesting that the catalytic mechanism of eukaryotic NADP-IDHs is more complex than that of EcIDH, and involves more fine-tuned conformational changes. PMID:18552125

Transportation Conformity Training and Presentations

EPA Pesticide Factsheets

EPA's OTAQ has provided multiple conformity training sessions in the past to assist state and local governments in implementing conformity requirements. As training information is prepared for other venues, it will be posted on this page.

Conformational isomerism of pyridoxal. Infrared matrix isolation and theoretical studies.

PubMed

Kwiatek, Anna; Mielke, Zofia

2015-01-25

A combined matrix isolation FTIR and theoretical DFT/B3LYP/6-311++G(2p,2d) study of pyridoxal was performed. The calculations resulted in five stable PLHB conformers stabilized by intramolecular O-H⋯O bonding between phenolic OH and carbonyl C=O groups and another thirteen conformers in which OH or/and aldehyde groups are rotated by 180° around CO or/and CC bonds leading, respectively, to formation of PLO, PLA and PLOA conformers. The analysis of the spectra of the as-deposited matrix indicated that two most stable PLHB1 and PLHB2 conformers with intramolecular hydrogen bond are present in the matrix. The exposure of the PL/Ar matrix to mercury lamp radiation (λ>345 nm) induced conformational change of PLHB isomers to PLOA ones. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Role of conformational dynamics in the evolution of novel enzyme function.

PubMed

Maria-Solano, Miguel A; Serrano-Hervás, Eila; Romero-Rivera, Adrian; Iglesias-Fernández, Javier; Osuna, Sílvia

2018-05-21

The free energy landscape concept that describes enzymes as an ensemble of differently populated conformational sub-states in dynamic equilibrium is key for evaluating enzyme activity, enantioselectivity, and specificity. Mutations introduced in the enzyme sequence can alter the populations of the pre-existing conformational states, thus strongly modifying the enzyme ability to accommodate alternative substrates, revert its enantiopreferences, and even increase the activity for some residual promiscuous reactions. In this feature article, we present an overview of the current experimental and computational strategies to explore the conformational free energy landscape of enzymes. We provide a series of recent publications that highlight the key role of conformational dynamics for the enzyme evolution towards new functions and substrates, and provide some perspectives on how conformational dynamism should be considered in future computational enzyme design protocols.

Molecular-dynamics simulation of polymethylene chain confined in cylindrical potentials. I. Nature of the conformational defects

NASA Astrophysics Data System (ADS)

Yamamoto, Takashi; Kimikawa, Yuichi

1992-10-01

The conformational motion of a polymethylene molecule constrained by a cylindrical potential is simulated up to 100 ps. The molecule consists of 60 CH2 groups and has variable bond lengths, bond angles, and dihedral angles. Our main concern here is the excitation and the dynamics of the conformational defects: kinks, jogs, etc. Under weaker constraint a number of gauche bonds are excited; they mostly form pairs such as gtḡ kinks or gtttḡ jogs. These conformational defects show no continuous drift in space. Instead they often annihilate and then recreate at different sites showing apparently random positional changes. The conformational defects produce characteristic strain fields around them. It seems that the conformational defects interact attractively through these strain fields. This is evidenced by remarkably correlated spatial distributions of the gauche bonds.

Reversible ratchet effects for vortices in conformal pinning arrays

DOE PAGES

Reichhardt, Charles; Ray, Dipanjan; Reichhardt, Cynthia Jane Olson

2015-05-04

A conformal transformation of a uniform triangular pinning array produces a structure called a conformal crystal which preserves the sixfold ordering of the original lattice but contains a gradient in the pinning density. Here we use numerical simulations to show that vortices in type-II superconductors driven with an ac drive over gradient pinning arrays produce the most pronounced ratchet effect over a wide range of parameters for a conformal array, while square gradient or random gradient arrays with equivalent pinning densities give reduced ratchet effects. In the conformal array, the larger spacing of the pinning sites in the direction transversemore » to the ac drive permits easy funneling of interstitial vortices for one driving direction, producing the enhanced ratchet effect. In the square array, the transverse spacing between pinning sites is uniform, giving no asymmetry in the funneling of the vortices as the driving direction switches, while in the random array, there are numerous easy-flow channels present for either direction of drive. We find multiple ratchet reversals in the conformal arrays as a function of vortex density and ac amplitude, and correlate the features with a reversal in the vortex ordering, which is greater for motion in the ratchet direction. In conclusion, the enhanced conformal pinning ratchet effect can also be realized for colloidal particles moving over a conformal array, indicating the general usefulness of conformal structures for controlling the motion of particles.« less

Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

PubMed

Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

2017-09-01

The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein.

PubMed

Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Roitberg, Adrian E; Fernandez-Alberti, Sebastian

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.

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.

Exploration of the relationship between topology and designability of conformations

NASA Astrophysics Data System (ADS)

Leelananda, Sumudu P.; Towfic, Fadi; Jernigan, Robert L.; Kloczkowski, Andrzej

2011-06-01

Protein structures are evolutionarily more conserved than sequences, and sequences with very low sequence identity frequently share the same fold. This leads to the concept of protein designability. Some folds are more designable and lots of sequences can assume that fold. Elucidating the relationship between protein sequence and the three-dimensional (3D) structure that the sequence folds into is an important problem in computational structural biology. Lattice models have been utilized in numerous studies to model protein folds and predict the designability of certain folds. In this study, all possible compact conformations within a set of two-dimensional and 3D lattice spaces are explored. Complementary interaction graphs are then generated for each conformation and are described using a set of graph features. The full HP sequence space for each lattice model is generated and contact energies are calculated by threading each sequence onto all the possible conformations. Unique conformation giving minimum energy is identified for each sequence and the number of sequences folding to each conformation (designability) is obtained. Machine learning algorithms are used to predict the designability of each conformation. We find that the highly designable structures can be distinguished from other non-designable conformations based on certain graphical geometric features of the interactions. This finding confirms the fact that the topology of a conformation is an important determinant of the extent of its designability and suggests that the interactions themselves are important for determining the designability.

Direct observations of conformational distributions of intrinsically disordered p53 peptides using UV Raman and explicit solvent simulations

PubMed Central

Xiong, Kan; Zwier, Matthew C.; Myshakina, Nataliya S.; Burger, Virginia M.; Asher, Sanford A.; Chong, Lillian T.

2011-01-01

We report the first experimental measurements of Ramachandran Ψ-angle distributions for intrinsically disordered peptides: the N-terminal peptide fragment of tumor suppressor p53 and its P27 mutant form. To provide atomically detailed views of the conformational distributions, we performed classical, explicit-solvent molecular dynamics simulations on the microsecond timescale. Upon binding its partner protein, MDM2, wild-type p53 peptide adopts an α-helical conformation. Mutation of Pro27 to serine results in the highest affinity yet observed for MDM2-binding of the p53 peptide. Both UV resonance Raman spectroscopy (UVRR) and simulations reveal that the P27S mutation decreases the extent of PPII helical content and increases the probability for conformations that are similar to the α-helical MDM2-bound conformation. In addition, UVRR measurements were performed on peptides that were isotopically labeled at the Leu26 residue preceding the Pro27 in order to determine the conformational distributions of Leu26 in the wild-type and mutant peptides. The UVRR and simulation results are in quantitative agreement in terms of the change in the population of non-PPII conformations involving Leu26 upon mutation of Pro27 to serine. Finally, our simulations reveal that the MDM2-bound conformation of the peptide is significantly populated in both the wild-type and mutant isolated peptide ensembles in their unbound states, suggesting that MDM2 binding of the p53 peptides may involve conformational selection. PMID:21528875

Quantum chemical calculations in the structural analysis of phloretin

NASA Astrophysics Data System (ADS)

Gómez-Zavaglia, Andrea

2009-07-01

In this work, a conformational search on the molecule of phloretin [2',4',6'-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone] has been performed. The molecule of phloretin has eight dihedral angles, four of them taking part in the carbon backbone and the other four, related with the orientation of the hydroxyl groups. A systematic search involving a random variation of the dihedral angles has been used to generate input structures for the quantum chemical calculations. Calculations at the DFT(B3LYP)/6-311++G(d,p) level of theory permitted the identification of 58 local minima belonging to the C 1 symmetry point group. The molecular structures of the conformers have been analyzed using hierarchical cluster analysis. This method allowed us to group conformers according to their similarities, and thus, to correlate the conformers' stability with structural parameters. The dendrogram obtained from the hierarchical cluster analysis depicted two main clusters. Cluster I included all the conformers with relative energies lower than 25 kJ mol -1 and cluster II, the remaining conformers. The possibility of forming intramolecular hydrogen bonds resulted the main factor contributing for the stability. Accordingly, all conformers depicting intramolecular H-bonds belong to cluster I. These conformations are clearly favored when the carbon backbone is as planar as possible. The values of the νC dbnd O and νOH vibrational modes were compared among all the conformers of phloretin. The redshifts associated with intramolecular H-bonds were correlated with the H-bonds distances and energies.

Structural and conformational analysis of pentostatin (2'-deoxycoformycin), a potent inhibitor of adenosine deaminase.

PubMed

Cox, M B; Arjunan, P; Arora, S K

1990-08-01

X-ray, NMR and molecular mechanics studies on pentostatin (C11H16N4O4), a potent inhibitor of the enzyme adenosine deaminase, have been carried out to study the structure and conformation. The crystals belong to the monoclinic space group P21 with the cell dimensions of a = 4.960(1), b = 10.746(3), c = 11.279(4)A, beta = 101.18(2) degrees and Z = 2. The structure was solved by direct methods and difference Fourier methods and refined to an R value of 0.047 for 997 reflections. The trihydrodiazepine ring is nonplanar and adopts a distorted sofa conformation with C(7) deviated from the mean plane by 0.66A. The deoxyribose ring adopts a C3'-endo conformation, different from coformycin where the sugar has a C2'-endo conformation. The observed glycosidic torsion angle (chi = -119.5 degrees) is in the anti range. The conformation about the C(4')-C(5') bond is gauche+. The conformation of the molecule is compared with that of coformycin and 2-azacoformycin. 1 and 2D NMR studies have been carried out and the dihedral angles obtained from coupling constants have been compared with those obtained from the crystal structure. The conformation of deoxyribose in solution is approximately 70% S and 30% N. Molecular mechanics studies were performed to obtain the energy minimized conformation, which is compared with X-ray and NMR results.

Infrared multiple photon dissociation action spectroscopy of deprotonated RNA mononucleotides: gas-phase conformations and energetics.

PubMed

Nei, Y-w; Crampton, K T; Berden, G; Oomens, J; Rodgers, M T

2013-10-17

The IRMPD action spectra of the deprotonated forms of the four common RNA mononucleotides, adenosine-5'-monophosphate (A5'p), guanosine-5'-monophosphate (G5'p), cytidine-5'-monophosphate (C5'p), and uridine-5'-monophosphate (U5'p), are measured to probe their gas-phase structures. The IRMPD action spectra of all four deprotonated RNA mononucleotides exhibit distinct IR signatures in the frequency region investigated, 570-1900 cm(-1), that allows these deprotonated mononucleotides to be easily differentiated from one other. Comparison of the measured IRMPD action spectra to the linear IR spectra calculated at the B3LYP/6-31+G(d,p) level of theory finds that the most stable conformations of the deprotonated forms of A5'p, C5'p, and U5'p are accessed in the experiments, and these conformers adopt the C3' endo conformation of the ribose moiety and the anti conformation of the nucleobase. In the case of deprotonated G5'p, the most stable conformer is also accessed in the experiments. However, the ground-state conformer differs from the other three deprotonated RNA mononucleotides in that it adopts the syn rather than anti conformation for the nucleobase. Present results are compared to results previously obtained for the deprotonated forms of the four common DNA mononucleotides to examine the fundamental conformational differences between these species, and thus elucidate the effects of the 2'-hydroxyl group on their structure, stability, and fragmentation behavior.

Insights into the conformational switching mechanism of the human vascular endothelial growth factor receptor type 2 kinase domain.

PubMed

Chioccioli, Matteo; Marsili, Simone; Bonaccini, Claudia; Procacci, Piero; Gratteri, Paola

2012-02-27

Human vascular endothelial growth factor receptor type 2 (h-VEFGR2) is a receptor tyrosine kinase involved in the angiogenesis process and regarded as an interesting target for the design of anticancer drugs. Its activation/inactivation mechanism is related to conformational changes in its cytoplasmatic kinase domain, involving first among all the αC-helix in N-lobe and the A-loop in C-lobe. Affinity of inhibitors for the active or inactive kinase form could dictate the open or closed conformation of the A-loop, thus making the different conformations of the kinase domain receptor (KDR) domain different drug targets in drug discovery. In this view, a detailed knowledge of the conformational landscape of KDR domain is of central relevance to rationalize the efficiency and selectivity of kinase inhibitors. Here, molecular dynamics simulations were used to gain insight into the conformational switching activity of the KDR domain and to identify intermediate conformations between the two limiting active and inactive conformations. Specific energy barriers have been selectively removed to induce, and hence highlight at the atomistic level, the regulation mechanism of the A-loop opening. The proposed strategy allowed to repeatedly observe the escape of the KDR domain from the DFG-out free energy basin and to identify rare intermediate conformations between the DFG-out and the DFG-in structures to be employed in a structure-based drug discovery process.

Maintaining and Enhancing Diversity of Sampled Protein Conformations in Robotics-Inspired Methods.

PubMed

Abella, Jayvee R; Moll, Mark; Kavraki, Lydia E

2018-01-01

The ability to efficiently sample structurally diverse protein conformations allows one to gain a high-level view of a protein's energy landscape. Algorithms from robot motion planning have been used for conformational sampling, and several of these algorithms promote diversity by keeping track of "coverage" in conformational space based on the local sampling density. However, large proteins present special challenges. In particular, larger systems require running many concurrent instances of these algorithms, but these algorithms can quickly become memory intensive because they typically keep previously sampled conformations in memory to maintain coverage estimates. In addition, robotics-inspired algorithms depend on defining useful perturbation strategies for exploring the conformational space, which is a difficult task for large proteins because such systems are typically more constrained and exhibit complex motions. In this article, we introduce two methodologies for maintaining and enhancing diversity in robotics-inspired conformational sampling. The first method addresses algorithms based on coverage estimates and leverages the use of a low-dimensional projection to define a global coverage grid that maintains coverage across concurrent runs of sampling. The second method is an automatic definition of a perturbation strategy through readily available flexibility information derived from B-factors, secondary structure, and rigidity analysis. Our results show a significant increase in the diversity of the conformations sampled for proteins consisting of up to 500 residues when applied to a specific robotics-inspired algorithm for conformational sampling. The methodologies presented in this article may be vital components for the scalability of robotics-inspired approaches.

Stabilization of Helivcal Order in the Thick Filaments by Blebbistatin: Further Evidence of Coexisting Multiple Conformations of Myosin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, S.; White, H; Offer, G

2009-01-01

The degree of helical order of the thick filament of mammalian skeletal muscle is highly dependent on temperature and the nature of the ligand. Previously, we showed that there was a close correlation between the conformation of the myosin heads on the surface of the thick filaments and the extent of their helical order. Helical order required the heads to be in the closed conformation. In addition, we showed that, with the same ligand bound at the active site, three conformations of myosin coexisted in equilibrium. Hitherto, however, there was no detectable helical order as measured by x-ray diffraction undermore » the temperatures studied for myosin with MgADP and the nucleotide-free myosin, raising the possibility that the concept of multiple conformations has limited validity. In this study, blebbistatin was used to stabilize the closed conformation of myosin. The degree of helical order is substantially improved with MgATP at low temperature or with MgADP or in the absence of nucleotide. The thermodynamic parameters of the disorder?order transition and the characteristics of the ordered array were not significantly altered by binding blebbistatin. The simplest explanation is that the binding of blebbistatin increases the proportion of myosin in the closed conformation from being negligible to substantial. These results provide further evidence for the coexistence of multiple conformations of myosin under a wide range of conditions and for the closed conformation being directly coupled to helical order.« less

Multichannel conformal blocks for scattering amplitudes

NASA Astrophysics Data System (ADS)

Belitsky, A. V.

2018-05-01

By performing resummation of small fermion-antifermion pairs within the pentagon form factor program to scattering amplitudes in planar N = 4 superYang-Mills theory, we construct multichannel conformal blocks within the flux-tube picture for N-sided NMHV polygons. This procedure is equivalent to summation of descendants of conformal primaries in the OPE framework. The resulting conformal partial waves are determined by multivariable hypergeometric series of Lauricella-Saran type.

Very special conformal field theories and their holographic duals

NASA Astrophysics Data System (ADS)

Nakayama, Yu

2018-03-01

Cohen and Glashow introduced the notion of very special relativity as viable space-time symmetry of elementary particle physics. As a natural generalization of their idea, we study the subgroup of the conformal group, dubbed very special conformal symmetry, which is an extension of the very special relativity. We classify all of them and construct field theory examples as well as holographic realization of the very special conformal field theories.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Henan, E-mail: wuhenanby@163.com; Chen, Qiufan; Yue, Xiaoqing

The Lie conformal algebra of loop Virasoro algebra, denoted by CW, is introduced in this paper. Explicitly, CW is a Lie conformal algebra with C[∂]-basis (L{sub i} | i∈Z) and λ-brackets [L{sub i} {sub λ} L{sub j}] = (−∂−2λ)L{sub i+j}. Then conformal derivations of CW are determined. Finally, rank one conformal modules and Z-graded free intermediate series modules over CW are classified.

Conformational equilibrium and hydrogen bonding in liquid 2-phenylethylamine explored by Raman spectroscopy and theoretical calculations.

PubMed

Xie, Min; Qi, Yajing; Hu, Yongjun

2011-04-14

2-Phenylethylamine (PEA) is the simplest aromatic amine neurotransmitter, as well as one of the most important. In this work, the conformational equilibrium and hydrogen bonding in liquid PEA were studied by means of Raman spectroscopy and theoretical calculations (DFT/MP2). By changing the orientation of the ethyl and the NH(2) group, nine possible conformers of PEA were found, including four degenerate conformers. Comparison of the experimental Raman spectra of liquid PEA and the calculated Raman spectra of the five typical conformers in selected regions (550-800 and 1250-1500 cm(-1)) revealed that the five conformers can coexist in conformational equilibrium in the liquid. The NH(2) stretching mode of the liquid is red-shifted by ca. 30 cm(-1) relative to that of an isolated PEA molecule (measured previously), implying that intermolecular N-H···N hydrogen bonds play an important role in liquid PEA. The relative intensity of the Raman band at 762 cm(-1) was found to increase with increasing temperature, indicating that the anti conformer might be favorable in liquid PEA at room temperature. The blue shift of the band for the bonded N-H stretch with increasing temperature also provides evidence of the existence of intermolecular N-H···N hydrogen bonds.

Discriminating the structure of exo-2-aminonorbornane using nuclear quadrupole coupling interactions.

PubMed

Écija, Patricia; Cocinero, Emilio J; Lesarri, Alberto; Millán, Judith; Basterretxea, Francisco; Fernández, José A; Castaño, Fernando

2011-04-28

The intrinsic conformational and structural properties of the bicycle exo-2-aminonorbornane have been probed in a supersonic jet expansion using Fourier-transform microwave (FT-MW) spectroscopy and quantum chemical calculations. The rotational spectrum revealed two different conformers arising from the internal rotation of the amino group, exhibiting small (MHz) hyperfine patterns originated by the (14)N nuclear quadrupole coupling interaction. Complementary ab initio (MP2) and DFT (B3LYP and M05-2X) calculations provided comparative predictions for the structural properties, rotational and centrifugal distortion data, hyperfine parameters, and isomerization barriers. Due to the similarity of the rotational constants, the structural assignment of the observed rotamers and the calculation of the torsion angles of the amino group were based on the conformational dependence of the (14)N nuclear quadrupole coupling hyperfine tensor. In the most stable conformation (ss), the two amino N-H bonds are staggered with respect to the adjacent C-H bond. In the second conformer (st), only one of the N-H bonds is staggered and the other is trans. A third predicted conformer (ts) was not detected, consistent with a predicted conformational relaxation to conformer ss through a low barrier of 5.2 kJ mol(-1).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Jin; He, Jianfeng, E-mail: Antti.Niemi@physics.uu.se, E-mail: hjf@bit.edu.cn; Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se, E-mail: hjf@bit.edu.cn

The Landau-Ginzburg-Wilson paradigm is proposed as a framework, to investigate the conformational landscape of intrinsically unstructured proteins. A universal Cα-trace Landau free energy is deduced from general symmetry considerations, with the ensuing all-atom structure modeled using publicly available reconstruction programs Pulchra and Scwrl. As an example, the conformational stability of an amyloid precursor protein intra-cellular domain (AICD) is inspected; the reference conformation is the crystallographic structure with code 3DXC in Protein Data Bank (PDB) that describes a heterodimer of AICD and a nuclear multi-domain adaptor protein Fe65. Those conformations of AICD that correspond to local or near-local minima of themore » Landau free energy are identified. For this, the response of the original 3DXC conformation to variations in the ambient temperature is investigated, using the Glauber algorithm. The conclusion is that in isolation the AICD conformation in 3DXC must be unstable. A family of degenerate conformations that minimise the Landau free energy is identified, and it is proposed that the native state of an isolated AICD is a superposition of these conformations. The results are fully in line with the presumed intrinsically unstructured character of isolated AICD and should provide a basis for a systematic analysis of AICD structure in future NMR experiments.« less

Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection*

PubMed Central

Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L.; Langeveld, Jan; Telling, Glenn C.; Kong, Qingzhong; Safar, Jiri G.

2013-01-01

The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. PMID:23974118

Dissociation of recombinant prion autocatalysis from infectivity.

PubMed

Noble, Geoffrey P; Supattapone, Surachai

2015-01-01

Within the mammalian prion field, the existence of recombinant prion protein (PrP) conformers with self-replicating (ie. autocatalytic) activity in vitro but little to no infectious activity in vivo challenges a key prediction of the protein-only hypothesis of prion replication--that autocatalytic PrP conformers should be infectious. To understand this dissociation of autocatalysis from infectivity, we recently performed a structural and functional comparison between a highly infectious and non-infectious pair of autocatalytic recombinant PrP conformers derived from the same initial prion strain. (1) We identified restricted, C-terminal structural differences between these 2 conformers and provided evidence that these relatively subtle differences prevent the non-infectious conformer from templating the conversion of native PrP(C) substrates containing a glycosylphosphatidylinositol (GPI) anchor. (1) In this article we discuss a model, consistent with these findings, in which recombinant PrP, lacking post-translational modifications and associated folding constraints, is capable of adopting a wide variety of autocatalytic conformations. Only a subset of these recombinant conformers can be adopted by post-translationally modified native PrP(C), and this subset represents the recombinant conformers with high specific infectivity. We examine this model's implications for the generation of highly infectious recombinant prions and the protein-only hypothesis of prion replication.

Myelography Iodinated Contrast Media. 2. Conformational Versatility of Iopamidol in the Solid State.

PubMed

Bellich, Barbara; Di Fonzo, Silvia; Tavagnacco, Letizia; Paolantoni, Marco; Masciovecchio, Claudio; Bertolotti, Federica; Giannini, Giovanna; De Zorzi, Rita; Geremia, Silvano; Maiocchi, Alessandro; Uggeri, Fulvio; Masciocchi, Norberto; Cesàro, Attilio

2017-02-06

The phenomenon of polymorphism is of great relevance in pharmaceutics, since different polymorphs have different physicochemical properties, e.g., solubility, hence, bioavailability. Coupling diffractometric and spectroscopic experiments with thermodynamic analysis and computational work opens to a methodological approach which provides information on both structure and dynamics in the solid as well as in solution. The present work reports on the conformational changes in crystalline iopamidol, which is characterized by atropisomerism, a phenomenon that influences both the solution properties and the distinct crystal phases. The conformation of iopamidol is discussed for three different crystal phases. In the anhydrous and monohydrate crystal forms, iopamidol molecules display a syn conformation of the long branches stemming out from the triiodobenzene ring, while in the pentahydrate phase the anti conformation is found. IR and Raman spectroscopic studies carried out on the three crystal forms, jointly with quantum chemical computations, revealed that the markedly different spectral features can be specifically attributed to the different molecular conformations. Our results on the conformational versatility of iopamidol in different crystalline phases, linking structural and spectroscopic evidence for the solution state and the solid forms, provide a definite protocol for grasping the signals that can be taken as conformational markers. This is the first step for understanding the crystallization mechanism occurring in supersaturated solution of iopamidol molecules.

Dogs (Canis familiaris) stick to what they have learned rather than conform to their conspecifics’ behavior

PubMed Central

Sultan, Amira; Kaminski, Juliane; Mojzisch, Andreas

2018-01-01

In recent years, an increasing number of studies has investigated majority influence in nonhuman animals. However, due to both terminological and methodological issues, evidence for conformity in nonhuman animals is scarce and controversial. Preliminary evidence suggests that wild birds, wild monkeys, and fish show conformity, that is, forgoing personal information in order to copy the majority. By contrast, chimpanzees seem to lack this tendency. The present study is the first to examine whether dogs (Canis familiaris) show conformity. Specifically, we tested whether dogs conform to a majority of conspecifics rather than stick to what they have previously learned. After dogs had acquired a behavioral preference via training (i.e., shaping), they were confronted with counter-preferential behavior of either no, one or three conspecifics. Traditional frequentist analyses show that the dogs’ behavior did not differ significantly between the three conditions. Complementary Bayesian analyses suggest that our data provide moderate evidence for the null hypothesis. In conclusion, our results suggest that dogs stick to what they have learned rather than conform to the counter-preferential behavior of others. We discuss the possible statistical and methodological limitations of this finding. Furthermore, we take a functional perspective on conformity and discuss under which circumstances dogs might show conformity after all. PMID:29570747

NMSim web server: integrated approach for normal mode-based geometric simulations of biologically relevant conformational transitions in proteins.

PubMed

Krüger, Dennis M; Ahmed, Aqeel; Gohlke, Holger

2012-07-01

The NMSim web server implements a three-step approach for multiscale modeling of protein conformational changes. First, the protein structure is coarse-grained using the FIRST software. Second, a rigid cluster normal-mode analysis provides low-frequency normal modes. Third, these modes are used to extend the recently introduced idea of constrained geometric simulations by biasing backbone motions of the protein, whereas side chain motions are biased toward favorable rotamer states (NMSim). The generated structures are iteratively corrected regarding steric clashes and stereochemical constraint violations. The approach allows performing three simulation types: unbiased exploration of conformational space; pathway generation by a targeted simulation; and radius of gyration-guided simulation. On a data set of proteins with experimentally observed conformational changes, the NMSim approach has been shown to be a computationally efficient alternative to molecular dynamics simulations for conformational sampling of proteins. The generated conformations and pathways of conformational transitions can serve as input to docking approaches or more sophisticated sampling techniques. The web server output is a trajectory of generated conformations, Jmol representations of the coarse-graining and a subset of the trajectory and data plots of structural analyses. The NMSim webserver, accessible at http://www.nmsim.de, is free and open to all users with no login requirement.

Effect of bisecting GlcNAc and core fucosylation on conformational properties of biantennary complex-type N-glycans in solution.

PubMed

Nishima, Wataru; Miyashita, Naoyuki; Yamaguchi, Yoshiki; Sugita, Yuji; Re, Suyong

2012-07-26

The introduction of bisecting GlcNAc and core fucosylation in N-glycans is essential for fine functional regulation of glycoproteins. In this paper, the effect of these modifications on the conformational properties of N-glycans is examined at the atomic level by performing replica-exchange molecular dynamics (REMD) simulations. We simulate four biantennary complex-type N-glycans, namely, unmodified, two single-substituted with either bisecting GlcNAc or core fucose, and disubstituted forms. By using REMD as an enhanced sampling technique, five distinct conformers in solution, each of which is characterized by its local orientation of the Manα1-6Man glycosidic linkage, are observed for all four N-glycans. The chemical modifications significantly change their conformational equilibria. The number of major conformers is reduced from five to two and from five to four upon the introduction of bisecting GlcNAc and core fucosylation, respectively. The population change is attributed to specific inter-residue hydrogen bonds, including water-mediated ones. The experimental NMR data, including nuclear Overhauser enhancement and scalar J-coupling constants, are well reproduced taking the multiple conformers into account. Our structural model supports the concept of "conformer selection", which emphasizes the conformational flexibility of N-glycans in protein-glycan interactions.

A Free-Energy Approach for All-Atom Protein Simulation

PubMed Central

Verma, Abhinav; Wenzel, Wolfgang

2009-01-01

All-atom free-energy methods offer a promising alternative to kinetic molecular mechanics simulations of protein folding and association. Here we report an accurate, transferable all-atom biophysical force field (PFF02) that stabilizes the native conformation of a wide range of proteins as the global optimum of the free-energy landscape. For 32 proteins of the ROSETTA decoy set and six proteins that we have previously folded with PFF01, we find near-native conformations with an average backbone RMSD of 2.14 Å to the native conformation and an average Z-score of −3.46 to the corresponding decoy set. We used nonequilibrium sampling techniques starting from completely extended conformations to exhaustively sample the energy surface of three nonhomologous hairpin-peptides, a three-stranded β-sheet, the all-helical 40 amino-acid HIV accessory protein, and a zinc-finger ββα motif, and find near-native conformations for the minimal energy for each protein. Using a massively parallel evolutionary algorithm, we also obtain a near-native low-energy conformation for the 54 amino-acid engrailed homeodomain. Our force field thus stabilized near-native conformations for a total of 20 proteins of all structure classes with an average RMSD of only 3.06 Å to their respective experimental conformations. PMID:19413955

Benchmarking Commercial Conformer Ensemble Generators.

PubMed

Friedrich, Nils-Ole; de Bruyn Kops, Christina; Flachsenberg, Florian; Sommer, Kai; Rarey, Matthias; Kirchmair, Johannes

2017-11-27

We assess and compare the performance of eight commercial conformer ensemble generators (ConfGen, ConfGenX, cxcalc, iCon, MOE LowModeMD, MOE Stochastic, MOE Conformation Import, and OMEGA) and one leading free algorithm, the distance geometry algorithm implemented in RDKit. The comparative study is based on a new version of the Platinum Diverse Dataset, a high-quality benchmarking dataset of 2859 protein-bound ligand conformations extracted from the PDB. Differences in the performance of commercial algorithms are much smaller than those observed for free algorithms in our previous study (J. Chem. Inf. 2017, 57, 529-539). For commercial algorithms, the median minimum root-mean-square deviations measured between protein-bound ligand conformations and ensembles of a maximum of 250 conformers are between 0.46 and 0.61 Å. Commercial conformer ensemble generators are characterized by their high robustness, with at least 99% of all input molecules successfully processed and few or even no substantial geometrical errors detectable in their output conformations. The RDKit distance geometry algorithm (with minimization enabled) appears to be a good free alternative since its performance is comparable to that of the midranked commercial algorithms. Based on a statistical analysis, we elaborate on which algorithms to use and how to parametrize them for best performance in different application scenarios.

Nature vs. nurture in human sociality: multi-level genomic analyses of social conformity.

PubMed

Chen, Biqing; Zhu, Zijian; Wang, Yingying; Ding, Xiaohu; Guo, Xiaobo; He, Mingguang; Fang, Wan; Zhou, Qin; Zhou, Shanbi; Lei, Han; Huang, Ailong; Chen, Tingmei; Ni, Dongsheng; Gu, Yuping; Liu, Jianing; Rao, Yi

2018-05-01

Social conformity is fundamental to human societies and has been studied for more than six decades, but our understanding of its mechanisms remains limited. Individual differences in conformity have been attributed to social and cultural environmental influences, but not to genes. Here we demonstrate a genetic contribution to conformity after analyzing 1,140 twins and single-nucleotide polymorphism (SNP)-based studies of 2,130 young adults. A two-step genome-wide association study (GWAS) revealed replicable associations in 9 genomic loci, and a meta-analysis of three GWAS with a sample size of ~2,600 further confirmed one locus, corresponding to the NAV3 (Neuron Navigator 3) gene which encodes a protein important for axon outgrowth and guidance. Further multi-level (haplotype, gene, pathway) GWAS strongly associated genes including NAV3, PTPRD (protein tyrosine phosphatase receptor type D), ARL10 (ADP ribosylation factor-like GTPase 10), and CTNND2 (catenin delta 2), with conformity. Magnetic resonance imaging of 64 subjects shows correlation of activation or structural features of brain regions with the SNPs of these genes, supporting their functional significance. Our results suggest potential moderate genetic influence on conformity, implicate several specific genetic elements in conformity and will facilitate further research on cellular and molecular mechanisms underlying human conformity.

A free-energy approach for all-atom protein simulation.

PubMed

Verma, Abhinav; Wenzel, Wolfgang

2009-05-06

All-atom free-energy methods offer a promising alternative to kinetic molecular mechanics simulations of protein folding and association. Here we report an accurate, transferable all-atom biophysical force field (PFF02) that stabilizes the native conformation of a wide range of proteins as the global optimum of the free-energy landscape. For 32 proteins of the ROSETTA decoy set and six proteins that we have previously folded with PFF01, we find near-native conformations with an average backbone RMSD of 2.14 A to the native conformation and an average Z-score of -3.46 to the corresponding decoy set. We used nonequilibrium sampling techniques starting from completely extended conformations to exhaustively sample the energy surface of three nonhomologous hairpin-peptides, a three-stranded beta-sheet, the all-helical 40 amino-acid HIV accessory protein, and a zinc-finger beta beta alpha motif, and find near-native conformations for the minimal energy for each protein. Using a massively parallel evolutionary algorithm, we also obtain a near-native low-energy conformation for the 54 amino-acid engrailed homeodomain. Our force field thus stabilized near-native conformations for a total of 20 proteins of all structure classes with an average RMSD of only 3.06 A to their respective experimental conformations.

Kinetics of protein unfolding at interfaces

NASA Astrophysics Data System (ADS)

Yano, Yohko F.

2012-12-01

The conformation of protein molecules is determined by a balance of various forces, including van der Waals attraction, electrostatic interaction, hydrogen bonding, and conformational entropy. When protein molecules encounter an interface, they are often adsorbed on the interface. The conformation of an adsorbed protein molecule strongly depends on the interaction between the protein and the interface. Recent time-resolved investigations have revealed that protein conformation changes during the adsorption process due to the protein-protein interaction increasing with increasing interface coverage. External conditions also affect the protein conformation. This review considers recent dynamic observations of protein adsorption at various interfaces and their implications for the kinetics of protein unfolding at interfaces.

The conformation of cyclo(-D-Pro-Ala4-) as a model for cyclic pentapeptides of the DL4 type.

PubMed

Heller, Markus; Sukopp, Martin; Tsomaia, Natia; John, Michael; Mierke, Dale F; Reif, Bernd; Kessler, Horst

2006-10-25

The conformation of the cyclic pentapeptide cyclo(-D-Pro-Ala(4)-) in solution and in the solid state was reinvestigated using modern NMR techniques. To allow unequivocal characterization of hydrogen bonds, relaxation behavior, and intramolecular distances, differently labeled isotopomers were synthesized. The NMR results, supported by extensive MD simulations, demonstrate unambiguously that the preferred conformation previously described by us, but recently questioned, is indeed correct. The validation of the conformational preferences of this cyclic peptide is important given that this system is a template for several bioactive compounds and for controlled "spatial screening" for the search of bioactive conformations.

Influence of solvents on the conformation of benzoin

NASA Astrophysics Data System (ADS)

Pawełka, Z.; Czarnik-Matusewicz, B.; Zeegers-Huyskens, Th.

2010-01-01

The conformation of benzoin in several organic solvents is investigated by infrared spectrometry and dipolometry. The frequencies, intensities, and band shapes of the ν(OH), ν(C dbnd O), and aromatic ring vibrations indicate that in solvents of low proton acceptor ability, the cis conformer with intramolecular OH···O hydrogen bonding is preserved. In solvents of large proton acceptor ability there is equilibrium between the cis and trans conformers. The dipole moments are less sensitive to conformational changes, but indicate the same trends. The results are discussed as a function of the specific solvation of the O atoms or OH groups of benzoin.

Influence of solvents on the conformation of benzoin.

PubMed

Pawełka, Z; Czarnik-Matusewicz, B; Zeegers-Huyskens, Th

2010-01-01

The conformation of benzoin in several organic solvents is investigated by infrared spectrometry and dipolometry. The frequencies, intensities, and band shapes of the nu(OH), nu(C=O), and aromatic ring vibrations indicate that in solvents of low proton acceptor ability, the cis conformer with intramolecular OH...O hydrogen bonding is preserved. In solvents of large proton acceptor ability there is equilibrium between the cis and trans conformers. The dipole moments are less sensitive to conformational changes, but indicate the same trends. The results are discussed as a function of the specific solvation of the O atoms or OH groups of benzoin. Copyright 2009 Elsevier B.V. All rights reserved.

Spacer conformation in biologically active molecules. Part 1. Structure and conformational preferences of 2-substituted benzoxazoles

NASA Astrophysics Data System (ADS)

Czylkowski, R.; Karolak-Wojciechowska, J.; Mrozek, A.; Yalçin, I.; Aki-Şener, E.

2001-12-01

The mutual position of two pharmacophoric elements in flexible biologically active molecules depends on the spacer conformation. This is true even for a two-atomic chain put to use as a spacer. It was established for 2-substituted-benzoxazoles containing two aromatic centres joined by -CH2-X- (X=S or O). From crystallographic studies of four molecules it was found that the role of heteroatom is essential for the whole molecule conformation. The spacer with X=S adopts the (-)synclinal conformation while for X=O the (+)antiperiplanar one. Such preferences were also found in the statistical data from Cambridge Structural Database (CSD).

Classical conformal blocks and accessory parameters from isomonodromic deformations

NASA Astrophysics Data System (ADS)

Lencsés, Máté; Novaes, Fábio

2018-04-01

Classical conformal blocks appear in the large central charge limit of 2D Virasoro conformal blocks. In the AdS3 /CFT2 correspondence, they are related to classical bulk actions and used to calculate entanglement entropy and geodesic lengths. In this work, we discuss the identification of classical conformal blocks and the Painlevé VI action showing how isomonodromic deformations naturally appear in this context. We recover the accessory parameter expansion of Heun's equation from the isomonodromic τ -function. We also discuss how the c = 1 expansion of the τ -function leads to a novel approach to calculate the 4-point classical conformal block.

Torsional anharmonicity in the conformational thermodynamics of flexible molecules

NASA Astrophysics Data System (ADS)

Miller, Thomas F., III; Clary, David C.

We present an algorithm for calculating the conformational thermodynamics of large, flexible molecules that combines ab initio electronic structure theory calculations with a torsional path integral Monte Carlo (TPIMC) simulation. The new algorithm overcomes the previous limitations of the TPIMC method by including the thermodynamic contributions of non-torsional vibrational modes and by affordably incorporating the ab initio calculation of conformer electronic energies, and it improves the conventional ab initio treatment of conformational thermodynamics by accounting for the anharmonicity of the torsional modes. Using previously published ab initio results and new TPIMC calculations, we apply the algorithm to the conformers of the adrenaline molecule.

X-ray and 1H-NMR spectroscopic studies of the structures and conformations of the new nootropic agents RU-35929, RU-47010 and RU-35965

NASA Astrophysics Data System (ADS)

Amato, Maria E.; Bandoli, Giuliano; Casellato, Umberto; Pappalardo, Giuseppe C.; Toja, Emilio

1990-10-01

The crystal and molecular structures of the nootropics (±)1-benzenesulphonyl-2-oxo-5-ethoxypyrrolidine ( 1), (±)1-(3-pyridinylsulphonyl)-2-oxo-5-ethoxypyrrolidine ( 2) and (±)1-benzenesulphonyl-2-oxo-5-isopropyloxypyrrolidine ( 3) have been determined by X-ray analysis. The solution conformation of 1, 2 and 3 has been investigated by 1H NMR spectroscopy. In the solid state, the main feature consists of the similar structural parameters and conformations, with the exception of the conformation adopted by the 5-ethoxy moiety which changes on passing from 1 to 2. The solid state overall enveloped conformation of the 2-pyrrolidinone ring for the three nootropics is found to be retained in solution on the basis of NMR evidence. Comparison between calculated and experimental coupling constant values shows that one of the two possible puckered opposite conformational isomers (half-chair shapes) occurs in solution. The relative pharmacological potencies of 1, 2 and 3 cannot therefore be interpreted in terms of the different conformation features presently detectable by available experimental methods.

Conformation of poly(γ-glutamic acid) in aqueous solution.

PubMed

Muroga, Yoshio; Nakaya, Asami; Inoue, Atsuki; Itoh, Daiki; Abiru, Masaya; Wada, Kaori; Takada, Masako; Ikake, Hiroki; Shimizu, Shigeru

2016-04-01

Local conformation and overall conformation of poly(γ-DL-glutamic acid) (PγDLGA) and poly(γ-L-glutamic acid) (PγLGA) in aqueous solution was studied as a function of degree of ionization ε by (1) H-NMR, circular dichroism, and potentiometric titration. It was clarified that their local conformation is represented by random coil over an entire ε range and their overall conformation is represented by expanded random-coil in a range of ε > ε(*) , where ε(*) is about 0.3, 0.35, 0.45, and 0.5 for added-salt concentration of 0.02M, 0.05M, 0.1M, and 0.2M, respectively. In a range of ε < ε(*) , however, ε dependence of their overall conformation is significantly differentiated from each other. PγDLGA tends to aggregate intramolecularly and/or intermolecularly with decreasing ε, but PγLGA still behaves as expanded random-coil. It is speculated that spatial arrangement of adjacent carboxyl groups along the backbone chain essentially affects the overall conformation of PγGA in acidic media. © 2015 Wiley Periodicals, Inc.

Chirality recognition in the glycidol···propylene oxide complex: a rotational spectroscopic study.

PubMed

Thomas, Javix; Sunahori, Fumie X; Borho, Nicole; Xu, Yunjie

2011-04-11

Chirality recognition in the hydrogen-bonded glycidol···propylene oxide complex has been studied by using rotational spectroscopy and ab initio calculations. An extensive conformational search has been performed for this binary adduct at the MP2/6-311++G(d,p) level of theory and a total of 28 homo- and heterochiral conformers were identified. The eight binary conformers, built of the two dominant glycidol monomeric conformers, g-G+ and g+G-, were predicted to be the most stable ones. Jet-cooled rotational spectra of six out of the eight conformers were observed and unambiguously assigned for the first time. The experimental stability ordering has been obtained and compared with the ab initio predictions. The relative stability of the two dominant glycidol monomeric conformers is reversed in some cases when binding to propylene oxide. The contributions of monomeric energy, deformation energy, and binary intermolecular interaction energy to the relative stability of the binary conformers are discussed. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Conformational Flexibility of Human Casein Kinase Catalytic Subunit Explored by Metadynamics

PubMed Central

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-01-01

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the γ phosphate from ATP to serine and threonine residues on protein substrates. In a number of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2α catalytic subunit. This variability reflects a high flexibility for two regions of CK2α: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, we present a computational study simulating the equilibrium between three conformations involving these regions. Simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provides a reference pathway describing the conformational changes being studied, based on analysis of free energy surfaces. The free energies of the three conformations were found to be close and the paths proposed had low activation barriers. Our results indicate that these conformations can exist in water. This information should be useful when designing inhibitors specific to one conformation. PMID:24606937

In God we trust? Neural measures reveal lower social conformity among non-religious individuals.

PubMed

Thiruchselvam, Ravi; Gopi, Yashoda; Kilekwang, Leonard; Harper, Jessica; Gross, James J

2017-06-01

Even in predominantly religious societies, there are substantial individual differences in religious commitment. Why is this? One possibility is that differences in social conformity (i.e. the tendency to think and behave as others do) underlie inclination towards religiosity. However, the link between religiosity and conformity has not yet been directly examined. In this study, we tested the notion that non-religious individuals show dampened social conformity, using both self-reported and neural (EEG-based ERPs) measures of sensitivity to others' influence. Non-religious vs religious undergraduate subjects completed an experimental task that assessed levels of conformity in a domain unrelated to religion (i.e. in judgments of facial attractiveness). Findings showed that, although both groups yielded to conformity pressures at the self-report level, non-religious individuals did not yield to such pressures in their neural responses. These findings highlight a novel link between religiosity and social conformity, and hold implications for prominent theories about the psychological functions of religion. © The Author (2017). Published by Oxford University Press.

Emotional reactions to deviance in groups: the relation between number of angry reactions, felt rejection, and conformity

PubMed Central

Heerdink, Marc W.; van Kleef, Gerben A.; Homan, Astrid C.; Fischer, Agneta H.

2015-01-01

How many members of a group need to express their anger in order to influence a deviant group member’s behavior? In two studies, we examine whether an increase in number of angry group members affects the extent to which a deviant individual feels rejected, and we investigate downstream effects on conformity. We show that each additional angry reaction linearly increases the extent to which a deviant individual feels rejected, and that this relation is independent of the total number of majority members (Study 1). This felt rejection is then shown to lead to anti-conformity unless two conditions are met: (1) the deviant is motivated to seek reacceptance in the group, and (2) conformity is instrumental in gaining reacceptance because it is observable by the majority (Study 2). These findings show that angry reactions are likely to trigger anti-conformity in a deviant, but they are also consistent with a motivational account of conformity, in which conformity is strategic behavior aimed at gaining reacceptance from the group. PMID:26124742

Molecular dynamics study of the phosphorylation effect on the conformational states of the C-terminal domain of RNA polymerase II.

PubMed

Yonezawa, Yasushige

2014-05-01

The carboxyl-terminal domain (CTD) of RNA polymerase II in eukaryotes regulates mRNA processing processes by recruiting various regulation factors. A main function of the CTD relies on the heptad consensus sequence (YSPTSPS). The CTD dynamically changes its conformational state to recognize and bind different regulation factors. The dynamical conformation changes are caused by modifications, mainly phosphorylation and dephosphorylation, to the serine residues. In this study, we investigate the conformational states of the unit consensus CTD peptide with various phosphorylation patterns of the serine residues by extended ensemble simulations. The results show that the CTD without phosphorylation has a flexible disordered structure distributed between twisted and extended states, but phosphorylation tends to reduce the conformational space. It was found that phosphorylation induces a β-turn around the phosphorylated serine residue and the cis conformation of the proline residue significantly inhibits the β-turn formation. The β-turn should contribute to specific CTD binding of the different regulation factors by changing the conformation propensity combined with induced fit.

Enhanced conformational sampling of carbohydrates by Hamiltonian replica-exchange simulation.

PubMed

Mishra, Sushil Kumar; Kara, Mahmut; Zacharias, Martin; Koca, Jaroslav

2014-01-01

Knowledge of the structure and conformational flexibility of carbohydrates in an aqueous solvent is important to improving our understanding of how carbohydrates function in biological systems. In this study, we extend a variant of the Hamiltonian replica-exchange molecular dynamics (MD) simulation to improve the conformational sampling of saccharides in an explicit solvent. During the simulations, a biasing potential along the glycosidic-dihedral linkage between the saccharide monomer units in an oligomer is applied at various levels along the replica runs to enable effective transitions between various conformations. One reference replica runs under the control of the original force field. The method was tested on disaccharide structures and further validated on biologically relevant blood group B, Lewis X and Lewis A trisaccharides. The biasing potential-based replica-exchange molecular dynamics (BP-REMD) method provided a significantly improved sampling of relevant conformational states compared with standard continuous MD simulations, with modest computational costs. Thus, the proposed BP-REMD approach adds a new dimension to existing carbohydrate conformational sampling approaches by enhancing conformational sampling in the presence of solvent molecules explicitly at relatively low computational cost.

Straight and Curved Conformations of FtsZ Are Regulated by GTP Hydrolysis

PubMed Central

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

2000-01-01

FtsZ assembles in vitro into protofilaments that can adopt two conformations—the straight conformation, which can assemble further into two-dimensional protofilament sheets, and the curved conformation, which forms minirings about 23 nm in diameter. Here, we describe the structure of FtsZ tubes, which are a variation of the curved conformation. In the tube the curved protofilament forms a shallow helix with a diameter of 23 nm and a pitch of 18 or 24°. We suggest that this shallow helix is the relaxed structure of the curved protofilament in solution. We provide evidence that GTP favors the straight conformation while GDP favors the curved conformation. In particular, exclusively straight protofilaments and protofilament sheets are assembled in GMPCPP, a nonhydrolyzable GTP analog, or in GTP following chelation of Mg, which blocks GTP hydrolysis. Assembly in GDP produces exclusively tubes. The transition from straight protofilaments to the curved conformation may provide a mechanism whereby the energy of GTP hydrolysis is used to generate force for the constriction of the FtsZ ring in cell division. PMID:10613876

Protein Allostery and Conformational Dynamics.

PubMed

Guo, Jingjing; Zhou, Huan-Xiang

2016-06-08

The functions of many proteins are regulated through allostery, whereby effector binding at a distal site changes the functional activity (e.g., substrate binding affinity or catalytic efficiency) at the active site. Most allosteric studies have focused on thermodynamic properties, in particular, substrate binding affinity. Changes in substrate binding affinity by allosteric effectors have generally been thought to be mediated by conformational transitions of the proteins or, alternatively, by changes in the broadness of the free energy basin of the protein conformational state without shifting the basin minimum position. When effector binding changes the free energy landscape of a protein in conformational space, the change affects not only thermodynamic properties but also dynamic properties, including the amplitudes of motions on different time scales and rates of conformational transitions. Here we assess the roles of conformational dynamics in allosteric regulation. Two cases are highlighted where NMR spectroscopy and molecular dynamics simulation have been used as complementary approaches to identify residues possibly involved in allosteric communication. Perspectives on contentious issues, for example, the relationship between picosecond-nanosecond local and microsecond-millisecond conformational exchange dynamics, are presented.

Conformation-Specific Spectroscopy of a Prototypical γ-PEPTIDE-WATER Complex: Ac-γ2-hPhe-NHMe-(H2O)1

NASA Astrophysics Data System (ADS)

Buchanan, Evan G.; James, William H., III; Zwier, Timothy S.; Guo, Li; Gellman, Samuel H.

2010-06-01

The prototypical γ-peptide, Ac-γ2-hPhe-NHMe, has been previously studied in a supersonic jet expansion, with three different conformers observed. Two of the monomers form nine atom, intramolecular hydrogen bonded rings, which differ by the position of the aromatic chromophore relative to the backbone. The third monomer conformer has no intramolecular H-bonds, but forms instead an intramolecular, amide-amide stacked structure unique to the γ-peptide backbone. This talk focuses attention on the conformation-specific IR spectra of the Ac-γ2-hPhe-NHMe-(H2O)1 complex, which is observed to form six unique conformational isomers, all of which preserve the two distinct monomer structural motifs. Three conformers are assigned to the nine atom intramolecular hydrogen bond family with the water hydrogen bonded to it as donor in different locations. The other three belong to the amide-amide stacking family with the water forming a bridge between the two amide planes. Infrared photodissocation of the water molecule from the complex to form γ-peptide monomer conformations will also be discussed.

Ethanol Dimer: Observation of Three New Conformers by Broadband Rotational Spectroscopy

NASA Astrophysics Data System (ADS)

Loru, Donatella; Peña, Isabel; Sanz, M. Eugenia

2017-06-01

The conformational behaviour of the hydrogen-bonded cluster ethanol dimer has been reinvestigated by chirped pulse Fourier transform microwave spectroscopy in the 2-8 GHz frequency region. Three new conformers ({tt}, {tg}+, and {g}-{g}+) have been identified together with the three ({g}+{g}+, {g}-{t}, and {g}+{t}) previously observed by Hearn et al. (J. Chem. Phys. 123, 134324, 2005) and their rotational and centrifugal distortion constants have been determined. By using different carrier gases in the supersonic expansion, the relative abundances of the observed conformers have been estimated. The monosubstituted ^{13}C species and some of the ^{18}O species of the most abundant conformers {g}+{g}+, {g}-{t}, and {tt} have been observed in their natural abundance, which led to the partial determination of their r_{s} structures, and the r_{0} structure for the {tt} conformer. The six observed conformers are stabilized by the delicate interplay of primary O-H...O and secondary C-H...O hydrogen bonds, and dispersion interactions between the methyl groups. Density functional and ab initio methods with different basis sets are benchmarked against the experimental data.

Emotional reactions to deviance in groups: the relation between number of angry reactions, felt rejection, and conformity.

PubMed

Heerdink, Marc W; van Kleef, Gerben A; Homan, Astrid C; Fischer, Agneta H

2015-01-01

How many members of a group need to express their anger in order to influence a deviant group member's behavior? In two studies, we examine whether an increase in number of angry group members affects the extent to which a deviant individual feels rejected, and we investigate downstream effects on conformity. We show that each additional angry reaction linearly increases the extent to which a deviant individual feels rejected, and that this relation is independent of the total number of majority members (Study 1). This felt rejection is then shown to lead to anti-conformity unless two conditions are met: (1) the deviant is motivated to seek reacceptance in the group, and (2) conformity is instrumental in gaining reacceptance because it is observable by the majority (Study 2). These findings show that angry reactions are likely to trigger anti-conformity in a deviant, but they are also consistent with a motivational account of conformity, in which conformity is strategic behavior aimed at gaining reacceptance from the group.

Weyl geometry

NASA Astrophysics Data System (ADS)

Wheeler, James T.

2018-07-01

We develop the properties of Weyl geometry, beginning with a review of the conformal properties of Riemannian spacetimes. Decomposition of the Riemann curvature into trace and traceless parts allows an easy proof that the Weyl curvature tensor is the conformally invariant part of the Riemann curvature, and shows the explicit change in the Ricci and Schouten tensors required to insure conformal invariance. We include a proof of the well-known condition for the existence of a conformal transformation to a Ricci-flat spacetime. We generalize this to a derivation of the condition for the existence of a conformal transformation to a spacetime satisfying the Einstein equation with matter sources. Then, enlarging the symmetry from Poincaré to Weyl, we develop the Cartan structure equations of Weyl geometry, the form of the curvature tensor and its relationship to the Riemann curvature of the corresponding Riemannian geometry. We present a simple theory of Weyl-covariant gravity based on a curvature-linear action, and show that it is conformally equivalent to general relativity. This theory is invariant under local dilatations, but not the full conformal group.

A molecular mechanics study of the effect of substitution in position 1 on the conformational space of the oxytocin/vasopressin ring

NASA Astrophysics Data System (ADS)

Tarnowska, Monika; Liwo, Adam; Shenderovich, Mark D.; Liepiņa, Inta; Golbraikh, Alexander A.; Grzonka, Zbigniew; Tempczyk, Anna

1993-12-01

The effect of the substitution in position 1 on the low-energy conformations of the oxytocin/vasopressin 20-membered ring was investigated by means of molecular mechanics. Three representative substitutions were considered: β'-mercapto-β,β-dimethyl)propionic acid (Dmp), (β'-mercapto-β,β-cyclopentamethylene)propionic acid (Cpp), both forming strong antagonists, and (α,α-dimethyl-β-mercapto)propionic acid (α-Dmp), forming analogs of strongly reduced biological activity, with the β-mercaptopropionic (Mpa) residue taken as reference. Both ECEPP/2 (rigid valence geometry) and AMBER (flexible valence geometry) force fields were employed in the calculations. Three basic types of backbone conformations were taken into account which are distinguished by the type of β-turn at residues 3 and 4: β1/βIII, βII, and βI'/βIII', all types containing one or two intra-annular hydrogen bonds. The allowed (ring-closed) disulfide-bridge conformations were searched by an algorithm formulated in terms of scanning the disulfide-bridge torsional angle Cβ-S-S-Cβ. The ECEPP/2 and AMBER energies of the obtained conformations were found to be in reasonable agreement. Two of the low-energy conformers of the [Mpa1]-compound agreed very well with the cyclic part of the two conformers found in the crystal structure of [Mpa1]-oxytocin. An analysis of the effect of β-substitution on relative energies showed that the conformations with the N-C'-CH2-CH2 (ψ'1) and C'-CH2-CH2-S (ϰ'1) angles of the first residue around (-100°, 60°) and (100°, -60°) are not affected; this in most cases implies a left-handed disulfide bridge. In the case of α-substitution the allowed values of ψ'1 are close to ± 60°. This requirement, being in contradiction to the one concerning β-substitution, could explain the very low biological activity of the α-substituted analogs. The conformational preferences of substituted compounds can largely be explained by the analysis of local interactions within the first residue. Based on the selection of the conformations which are low in energy for both the reference and β-substituted compounds, two distinct types of possible binding conformations were proposed, the first one being similar to the crystal conformer with a left-handed disulfide bridge, the second one having a right-handed bridge, but a geometry different from that of the crystal conformer with the right-handed bridge. The first type of disulfide-bridge arrangement is equally favorable for both βI/βIII and βII types of backbone structure, while the second one is allowed only for the βII type of backbone. No conformation of the βI'/βIII' type has a low enough energy to be considered as a possible binding conformation for all of the active compounds studied in this work.

Conformations of eight-membered cyclosiloxanes

NASA Astrophysics Data System (ADS)

Palyulin, V. A.; Zefirov, N. S.; Shklover, V. E.; Struchkov, Yu. T.

1981-01-01

Using the Cremer—Pople approach the classification and quantitative description of the conformations of eight-membered rings has been accomplished. The conformations of eight-membered cyclosiloxanes are considered and classified on the basis of available X-ray structural data.

Conformations of Substituted Ethanes.

ERIC Educational Resources Information Center

Kingsbury, Charles A.

1979-01-01

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

Hom Gel'fand-Dorfman bialgebras and Hom-Lie conformal algebras

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Lamei, E-mail: lmyuan@hit.edu.cn

2014-04-15

The aim of this paper is to introduce the notions of Hom Gel'fand-Dorfman bialgebra and Hom-Lie conformal algebra. In this paper, we give four constructions of Hom Gel'fand-Dorfman bialgebras. Also, we provide a general construction of Hom-Lie conformal algebras from Hom-Lie algebras. Finally, we prove that a Hom Gel'fand-Dorfman bialgebra is equivalent to a Hom-Lie conformal algebra of degree 2.

Conformal Electromagnetic Particle in Cell: A Review

DOE PAGES

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

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.

Conformational dynamics of ATP/Mg:ATP in motor proteins via data mining and molecular simulation.

PubMed

Bojovschi, A; Liu, Ming S; Sadus, Richard J

2012-08-21

The conformational diversity of ATP/Mg:ATP in motor proteins was investigated using molecular dynamics and data mining. Adenosine triphosphate (ATP) conformations were found to be constrained mostly by inter cavity motifs in the motor proteins. It is demonstrated that ATP favors extended conformations in the tight pockets of motor proteins such as F(1)-ATPase and actin whereas compact structures are favored in motor proteins such as RNA polymerase and DNA helicase. The incorporation of Mg(2+) leads to increased flexibility of ATP molecules. The differences in the conformational dynamics of ATP/Mg:ATP in various motor proteins was quantified by the radius of gyration. The relationship between the simulation results and those obtained by data mining of motor proteins available in the protein data bank is analyzed. The data mining analysis of motor proteins supports the conformational diversity of the phosphate group of ATP obtained computationally.

Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism

PubMed Central

Hughes, Travis S.; Chalmers, Michael J.; Novick, Scott; Kuruvilla, Dana S.; Chang, Mi Ra; Kamenecka, Theodore M.; Rance, Mark; Johnson, Bruce A.; Burris, Thomas P.; Griffin, Patrick R.; Kojetin, Douglas J.

2011-01-01

SUMMARY Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution NMR studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators. PMID:22244763

Conformational equilibrium of phenylacetic acid and its halogenated analogues through theoretical studies, NMR and IR spectroscopy

NASA Astrophysics Data System (ADS)

Levandowski, Mariana N.; Rozada, Thiago C.; Melo, Ulisses Z.; Basso, Ernani A.; Fiorin, Barbara C.

2017-03-01

This paper presents a study on the conformational preferences of phenylacetic acid (PA) and its halogenated analogues (FPA, CPA, BPA). To clarify the effects that rule these molecules' behaviour, theoretical calculations were used, for both the isolated phase and solution, combined with nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. Most conformations of phenylacetic acid and its halogenated derivatives are stabilized through the hyperconjugative effect, which rules the conformational preference. NMR analyses showed that even with the variation in medium polarity, there was no significant change in the conformation population. Infrared spectroscopy showed similar results for all compounds under study. In most spectra, two bands were found through the carbonyl deconvolution, which is in accordance with the theoretical data. It was possible to prove that variation in the nature of the substituent in the ortho position had no significant influence on the conformational equilibrium.

Adolescents' Acceptance of Same-Sex Peers Based on Sexual Orientation and Gender Expression.

PubMed

Horn, Staccy S

2007-04-01

This study investigated tenth- and twelfth-grade adolescents' (N ≤ 264) judgments about the acceptability of same-sex peers who varied in terms of their sexual orientation (straight, gay or lesbian) and their conformity to gender conventions or norms in regard appearance and mannerisms or activity. Overall, the results of this study suggest that adolescents' conceptions of the acceptability of their peers are related not just to sexual orientation but also conformity to gender conventions. Both straight and gay or lesbian individuals who were non-conventional in their appearance and mannerisms were rated as less acceptable than individuals who conformed to gender conventions or those who participated in non-conventional activities. Most surprisingly, for boys, the straight individual who was non-conforming in appearance was rated less acceptable than either the gay individual who conformed to gender norms or was gender non-conforming in choice of activity.

Characterizing Conformational Dynamics of Proteins Using Evolutionary Couplings.

PubMed

Feng, Jiangyan; Shukla, Diwakar

2018-01-25

Understanding of protein conformational dynamics is essential for elucidating molecular origins of protein structure-function relationship. Traditionally, reaction coordinates, i.e., some functions of protein atom positions and velocities have been used to interpret the complex dynamics of proteins obtained from experimental and computational approaches such as molecular dynamics simulations. However, it is nontrivial to identify the reaction coordinates a priori even for small proteins. Here, we evaluate the power of evolutionary couplings (ECs) to capture protein dynamics by exploring their use as reaction coordinates, which can efficiently guide the sampling of a conformational free energy landscape. We have analyzed 10 diverse proteins and shown that a few ECs are sufficient to characterize complex conformational dynamics of proteins involved in folding and conformational change processes. With the rapid strides in sequencing technology, we expect that ECs could help identify reaction coordinates a priori and enhance the sampling of the slow dynamical process associated with protein folding and conformational change.

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

Small Angle Neutron Scattering (sans) Studies on "SIDE-END FIXED" and "SIDE-ON FIXED" Liquid Crystal Polymers

NASA Astrophysics Data System (ADS)

Hardouin, F.; Noirez, L.; Keller, P.; Leroux, N.; Cotton, J. P.

The following sections are included: * Introduction * Experimental * Results and discussion * Determination of the backbone conformation in the nematic and smectic A phases of "side-end fixed" L.C. polymethacrylates (PMA) or polyacrylates (PA) * Determination of the global and backbone conformation in the nematic and smectic A phases of "side-end fixed" L.C. polysiloxanes (PMS) * Determination of the backbone conformation in the unique nematic phase (without smectic A phase) or in the reentrant nematic phase (below smectic A phase) of "side-end fixed" L.C. polyacrylates (PA) * Determination of the global conformation in the nematic phase of "side-on fixed" L.C. polysiloxanes (PMS) * Determination of the global conformation in the nematic phase of "diluted side-on fixed" L.C. copolysiloxanes * Determination of the backbone conformation in the nematic phase of "side-on fixed" L.C. polyacrylates * Conclusions * References

From spinning conformal blocks to matrix Calogero-Sutherland models

NASA Astrophysics Data System (ADS)

Schomerus, Volker; Sobko, Evgeny

2018-04-01

In this paper we develop further the relation between conformal four-point blocks involving external spinning fields and Calogero-Sutherland quantum mechanics with matrix-valued potentials. To this end, the analysis of [1] is extended to arbitrary dimensions and to the case of boundary two-point functions. In particular, we construct the potential for any set of external tensor fields. Some of the resulting Schrödinger equations are mapped explicitly to the known Casimir equations for 4-dimensional seed conformal blocks. Our approach furnishes solutions of Casimir equations for external fields of arbitrary spin and dimension in terms of functions on the conformal group. This allows us to reinterpret standard operations on conformal blocks in terms of group-theoretic objects. In particular, we shall discuss the relation between the construction of spinning blocks in any dimension through differential operators acting on seed blocks and the action of left/right invariant vector fields on the conformal group.

The evolution of conformist transmission in social learning when the environment changes periodically.

PubMed

Nakahashi, Wataru

2007-08-01

Conformity is often observed in human social learning. Social learners preferentially imitate the majority or most common behavior in many situations, though the strength of conformity varies with the situation. Why has such a psychological tendency evolved? I investigate this problem by extending a standard model of social learning evolution with infinite environmental states (Feldman, M.W., Aoki, K., Kumm, J., 1996. Individual versus social learning: evolutionary analysis in a fluctuating environment. Anthropol. Sci. 104, 209-231) to include conformity bias. I mainly focus on the relationship between the strength of conformity bias that evolves and environmental stability, which is one of the most important factors in the evolution of social learning. Using the evolutionarily stable strategy (ESS) approach, I show that conformity always evolves when environmental stability and the cost of adopting a wrong behavior are small, though environmental stability and the cost of individual learning both negatively affect the strength of conformity.

Direct observation of fast protein conformational switching.

PubMed

Ishikawa, Haruto; Kwak, Kyungwon; Chung, Jean K; Kim, Seongheun; Fayer, Michael D

2008-06-24

Folded proteins can exist in multiple conformational substates. Each substate reflects a local minimum on the free-energy landscape with a distinct structure. By using ultrafast 2D-IR vibrational echo chemical-exchange spectroscopy, conformational switching between two well defined substates of a myoglobin mutant is observed on the approximately 50-ps time scale. The conformational dynamics are directly measured through the growth of cross peaks in the 2D-IR spectra of CO bound to the heme active site. The conformational switching involves motion of the distal histidine/E helix that changes the location of the imidazole side group of the histidine. The exchange between substates changes the frequency of the CO, which is detected by the time dependence of the 2D-IR vibrational echo spectrum. These results demonstrate that interconversion between protein conformational substates can occur on very fast time scales. The implications for larger structural changes that occur on much longer time scales are discussed.

Finite conformal quantum gravity and spacetime singularities

NASA Astrophysics Data System (ADS)

Modesto, Leonardo; Rachwał, Lesław

2017-12-01

We show that a class of finite quantum non-local gravitational theories is conformally invariant at classical as well as at quantum level. This is actually a range of conformal anomaly-free theories in the spontaneously broken phase of the Weyl symmetry. At classical level we show how the Weyl conformal invariance is able to tame all the spacetime singularities that plague not only Einstein gravity, but also local and weakly non-local higher derivative theories. The latter statement is proved by a singularity theorem that applies to a large class of weakly non-local theories. Therefore, we are entitled to look for a solution of the spacetime singularity puzzle in a missed symmetry of nature, namely the Weyl conformal symmetry. Following the seminal paper by Narlikar and Kembhavi, we provide an explicit construction of singularity-free black hole exact solutions in a class of conformally invariant theories.

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.

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.

Trace anomaly and invariance under transformation of units

NASA Astrophysics Data System (ADS)

Namavarian, Nadereh

2017-05-01

Paying attention to conformal invariance as the invariance under local transformations of units of measure, we take a conformal-invariant quantum field as a quantum matter theory in which one has the freedom to choose the values of units of mass, length, and time arbitrarily at each point. To be able to have this view, it is necessary that the background on which the quantum field is based be conformal invariant as well. Consequently, defining the unambiguous expectation value of the energy-momentum tensor of such a quantum field through the Wald renormalizing prescription necessitates breaking down the conformal symmetry of the background. Then, noticing the field equations suitable for describing the backreaction effect, we show that the existence of the "trace anomaly," known for indicating the brokenness of conformal symmetry in quantum field theory, can also indicate the above "gravitational" conformal symmetry brokenness.

Automated identification of functional dynamic networks from X-ray crystallography

PubMed Central

van den Bedem, Henry; Bhabha, Gira; Yang, Kun; Wright, Peter E.; Fraser, James S.

2013-01-01

Protein function often depends on the exchange between conformational substates. Allosteric ligand binding or distal mutations can stabilize specific active site conformations and consequently alter protein function. In addition to comparing independently determined X-ray crystal structures, alternative conformations observed at low levels of electron density have the potential to provide mechanistic insights into conformational dynamics. Here, we report a new multi-conformer contact network algorithm (CONTACT) that identifies networks of conformationally heterogeneous residues directly from high-resolution X-ray crystallography data. Contact networks in Escherichia coli dihydrofolate reductase (ecDHFR) predict the long-range pattern of NMR chemical shift perturbations of an allosteric mutation. A comparison of contact networks in wild type and mutant ecDHFR suggests how mutations that alter optimized networks of coordinated motions can impair catalytic function. Thus, CONTACT-guided mutagenesis will allow the structure-dynamics-function relationship to be exploited in protein engineering and design. PMID:23913260

From global to heavy-light: 5-point conformal blocks

NASA Astrophysics Data System (ADS)

Alkalaev, Konstantin; Belavin, Vladimir

2016-03-01

We consider Virasoro conformal blocks in the large central charge limit. There are different regimes depending on the behavior of the conformal dimensions. The most simple regime is reduced to the global sl(2,C) conformal blocks while the most complicated one is known as the classical conformal blocks. Recently, Fitzpatrick, Kaplan, and Walters showed that the two regimes are related through the intermediate stage of the so-called heavy-light semiclassical limit. We study this idea in the particular case of the 5-point conformal block. To find the 5-point global block we use the projector technique and the Casimir operator approach. Furthermore, we discuss the relation between the global and the heavy-light limits and construct the heavy-light block from the global block. In this way we reproduce our previous results for the 5-point perturbative classical block obtained by means of the monodromy method.

Agravity up to infinite energy

NASA Astrophysics Data System (ADS)

Salvio, Alberto; Strumia, Alessandro

2018-02-01

The self-interactions of the conformal mode of the graviton are controlled, in dimensionless gravity theories (agravity), by a coupling f_0 that is not asymptotically free. We show that, nevertheless, agravity can be a complete theory valid up to infinite energy. When f_0 grows to large values, the conformal mode of the graviton decouples from the rest of the theory and does not hit any Landau pole provided that scalars are asymptotically conformally coupled and all other couplings approach fixed points. Then agravity can flow to conformal gravity at infinite energy. We identify scenarios where the Higgs mass does not receive unnaturally large physical corrections. We also show a useful equivalence between agravity and conformal gravity plus two extra conformally coupled scalars, and we give a simpler form for the renormalization group equations of dimensionless couplings as well as of massive parameters in the presence of the most general matter sector.

A finite element-boundary integral method for conformal antenna arrays on a circular cylinder

NASA Technical Reports Server (NTRS)

Kempel, Leo C.; Volakis, John L.; Woo, Alex C.; Yu, C. Long

1992-01-01

Conformal antenna arrays offer many cost and weight advantages over conventional antenna systems. In the past, antenna designers have had to resort to expensive measurements in order to develop a conformal array design. This is due to the lack of rigorous mathematical models for conformal antenna arrays, and as a result the design of conformal arrays is primarily based on planar antenna design concepts. Recently, we have found the finite element-boundary integral method to be very successful in modeling large planar arrays of arbitrary composition in a metallic plane. Herewith we shall extend this formulation for conformal arrays on large metallic cylinders. In this we develop the mathematical formulation. In particular we discuss the finite element equations, the shape elements, and the boundary integral evaluation, and it is shown how this formulation can be applied with minimal computation and memory requirements. The implementation shall be discussed in a later report.

A finite element-boundary integral method for conformal antenna arrays on a circular cylinder

NASA Technical Reports Server (NTRS)

Kempel, Leo C.; Volakis, John L.

1992-01-01

Conformal antenna arrays offer many cost and weight advantages over conventional antenna systems. In the past, antenna designers have had to resort to expensive measurements in order to develop a conformal array design. This was due to the lack of rigorous mathematical models for conformal antenna arrays. As a result, the design of conformal arrays was primarily based on planar antenna design concepts. Recently, we have found the finite element-boundary integral method to be very successful in modeling large planar arrays of arbitrary composition in a metallic plane. We are extending this formulation to conformal arrays on large metallic cylinders. In doing so, we will develop a mathematical formulation. In particular, we discuss the finite element equations, the shape elements, and the boundary integral evaluation. It is shown how this formulation can be applied with minimal computation and memory requirements.

Mapping transiently formed and sparsely populated conformations on a complex energy landscape.

PubMed

Wang, Yong; Papaleo, Elena; Lindorff-Larsen, Kresten

2016-08-23

Determining the structures, kinetics, thermodynamics and mechanisms that underlie conformational exchange processes in proteins remains extremely difficult. Only in favourable cases is it possible to provide atomic-level descriptions of sparsely populated and transiently formed alternative conformations. Here we benchmark the ability of enhanced-sampling molecular dynamics simulations to determine the free energy landscape of the L99A cavity mutant of T4 lysozyme. We find that the simulations capture key properties previously measured by NMR relaxation dispersion methods including the structure of a minor conformation, the kinetics and thermodynamics of conformational exchange, and the effect of mutations. We discover a new tunnel that involves the transient exposure towards the solvent of an internal cavity, and show it to be relevant for ligand escape. Together, our results provide a comprehensive view of the structural landscape of a protein, and point forward to studies of conformational exchange in systems that are less characterized experimentally.

Geometric decomposition of the conformation tensor in viscoelastic turbulence

NASA Astrophysics Data System (ADS)

Hameduddin, Ismail; Meneveau, Charles; Zaki, Tamer A.; Gayme, Dennice F.

2018-05-01

This work introduces a mathematical approach to analysing the polymer dynamics in turbulent viscoelastic flows that uses a new geometric decomposition of the conformation tensor, along with associated scalar measures of the polymer fluctuations. The approach circumvents an inherent difficulty in traditional Reynolds decompositions of the conformation tensor: the fluctuating tensor fields are not positive-definite and so do not retain the physical meaning of the tensor. The geometric decomposition of the conformation tensor yields both mean and fluctuating tensor fields that are positive-definite. The fluctuating tensor in the present decomposition has a clear physical interpretation as a polymer deformation relative to the mean configuration. Scalar measures of this fluctuating conformation tensor are developed based on the non-Euclidean geometry of the set of positive-definite tensors. Drag-reduced viscoelastic turbulent channel flow is then used an example case study. The conformation tensor field, obtained using direct numerical simulations, is analysed using the proposed framework.

Probing Selection Mechanism of the Most Favorable Conformation of a Dipeptide in Chaotropic and Kosmotropic Solution.

PubMed

Jas, Gouri S; Middaugh, C Russell; Kuczera, Krzysztof

2016-07-21

Chaotropes like urea and guanidinium chloride (GdmCl) tend to destabilize, and kosmotropes like proline tend to stabilize folded structures of peptides and proteins. Here, we combine fluorescence anisotropy decay measurements and molecular dynamics simulations to gain a microscopic understanding of the molecular mechanism for shifting conformational preferences in aqueous, GdmCl, urea, and proline solutions of a simple model dipeptide, N-acetyl-tryptophan-amide (NATA). Measured anisotropy decay of NATA as a function of temperature, pH, and cosolvent concentrations showed reorientations moderately slower in GdmCl and urea and substantially slower in proline compared to those of aqueous environment. A small change in pH significantly slows orientation time in water and GdmCl and less markedly in urea. Computationally, we use molecular dynamics with dihedral restraints to separately analyze the motions and interactions of the representative NATA conformers in the four different solvent environments. This novel analysis provides a dissection of the observed overall diffusion rates into contributions from individual dipeptide conformations. The variation of rotational diffusion rates with conformation are quite large. Population-weighted averaging or using properties of the major cluster reproduces the dynamical features of the full unrestrained dynamics. Additionally, we correlate the observable diffusion rates with microscopic features of conformer size, shape, and solvation. This analysis uncovered underlying differences in detailed atomistic behavior of the three cosolvents-urea, GdmCl, and proline. For both urea and the pure water system we find good agreement with hydrodynamic theory, with diffusion rates primarily correlated with conformer size and shape. In contrast, for GdmCl and proline solutions, the variation in conformer diffusion rates was mostly determined by specific interactions with the cosolvents. We also find preferences for different molecular shapes by the three cosolvents, with increased preferential solvation of smaller and more spherical conformers by urea and larger and more elongated conformers by GdmCl and proline. Additionally, our results provide a basis for a simple approximate model of the effects of pH lowering on dipeptide conformational equilibria. The translational diffusion rates of NATA are less sensitive to conformations, but variation with solvation strength is similar to rotational diffusion. Our results, combining experiment and simulation, show that we can identify the individual peptide conformers with definite microscopic properties of shape, size, and solvation, that are responsible for producing physical observables, such as translational and orientational diffusion in the complex solvent environments of denaturants and osmolytes.

Influence of OH⋯N and NH⋯O inter- and intramolecular hydrogen bonds in the conformational equilibrium of some 1,3-disubstituted cyclohexanes through NMR spectroscopy and theoretical calculations

NASA Astrophysics Data System (ADS)

de Oliveira, Paulo R.; Viesser, Renan V.; Guerrero, Palimécio G., Jr.; Rittner, Roberto

2011-05-01

The analysis of concentration effects in the 1H NMR data of cis-3-aminocyclohexanol ( ACOL) showed that its diequatorial conformer changes from 60% at 0.01 mol L -1 to 70% at 0.40 mol L -1 in acetone-d 6. A similar increase was also observed for the diequatorial conformer of cis-3-N-methylaminocyclohexanol ( MCOL), from 32% (CDCl 3 0.01 mol L -1) to 55% (CDCl 3 0.40 mol L -1). The increase in solvent basicity leads to a large stabilization effect for the diequatorial conformer of both compounds too. For ACOL, it changes from 47% (Δ Geqeq- axax = 0.06 kcal mol -1) in CCl 4 to 93% (Δ Geqeq- axax = -1.53 kcal mol -1) in DMSO, while for MCOL it goes from 7% (Δ Geqeq- axax = 1.54 kcal mol -1) in CCl 4 to 82% (Δ Geqeq- axax = -0.88 kcal mol -1) in pyridine-d 6. These results indicate that the intr amolecular hydrogen bonds (IAHB) OH⋯N and NH⋯O stabilize the diaxial conformers of these compounds in a non-polar solvent. For cis-3-amino-1-methoxycyclohexane ( ACNE) and cis-3-N-methylamino-1-methoxy-cyclohexane ( MCNE) no changes were observed in equilibrium with the variation of solvent polarity. These results indicate for the first time that the IAHB NH⋯O is not strong enough to stabilize the diaxial conformer of these compounds and that the conformation equilibria of the cis isomers of compounds ACOL and MCOL are influenced only by the IAHB OH⋯N. Moreover, the presence of a secondary amino group (93% of diaxial conformer in CCl 4) leads to an IAHB OH⋯N stronger than in primary and tertiary amino-derivatives (53 and 54% of diaxial conformer, respectively) for 1,3-disubstituted cyclohexanes. Values obtained from the theoretical data through the B3LYP functional are in agreement with the experimental results and indicate that the IAHB strength that influences the conformational equilibrium of these compounds is the IAHB OH⋯N. Thus, the IAHB NH⋯O do not stabilize the diaxial conformer of the cis isomer of compounds ACNE and MCNE showing that the diequatorial conformer will always be more stable than the diaxial conformer, independent of concentration or solvent.

Charge neutralization in the active site of the catalytic trimer of aspartate transcarbamoylase promotes diverse structural changes.

PubMed

Endrizzi, James A; Beernink, Peter T

2017-11-01

A classical model for allosteric regulation of enzyme activity posits an equilibrium between inactive and active conformations. An alternative view is that allosteric activation is achieved by increasing the potential for conformational changes that are essential for catalysis. In the present study, substitution of a basic residue in the active site of the catalytic (C) trimer of aspartate transcarbamoylase with a non-polar residue results in large interdomain hinge changes in the three chains of the trimer. One conformation is more open than the chains in both the wild-type C trimer and the catalytic chains in the holoenzyme, the second is closed similar to the bisubstrate-analog bound conformation and the third hinge angle is intermediate to the other two. The active-site 240s loop conformation is very different between the most open and closed chains, and is disordered in the third chain, as in the holoenzyme. We hypothesize that binding of anionic substrates may promote similar structural changes. Further, the ability of the three catalytic chains in the trimer to access the open and closed active-site conformations simultaneously suggests a cyclic catalytic mechanism, in which at least one of the chains is in an open conformation suitable for substrate binding whereas another chain is closed for catalytic turnover. Based on the many conformations observed for the chains in the isolated catalytic trimer to date, we propose that allosteric activation of the holoenzyme occurs by release of quaternary constraint into an ensemble of active-site conformations. © 2017 The Protein Society.

Characterizing Solution Surface Loop Conformational Flexibility of the GM2 Activator Protein

PubMed Central

2015-01-01

GM2AP has a β-cup topology with numerous X-ray structures showing multiple conformations for some of the surface loops, revealing conformational flexibility that may be related to function, where function is defined as either membrane binding associated with ligand binding and extraction or interaction with other proteins. Here, site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy and molecular dynamic (MD) simulations are used to characterize the mobility and conformational flexibility of various structural regions of GM2AP. A series of 10 single cysteine amino acid substitutions were generated, and the constructs were chemically modified with the methanethiosulfonate spin label. Continuous wave (CW) EPR line shapes were obtained and subsequently simulated using the microscopic order macroscopic disorder (MOMD) program. Line shapes for sites that have multiple conformations in the X-ray structures required two spectral components, whereas spectra of the remaining sites were adequately fit with single-component parameters. For spin labeled sites L126C and I66C, spectra were acquired as a function of temperature, and simulations provided for the determination of thermodynamic parameters associated with conformational change. Binding to GM2 ligand did not alter the conformational flexibility of the loops, as evaluated by EPR and NMR spectroscopies. These results confirm that the conformational flexibility observed in the surface loops of GM2AP crystals is present in solution and that the exchange is slow on the EPR time scale (>ns). Furthermore, MD simulation results are presented and agree well with the conformational heterogeneity revealed by SDSL. PMID:25127419

Characterizing highly dynamic conformational states: The transcription bubble in RNAP-promoter open complex as an example

NASA Astrophysics Data System (ADS)

Lerner, Eitan; Ingargiola, Antonino; Weiss, Shimon

2018-03-01

Bio-macromolecules carry out complicated functions through structural changes. To understand their mechanism of action, the structure of each step has to be characterized. While classical structural biology techniques allow the characterization of a few "structural snapshots" along the enzymatic cycle (usually of stable conformations), they do not cover all (and often fast interconverting) structures in the ensemble, where each may play an important functional role. Recently, several groups have demonstrated that structures of different conformations in solution could be solved by measuring multiple distances between different pairs of residues using single-molecule Förster resonance energy transfer (smFRET) and using them as constrains for hybrid/integrative structural modeling. However, this approach is limited in cases where the conformational dynamics is faster than the technique's temporal resolution. In this study, we combine existing tools that elucidate sub-millisecond conformational dynamics together with hybrid/integrative structural modeling to study the conformational states of the transcription bubble in the bacterial RNA polymerase-promoter open complex (RPo). We measured microsecond alternating laser excitation-smFRET of differently labeled lacCONS promoter dsDNA constructs. We used a combination of burst variance analysis, photon-by-photon hidden Markov modeling, and the FRET-restrained positioning and screening approach to identify two conformational states for RPo. The experimentally derived distances of one conformational state match the known crystal structure of bacterial RPo. The experimentally derived distances of the other conformational state have characteristics of a scrunched RPo. These findings support the hypothesis that sub-millisecond dynamics in the transcription bubble are responsible for transcription start site selection.

Molecular Dynamics Simulations of the Human Glucose Transporter GLUT1

PubMed Central

Park, Min-Sun

2015-01-01

Glucose transporters (GLUTs) provide a pathway for glucose transport across membranes. Human GLUTs are implicated in devastating diseases such as heart disease, hyper- and hypo-glycemia, type 2 diabetes and caner. The human GLUT1 has been recently crystalized in the inward-facing open conformation. However, there is no other structural information for other conformations. The X-ray structures of E. coli Xylose permease (XylE), a glucose transporter homolog, are available in multiple conformations with and without the substrates D-xylose and D-glucose. XylE has high sequence homology to human GLUT1 and key residues in the sugar-binding pocket are conserved. Here we construct a homology model for human GLUT1 based on the available XylE crystal structure in the partially occluded outward-facing conformation. A long unbiased all atom molecular dynamics simulation starting from the model can capture a new fully opened outward-facing conformation. Our investigation of molecular interactions at the interface between the transmembrane (TM) domains and the intracellular helices (ICH) domain in the outward- and inward-facing conformation supports that the ICH domain likely stabilizes the outward-facing conformation in GLUT1. Furthermore, inducing a conformational transition, our simulations manifest a global asymmetric rocker switch motion and detailed molecular interactions between the substrate and residues through the water-filled selective pore along a pathway from the extracellular to the intracellular side. The results presented here are consistent with previously published biochemical, mutagenesis and functional studies. Together, this study shed light on the structure and functional relationships of GLUT1 in multiple conformational states. PMID:25919356

Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin

NASA Astrophysics Data System (ADS)

Shute, Richard E.; Jackson, David E.; Bycroft, Barrie W.

1989-06-01

The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic β-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3 R-compounds possess notable Gram-positive antibacterial activity and potent β-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain β-lactamase inhibitory activity. Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3 R, and 3 S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3 R and the 3 S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains of both the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3 R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, `bioactive' conformer for the classical β-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S2-subsite, specific for the side-chain aromatic moiety, and the 3 α-carboxylate functionality is presented.

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.

Irreversibility and higher-spin conformal field theory

NASA Astrophysics Data System (ADS)

Anselmi, Damiano

2000-08-01

I discuss the properties of the central charges c and a for higher-derivative and higher-spin theories (spin 2 included). Ordinary gravity does not admit a straightforward identification of c and a in the trace anomaly, because it is not conformal. On the other hand, higher-derivative theories can be conformal, but have negative c and a. A third possibility is to consider higher-spin conformal field theories. They are not unitary, but have a variety of interesting properties. Bosonic conformal tensors have a positive-definite action, equal to the square of a field strength, and a higher-derivative gauge invariance. There exists a conserved spin-2 current (not the canonical stress tensor) defining positive central charges c and a. I calculate the values of c and a and study the operator-product structure. Higher-spin conformal spinors have no gauge invariance, admit a standard definition of c and a and can be coupled to Abelian and non-Abelian gauge fields in a renormalizable way. At the quantum level, they contribute to the one-loop beta function with the same sign as ordinary matter, admit a conformal window and non-trivial interacting fixed points. There are composite operators of high spin and low dimension, which violate the Ferrara-Gatto-Grillo theorem. Finally, other theories, such as conformal antisymmetric tensors, exhibit more severe internal problems. This research is motivated by the idea that fundamental quantum field theories should be renormalization-group (RG) interpolations between ultraviolet and infrared conformal fixed points, and quantum irreversibility should be a general principle of nature.

Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution.

PubMed

Haensele, Elke; Mele, Nawel; Miljak, Marija; Read, Christopher M; Whitley, David C; Banting, Lee; Delépée, Carla; Sopkova-de Oliveira Santos, Jana; Lepailleur, Alban; Bureau, Ronan; Essex, Jonathan W; Clark, Timothy

2017-02-27

Conformation and dynamics of the vasoconstrictive peptides human urotensin II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring conformations, open and folded, with rapidly interchanging subtypes. The open states are characterized by turns of various types centered at K 8 Y 9 or F 6 W 7 predominantly with no or only sparsely populated transannular hydrogen bonds. The folded conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F 6 W 7 K 8 or W 7 K 8 Y 9 . Some of these conformations have not been characterized previously. The equilibrium populations that are experimentally difficult to access were estimated by replica-exchange MD simulations and validated by comparison of experimental NMR data with chemical shifts calculated with density-functional theory. UII exhibits approximately 72% open:28% folded conformations in aqueous solution. URP shows very similar ring conformations as UII but differs in an open:folded equilibrium shifted further toward open conformations (86:14) possibly arising from the absence of folded N-terminal tail-ring interaction. The results suggest that the different biological effects of UII and URP are not caused by differences in ring conformations but rather by different interactions with UTR.

Conformational diversity analysis reveals three functional mechanisms in proteins

PubMed Central

Fornasari, María Silvina

2017-01-01

Protein motions are a key feature to understand biological function. Recently, a large-scale analysis of protein conformational diversity showed a positively skewed distribution with a peak at 0.5 Å C-alpha root-mean-square-deviation (RMSD). To understand this distribution in terms of structure-function relationships, we studied a well curated and large dataset of ~5,000 proteins with experimentally determined conformational diversity. We searched for global behaviour patterns studying how structure-based features change among the available conformer population for each protein. This procedure allowed us to describe the RMSD distribution in terms of three main protein classes sharing given properties. The largest of these protein subsets (~60%), which we call “rigid” (average RMSD = 0.83 Å), has no disordered regions, shows low conformational diversity, the largest tunnels and smaller and buried cavities. The two additional subsets contain disordered regions, but with differential sequence composition and behaviour. Partially disordered proteins have on average 67% of their conformers with disordered regions, average RMSD = 1.1 Å, the highest number of hinges and the longest disordered regions. In contrast, malleable proteins have on average only 25% of disordered conformers and average RMSD = 1.3 Å, flexible cavities affected in size by the presence of disordered regions and show the highest diversity of cognate ligands. Proteins in each set are mostly non-homologous to each other, share no given fold class, nor functional similarity but do share features derived from their conformer population. These shared features could represent conformational mechanisms related with biological functions. PMID:28192432

Cytochrome c conformations resolved by the photon counting histogram: Watching the alkaline transition with single-molecule sensitivity

PubMed Central

Perroud, Thomas D.; Bokoch, Michael P.; Zare, Richard N.

2005-01-01

We apply the photon counting histogram (PCH) model, a fluorescence technique with single-molecule sensitivity, to study pH-induced conformational changes of cytochrome c. PCH is able to distinguish different protein conformations based on the brightness of a fluorophore sensitive to its local environment. We label cytochrome c through its single free cysteine with tetramethylrhodamine-5-maleimide (TMR), a fluorophore with specific brightnesses that we associate with specific protein conformations. Ensemble measurements demonstrate two different fluorescence responses with increasing pH: (i) a decrease in fluorescence intensity caused by the alkaline transition of cytochrome c (pH 7.0–9.5), and (ii) an increase in intensity when the protein unfolds (pH 9.5–10.8). The magnitudes of these two responses depend strongly on the molar ratio of TMR used to label cytochrome c. Using PCH we determine that this effect arises from the proportion of a nonfunctional conformation in the sample, which can be differentiated from the functional conformation. We further determine the causes of each ensemble fluorescence response: (i) during the alkaline transition, the fluorophore enters a dark state and discrete conformations are observed, and (ii) as cytochrome c unfolds, the fluorophore incrementally brightens, but discrete conformations are no longer resolved. Moreover, we also show that functional TMR-cytochrome c undergoes a response of identical magnitude regardless of the proportion of nonfunctional protein in the sample. As expected for a technique with single-molecule sensitivity, we demonstrate that PCH can directly observe the most relevant conformation, unlike ensemble fluorometry. PMID:16314563

The geometry of organophosphonates: Fourier-transform microwave spectroscopy and ab initio study of diethyl methylphosphonate, diethyl ethylphosphonate, and diisopropyl methylphosphonate

NASA Astrophysics Data System (ADS)

DaBell, Ryan S.; Suenram, Richard D.; Lavrich, Richard J.; Lochner, J. Michael; Ellzy, Michael W.; Sumpter, Kenneth; Jensen, James O.; Samuels, Alan C.

2004-12-01

The rotational spectra of diethyl methylphosphonate (DEMP), diethyl ethylphosphonate (DEEP), and diisopropyl methylphosphonate (DIMP) in supersonic expansions have been acquired using Fourier-transform microwave spectroscopy. Spectroscopic constants have been determined for five distinct conformers of the three molecules. Experimental data have been compared to ab initio calculations performed for each species. For both DEMP and DEEP, the calculations indicate the presence of several low-energy conformers (i.e., ⩽˜400 cm -1 above the ground state) may be present at room temperature (300 K) for both DEMP and DEEP. When entrained in a supersonic expansion, the rotational temperatures of the samples are much colder (˜2 K); nonetheless, spectra from three conformers of DEEP are still observed experimentally, whereas only one conformer of DEMP is observed. In contrast, only a single low-energy conformer of DIMP is predicted by theory, and is present in the molecular beam. The relative abundance of low-energy conformers of DEMP and DEEP is attributed to the flexibility of the ethoxy groups within each molecule. The presence of multiple DEEP conformers in the supersonic beam indicates a more complex potential energy surface for this molecule that is directly related to conformational shifts of the PCH 2CH 3 group. Conversely, the absence of low-energy conformers of DIMP is attributed to steric hindrance between isopropoxy groups in the molecule. The internal rotation barrier for the PCH 3 group in DEMP and DIMP is compared to that found in DMMP and several phosphonate-based chemical weapon agents.

Galactic conformity measured in semi-analytic models

NASA Astrophysics Data System (ADS)

Lacerna, I.; Contreras, S.; González, R. E.; Padilla, N.; Gonzalez-Perez, V.

2018-03-01

We study the correlation between the specific star formation rate of central galaxies and neighbour galaxies, also known as `galactic conformity', out to 20 h^{-1} {Mpc} using three semi-analytic models (SAMs, one from L-GALAXIES and other two from GALFORM). The aim is to establish whether SAMs are able to show galactic conformity using different models and selection criteria. In all the models, when the selection of primary galaxies is based on an isolation criterion in real space, the mean fraction of quenched (Q) galaxies around Q primary galaxies is higher than that around star-forming primary galaxies of the same stellar mass. The overall signal of conformity decreases when we remove satellites selected as primary galaxies, but the effect is much stronger in GALFORM models compared with the L-GALAXIES model. We find this difference is partially explained by the fact that in GALFORM once a galaxy becomes a satellite remains as such, whereas satellites can become centrals at a later time in L-GALAXIES. The signal of conformity decreases down to 60 per cent in the L-GALAXIES model after removing central galaxies that were ejected from their host halo in the past. Galactic conformity is also influenced by primary galaxies at fixed stellar mass that reside in dark matter haloes of different masses. Finally, we explore a proxy of conformity between distinct haloes. In this case, the conformity is weak beyond ˜3 h^{-1} {Mpc} (<3 per cent in L-GALAXIES, <1-2 per cent in GALFORM models). Therefore, it seems difficult that conformity is directly related with a long-range effect.

How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures?

NASA Astrophysics Data System (ADS)

Chen, Shu-Hua; Russell, David H.

2015-09-01

Here, we critically evaluate the effects of changes in the ion internal energy (Eint) on ion-neutral collision cross sections (CCS) of ions of two structurally diverse proteins, specifically the [M + 6H]6+ ion of ubiquitin (ubq6+), the [M + 5H]5+ ion of the intrinsically disordered protein (IDP) apo-metallothionein-2A (MT), and its partially- and fully-metalated isoform, the [CdiMT]5+ ion. The ion-neutral CCS for ions formed by "native-state" ESI show a strong dependence on Eint. Collisional activation is used to increase Eint prior to the ions entering and within the traveling wave (TW) ion mobility analyzer. Comparisons of experimental CCSs with those generated by molecular dynamics (MD) simulation for solution-phase ions and solvent-free ions as a function of temperature provide new insights about conformational preferences and retention of solution conformations. The Eint-dependent CCSs, which reveal increased conformational diversity of the ion population, are discussed in terms of folding/unfolding of solvent-free ions. For example, ubiquitin ions that have low internal energies retain native-like conformations, whereas ions that are heated by collisional activation possess higher internal energies and yield a broader range of CCS owing to increased conformational diversity due to losses of secondary and tertiary structures. In contrast, the CCS profile for the IDP apoMT is consistent with kinetic trapping of an ion population composed of a wide range of conformers, and as the Eint is increased, these structurally labile conformers unfold to an elongated conformation.

Sparse networks of directly coupled, polymorphic, and functional side chains in allosteric proteins.

PubMed

Soltan Ghoraie, Laleh; Burkowski, Forbes; Zhu, Mu

2015-03-01

Recent studies have highlighted the role of coupled side-chain fluctuations alone in the allosteric behavior of proteins. Moreover, examination of X-ray crystallography data has recently revealed new information about the prevalence of alternate side-chain conformations (conformational polymorphism), and attempts have been made to uncover the hidden alternate conformations from X-ray data. Hence, new computational approaches are required that consider the polymorphic nature of the side chains, and incorporate the effects of this phenomenon in the study of information transmission and functional interactions of residues in a molecule. These studies can provide a more accurate understanding of the allosteric behavior. In this article, we first present a novel approach to generate an ensemble of conformations and an efficient computational method to extract direct couplings of side chains in allosteric proteins, and provide sparse network representations of the couplings. We take the side-chain conformational polymorphism into account, and show that by studying the intrinsic dynamics of an inactive structure, we are able to construct a network of functionally crucial residues. Second, we show that the proposed method is capable of providing a magnified view of the coupled and conformationally polymorphic residues. This model reveals couplings between the alternate conformations of a coupled residue pair. To the best of our knowledge, this is the first computational method for extracting networks of side chains' alternate conformations. Such networks help in providing a detailed image of side-chain dynamics in functionally important and conformationally polymorphic sites, such as binding and/or allosteric sites. © 2014 Wiley Periodicals, Inc.

Probing messenger RNA conformational heterogeneity using single-molecule fluorescence anisotropy

NASA Astrophysics Data System (ADS)

Sinha, Deepak; Sastry, Srikanth; Shivashankar, G. V.

2006-03-01

In this letter we describe a method to probe biomolecular conformations and their dynamics at the single molecule level. We show, using fluorescence anisotropy based methods, that the hydrodynamic volume of biomolecules captures the intrinsic heterogeneity within a population. Population distributions of conformations and their dynamics are studied by making anisotropy measurements on one molecule at a time within a confocal volume. The mean anisotropy of mRNA is lowered on addition of salt while the spread remains the same. The intrinsic heterogeneity is revealed when conformational transitions are frozen, resulting in a drastic increase in the spread of the anisotropy. These studies reveal that mRNA samples a broad range of conformations.

Exploration of conformational spaces of high-mannose-type oligosaccharides by an NMR-validated simulation.

PubMed

Yamaguchi, Takumi; Sakae, Yoshitake; Zhang, Ying; Yamamoto, Sayoko; Okamoto, Yuko; Kato, Koichi

2014-10-06

Exploration of the conformational spaces of flexible biomacromolecules is essential for quantitatively understanding the energetics of their molecular recognition processes. We employed stable isotope- and lanthanide-assisted NMR approaches in conjunction with replica-exchange molecular dynamics (REMD) simulations to obtain atomic descriptions of the conformational dynamics of high-mannose-type oligosaccharides, which harbor intracellular glycoprotein-fate determinants in their triantennary structures. The experimentally validated REMD simulation provided quantitative views of the dynamic conformational ensembles of the complicated, branched oligosaccharides, and indicated significant expansion of the conformational space upon removal of a terminal mannose residue during the functional glycan-processing pathway. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The calculations of small molecular conformation energy differences by density functional method

NASA Astrophysics Data System (ADS)

Topol, I. A.; Burt, S. K.

1993-03-01

The differences in the conformational energies for the gauche (G) and trans(T) conformers of 1,2-difluoroethane and for myo-and scyllo-conformer of inositol have been calculated by local density functional method (LDF approximation) with geometry optimization using different sets of calculation parameters. It is shown that in the contrast to Hartree—Fock methods, density functional calculations reproduce the correct sign and value of the gauche effect for 1,2-difluoroethane and energy difference for both conformers of inositol. The results of normal vibrational analysis for1,2-difluoroethane showed that harmonic frequencies calculated in LDF approximation agree with experimental data with the accuracy typical for scaled large basis set Hartree—Fock calculations.

Lattice Simulations and Infrared Conformality

DOE PAGES

Appelquist, Thomas; Fleming, George T.; Lin, Meifeng; ...

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

The Structure of the Elusive Simplest Dipeptide Gly-Gly.

PubMed

Cabezas, Carlos; Varela, Marcelino; Alonso, José L

2017-06-01

Among the hundreds of peptide compounds for which conformations have been determined by using different spectroscopic techniques, the structure of the simplest dipeptide glycylglycine (Gly-Gly) is conspicuously absent. Herein, for the first time, solid samples of Gly-Gly have been vaporized by laser ablation and three different structures have been revealed in a supersonic expansion by Fourier transform microwave spectroscopy. The intramolecular hydrogen bonding interactions that stabilize the observed forms have been established based on the 14 N nuclear quadrupole hyperfine structure. We have illustrated how conformer interconversion distorts the equilibrium conformational distribution, giving rise to missing conformers in the conformational landscape. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Incompleteness of Bluetooth protocol conformance test cases

NASA Astrophysics Data System (ADS)

Wu, Peng; Gao, Qiang

2001-10-01

This paper describes a formal method to verify the completeness of conformance testing, in which not only Implementation Under Test (IUT) is formalized in SDL, but also conformance tester is described in SDL so that conformance testing can be performed in simulator provided with CASE tool. The protocol set considered is Bluetooth, an open wireless communication technology. Our research results show that Bluetooth conformance test specification is not complete in that it has only limited coverage and many important capabilities defined in Bluetooth core specification are not tested. We also give a detail report on the missing test cases against Bluetooth core specification, and provide a guide on further test case generation in the future.

NLO evolution of color dipoles in N=4 SYM

DOE PAGES

Chirilli, Giovanni A.; Balitsky, Ian

2009-07-04

Here, high-energy behavior of amplitudes in a gauge theory can be reformulated in terms of the evolution of Wilson-line operators. In the leading logarithmic approximation it is given by the conformally invariant BK equation for the evolution of color dipoles. In QCD, the next-to-leading order BK equation has both conformal and non-conformal parts, the latter providing the running of the coupling constant. To separate the conformally invariant effects from the running-coupling effects, we calculate the NLO evolution of the color dipoles in the conformalmore » $${\\cal N}$$=4 SYM theory. We define the "composite dipole operator" with the rapidity cutoff preserving conformal invariance.« less

Conformal symmetries of Einstein's field equations and initial data

NASA Astrophysics Data System (ADS)

Sharma, Ramesh

2005-04-01

This paper examines the initial data for the evolution of the space-time solution of Einstein's equations admitting a conformal symmetry. Under certain conditions on the extrinsic curvature of the initial complete spacelike hypersurface and sectional curvature of the space-time with respect to sections containing the normal vector field, we have shown that the initial hypersurface is conformally diffeomorphic to a sphere or a flat space or a hyperbolic space or the product of an open real interval and a complete 2-manifold. It has been further shown that if the initial hypersurface is compact, then it is conformally diffeomorphic to a sphere. Finally, the conformal symmetries of a generalized Robertson-Walker space-time have been described.

A computational study of open-chain epothilone analogue

NASA Astrophysics Data System (ADS)

Kamel, Karol; Rusinska-Roszak, Danuta

Molecular mechanics (MM/Ambers) calculations were applied to probe the conformational profile of open-chain epothilone analogue [Org Lett 2006, 8, 685], cytotoxic against some cell lines. Geometries of the most stable conformers were optimized at DFT level using the B3LYP functional and then compared to known both experimental and virtual conformers of epothilone. One of the most stable structures is III (1.47 kcal/mol above global minimum) which represents high similarity to the appropriate fragment of the Taylor's model of epothilone A, but two other conformers: XIV and XX, although they have almost the same conformation as the mother structure, are very unstable (6.7 and 12.4 kcal/mol above the global minimum).0

Cyclo-biphenalenyl biradicaloid molecular materials: conformation, rearrangement, magnetism, and thermochromism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Jingsong; Sumpter, Bobby G; Meunier, Vincent

2010-01-01

Cyclo-biphenalenyl biradicaloid molecular materials with chair- and boat-conformations are studied by restricted and broken-symmetry DFT using the M06 family of meta-GGA functionals. The global minima of these molecular materials are magnetically silent due to the sigma-bond connecting the two phenalenyls, while the sigma-bond may undergo low-barrier sigmatropic rearrangements via pi-pi bonded paramagnetic intermediates. The validation of theory is performed for the chair-conformation by comparing the sigma-bonded structures and the rearrangement barriers with experimental data. The boat-conformation is then studied using the validated functional. The electronic spectra of both chair- and boat-conformations are calculated and their applications in thermochromism are discussed.

Conformation-sensitive infrared bands of uridine-5'-monophosphate

NASA Astrophysics Data System (ADS)

Carmona, P.; Molina, M.; Escobar, R.

1991-03-01

Infrared spectra are presented for six compounds containing ribose residues with various conformations. The assignments are based chiefly on comparison of the vibrational data observed for these compounds with those for uracil and D-ribose-5-phosphate and on a previous normal coordinate calculation. A spectral feature in the 1300-1260 cm -1 region seems to be sensitive to the ribofuranose conformation, and the usefulness of these structure-spectrum correlations in the conformation studies of polynucleotides is also discussed.

Toward a general mixed quantum/classical method for the calculation of the vibronic ECD of a flexible dye molecule with different stable conformers: Revisiting the case of 2,2,2-trifluoro-anthrylethanol.

PubMed

Cerezo, Javier; Aranda, Daniel; Avila Ferrer, Francisco J; Prampolini, Giacomo; Mazzeo, Giuseppe; Longhi, Giovanna; Abbate, Sergio; Santoro, Fabrizio

2018-06-01

We extend a recently proposed mixed quantum/classical method for computing the vibronic electronic circular dichroism (ECD) spectrum of molecules with different conformers, to cases where more than one hindered rotation is present. The method generalizes the standard procedure, based on the simple Boltzmann average of the vibronic spectra of the stable conformers, and includes the contribution of structures that sample all the accessible conformational space. It is applied to the simulation of the ECD spectrum of (S)-2,2,2-trifluoroanthrylethanol, a molecule with easily interconvertible conformers, whose spectrum exhibits a pattern of alternating positive and negative vibronic peaks. Results are in very good agreement with experiment and show that spectra averaged over all the sampled conformational space can deviate significantly from the simple average of the contributions of the stable conformers. The present mixed quantum/classical method is able to capture the effect of the nonlinear dependence of the rotatory strength on the molecular structure and of the anharmonic couplings among the modes responsible for molecular flexibility. Despite its computational cost, the procedure is still affordable and promises to be useful in all cases where the ECD shape arises from a subtle balance between vibronic effects and conformational variety. © 2018 Wiley Periodicals, Inc.

Effect of the Crystal Environment on Side-Chain Conformational Dynamics in Cyanovirin-N Investigated through Crystal and Solution Molecular Dynamics Simulations

PubMed Central

Ahlstrom, Logan S.; Vorontsov, Ivan I.; Shi, Jun; Miyashita, Osamu

2017-01-01

Side chains in protein crystal structures are essential for understanding biochemical processes such as catalysis and molecular recognition. However, crystal packing could influence side-chain conformation and dynamics, thus complicating functional interpretations of available experimental structures. Here we investigate the effect of crystal packing on side-chain conformational dynamics with crystal and solution molecular dynamics simulations using Cyanovirin-N as a model system. Side-chain ensembles for solvent-exposed residues obtained from simulation largely reflect the conformations observed in the X-ray structure. This agreement is most striking for crystal-contacting residues during crystal simulation. Given the high level of correspondence between our simulations and the X-ray data, we compare side-chain ensembles in solution and crystal simulations. We observe large decreases in conformational entropy in the crystal for several long, polar and contacting residues on the protein surface. Such cases agree well with the average loss in conformational entropy per residue upon protein folding and are accompanied by a change in side-chain conformation. This finding supports the application of surface engineering to facilitate crystallization. Our simulation-based approach demonstrated here with Cyanovirin-N establishes a framework for quantitatively comparing side-chain ensembles in solution and in the crystal across a larger set of proteins to elucidate the effect of the crystal environment on protein conformations. PMID:28107510

NMR Mapping of Protein Conformational Landscapes using Coordinated Behavior of Chemical Shifts upon Ligand Binding

PubMed Central

Cembran, Alessandro; Kim, Jonggul; Gao, Jiali; Veglia, Gianluigi

2014-01-01

Proteins exist as an ensemble of conformers that are distributed on free energy landscapes resembling folding funnels. While the most stable conformers populate low energy basins, protein function is often carried out through low-populated conformational states that occupy high energy basins. Ligand binding shifts the populations of these states, changing the distribution of these conformers. Understanding how the equilibrium among the states is altered upon ligand binding, interaction with other binding partners, and/or mutations and post-translational modifications is of critical importance for explaining allosteric signaling in proteins. Here, we propose a statistical analysis of the chemical shifts (CONCISE, COordiNated ChemIcal Shifts bEhavior) for the interpretation of protein conformational equilibria following linear trajectories of NMR chemical shifts. CONCISE enables one to quantitatively measure the population shifts associated with ligand titrations and estimate the degree of collectiveness of the protein residues’ response to ligand binding, giving a concise view of the structural transitions. The combination of CONCISE with thermocalorimetric and kinetic data allows one to depict a protein’s approximate conformational energy landscape. We tested this method with the catalytic subunit of cAMP-dependent protein kinase A, a ubiquitous enzyme that undergoes conformational transitions upon both nucleotide and pseudo-substrate binding. When complemented with chemical shift covariance analysis (CHESCA), this new method offers both collective response and residue-specific correlations for ligand binding to proteins. PMID:24604024

Steric interactions determine side-chain conformations in protein cores.

PubMed

Caballero, D; Virrueta, A; O'Hern, C S; Regan, L

2016-09-01

We investigate the role of steric interactions in defining side-chain conformations in protein cores. Previously, we explored the strengths and limitations of hard-sphere dipeptide models in defining sterically allowed side-chain conformations and recapitulating key features of the side-chain dihedral angle distributions observed in high-resolution protein structures. Here, we show that modeling residues in the context of a particular protein environment, with both intra- and inter-residue steric interactions, is sufficient to specify which of the allowed side-chain conformations is adopted. This model predicts 97% of the side-chain conformations of Leu, Ile, Val, Phe, Tyr, Trp and Thr core residues to within 20°. Although the hard-sphere dipeptide model predicts the observed side-chain dihedral angle distributions for both Thr and Ser, the model including the protein environment predicts side-chain conformations to within 20° for only 60% of core Ser residues. Thus, this approach can identify the amino acids for which hard-sphere interactions alone are sufficient and those for which additional interactions are necessary to accurately predict side-chain conformations in protein cores. We also show that our approach can predict alternate side-chain conformations of core residues, which are supported by the observed electron density. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Histone H3 Tails Containing Dimethylated Lysine and Adjacent Phosphorylated Serine Modifications Adopt a Specific Conformation during Mitosis and Meiosis▿ †

PubMed Central

Eberlin, Adrien; Grauffel, Cédric; Oulad-Abdelghani, Mustapha; Robert, Flavie; Torres-Padilla, Maria-Elena; Lambrot, Romain; Spehner, Danièle; Ponce-Perez, Lourdes; Würtz, Jean-Marie; Stote, Roland H.; Kimmins, Sarah; Schultz, Patrick; Dejaegere, Annick; Tora, Laszlo

2008-01-01

Condensation of chromatin, mediated in part by posttranslational modifications of histones, is essential for cell division during mitosis. Histone H3 tails are dimethylated on lysine (Kme2) and become phosphorylated on serine (Sp) residues during mitosis. We have explored the possibility that these double modifications are involved in the establishment of H3 tail conformations during the cell cycle. Here we describe a specific chromatin conformation occurring at Kme2 and adjacently phosphorylated S of H3 tails upon formation of a hydrogen bond. This conformation appears exclusively between early prophase and early anaphase of the mitosis, when chromatin condensation is highest. Moreover, we observed that the conformed H3Kme2Sp tail is present at the diplotene and metaphase stages in spermatocytes and oocytes. Our data together with results obtained by cryoelectron microscopy suggest that the conformation of Kme2Sp-modified H3 tails changes during mitosis and meiosis. This is supported by biostructural modeling of a modified histone H3 tail bound by an antibody, indicating that Kme2Sp-modified H3 tails can adopt at least two different conformations. Thus, the H3K9me2S10p and the H3K27me2S28p sites are involved in the acquisition of specific chromatin conformations during chromatin condensation for cell division. PMID:18180282

Effect of the Crystal Environment on Side-Chain Conformational Dynamics in Cyanovirin-N Investigated through Crystal and Solution Molecular Dynamics Simulations.

PubMed

Ahlstrom, Logan S; Vorontsov, Ivan I; Shi, Jun; Miyashita, Osamu

2017-01-01

Side chains in protein crystal structures are essential for understanding biochemical processes such as catalysis and molecular recognition. However, crystal packing could influence side-chain conformation and dynamics, thus complicating functional interpretations of available experimental structures. Here we investigate the effect of crystal packing on side-chain conformational dynamics with crystal and solution molecular dynamics simulations using Cyanovirin-N as a model system. Side-chain ensembles for solvent-exposed residues obtained from simulation largely reflect the conformations observed in the X-ray structure. This agreement is most striking for crystal-contacting residues during crystal simulation. Given the high level of correspondence between our simulations and the X-ray data, we compare side-chain ensembles in solution and crystal simulations. We observe large decreases in conformational entropy in the crystal for several long, polar and contacting residues on the protein surface. Such cases agree well with the average loss in conformational entropy per residue upon protein folding and are accompanied by a change in side-chain conformation. This finding supports the application of surface engineering to facilitate crystallization. Our simulation-based approach demonstrated here with Cyanovirin-N establishes a framework for quantitatively comparing side-chain ensembles in solution and in the crystal across a larger set of proteins to elucidate the effect of the crystal environment on protein conformations.

Free energy surface of two- and three-dimensional transitions of Au 12 nanoclusters obtained by ab initio metadynamics

NASA Astrophysics Data System (ADS)

Santarossa, Gianluca; Vargas, Angelo; Iannuzzi, Marcella; Baiker, Alfons

2010-05-01

The description of the conformational space generated by metal nanoparticles is a fundamental issue for the study of their physicochemical properties. In this investigation, an exhaustive exploration and a unified view of the conformational space of a gold nanocluster is provided using a Au 12 cluster as an example. Such system is characterized by coexisting planar/quasiplanar and tridimensional conformations separated by high-energy barriers. The conformational space of Au 12 has been explored by means of Born-Oppenheimer ab initio metadynamics, i.e., a molecular dynamics simulation coupled with a history dependent potential to accelerate events that might occur on a long time scale compared to the time step used in the simulations (rare events). The sampled conformations have complex, in general not intuitive topologies that we have classified as planar/quasiplanar or tridimensional, belonging to different regions of the free energy surface. Three conformational free energy basins were identified, one for the planar/quasiplanar and two for the tridimensional structures. At thermodynamic equilibrium, the planar/quasi-planar and tridimensional conformations were found to coexist, to be fluxional and to be separated by high-free-energy barriers. The comparison between the free energy and the potential energy revealed the relevance of the entropic contribution in the equilibrium distribution of the conformations of the cluster.

Conformational sampling with stochastic proximity embedding and self-organizing superimposition: establishing reasonable parameters for their practical use.

PubMed

Tresadern, Gary; Agrafiotis, Dimitris K

2009-12-01

Stochastic proximity embedding (SPE) and self-organizing superimposition (SOS) are two recently introduced methods for conformational sampling that have shown great promise in several application domains. Our previous validation studies aimed at exploring the limits of these methods and have involved rather exhaustive conformational searches producing a large number of conformations. However, from a practical point of view, such searches have become the exception rather than the norm. The increasing popularity of virtual screening has created a need for 3D conformational search methods that produce meaningful answers in a relatively short period of time and work effectively on a large scale. In this work, we examine the performance of these algorithms and the effects of different parameter settings at varying levels of sampling. Our goal is to identify search protocols that can produce a diverse set of chemically sensible conformations and have a reasonable probability of sampling biologically active space within a small number of trials. Our results suggest that both SPE and SOS are extremely competitive in this regard and produce very satisfactory results with as few as 500 conformations per molecule. The results improve even further when the raw conformations are minimized with a molecular mechanics force field to remove minor imperfections and any residual strain. These findings provide additional evidence that these methods are suitable for many everyday modeling tasks, both high- and low-throughput.

Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam.

PubMed

Luchian, Raluca; Vinţeler, Emil; Chiş, Cosmina; Vasilescu, Mihai; Leopold, Nicolae; Prates Ramalho, João P; Chiş, Vasile

2017-12-01

The analysis of the possible conformers and the conformational change between solid and liquid states of a particular drug molecule are mandatory not only for describing reliably its spectroscopical properties but also for understanding the interaction with the receptor and its mechanism of action. Therefore, here we investigated the free-energy conformational landscape of levetiracetam (LEV) in gas phase as well as in water and ethanol, aiming to describe the 3-dimensional structure and energetic stability of its conformers. Twenty-two unique conformers were identified, and their energetic stability was determined at density functional theory B3LYP/6-31+G(2d,2p) level of theory. The 6 most stable monomers in water, within a relative free-energy window of 0.71 kcal mol -1 and clearly separated in energy from the remaining subset of 16 conformers, as well as the 3 most stable dimers were then used to compute the Boltzmann populations-averaged UV-Vis and NMR spectra of LEV. The conformational landscape in solution is distinctly different from that corresponding to gas phase, particularly due to the relative orientations of the butanamide group. Aiming to clarify the stability of the possible dimers of LEV, we also investigated computationally the structure of a set of 11 nonhydrated and hydrated homochiral hydrogen-bonded LEV dimers. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Fast, clash-free RNA conformational morphing using molecular junctions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heliou, Amelie; Budday, Dominik; Fonseca, Rasmus

Non-coding ribonucleic acids (ncRNA) are functional RNA molecules that are not translated into protein. They are extremely dynamic, adopting diverse conformational substates, which enables them to modulate their interaction with a large number of other molecules. The flexibility of ncRNA provides a challenge for probing their complex 3D conformational landscape, both experimentally and computationally. As a result, despite their conformational diversity, ncRNAs mostly preserve their secondary structure throughout the dynamic ensemble. Here we present a kinematics-based procedure to morph an RNA molecule between conformational substates, while avoiding inter-atomic clashes. We represent an RNA as a kinematic linkage, with fixed groupsmore » of atoms as rigid bodies and rotatable bonds as degrees of freedom. Our procedure maintains RNA secondary structure by treating hydrogen bonds between base pairs as constraints. The constraints define a lower-dimensional, secondary-structure constraint manifold in conformation space, where motions are largely governed by molecular junctions of unpaired nucleotides. On a large benchmark set, we show that our morphing procedure compares favorably to peer algorithms, and can approach goal conformations to within a low all-atom RMSD by directing fewer than 1% of its atoms. Furthermore, our results suggest that molecular junctions can modulate 3D structural rearrangements, while secondary structure elements guide large parts of the molecule along the transition to the correct final conformation.« less

Conformational Changes of Trialanine in Water Induced by Vibrational Relaxation of the Amide I Mode.

PubMed

Bastida, Adolfo; Zúñiga, José; Requena, Alberto; Miguel, Beatriz; Candela, María Emilia; Soler, Miguel Angel

2016-01-21

Most of the protein-based diseases are caused by anomalies in the functionality and stability of these molecules. Experimental and theoretical studies of the conformational dynamics of proteins are becoming in this respect essential to understand the origin of these anomalies. However, a description of the conformational dynamics of proteins based on mechano-energetic principles still remains elusive because of the intrinsic high flexibility of the peptide chains, the participation of weak noncovalent interactions, and the role of the ubiquitous water solvent. In this work, the conformational dynamics of trialanine dissolved in water (D2O) is investigated through Molecular Dynamics (MD) simulations combined with instantaneous normal modes (INMs) analysis both at equilibrium and after the vibrational excitation of the C-terminal amide I mode. The conformational equilibrium between α and pPII conformers is found to be altered by the intramolecular relaxation of the amide I mode as a consequence of the different relaxation pathways of each conformer which modify the amount of vibrational energy stored in the torsional motions of the tripeptide, so the α → pPII and pPII → α conversion rates are increased differently. The selectivity of the process comes from the shifts of the vibrational frequencies with the conformational changes that modify the resonance conditions driving the intramolecular energy flows.

Conformational effects in photoelectron circular dichroism

NASA Astrophysics Data System (ADS)

Turchini, S.

2017-12-01

Photoelectron circular dichroism (PECD) is a novel type of spectroscopy, which presents surprising sensitivity to conformational effects in chiral systems. While classical photoelectron spectroscopy mainly responds to conformational effects in terms of energy level shifts, PECD provides a rich and detailed response to tiny changes in electronic and structural properties by means of the intensity dispersion of the circular dichroism as a function of photoelectron kinetic energy. In this work, the basics of PECD will be outlined, emphasizing the role of interference from the l,l+/- 1 outgoing partial wave of the photoelectron in the PECD transition matrix element, which is responsible for the extreme sensitivity to conformational effects. Examples using molecular systems and interfaces will shed light on the powerful application of PECD to classical conformational effects such as group substitution, isomerism, conformer population and clustering. Moreover, the PECD results will be reported in challenging new fields where conformations play a key role, such as vibrational effects, transient chirality and time- resolved experiments. To date, PECD has mostly been based on synchrotron radiation facilities, but it also has a future as a table-top lab experiment by means of multiphoton ionization. An important application of PECD as an analytical tool will be reported. The aim of this review is to illustrate that in PECD, the presence of conformational effects is essential for understanding a wide range of effects from a new perspective, making it different from classical spectroscopy.

Conformational Plasticity of the Influenza A M2 Transmembrane Helix in Lipid Bilayers Under Varying pH, Drug Binding and Membrane Thickness

PubMed Central

Hu, Fanghao; Luo, Wenbin; Cady, Sarah D.; Hong, Mei

2010-01-01

Membrane proteins change their conformations to respond to environmental cues, thus conformational plasticity is important for function. The influenza A M2 protein forms an acid-activated proton channel important for the virus lifecycle. Here we have used solid-state NMR spectroscopy to examine the conformational plasticity of membrane-bound transmembrane domain of M2 (M2TM). 13C and 15N chemical shifts indicate coupled conformational changes of several pore-facing residues due to changes in bilayer thickness, drug binding and pH. The structural changes are attributed to the formation of a well-defined helical kink at G34 in the drug-bound state and in thick lipid bilayers, non-ideal backbone conformation of the secondary-gate residue V27 in the presence of drug, and non-ideal conformation of the proton-sensing residue H37 at high pH. The chemical shifts constrained the (ϕ, ψ) torsion angles for three basis states, the equilibrium among which explains the multiple resonances per site in the NMR spectra under different combinations of bilayer thickness, drug binding and pH conditions. Thus, conformational plasticity is important for the proton conduction and inhibition of M2TM. The study illustrates the utility of NMR chemical shifts for probing the structural plasticity and folding of membrane proteins. PMID:20883664

The conformational free-energy landscape of β-D-mannopyranose: evidence for a (1)S(5) → B(2,5) → (O)S(2) catalytic itinerary in β-mannosidases.

PubMed

Ardèvol, Albert; Biarnés, Xevi; Planas, Antoni; Rovira, Carme

2010-11-17

The mechanism of glycosidic bond cleavage by glycosidases involves substrate ring distortions in the Michaelis complex that favor catalysis. Retaining β-mannosidases bind the substrate in a (1)S(5) conformation, and recent experiments have proposed an unusual substrate conformational pathway ((1)S(5) → B(2,5) → (O)S(2)) for the hydrolysis reaction. By means of Car-Parrinello metadynamics simulations, we have obtained the conformational free-energy surface (FES) of a β-d-mannopyranose molecule associated with the ideal Stoddart conformational diagram. We have found that (1)S(5) is among the most stable conformers and simultaneously is the most preactivated conformation in terms of elongation/shortening of the C1-O1/C1-O5 bonds, C1-O1 orientation, and charge development at the anomeric carbon. Analysis of the computed FES gives support to the proposed (1)S(5) → B(2,5) → (O)S(2) catalytic itinerary, showing that the degree of preactivation of the substrate in glycoside hydrolases (GHs) is related to the properties of an isolated sugar ring. We introduce a simple preactivation index integrating several structural, electronic, and energetic properties that can be used to predict the conformation of the substrate in the Michaelis complex of any GH.

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.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo

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 inmore » 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.« less

Fast, clash-free RNA conformational morphing using molecular junctions

DOE PAGES

Heliou, Amelie; Budday, Dominik; Fonseca, Rasmus; ...

2017-03-13

Non-coding ribonucleic acids (ncRNA) are functional RNA molecules that are not translated into protein. They are extremely dynamic, adopting diverse conformational substates, which enables them to modulate their interaction with a large number of other molecules. The flexibility of ncRNA provides a challenge for probing their complex 3D conformational landscape, both experimentally and computationally. As a result, despite their conformational diversity, ncRNAs mostly preserve their secondary structure throughout the dynamic ensemble. Here we present a kinematics-based procedure to morph an RNA molecule between conformational substates, while avoiding inter-atomic clashes. We represent an RNA as a kinematic linkage, with fixed groupsmore » of atoms as rigid bodies and rotatable bonds as degrees of freedom. Our procedure maintains RNA secondary structure by treating hydrogen bonds between base pairs as constraints. The constraints define a lower-dimensional, secondary-structure constraint manifold in conformation space, where motions are largely governed by molecular junctions of unpaired nucleotides. On a large benchmark set, we show that our morphing procedure compares favorably to peer algorithms, and can approach goal conformations to within a low all-atom RMSD by directing fewer than 1% of its atoms. Furthermore, our results suggest that molecular junctions can modulate 3D structural rearrangements, while secondary structure elements guide large parts of the molecule along the transition to the correct final conformation.« less

Transferability of different classical force fields for right and left handed α-helices constructed from enantiomeric amino acids.

PubMed

Biswas, Santu; Sarkar, Sujit; Pandey, Prithvi Raj; Roy, Sudip

2016-02-21

Amino acids can form d and l enantiomers, of which the l enantiomer is abundant in nature. The naturally occurring l enantiomer has a greater preference for a right handed helical conformation, and the d enantiomer for a left handed helical conformation. The other conformations, that is, left handed helical conformations of the l enantiomers and right handed helical conformations of the d enantiomers, are not common. The energetic differences between left and right handed alpha helical peptide chains constructed from enantiomeric amino acids are investigated using quantum chemical calculations (using the M06/6-311g(d,p) level of theory). Further, the performances of commonly used biomolecular force fields (OPLS/AA, CHARMM27/CMAP and AMBER) to represent the different helical conformations (left and right handed) constructed from enantiomeric (D and L) amino acids are evaluated. 5- and 10-mer chains from d and l enantiomers of alanine, leucine, lysine, and glutamic acid, in right and left handed helical conformations, are considered in the study. Thus, in total, 32 α-helical polypeptides (4 amino acids × 4 conformations of 5-mer and 10-mer) are studied. Conclusions, with regards to the performance of the force fields, are derived keeping the quantum optimized geometry as the benchmark, and on the basis of phi and psi angle calculations, hydrogen bond analysis, and different long range helical order parameters.

Molecular dynamics simulations of certain RGD-based peptides from Kistrin provide insight into the higher activity of REI-RGD34 protein at higher temperature.

PubMed

Upadhyay, Sanjay K

2014-05-01

To determine the bioactive conformation required to bind with receptor aIIbb3, the peptide sequence RIPRGDMP from Kistrin was inserted into CDR 1 loop region of REI protein, resulting in REI-RGD34. The activity of REI-RGD34 was observed to increase at higher temperature towards the receptor aIIbb3. It could be justified in either way: the modified complex forces the restricted peptide to adapt bioactive conformation or it unfolds the peptide in a way that opens its binding surface with high affinity for receptor. Here, we model the conformational preference of RGD sequence in RIPRGDMP at 25 and 42 °C using multiple MD simulations. Further, we model the peptide sequence RGD, PRGD and PRGDMP from kistrin to observe the effect of flanking residues on conformational sampling of RGD. The presence of flanking residues around RGD peptide greatly influenced the conformational sampling. A transition from bend to turn conformation was observed for RGD sequence at 42 °C. The turn conformation shows pharmacophoric parameters required to recognize the receptor aIIbb3. Thus, the temperaturedependent activity of RIPRGDMP when inserted into the loop region of REI can be explained by the presence of the turn conformation. This study will help in designing potential antagonist for the receptor aIIbb3.

Conformational preferences of DNA following damage by aristolochic acids: Structural and energetic insights into the different mutagenic potential of the ALI and ALII-N(6)-dA adducts.

PubMed

Kathuria, Preetleen; Sharma, Purshotam; Abendong, Minette N; Wetmore, Stacey D

2015-04-21

Aristolochic acids (AAI and AAII), produced by the Aristolochiaceae family of plants, are classified as group I (human) carcinogens by the International Agency for Research on Cancer. These acids are metabolized in cells to yield aristolactams (ALI and ALII, respectively), which further form bulky adducts with the purine nucleobases. Specifically, the adenine lesions are more persistent in cells and have been associated with chronic renal diseases and related carcinogenesis. To understand the structural basis of the nephrotoxicity induced by AAs, the ALI-N(6)-dA and ALII-N(6)-dA lesions are systematically studied using computational methods. Density functional theory calculations indicate that the aristolactam moiety intrinsically prefers a planar conformation with respect to adenine. Nucleoside and nucleotide models suggest that the anti and syn orientations about the glycosidic bond are isoenergetic for both adducts. Molecular dynamics simulations and free energy calculations reveal that the anti base-displaced intercalated conformation is the most stable conformer for both types of AL-N(6)-dA adducted DNA, which agrees with previous experimental work on the ALII-N(6)-dA adduct and thereby validates our approach. Interestingly, this conformer differs from the dominant conformations adopted by other N6-linked adenine lesions, including those derived from polycyclic aromatic hydrocarbons. Furthermore, the second most stable syn base-displaced intercalated conformation lies closer in energy to the anti base-displaced intercalated conformation for ALI-N(6)-dA compared to ALII-N(6)-dA. This indicates that a mixture of conformations may be detectable for ALI-N(6)-dA in DNA. If this enhanced conformational flexibility of double-stranded DNA persists when bound to a lesion-bypass polymerase, this provides a possible structural explanation for the previously observed greater nephrotoxic potential for the ALI versus ALII-N(6)-dA adduct. In addition, the structural characteristics of the preferred conformations of adducted DNA explain the resistance of these adducts to repair and thereby add to our current understanding of the toxicity of AAs within living cells.

The comparison of automated clustering algorithms for resampling representative conformer ensembles with RMSD matrix.

PubMed

Kim, Hyoungrae; Jang, Cheongyun; Yadav, Dharmendra K; Kim, Mi-Hyun

2017-03-23

The accuracy of any 3D-QSAR, Pharmacophore and 3D-similarity based chemometric target fishing models are highly dependent on a reasonable sample of active conformations. Since a number of diverse conformational sampling algorithm exist, which exhaustively generate enough conformers, however model building methods relies on explicit number of common conformers. In this work, we have attempted to make clustering algorithms, which could find reasonable number of representative conformer ensembles automatically with asymmetric dissimilarity matrix generated from openeye tool kit. RMSD was the important descriptor (variable) of each column of the N × N matrix considered as N variables describing the relationship (network) between the conformer (in a row) and the other N conformers. This approach used to evaluate the performance of the well-known clustering algorithms by comparison in terms of generating representative conformer ensembles and test them over different matrix transformation functions considering the stability. In the network, the representative conformer group could be resampled for four kinds of algorithms with implicit parameters. The directed dissimilarity matrix becomes the only input to the clustering algorithms. Dunn index, Davies-Bouldin index, Eta-squared values and omega-squared values were used to evaluate the clustering algorithms with respect to the compactness and the explanatory power. The evaluation includes the reduction (abstraction) rate of the data, correlation between the sizes of the population and the samples, the computational complexity and the memory usage as well. Every algorithm could find representative conformers automatically without any user intervention, and they reduced the data to 14-19% of the original values within 1.13 s per sample at the most. The clustering methods are simple and practical as they are fast and do not ask for any explicit parameters. RCDTC presented the maximum Dunn and omega-squared values of the four algorithms in addition to consistent reduction rate between the population size and the sample size. The performance of the clustering algorithms was consistent over different transformation functions. Moreover, the clustering method can also be applied to molecular dynamics sampling simulation results.

48 CFR 46.315 - Certificate of conformance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Certificate of conformance. 46.315 Section 46.315 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT QUALITY ASSURANCE Contract Clauses 46.315 Certificate of conformance. The contracting officer...

48 CFR 246.504 - Certificate of conformance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Certificate of conformance. 246.504 Section 246.504 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT QUALITY ASSURANCE Acceptance 246.504 Certificate of conformance...

15 CFR 286.2 - Scope.

Code of Federal Regulations, 2014 CFR

2014-01-01

... accreditation body which satisfies the established requirements. (b) NIST operates the NVCASE program as follows: (1) Conformity level: Under this program NIST accepts requests for evaluations of U.S. bodies involved in activities related to conformity assessment. NIST does not perform conformity assessments as...

15 CFR 286.2 - Scope.

Code of Federal Regulations, 2012 CFR

2012-01-01

... accreditation body which satisfies the established requirements. (b) NIST operates the NVCASE program as follows: (1) Conformity level: Under this program NIST accepts requests for evaluations of U.S. bodies involved in activities related to conformity assessment. NIST does not perform conformity assessments as...

15 CFR 286.2 - Scope.

Code of Federal Regulations, 2011 CFR

2011-01-01

... accreditation body which satisfies the established requirements. (b) NIST operates the NVCASE program as follows: (1) Conformity level: Under this program NIST accepts requests for evaluations of U.S. bodies involved in activities related to conformity assessment. NIST does not perform conformity assessments as...

15 CFR 286.2 - Scope.

Code of Federal Regulations, 2010 CFR

2010-01-01

... accreditation body which satisfies the established requirements. (b) NIST operates the NVCASE program as follows: (1) Conformity level: Under this program NIST accepts requests for evaluations of U.S. bodies involved in activities related to conformity assessment. NIST does not perform conformity assessments as...

15 CFR 286.2 - Scope.

Code of Federal Regulations, 2013 CFR

2013-01-01

... accreditation body which satisfies the established requirements. (b) NIST operates the NVCASE program as follows: (1) Conformity level: Under this program NIST accepts requests for evaluations of U.S. bodies involved in activities related to conformity assessment. NIST does not perform conformity assessments as...

Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations

PubMed Central

2016-01-01

Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM. PMID:25906170

Tilting the balance between canonical and noncanonical conformations for the H1 hypervariable loop of a llama VHH through point mutations.

PubMed

Mahajan, Sai Pooja; Velez-Vega, Camilo; Escobedo, Fernando A

2013-01-10

Nanobodies are single-domain antibodies found in camelids. These are the smallest naturally occurring binding domains and derive functionality via three hypervariable loops (H1-H3) that form the binding surface. They are excellent candidates for antibody engineering because of their favorable characteristics like small size, high solubility, and stability. To rationally engineer antibodies with affinity for a specific target, the hypervariable loops can be tailored to obtain the desired binding surface. As a first step toward such a goal, we consider the design of loops with a desired conformation. In this study, we focus on the H1 loop of the anti-hCG llama nanobody that exhibits a noncanonical conformation. We aim to "tilt" the stability of the H1 loop structure from a noncanonical conformation to a (humanized) type 1 canonical conformation by studying the effect of selected mutations to the amino acid sequence of the H1, H2, and proximal residues. We use all-atomistic, explicit-solvent, biased molecular dynamic simulations to simulate the wild-type and mutant loops in a prefolded framework. We thus find mutants with increasing propensity to form a stable type 1 canonical conformation of the H1 loop. Free energy landscapes reveal the existence of conformational isomers of the canonical conformation that may play a role in binding different antigenic surfaces. We also elucidate the approximate mechanism and kinetics of transitions between such conformational isomers by using a Markovian model. We find that a particular three-point mutant has the strongest thermodynamic propensity to form the H1 type 1 canonical structure but also to exhibit transitions between conformational isomers, while a different, more rigid three-point mutant has the strongest propensity to be kinetically trapped in such a canonical structure.

Conformational Specific Infrared and Ultraviolet Spectroscopy of Cold YA(D-Pro)AA\\cdotH+ Ions: a Sterochemical "twist" on the Proline Effect

NASA Astrophysics Data System (ADS)

Harrilal, Christopher P.; DeBlase, Andrew F.; Burke, Nicole L.; McLuckey, Scott A.; Zwier, Timothy S.

2016-06-01

The "proline effect" is a well-known fragmentation phenomenon in mass spectrometry, in which y-fragments are produced preferentially over b-fragments during the collision induced dissociation of protonated L-proline containing peptide ions. This specific fragmentation channel is favored because of the high basicity of the secondary amine intermediate and the ring instability in alternative bn+ products [ASMS 2014, 25, 1705]. In contrast, peptides containing the D-Pro stereoisomer have been shown to largely favor the production of b4+ ions over y3+ ions. This strongly suggests that differences in the conformational preferences between the D-Pro and L-Pro diastereomers are likely to be responsible but structural evidence has been lacking to date. Using tandem mass spectrometry and IR-UV double resonant action spectroscopy we are able to compare the 3D structures of cold [YA(D-Pro)AA+H]+ to [YA(L-Pro)AA+H]+ ions. The UV action spectra reveals two major conformers in [YA(D-Pro)AA+H]+ and one major conformer in [YA(L-Pro)AA+H]+. Clear differences in the hydrogen bonding patterns are apparent between the two conformers observed in the D-Pro specie which are both distinct from the L-Pro diastereomer. Furthermore, conformer and diastereomer specific photofragmentation patterns are observed. It is also noted that a ten-fold photofragment enhancement unique to one of the D-Pro conformers is observed upon absorption of a resonant IR photon after UV excitation. Differences in the excited state photophysics between the two D-Pro conformers suggest that vibrational excitation of S1 turns on coupling to the dissociative -Tyr channel in one conformer, while this coupling is already present in the vibronic ground state of the other. Calculated harmonic spectra (M052X/6-31+G*) of conformers obtained from Monte Carlo searches to the experimental spectra.

Pilot Non-Conformance to Alerting System Commands During Closely Spaced Parallel Approaches

NASA Technical Reports Server (NTRS)

Pritchett, Amy Ruth; Hansman, R. John; Corker, Kevin (Technical Monitor)

1997-01-01

Cockpit alerting systems monitor potentially hazardous situations, both inside and outside the aircraft. When a hazard is projected to occur, the alerting system displays alerts and/or command decisions to the pilot. However, pilots have been observed to not conform to alerting system commands by delaying their response or by not following the automatic commands exactly. This non-conformance to the automatic alerting system can reduce its benefit. Therefore, a need exists to understand the causes and effects of pilot non-conformance in order to develop automatic alerting systems whose commands the pilots are more likely to follow. These considerations were examined through flight simulator evaluations of the collision avoidance task during closely spaced parallel approaches. This task provided a useful case-study because the effects of non-conformance can be significant, given the time-critical nature of the task. A preliminary evaluation of alerting systems identified non-conformance in over 40% of the cases and a corresponding drop in collision avoidance performance. A follow-on experiment found subjects' alerting and maneuver selection criteria were consistent with different strategies than those used by automatic systems, indicating the pilot may potentially disagree with the alerting system if the pilot attempts to verify automatic alerts and commanded avoidance maneuvers. A final experiment found supporting automatic alerts with the explicit display of its underlying criteria resulted in more consistent subject reactions. In light of these experimental results, a general discussion of pilot non-conformance is provided. Contributing factors in pilot non-conformance include a lack of confidence in the automatic system and mismatches between the alerting system's commands and the pilots' own decisions based on the information available to them. The effects of non-conformance on system performance are discussed. Possible methods of reconciling mismatches are given, and design considerations for alerting systems which alleviate the problem of non-conformance are provided.

Infrared-induced conformational isomerization and vibrational relaxation dynamics in melatonin and 5-methoxy-N-acetyl tryptophan methyl amide

NASA Astrophysics Data System (ADS)

Dian, Brian C.; Florio, Gina M.; Clarkson, Jasper R.; Longarte, Asier; Zwier, Timothy S.

2004-05-01

The conformational isomerization dynamics of melatonin and 5-methoxy N-acetyltryptophan methyl amide (5-methoxy NATMA) have been studied using the methods of IR-UV hole-filling spectroscopy and IR-induced population transfer spectroscopy. Using these techniques, single conformers of melatonin were excited via a well-defined NH stretch fundamental with an IR pump laser. This excess energy was used to drive conformational isomerization. By carrying out the infrared excitation early in a supersonic expansion, the excited molecules were re-cooled into their zero-point levels, partially re-filling the hole created in the ground state population of the excited conformer, and creating gains in population of the other conformers. These changes in population were detected using laser-induced fluorescence downstream in the expansion via an UV probe laser. The isomerization quantum yields for melatonin show some conformation specificity but no hint of vibrational mode specificity. In 5-methoxy NATMA, no isomerization was observed out of the single conformational well populated in the expansion in the absence of the infrared excitation. In order to study the dependence of the isomerization on the cooling rate, the experimental arrangement was modified so that faster cooling conditions could be studied. In this arrangement, the pump and probe lasers were overlapped in space in the high density region of the expansion, and the time dependence of the zero-point level populations of the conformers was probed following selective excitation of a single conformation. The analysis needed to extract isomerization quantum yields from the timing scans was developed and applied to the melatonin timing scans. Comparison between the frequency and time domain isomerization quantum yields under identical experimental conditions produced similar results. Under fast cooling conditions, the product quantum yields were shifted from their values under standard conditions. The results for melatonin are compared with those for N-acetyl tryptophan methyl amide.

Prediction of protein loop conformations using multiscale modeling methods with physical energy scoring functions.

PubMed

Olson, Mark A; Feig, Michael; Brooks, Charles L

2008-04-15

This article examines ab initio methods for the prediction of protein loops by a computational strategy of multiscale conformational sampling and physical energy scoring functions. Our approach consists of initial sampling of loop conformations from lattice-based low-resolution models followed by refinement using all-atom simulations. To allow enhanced conformational sampling, the replica exchange method was implemented. Physical energy functions based on CHARMM19 and CHARMM22 parameterizations with generalized Born (GB) solvent models were applied in scoring loop conformations extracted from the lattice simulations and, in the case of all-atom simulations, the ensemble of conformations were generated and scored with these models. Predictions are reported for 25 loop segments, each eight residues long and taken from a diverse set of 22 protein structures. We find that the simulations generally sampled conformations with low global root-mean-square-deviation (RMSD) for loop backbone coordinates from the known structures, whereas clustering conformations in RMSD space and scoring detected less favorable loop structures. Specifically, the lattice simulations sampled basins that exhibited an average global RMSD of 2.21 +/- 1.42 A, whereas clustering and scoring the loop conformations determined an RMSD of 3.72 +/- 1.91 A. Using CHARMM19/GB to refine the lattice conformations improved the sampling RMSD to 1.57 +/- 0.98 A and detection to 2.58 +/- 1.48 A. We found that further improvement could be gained from extending the upper temperature in the all-atom refinement from 400 to 800 K, where the results typically yield a reduction of approximately 1 A or greater in the RMSD of the detected loop. Overall, CHARMM19 with a simple pairwise GB solvent model is more efficient at sampling low-RMSD loop basins than CHARMM22 with a higher-resolution modified analytical GB model; however, the latter simulation method provides a more accurate description of the all-atom energy surface, yet demands a much greater computational cost. (c) 2007 Wiley Periodicals, Inc.

The effect of conformation on orthopaedic health and performance in a cohort of National Hunt racehorses: preliminary results.

PubMed

Weller, R; Pfau, T; Verheyen, K; May, S A; Wilson, A M

2006-11-01

There is a lack of scientific data and studies on the effect of conformation on performance or on orthopaedic health. To investigate the relationship between conformation, injury and performance in racehorses used for racing over fences. Over 2 years, 108 National Hunt racehorses were followed and their medical and performance data recorded. Conformation was measured in 3D with a computerised motion analysis system. Linear multiple regression models were used to evaluate the effect of conformation on measures of race performance and stepwise forward logistic regression models to assess the effect on risk of injury. An increase in intermandibular width, flexor angle of the shoulder joint and coxal angle (the angle between the ilium and ischium) was demonstrated to have a positive effect on performance. Performance decreased with increasing girth, length of the hind digit and valgus conformation of the metacarpophalangeal joint. The risk of suffering from superficial digital flexor tendon injury increased with increasing metacarpophalangeal joint angle and with carpus valgus conformation. The risk of pelvic fracture increased with valgus conformation of the tarsus and decreased with an increasing coxal angle. Valgus deformation was demonstrated to be detrimental to performance or increased risk of injury, perhaps resulting in higher loads on musculoskeletal structures. The coxal angle was the only parameter to have an effect on both risk of injury and performance. An alignment of the muscles with the axis of the pelvis may be beneficial for force transmission and decrease the bending moment of the muscles on the bones. The statistical power of this study is limited, however it provides preliminary data necessary for the planning of a larger scale study on the effect of conformation on performance and risk of injury. Studies of the effects of conformation on performance and risk of injury may aid in identifying individuals likely to perform well on the racecourse and avoid risks of injury.

Conformational analysis of some 4‧-substituted 2-(phenylselanyl)- 2-(methoxy)- acetophenones

NASA Astrophysics Data System (ADS)

Traesel, Henrique J.; Olivato, Paulo R.; Valença, J.; Rodrigues, Daniel N. S.; Zukerman-Schpector, Julio; Colle, Maurizio Dal

2018-04-01

A conformational study of some 4‧-substituited 2-(phenylselanyl)-2-(methoxy)-acetophenones (OMe 1, H 2, and Cl 3) was performed using IR carbonyl stretching band analysis supported by NBO and PCM calculations at the B3LYP/6-31 + G (d,p) level for 1-3 and using X-ray diffraction for 1 and 2. The computational results indicated the existence of three stable conformers for the series (c2, c3, and c1 in order of decreasing stability), whose relative abundance changes with solvent permittivity. The experimental trend observed for the components of the triplet carbonyl band in all solvents matches well with computational results and thus allows for their assignment to distinct conformers. The relative population of the c1 conformer increases in more polar solvents, becoming the most stable conformer in the highest permittivity solvent, acetonitrile, as indicated by IR spectra and PCM calculations. These findings are related to the quasi parallel geometry assumed by the Cδ+ = Oδ- and Cδ+-Oδ- dipoles, which favour stronger solvation. NBO analysis shows that the sum of the energies (ΣE) of the relevant orbital interactions stabilizes the c3 conformer of 1-3 slightly, likely due to the minor contribution of the LPO5→σ*C3sbnd Se10 interaction. However, only the c1 conformer is significantly destabilized by the Oδ-(1)CO … Oδ-(5)OMe short contact electrostatic repulsion, which is also responsible for its highest νCO frequency. In addition, the LPO5→ σ*C2sbnd C3 orbital interaction accounts for the lowest νCO frequency of c3 conformer. X-ray single crystal analysis of compounds 1 and 2 indicates that in the solid state they assume the least stable c1 conformation found in the gas phase. Molecules of these compounds are stabilized in the crystal through a series of Csbnd H⋯O and Csbnd H … π intermolecular interactions.

Thermally induced conformational changes in polyethylene studied by two-dimensional near-infrared infrared hetero-spectral correlation spectroscopy

NASA Astrophysics Data System (ADS)

Watanabe, Shin; Noda, Isao; Ozaki, Yukihiro

2008-07-01

The amount of nonplanar gauche bonds was monitored as a function of increasing temperature in three different polyethylene (PE) samples by means of mid-infrared (MIR) and near-infrared (NIR) spectroscopy. The hetero-spectral two-dimensional (2D) correlation analysis was carried out between the NIR spectral region of 4365-4235 cm -1 and the well-established MIR spectral region of 1375-1265 cm -1, where bands due to nonplanar conformer are detected. This approach allowed us to identify the NIR band at 4265 cm -1, which behaves in a way similar to MIR bands originating from conformational-defect sequences. By combining the result of our current study and that of our previous report obtained on different types of PE, it is suggested that the NIR band originates from conformational-defect sequences in PE. This finding opens up a unique and useful way to study the state of conformational disorder in PE crystal by NIR spectroscopy, monitoring the intensity of the NIR band at 4265 cm -1. The use of NIR spectroscopy allows researchers to directly probe the degree in the formation of conformational-defect sequences in thick, real-world PE samples that cannot be studied by conventional MIR spectroscopy. The 2D correlation spectroscopy analysis among the MIR CH 2 wagging conformational-defect-mode bands on linear low-density PE (LLDPE) and low-density PE (LDPE) revealed the formation of nonplanar conformer represented by the band at 1368 cm -1 proceeds prior to those by other band at 1308 cm -1. This result agrees well with our previous finding on high-density PE (HDPE). We therefore propose with strong confidence that the bands at 1368 and 1308 cm -1 arise from different conformational-defect sequences, even though both of the bands have been proposed to arise from the same conformer of gtg' ( kink) + gtg sequence.

Secondary Structures of Ubiquitin Ions Soft-Landed onto Self-Assembled Monolayer Surfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Qichi; Laskin, Julia

2016-06-09

The secondary structures of multiply charged ubiquitin ions soft-landed onto self-assembled monolayer (SAM) surfaces were studied using in situ infrared reflection-absorption spectroscopy (IRRAS). Two charge states of ubiquitin, 5+ and 13+, were mass selected separately from a mixture of different charge states produced by electrospray ionization (ESI). The low 5+ charge state represents a native-like folded state of ubiquitin, while the high 13+ charge state assumes an extended, almost linear conformation. Each of the two charge states was soft-landed onto a CH 3- and COOH-terminated SAM of alkylthiols on gold (HSAM and COOH-SAM). HSAM is a hydrophobic surface known tomore » stabilize helical conformations of soft-landed protonated peptides, whereas COOH-SAM is a hydrophilic surface that preferentially stabilizes β-sheet conformations. IRRAS spectra of the soft-landed ubiquitin ions were acquired as a function of time during and after ion soft-landing. Similar to smaller peptide ions, helical conformations of ubiquitin are found to be more abundant on HSAM, while the relative abundance of β-sheet conformations increases on COOH-SAM. The initial charge state of ubiquitin also has a pronounced effect on its conformation on the surface. Specifically, on both surfaces, a higher relative abundance of helical conformations and lower relative abundance of β-sheet conformations is observed for the 13+ charge state compared to the 5+ charge state. Time-resolved experiments indicate that the α-helical band in the spectrum of the 13+ charge state slowly increases with time on the HSAM surface and decreases in the spectrum of the 13+ charge state on COOH-SAM. These results further support the preference of the hydrophobic HSAM surface toward helical conformations and demonstrate that soft-landed protein ions may undergo slow conformational changes during and after deposition.« less

Spectral analysis and quantum chemical studies of chair and twist-boat conformers of cycloheximide in gas and solution phases

NASA Astrophysics Data System (ADS)

Tokatli, A.; Ucun, F.; Sütçü, K.; Osmanoğlu, Y. E.; Osmanoğlu, Ş.

2018-02-01

In this study the conformational behavior of cycloheximide in the gas and solution (CHCl3) phases has theoretically been investigated by spectroscopic and quantum chemical properties using density functional theory (wB97X-D) method with 6-31++G(d,p) basis set, for the first time. The calculated IR results reveal that in the ground state the molecule exits as a mixture of the chair and twist-boat conformers in the gas phase, while the calculated NMR results reveal that it only exits as the chair conformer in the solution phase. In order to obtain the contributions coming from intramolecular interactions to the stability of the conformers in the gas and solution phases, the quantum theory of atoms in molecules (QTAIM), noncovalent interactions (NCI) method, and natural bond orbital analysis (NBO) have been employed. The QTAIM and NCI methods indicated that by intramolecular interactions with bond critical point (BCP) the twist-boat conformer is more stabilized than the chair conformer, while by steric interactions it is more destabilized. Considering that these interactions balance each other, the stabilities of the conformers are understood to be dictated by the van der Waals interactions. The NBO analyses show that the hyperconjugative and steric effects play an important role in the stabilization in the gas and solution phases. Furthermore, to get a better understanding of the chemical behavior of this important antibiotic drug we have evaluated and, commented the global and local reactivity descriptors of the both conformers. Finally, the EPR analysis of γ-irradiated cycloheximide has been done. The comparison of the experimental and calculated data have showed the inducement of a radical structure of (CH2)2ĊCH2 in the molecule. The experimental EPR spectrum has also confirmed that the molecule simultaneously exists in the chair and twist-boat conformers in the solid phase.

Conformational Analysis of Free and Bound Retinoic Acid

PubMed Central

Fu, Zheng; Li, Xue; Merz, Kenneth M.

2012-01-01

The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and forty-eight 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single-point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the re-refined RA conformers the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug-target structural information for use in structure-based drug discovery applications. PMID:22844234

Loop propensity of the sequence YKGQP from staphylococcal nuclease: implications for the folding of nuclease.

PubMed

Patel, Sunita; Sasidhar, Yellamraju U

2007-10-01

Recently we performed molecular dynamics (MD) simulations on the folding of the hairpin peptide DTVKLMYKGQPMTFR from staphylococcal nuclease in explicit water. We found that the peptide folds into a hairpin conformation with native and nonnative hydrogen-bonding patterns. In all the folding events observed in the folding of the hairpin peptide, loop formation involving the region YKGQP was an important event. In order to trace the origins of the loop propensity of the sequence YKGQP, we performed MD simulations on the sequence starting from extended, polyproline II and native type I' turn conformations for a total simulation length of 300 ns, using the GROMOS96 force field under constant volume and temperature (NVT) conditions. The free-energy landscape of the peptide YKGQP shows minima corresponding to loop conformation with Tyr and Pro side-chain association, turn and extended conformational forms, with modest free-energy barriers separating the minima. To elucidate the role of Gly in facilitating loop formation, we also performed MD simulations of the mutated peptide YKAQP (Gly --> Ala mutation) under similar conditions starting from polyproline II conformation for 100 ns. Two minima corresponding to bend/turn and extended conformations were observed in the free-energy landscape for the peptide YKAQP. The free-energy barrier between the minima in the free-energy landscape of the peptide YKAQP was also modest. Loop conformation is largely sampled by the YKGQP peptide, while extended conformation is largely sampled by the YKAQP peptide. We also explain why the YKGQP sequence samples type II turn conformation in these simulations, whereas the sequence as part of the hairpin peptide DTVKLMYKGQPMTFR samples type I' turn conformation both in the X-ray crystal structure and in our earlier simulations on the folding of the hairpin peptide. We discuss the implications of our results to the folding of the staphylococcal nuclease. Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.

Conformational and functional analysis of molecular dynamics trajectories by Self-Organising Maps

PubMed Central

2011-01-01

Background Molecular dynamics (MD) simulations are powerful tools to investigate the conformational dynamics of proteins that is often a critical element of their function. Identification of functionally relevant conformations is generally done clustering the large ensemble of structures that are generated. Recently, Self-Organising Maps (SOMs) were reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data mining problems. We present a novel strategy to analyse and compare conformational ensembles of protein domains using a two-level approach that combines SOMs and hierarchical clustering. Results The conformational dynamics of the α-spectrin SH3 protein domain and six single mutants were analysed by MD simulations. The Cα's Cartesian coordinates of conformations sampled in the essential space were used as input data vectors for SOM training, then complete linkage clustering was performed on the SOM prototype vectors. A specific protocol to optimize a SOM for structural ensembles was proposed: the optimal SOM was selected by means of a Taguchi experimental design plan applied to different data sets, and the optimal sampling rate of the MD trajectory was selected. The proposed two-level approach was applied to single trajectories of the SH3 domain independently as well as to groups of them at the same time. The results demonstrated the potential of this approach in the analysis of large ensembles of molecular structures: the possibility of producing a topological mapping of the conformational space in a simple 2D visualisation, as well as of effectively highlighting differences in the conformational dynamics directly related to biological functions. Conclusions The use of a two-level approach combining SOMs and hierarchical clustering for conformational analysis of structural ensembles of proteins was proposed. It can easily be extended to other study cases and to conformational ensembles from other sources. PMID:21569575

Conformational Sampling and Binding Site Assessment of Suppression of Tumorigenicity 2 Ectodomain

PubMed Central

Yang, Chao-Yie; Delproposto, James; Chinnaswamy, Krishnapriya; Brown, William Clay; Wang, Shuying; Stuckey, Jeanne A.; Wang, Xinquan

2016-01-01

Suppression of Tumorigenicity 2 (ST2), a member of the interleukin-1 receptor (IL-1R) family, activates type 2 immune responses to pathogens and tissue damage via binding to IL-33. Dysregulated responses contribute to asthma, graft-versus-host and autoinflammatory diseases and disorders. To study ST2 structure for inhibitor development, we performed the principal component (PC) analysis on the crystal structures of IL1-1R1, IL1-1R2, ST2 and the refined ST2 ectodomain (ST2ECD) models, constructed from previously reported small-angle X-ray scattering data. The analysis facilitates mapping of the ST2ECD conformations to PC subspace for characterizing structural changes. Extensive coverage of ST2ECD conformations was then obtained using the accelerated molecular dynamics simulations started with the IL-33 bound ST2ECD structure as instructed by their projected locations on the PC subspace. Cluster analysis of all conformations further determined representative conformations of ST2ECD ensemble in solution. Alignment of the representative conformations with the ST2/IL-33 structure showed that the D3 domain of ST2ECD (containing D1-D3 domains) in most conformations exhibits no clashes with IL-33 in the crystal structure. Our experimental binding data informed that the D1-D2 domain of ST2ECD contributes predominantly to the interaction between ST2ECD and IL-33 underscoring the importance of the D1-D2 domain in binding. Computational binding site assessment revealed one third of the total detected binding sites in the representative conformations may be suitable for binding to potent small molecules. Locations of these sites include the D1-D2 domain ST2ECD and modulation sites conformed to ST2ECD conformations. Our study provides structural models and analyses of ST2ECD that could be useful for inhibitor discovery. PMID:26735493

Conformational Entropy of Intrinsically Disordered Proteins from Amino Acid Triads

PubMed Central

Baruah, Anupaul; Rani, Pooja; Biswas, Parbati

2015-01-01

This work quantitatively characterizes intrinsic disorder in proteins in terms of sequence composition and backbone conformational entropy. Analysis of the normalized relative composition of the amino acid triads highlights a distinct boundary between globular and disordered proteins. The conformational entropy is calculated from the dihedral angles of the middle amino acid in the amino acid triad for the conformational ensemble of the globular, partially and completely disordered proteins relative to the non-redundant database. Both Monte Carlo (MC) and Molecular Dynamics (MD) simulations are used to characterize the conformational ensemble of the representative proteins of each group. The results show that the globular proteins span approximately half of the allowed conformational states in the Ramachandran space, while the amino acid triads in disordered proteins sample the entire range of the allowed dihedral angle space following Flory’s isolated-pair hypothesis. Therefore, only the sequence information in terms of the relative amino acid triad composition may be sufficient to predict protein disorder and the backbone conformational entropy, even in the absence of well-defined structure. The predicted entropies are found to agree with those calculated using mutual information expansion and the histogram method. PMID:26138206

Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules.

PubMed

Iuzzolino, Luca; Reilly, Anthony M; McCabe, Patrick; Price, Sarah L

2017-10-10

Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles.

A computational study of vicinal fluorination in 2,3-difluorobutane: implications for conformational control in alkane chains.

PubMed

Fox, Stephen J; Gourdain, Stephanie; Coulthurst, Anton; Fox, Clare; Kuprov, Ilya; Essex, Jonathan W; Skylaris, Chris-Kriton; Linclau, Bruno

2015-01-19

A comprehensive conformational analysis of both 2,3-difluorobutane diastereomers is presented based on density functional theory calculations in vacuum and in solution, as well as NMR experiments in solution. While for 1,2-difluoroethane the fluorine gauche effect is clearly the dominant effect determining its conformation, it was found that for 2,3-difluorobutane there is a complex interplay of several effects, which are of similar magnitude but often of opposite sign. As a result, unexpected deviations in dihedral angles, relative conformational energies and populations are observed which cannot be rationalised only by chemical intuition. Furthermore, it was found that it is important to consider the free energies of the various conformers, as these lead to qualitatively different results both in vacuum and in solvent, when compared to calculations based only on the electronic energies. In contrast to expectations, it was found that vicinal syn-difluoride introduction in the butane and by extension, longer hydrocarbon chains, is not expected to lead to an effective stabilisation of the linear conformation. Our findings have implications for the use of the vicinal difluoride motif for conformational control. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A theoretical and matrix-isolation FT-IR investigation of the conformational landscape of N-acetylcysteine

NASA Astrophysics Data System (ADS)

Boeckx, Bram; Ramaekers, Riet; Maes, Guido

2010-06-01

The conformational landscape of N-acetylcysteine (NAC) has been investigated by a combined experimental matrix-isolation FT-IR and theoretical methodology. This combination is a powerful tool to study the conformational behavior of relatively small molecules. Geometry optimizations at the HF/3-21 level resulted in 438 different geometries with an energy difference smaller than 22 kJ mol -1. Among these, six conformations were detected with a relative energy difference smaller than 10 kJ mol -1 at the DFT(B3LYP)/6-31++G∗∗ level of theory. These were finally subjected to MP2/6-31++G∗∗ optimizations which resulted in five minima. The vibrational and thermodynamical properties of these conformations were calculated at both the DFT and MP2 methodologies. Experimentally NAC was isolated in an argon matrix at 16 K after being sublimated at 323 K. The most stable MP2 form appeared to be dominant in the experimental spectra but the presence of three other conformations with Δ EMP2 < 10 kJ mol -1 was also demonstrated. The experimentally observed abundance of the H-bond containing conformations appeared to be in good accordance with the predicted MP2 value.

Molecular Level Characterization of the Structure and Interactions in Peptide-Functionalized Metal-Organic Frameworks.

PubMed

Todorova, Tanya K; Rozanska, Xavier; Gervais, Christel; Legrand, Alexandre; Ho, Linh N; Berruyer, Pierrick; Lesage, Anne; Emsley, Lyndon; Farrusseng, David; Canivet, Jérôme; Mellot-Draznieks, Caroline

2016-11-07

We use density functional theory, newly parameterized molecular dynamics simulations, and last generation 15 N dynamic nuclear polarization surface enhanced solid-state NMR spectroscopy (DNP SENS) to understand graft-host interactions and effects imposed by the metal-organic framework (MOF) host on peptide conformations in a peptide-functionalized MOF. Focusing on two grafts typified by MIL-68-proline (-Pro) and MIL-68-glycine-proline (-Gly-Pro), we identified the most likely peptide conformations adopted in the functionalized hybrid frameworks. We found that hydrogen bond interactions between the graft and the surface hydroxyl groups of the MOF are essential in determining the peptides conformation(s). DNP SENS methodology shows unprecedented signal enhancements when applied to these peptide-functionalized MOFs. The calculated chemical shifts of selected MIL-68-NH-Pro and MIL-68-NH-Gly-Pro conformations are in a good agreement with the experimentally obtained 15 N NMR signals. The study shows that the conformations of peptides when grafted in a MOF host are unlikely to be freely distributed, and conformational selection is directed by strong host-guest interactions. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

NMR based solvent exchange experiments to understand the conformational preference of intrinsically disordered proteins using FG-nucleoporin peptide as a model

PubMed Central

Heisel, Kurt A.; Krishnan, V. V.

2014-01-01

The conformational preference of a peptide with three phenylalanine-glycine (FG) repeats from the intrinsically disordered domain of nucleoporin 159 (nup159) from the yeast nucleopore complex (NPC) is studied. Conformational states of this FG-peptide in dimethyl sulfoxide (DMSO), a non-native solvent are first studied. A solvent exchange scheme is designed and performed to understand how the conformational preferences of the peptide are altered as the solvent shifts from DMSO to water. An ensemble of structures of a 19-residue peptide is determined based on 13Cα, 1Hα, and 1HN chemical shifts and with inter-proton distances. An experimental model is then presented where chemical shifts and amide-proton temperature dependence is probed at changing DMSO to water ratios. These co-solvent experiments provide evidence of a conformational change as the fraction of water increases by the stark change in the behavior of amide protons under varied temperature. This investigation provides a NMR based experimental method in the field of intrinsically disordered proteins to realize conformational transitions from a non-native set of structures (in DMSO) to a native set of disordered conformers (in water). PMID:24037535

Fourier transformation microwave spectroscopy of the methyl glycolate-H2O complex

NASA Astrophysics Data System (ADS)

Fujitake, Masaharu; Tanaka, Toshihiro; Ohashi, Nobukimi

2018-01-01

The rotational spectrum of one conformer of the methyl glycolate-H2O complex has been measured by means of the pulsed jet Fourier transform microwave spectrometer. The observed a- and b-type transitions exhibit doublet splittings due to the internal rotation of the methyl group. On the other hand, most of the c-type transitions exhibit quartet splittings arising from the methyl internal rotation and the inversion motion between two equivalent conformations. The spectrum was analyzed using parameterized expressions of the Hamiltonian matrix elements derived by applying the tunneling matrix formalism. Based on the results obtained from ab initio calculation, the observed complex of methyl glycolate-H2O was assigned to the most stable conformer of the insertion complex, in which a non-planer seven membered-ring structure is formed by the intermolecular hydrogen bonds between methyl glycolate and H2O subunits. The inversion motion observed in the c-type transitions is therefore a kind of ring-inversion motion between two equivalent conformations. Conformational flexibility, which corresponds to the ring-inversion between two equivalent conformations and to the isomerization between two possible conformers of the insertion complex, was investigated with the help of the ab initio calculation.

Vibrational cross-angles in condensed molecules: a structural tool.

PubMed

Chen, Hailong; Zhang, Yufan; Li, Jiebo; Liu, Hongjun; Jiang, De-En; Zheng, Junrong

2013-09-05

The fluctuations of three-dimensional molecular conformations of a molecule in different environments play critical roles in many important chemical and biological processes. X-ray diffraction (XRD) techniques and nuclear magnetic resonance (NMR) methods are routinely applied to monitor the molecular conformations in condensed phases. However, some special requirements of the methods have prevented them from exploring many molecular phenomena at the current stage. Here, we introduce another method to resolve molecular conformations based on an ultrafast MIR/T-Hz multiple-dimensional vibrational spectroscopic technique. The model molecule (4'-methyl-2'-nitroacetanilide, MNA) is prepared in two of its crystalline forms and liquid samples. Two polarized ultrafast infrared pulses are then used to determine the cross-angles of vibrational transition moment directions by exciting one vibrational band and detecting the induced response on another vibrational band of the molecule. The vibrational cross-angles are then converted into molecular conformations with the aid of calculations. The molecular conformations determined by the method are supported by X-ray diffraction and molecular dynamics simulation results. The experimental results suggest that thermodynamic interactions with solvent molecules are not altering the molecular conformations of MNA in the solutions to control their ultimate conformations in the crystals.

Neural Basis of Two Kinds of Social Influence: Obedience and Conformity

PubMed Central

Xie, Ying; Chen, Mingliang; Lai, Hongxia; Zhang, Wuke; Zhao, Zhen; Anwar, Ch. Mahmood

2016-01-01

Event-related potentials (ERPs) were used in this study to explore the neural mechanism of obedience and conformity on the model of online book purchasing. Participants were asked to decide as quickly as possible whether to buy a book based on limited information including its title, keywords and number of positive and negative reviews. Obedience was induced by forcing participants to buy books which received mostly negative reviews. In contrast, conformity was aroused by majority influence (caused by positive and negative comments). P3 and N2, two kinds of ERP components related to social cognitive process, were measured and recorded with electroencephalogram (EEG) test. The results show that compared with conformity decisions, obedience decisions induced greater cognitive conflicts. In ERP measurements, greater amplitudes of N2 component were observed in the context of obedience. However, consistency level did not make a difference on P3 peak latency for both conformity and obedience. This shows that classification process is implicit in both conformity and obedience decision-making. In addition, for both conformity and obedience decisions, augmented P3 was observed when the reviews consistency (either negative or positive) was higher. PMID:26941632

Conformational flexibility of human casein kinase catalytic subunit explored by metadynamics.

PubMed

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-03-04

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the γ phosphate from ATP to serine and threonine residues on protein substrates. In a number of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2α catalytic subunit. This variability reflects a high flexibility for two regions of CK2α: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, we present a computational study simulating the equilibrium between three conformations involving these regions. Simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provides a reference pathway describing the conformational changes being studied, based on analysis of free energy surfaces. The free energies of the three conformations were found to be close and the paths proposed had low activation barriers. Our results indicate that these conformations can exist in water. This information should be useful when designing inhibitors specific to one conformation. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Thermodynamic contribution of backbone conformational entropy in the binding between SH3 domain and proline-rich motif.

PubMed

Zeng, Danyun; Shen, Qingliang; Cho, Jae-Hyun

2017-02-26

Biological functions of intrinsically disordered proteins (IDPs), and proteins containing intrinsically disordered regions (IDRs) are often mediated by short linear motifs, like proline-rich motifs (PRMs). Upon binding to their target proteins, IDPs undergo a disorder-to-order transition which is accompanied by a large conformational entropy penalty. Hence, the molecular mechanisms underlying control of conformational entropy are critical for understanding the binding affinity and selectivity of IDPs-mediated protein-protein interactions (PPIs). Here, we investigated the backbone conformational entropy change accompanied by binding of the N-terminal SH3 domain (nSH3) of CrkII and PRM derived from guanine nucleotide exchange factor 1 (C3G). In particular, we focused on the estimation of conformational entropy change of disordered PRM upon binding to the nSH3 domain. Quantitative characterization of conformational dynamics of disordered peptides like PRMs is limited. Hence, we combined various methods, including NMR model-free analysis, δ2D, DynaMine, and structure-based calculation of entropy loss. This study demonstrates that the contribution of backbone conformational entropy change is significant in the PPIs mediated by IDPs/IDRs. Copyright © 2017 Elsevier Inc. All rights reserved.

Extraction of conformal data in critical quantum spin chains using the Koo-Saleur formula

NASA Astrophysics Data System (ADS)

Milsted, Ashley; Vidal, Guifre

2017-12-01

We study the emergence of two-dimensional conformal symmetry in critical quantum spin chains on the finite circle. Our goal is to characterize the conformal field theory (CFT) describing the universality class of the corresponding quantum phase transition. As a means to this end, we propose and demonstrate automated procedures which, using only the lattice Hamiltonian H =∑jhj as an input, systematically identify the low-energy eigenstates corresponding to Virasoro primary and quasiprimary operators, and assign the remaining low-energy eigenstates to conformal towers. The energies and momenta of the primary operator states are needed to determine the primary operator scaling dimensions and conformal spins, an essential part of the conformal data that specifies the CFT. Our techniques use the action, on the low-energy eigenstates of H , of the Fourier modes Hn of the Hamiltonian density hj. The Hn were introduced as lattice representations of the Virasoro generators by Koo and Saleur [Nucl. Phys. B 426, 459 (1994), 10.1016/0550-3213(94)90018-3]. In this paper, we demonstrate that these operators can be used to extract conformal data in a nonintegrable quantum spin chain.

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

Solvent-induced conformational flexibility of a bicyclic proline analogue: Octahydroindole-2-carboxylic acid.

PubMed

Torras, Juan; Warren, Javier G; Revilla-López, Guillem; Jiménez, Ana I; Cativiela, Carlos; Alemán, Carlos

2014-03-01

The conformational preferences of the N-acetyl-N'-methylamide derivatives of the four octahydroindole-2-carboxylic acid (Oic) stereoisomers have been investigated in the gas-phase and in aqueous solution using quantum mechanical calculations. In addition to the conformational effects provoked by the stereochemical diversity of Oic, which presents three chiral centers, results provide evidence of interesting and rather unusual features. The conformational preferences of the Oic stereoisomers in solution are only well described by applying a complete and systematic search process, results achieved by simple re-optimization of the gas-phase minima being very imprecise. This is because the conformational rigidity detected in the gas-phase, which is imposed by the chemical restrictions of the fused bicyclic skeleton, disappears in aqueous solution, the four stereoisomers behaving as flexible molecules in this environment. Thus, in general, the γ-turn is the only minimum energy conformation in the gas-phase while in aqueous solution the helical, polyproline-II and γ-turn motifs are energetically favored. Molecular dynamics simulations indicate that the conformational flexibility predicted by quantum mechanical calculations for the four Oic stereoisomers in solution is satisfactorily reproduced by classical force-fields. Copyright © 2014 Wiley Periodicals, Inc.

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

Loop conformation and dynamics of the Escherichia coli HPPK apo-enzyme and its binary complex with MgATP.

PubMed

Yang, Rong; Lee, Matthew C; Yan, Honggao; Duan, Yong

2005-07-01

Comparison of the crystallographic and NMR structures of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) suggests that the enzyme may undergo significant conformational change upon binding to its first substrate, ATP. Two of the three surface loops (loop 2 and loop 3) accounting for most of the conformational differences appear to be confined by crystal contacts, raising questions about the putative large-scale induced-fit conformational change of HPPK and the functional roles of the conserved side-chain residues on the loops. To investigate the loop dynamics in crystal-free environment, we carried out molecular dynamics and locally enhanced sampling simulations of the apo-enzyme and the HPPK.MgATP complex. Our simulations showed that the crystallographic B-factors underestimated the loop dynamics considerably. We found that the open-conformation of loop 3 in the binary complex is accessible to the apo-enzyme and is the favored conformation in solution phase. These results revise our previous view of HPPK-substrate interactions and the associated functional mechanism of conformational change. The lessons learned here offer valuable structural insights into the workings of HPPK and should be useful for structure-based drug design.

Hydration and conformational equilibria of simple hydrophobic and amphiphilic solutes.

PubMed Central

Ashbaugh, H S; Kaler, E W; Paulaitis, M E

1998-01-01

We consider whether the continuum model of hydration optimized to reproduce vacuum-to-water transfer free energies simultaneously describes the hydration free energy contributions to conformational equilibria of the same solutes in water. To this end, transfer and conformational free energies of idealized hydrophobic and amphiphilic solutes in water are calculated from explicit water simulations and compared to continuum model predictions. As benchmark hydrophobic solutes, we examine the hydration of linear alkanes from methane through hexane. Amphiphilic solutes were created by adding a charge of +/-1e to a terminal methyl group of butane. We find that phenomenological continuum parameters fit to transfer free energies are significantly different from those fit to conformational free energies of our model solutes. This difference is attributed to continuum model parameters that depend on solute conformation in water, and leads to effective values for the free energy/surface area coefficient and Born radii that best describe conformational equilibrium. In light of these results, we believe that continuum models of hydration optimized to fit transfer free energies do not accurately capture the balance between hydrophobic and electrostatic contributions that determines the solute conformational state in aqueous solution. PMID:9675177

Evidence for conformational capture mechanism for damage recognition by NER protein XPC/Rad4.

NASA Astrophysics Data System (ADS)

Chakraborty, Sagnik; Steinbach, Peter J.; Paul, Debamita; Min, Jung-Hyun; Ansari, Anjum

Altered flexibility of damaged DNA sites is considered to play an important role in damage recognition by DNA repair proteins. Characterizing lesion-induced DNA dynamics has remained a challenge. We have combined ps-resolved fluorescence lifetime measurements with cytosine analog FRET pair uniquely sensitive to local unwinding/twisting to analyze DNA conformational distributions. This innovative approach maps out with unprecedented sensitivity the alternative conformations accessible to a series of DNA constructs containing 3-base-pair mismatch, suitable model lesions for the DNA repair protein xeroderma pigmentosum C (XPC) complex. XPC initiates eukaryotic nucleotide excision repair by recognizing various DNA lesions primarily through DNA deformability. Structural studies show that Rad4 (yeast ortholog of XPC) unwinds DNA at the lesion site and flips out two nucleotide pairs. Our results elucidate a broad range of conformations accessible to mismatched DNA even in the absence of the protein. Notably, the most severely distorted conformations share remarkable resemblance to the deformed conformation seen in the crystal structure of the Rad4-bound ``recognition'' complex supporting for the first time a possible ``conformational capture'' mechanism for damage recognition by XPC/Rad4. NSF Univ of Illinois-Chicago.

Quantification Bias Caused by Plasmid DNA Conformation in Quantitative Real-Time PCR Assay

PubMed Central

Lin, Chih-Hui; Chen, Yu-Chieh; Pan, Tzu-Ming

2011-01-01

Quantitative real-time PCR (qPCR) is the gold standard for the quantification of specific nucleic acid sequences. However, a serious concern has been revealed in a recent report: supercoiled plasmid standards cause significant over-estimation in qPCR quantification. In this study, we investigated the effect of plasmid DNA conformation on the quantification of DNA and the efficiency of qPCR. Our results suggest that plasmid DNA conformation has significant impact on the accuracy of absolute quantification by qPCR. DNA standard curves shifted significantly among plasmid standards with different DNA conformations. Moreover, the choice of DNA measurement method and plasmid DNA conformation may also contribute to the measurement error of DNA standard curves. Due to the multiple effects of plasmid DNA conformation on the accuracy of qPCR, efforts should be made to assure the highest consistency of plasmid standards for qPCR. Thus, we suggest that the conformation, preparation, quantification, purification, handling, and storage of standard plasmid DNA should be described and defined in the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) to assure the reproducibility and accuracy of qPCR absolute quantification. PMID:22194997

Structural alphabets derived from attractors in conformational space

PubMed Central

2010-01-01

Background The hierarchical and partially redundant nature of protein structures justifies the definition of frequently occurring conformations of short fragments as 'states'. Collections of selected representatives for these states define Structural Alphabets, describing the most typical local conformations within protein structures. These alphabets form a bridge between the string-oriented methods of sequence analysis and the coordinate-oriented methods of protein structure analysis. Results A Structural Alphabet has been derived by clustering all four-residue fragments of a high-resolution subset of the protein data bank and extracting the high-density states as representative conformational states. Each fragment is uniquely defined by a set of three independent angles corresponding to its degrees of freedom, capturing in simple and intuitive terms the properties of the conformational space. The fragments of the Structural Alphabet are equivalent to the conformational attractors and therefore yield a most informative encoding of proteins. Proteins can be reconstructed within the experimental uncertainty in structure determination and ensembles of structures can be encoded with accuracy and robustness. Conclusions The density-based Structural Alphabet provides a novel tool to describe local conformations and it is specifically suitable for application in studies of protein dynamics. PMID:20170534

Evaluations of the conformational search accuracy of CAMDAS using experimental three-dimensional structures of protein-ligand complexes

NASA Astrophysics Data System (ADS)

Oda, A.; Yamaotsu, N.; Hirono, S.; Takano, Y.; Fukuyoshi, S.; Nakagaki, R.; Takahashi, O.

2013-08-01

CAMDAS is a conformational search program, through which high temperature molecular dynamics (MD) calculations are carried out. In this study, the conformational search ability of CAMDAS was evaluated using structurally known 281 protein-ligand complexes as a test set. For the test, the influences of initial settings and initial conformations on search results were validated. By using the CAMDAS program, reasonable conformations whose root mean square deviations (RMSDs) in comparison with crystal structures were less than 2.0 Å could be obtained from 96% of the test set even though the worst initial settings were used. The success rate was comparable to those of OMEGA, and the errors of CAMDAS were less than those of OMEGA. Based on the results obtained using CAMDAS, the worst RMSD was around 2.5 Å, although the worst value obtained was around 4.0 Å using OMEGA. The results indicated that CAMDAS is a robust and versatile conformational search method and that it can be used for a wide variety of small molecules. In addition, the accuracy of a conformational search in relation to this study was improved by longer MD calculations and multiple MD simulations.

Air Quality Conformity for Fiscal Years 1997-2000 Transportation Improvement Program for the Cincinnati Nonattainment Region

DOT National Transportation Integrated Search

1996-06-01

The Clean Air Act Amendments (CAAA) of 1990 required emissions reductions in : nonattainment areas. The CAAA contains conformity provisions requiring : transportation plans and programs to conform to air quality plans. Based on the : documented analy...

pH-directed self-assembling helical peptide conformation

USDA-ARS?s Scientific Manuscript database

The beta-sheet and alpha-helix peptide conformation are two of the most fundamentally ordered secondary structures found in proteins and peptides. They also give rise to self-assembling motifs that form macromolecular channels and nanostructures. Through design these conformations can yield enhance...

47 CFR 15.101 - Equipment authorization of unintentional radiators.

Code of Federal Regulations, 2014 CFR

2014-10-01

.... TV interface device Declaration of Conformity or Certification. Cable system terminal device Declaration of Conformity. Stand-alone cable input selector switch Verification. Class B personal computers... used with Class B personal computers Declaration of Conformity or Certification. 1 Class B personal...

47 CFR 15.101 - Equipment authorization of unintentional radiators.

Code of Federal Regulations, 2010 CFR

2010-10-01

.... TV interface device Declaration of Conformity or Certification. Cable system terminal device Declaration of Conformity. Stand-alone cable input selector switch Verification. Class B personal computers... used with Class B personal computers Declaration of Conformity or Certification. 1 Class B personal...

47 CFR 15.101 - Equipment authorization of unintentional radiators.

Code of Federal Regulations, 2012 CFR

2012-10-01

.... TV interface device Declaration of Conformity or Certification. Cable system terminal device Declaration of Conformity. Stand-alone cable input selector switch Verification. Class B personal computers... used with Class B personal computers Declaration of Conformity or Certification. 1 Class B personal...

47 CFR 15.101 - Equipment authorization of unintentional radiators.

Code of Federal Regulations, 2011 CFR

2011-10-01

.... TV interface device Declaration of Conformity or Certification. Cable system terminal device Declaration of Conformity. Stand-alone cable input selector switch Verification. Class B personal computers... used with Class B personal computers Declaration of Conformity or Certification. 1 Class B personal...

47 CFR 15.101 - Equipment authorization of unintentional radiators.

Code of Federal Regulations, 2013 CFR

2013-10-01

.... TV interface device Declaration of Conformity or Certification. Cable system terminal device Declaration of Conformity. Stand-alone cable input selector switch Verification. Class B personal computers... used with Class B personal computers Declaration of Conformity or Certification. 1 Class B personal...

Hawking radiation by Kerr black holes and conformal symmetry.

PubMed

Agullo, Ivan; Navarro-Salas, José; Olmo, Gonzalo J; Parker, Leonard

2010-11-19

The exponential blueshift associated with the event horizon of a black hole makes conformal symmetry play a fundamental role in accounting for its thermal properties. Using a derivation based on two-point functions, we show that the full spectrum of thermal radiation of scalar particles by Kerr black holes can be explicitly derived on the basis of a conformal symmetry arising in the wave equation near the horizon. The simplicity of our approach emphasizes the depth of the connection between conformal symmetry and black hole radiance.

Pyruvate Dehydrogenase Kinase-4 Structures Reveal a Metastable Open Conformation Fostering Robust Core-free Basal Activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wynn, R. Max; Kato, Masato; Chuang, Jacinta L.

2008-10-21

Human pyruvate dehydrogenase complex (PDC) is down-regulated by pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization. Here we show that human PDK4 has robust core-free basal activity, which is considerably higher than activity levels of other PDK isoforms stimulated by the PDC core. PDK4 binds the L3 lipoyl domain, but its activity is not significantly stimulated by any individual lipoyl domains or the core of PDC. The 2.0-{angstrom} crystal structures of the PDK4 dimer with bound ADP reveal an open conformation with a wider active-site cleft, comparedmore » with that in the closed conformation epitomized by the PDK2-ADP structure. The open conformation in PDK4 shows partially ordered C-terminal cross-tails, in which the conserved DW (Asp{sup 394}-Trp{sup 395}) motif from one subunit anchors to the N-terminal domain of the other subunit. The open conformation fosters a reduced binding affinity for ADP, facilitating the efficient removal of product inhibition by this nucleotide. Alteration or deletion of the DW-motif disrupts the C-terminal cross-tail anchor, resulting in the closed conformation and the nearly complete inactivation of PDK4. Fluorescence quenching and enzyme activity data suggest that compounds AZD7545 and dichloroacetate lock PDK4 in the open and the closed conformational states, respectively. We propose that PDK4 with bound ADP exists in equilibrium between the open and the closed conformations. The favored metastable open conformation is responsible for the robust basal activity of PDK4 in the absence of the PDC core.« less

Flaws in foldamers: conformational uniformity and signal decay in achiral helical peptide oligomers† †Electronic supplementary information (ESI) available: Synthesis and characterisation of all new compounds. See DOI: 10.1039/c4sc03944k Click here for additional data file.

PubMed Central

Le Bailly, Bryden A. F.; Byrne, Liam; Diemer, Vincent; Foroozandeh, Mohammadali; Morris, Gareth A.

2015-01-01

Although foldamers, by definition, are extended molecular structures with a well-defined conformation, minor conformers must be populated at least to some extent in solution. We present a quantitative analysis of these minor conformers for a series of helical oligomers built from achiral but helicogenic α-amino acids. By measuring the chain length dependence or chain position dependence of NMR or CD quantities that measure screw-sense preference in a helical oligomer, we quantify values for the decay constant of a conformational signal as it passes through the molecular structure. This conformational signal is a perturbation of the racemic mixture of M and P helices that such oligomers typically adopt by the inclusion of an N or C terminal chiral inducer. We show that decay constants may be very low (<1% signal loss per residue) in non-polar solvents, and we evaluate the increase in decay constant that results in polar solvents, at higher temperatures, and with more conformationally flexible residues such as Gly. Decay constants are independent of whether the signal originates from the N or the C terminus. By interpreting the decay constant in terms of the probability with which conformations containing a screw-sense reversal are populated, we quantify the populations of these alternative minor conformers within the overall ensemble of secondary structures adopted by the foldamer. We deduce helical persistence lengths for Aib polymers that allow us to show that in a non-polar solvent a peptide helix, even in the absence of chiral residues, may continue with the same screw sense for approximately 200 residues. PMID:29308146

Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation

PubMed Central

Li, Jing; Boulanger, Eliot; Rui, Huan; Perozo, Eduardo; Roux, Benoît

2017-01-01

In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a “constricted” conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation. PMID:28973956

Distance geometry protocol to generate conformations of natural products to structurally interpret ion mobility-mass spectrometry collision cross sections.

PubMed

Stow, Sarah M; Goodwin, Cody R; Kliman, Michal; Bachmann, Brian O; McLean, John A; Lybrand, Terry P

2014-12-04

Ion mobility-mass spectrometry (IM-MS) allows the separation of ionized molecules based on their charge-to-surface area (IM) and mass-to-charge ratio (MS), respectively. The IM drift time data that is obtained is used to calculate the ion-neutral collision cross section (CCS) of the ionized molecule with the neutral drift gas, which is directly related to the ion conformation and hence molecular size and shape. Studying the conformational landscape of these ionized molecules computationally provides interpretation to delineate the potential structures that these CCS values could represent, or conversely, structural motifs not consistent with the IM data. A challenge in the IM-MS community is the ability to rapidly compute conformations to interpret natural product data, a class of molecules exhibiting a broad range of biological activity. The diversity of biological activity is, in part, related to the unique structural characteristics often observed for natural products. Contemporary approaches to structurally interpret IM-MS data for peptides and proteins typically utilize molecular dynamics (MD) simulations to sample conformational space. However, MD calculations are computationally expensive, they require a force field that accurately describes the molecule of interest, and there is no simple metric that indicates when sufficient conformational sampling has been achieved. Distance geometry is a computationally inexpensive approach that creates conformations based on sampling different pairwise distances between the atoms within the molecule and therefore does not require a force field. Progressively larger distance bounds can be used in distance geometry calculations, providing in principle a strategy to assess when all plausible conformations have been sampled. Our results suggest that distance geometry is a computationally efficient and potentially superior strategy for conformational analysis of natural products to interpret gas-phase CCS data.

Ligand binding turns moth pheromone-binding protein into a pH sensor: effect on the Antheraea polyphemus PBP1 conformation.

PubMed

Katre, Uma V; Mazumder, Suman; Prusti, Rabi K; Mohanty, Smita

2009-11-13

In moths, pheromone-binding proteins (PBPs) are responsible for the transport of the hydrophobic pheromones to the membrane-bound receptors across the aqueous sensillar lymph. We report here that recombinant Antheraea polyphemus PBP1 (ApolPBP1) picks up hydrophobic molecule(s) endogenous to the Escherichia coli expression host that keeps the protein in the "open" (bound) conformation at high pH but switches to the "closed" (free) conformation at low pH. This finding has bearing on the solution structures of undelipidated lepidopteran moth PBPs determined thus far. Picking up a hydrophobic molecule from the host expression system could be a common feature for lipid-binding proteins. Thus, delipidation is critical for bacterially expressed lipid-binding proteins. We have shown for the first time that the delipidated ApolPBP1 exists primarily in the closed form at all pH levels. Thus, current views on the pH-induced conformational switch of PBPs hold true only for the ligand-bound open conformation of the protein. Binding of various ligands to delipidated ApolPBP1 studied by solution NMR revealed that the protein in the closed conformation switches to the open conformation only at or above pH 6.0 with a protein to ligand stoichiometry of approximately 1:1. Mutation of His(70) and His(95) to alanine drives the equilibrium toward the open conformation even at low pH for the ligand-bound protein by eliminating the histidine-dependent pH-induced conformational switch. Thus, the delipidated double mutant can bind ligand even at low pH in contrast to the wild type protein as revealed by fluorescence competitive displacement assay using 1-aminoanthracene and solution NMR.

Distance Geometry Protocol to Generate Conformations of Natural Products to Structurally Interpret Ion Mobility-Mass Spectrometry Collision Cross Sections

PubMed Central

2015-01-01

Ion mobility-mass spectrometry (IM-MS) allows the separation of ionized molecules based on their charge-to-surface area (IM) and mass-to-charge ratio (MS), respectively. The IM drift time data that is obtained is used to calculate the ion-neutral collision cross section (CCS) of the ionized molecule with the neutral drift gas, which is directly related to the ion conformation and hence molecular size and shape. Studying the conformational landscape of these ionized molecules computationally provides interpretation to delineate the potential structures that these CCS values could represent, or conversely, structural motifs not consistent with the IM data. A challenge in the IM-MS community is the ability to rapidly compute conformations to interpret natural product data, a class of molecules exhibiting a broad range of biological activity. The diversity of biological activity is, in part, related to the unique structural characteristics often observed for natural products. Contemporary approaches to structurally interpret IM-MS data for peptides and proteins typically utilize molecular dynamics (MD) simulations to sample conformational space. However, MD calculations are computationally expensive, they require a force field that accurately describes the molecule of interest, and there is no simple metric that indicates when sufficient conformational sampling has been achieved. Distance geometry is a computationally inexpensive approach that creates conformations based on sampling different pairwise distances between the atoms within the molecule and therefore does not require a force field. Progressively larger distance bounds can be used in distance geometry calculations, providing in principle a strategy to assess when all plausible conformations have been sampled. Our results suggest that distance geometry is a computationally efficient and potentially superior strategy for conformational analysis of natural products to interpret gas-phase CCS data. PMID:25360896

Evolutionary-inspired probabilistic search for enhancing sampling of local minima in the protein energy surface

PubMed Central

2012-01-01

Background Despite computational challenges, elucidating conformations that a protein system assumes under physiologic conditions for the purpose of biological activity is a central problem in computational structural biology. While these conformations are associated with low energies in the energy surface that underlies the protein conformational space, few existing conformational search algorithms focus on explicitly sampling low-energy local minima in the protein energy surface. Methods This work proposes a novel probabilistic search framework, PLOW, that explicitly samples low-energy local minima in the protein energy surface. The framework combines algorithmic ingredients from evolutionary computation and computational structural biology to effectively explore the subspace of local minima. A greedy local search maps a conformation sampled in conformational space to a nearby local minimum. A perturbation move jumps out of a local minimum to obtain a new starting conformation for the greedy local search. The process repeats in an iterative fashion, resulting in a trajectory-based exploration of the subspace of local minima. Results and conclusions The analysis of PLOW's performance shows that, by navigating only the subspace of local minima, PLOW is able to sample conformations near a protein's native structure, either more effectively or as well as state-of-the-art methods that focus on reproducing the native structure for a protein system. Analysis of the actual subspace of local minima shows that PLOW samples this subspace more effectively that a naive sampling approach. Additional theoretical analysis reveals that the perturbation function employed by PLOW is key to its ability to sample a diverse set of low-energy conformations. This analysis also suggests directions for further research and novel applications for the proposed framework. PMID:22759582

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

Probing Na+ Induced Changes in the HIV-1 TAR Conformational Dynamics using NMR Residual Dipolar Couplings: New Insights into the Role of Counterions and Electrostatic Interactions in Adaptive Recognition†

PubMed Central

Casiano-Negroni, Anette; Sun, Xiaoyan; Al-Hashimi, Hashim M.

2012-01-01

Many regulatory RNAs undergo large changes in structure upon recognition of proteins and ligands but the mechanism by which this occur remains poorly understood. Using NMR residual dipolar coupling (RDCs), we characterized Na+ induced changes in the structure and dynamics of the bulge-containing HIV-1 transactivation response element (TAR) RNA that mirror changes induced by small molecules bearing a different number of cationic groups. Increasing the Na+ concentration from 25 mM to 320 mM led to a continuous reduction in the average inter-helical bend angle (from 46° to 22°), inter-helical twist angle (from 66° to −18°) and inter-helix flexibility (as measured by an increase in the internal generalized degree of order from 0.56 to 0.74). Similar conformational changes were observed with Mg2+, indicating that non-specific electrostatic interactions drive the conformational transition, although results also suggest that Na+ and Mg2+ may associate with TAR in distinct modes. The transition can be rationalized based on a population-weighted average of two ensembles comprising an electrostatically relaxed bent and flexible TAR conformation that is weakly associated with counterions, and a globally rigid coaxial conformation which has stronger electrostatic potential and association with counterions. The TAR inter-helical orientations that are stabilized by small molecules fall around the metal-induced conformational pathway, indicating that counterions may help predispose the TAR conformation for target recognition. Our results underscore the intricate sensitivity of RNA conformational dynamics to environmental conditions and demonstrate the ability to detect subtle conformational changes using NMR RDCs. PMID:17488097

Role and structural mechanism of WASP-triggered conformational changes in branched actin filament nucleation by Arp2/3 complex.

PubMed

Rodnick-Smith, Max; Luan, Qing; Liu, Su-Ling; Nolen, Brad J

2016-07-05

The Arp2/3 (Actin-related proteins 2/3) complex is activated by WASP (Wiskott-Aldrich syndrome protein) family proteins to nucleate branched actin filaments that are important for cellular motility. WASP recruits actin monomers to the complex and stimulates movement of Arp2 and Arp3 into a "short-pitch" conformation that mimics the arrangement of actin subunits within filaments. The relative contribution of these functions in Arp2/3 complex activation and the mechanism by which WASP stimulates the conformational change have been unknown. We purified budding yeast Arp2/3 complex held in or near the short-pitch conformation by an engineered covalent cross-link to determine if the WASP-induced conformational change is sufficient for activity. Remarkably, cross-linked Arp2/3 complex bypasses the need for WASP in activation and is more active than WASP-activated Arp2/3 complex. These data indicate that stimulation of the short-pitch conformation is the critical activating function of WASP and that monomer delivery is not a fundamental requirement for nucleation but is a specific requirement for WASP-mediated activation. During activation, WASP limits nucleation rates by releasing slowly from nascent branches. The cross-linked complex is inhibited by WASP's CA region, even though CA potently stimulates cross-linking, suggesting that slow WASP detachment masks the activating potential of the short-pitch conformational switch. We use structure-based mutations and WASP-Arp fusion chimeras to determine how WASP stimulates movement toward the short-pitch conformation. Our data indicate that WASP displaces the autoinhibitory Arp3 C-terminal tail from a hydrophobic groove at Arp3's barbed end to destabilize the inactive state, providing a mechanism by which WASP stimulates the short-pitch conformation and activates Arp2/3 complex.

Peptide models XLV: conformational properties of N-formyl-L-methioninamide and its relevance to methionine in proteins.

PubMed

Láng, András; Csizmadia, Imre G; Perczel, András

2005-02-15

The conformational space of the most biologically significant backbone folds of a suitable methionine peptide model was explored by density functional computational method. Using a medium [6-31G(d)] and a larger basis set [6-311++G(2d,2p)], the systematic exploration of low-energy backbone structures restricted for the "L-region" in the Ramachandran map of N-formyl-L-methioninamide results in conformers corresponding to the building units of an extended backbone structure (betaL), an inverse gamma-turn (gammaL), or a right-handed helical structure (alphaL). However, no poly-proline II type (epsilonL) fold was found, indicating that this conformer has no intrinsic stability, and highlighting the effect of molecular environment in stabilizing this backbone structure. This is in agreement with the abundance of the epsilonL-type backbone conformation of methionine found in proteins. Stability properties (DeltaE) and distinct backbone-side-chain interactions support the idea that specific intramolecular contacts are operative in the selection of the lowest energy conformers. Apart from the number of different folds, all stable conformers are within a 10 kcal x mol(-1) energy range, indicating the highly flexible behavior of methionine. This conformational feature can be important in supporting catalytic processes, facilitating protein folding and dimerization via metal ion binding. In both of the biological examples discussed (HIV-1 reverse transcriptase and PcoC copper-resistant protein), the conformational properties of Met residues were found to be of key importance. Spatial proximity to other types of residues or the same type of residue seems to be crucial for the structural integrity of a protein, whether Met is buried or exposed.

Modeling of a C-end rule peptide adsorbed onto gold nanoparticles.

PubMed

Triguero, Jordi; Flores-Ortega, Alejandra; Zanuy, David; Alemán, Carlos

2018-01-01

The RPAR peptide, a prototype C-end Rule (CendR) sequence that binds to neuropilin-1 (NRP-1), has potential therapeutic uses as internalization trigger in anticancer nanodevices. Recently, the functionalization of gold nanoparticles with CendR peptides has been proved to be a successful strategy to target the NRP-1 receptor in prostate cancer cells. In this work, we investigate the influence of two gold surface facets, (100) and (111), on the conformational preferences of RPAR using molecular dynamics simulations. Both clustering and conformational analyses revealed that the peptide backbone becomes very rigid upon adsorption onto gold, which is a very fast and favored process, the only flexibility being attributed to the side chains of the two Arg residues. Thus, the different components of RPAR tend to adopt an elongated shape, which is characterized by the pseudo-extended conformation of both the backbone and the Arg side chains. This conformation is very different from the already known bioactive conformation, indicating that RPAR is drastically affected by the substrate. Interestingly, the preferred conformations of the peptide adsorbed onto gold facets are not stabilized by salt bridges and/or specific intramolecular hydrogen bonds, which represent an important difference with respect to the conformations found in other environments (e.g. the peptide in solution and interacting with NRP-1 receptor). However, the conformational changes induced by the substrate are not detrimental for the use of gold nanoparticles as appropriate vehicles for the transport and targeted delivery of the RPAR. Thus, once their high affinity for the NRP-1 receptor induces the targeted delivery of the elongated peptide molecules from the gold nanoparticles, the lack of intramolecular interactions facilitates their evolution towards the bioactive conformation, increasing the therapeutic efficacy of the peptide. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity.

PubMed

Wynn, R Max; Kato, Masato; Chuang, Jacinta L; Tso, Shih-Chia; Li, Jun; Chuang, David T

2008-09-12

Human pyruvate dehydrogenase complex (PDC) is down-regulated by pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization. Here we show that human PDK4 has robust core-free basal activity, which is considerably higher than activity levels of other PDK isoforms stimulated by the PDC core. PDK4 binds the L3 lipoyl domain, but its activity is not significantly stimulated by any individual lipoyl domains or the core of PDC. The 2.0-A crystal structures of the PDK4 dimer with bound ADP reveal an open conformation with a wider active-site cleft, compared with that in the closed conformation epitomized by the PDK2-ADP structure. The open conformation in PDK4 shows partially ordered C-terminal cross-tails, in which the conserved DW (Asp(394)-Trp(395)) motif from one subunit anchors to the N-terminal domain of the other subunit. The open conformation fosters a reduced binding affinity for ADP, facilitating the efficient removal of product inhibition by this nucleotide. Alteration or deletion of the DW-motif disrupts the C-terminal cross-tail anchor, resulting in the closed conformation and the nearly complete inactivation of PDK4. Fluorescence quenching and enzyme activity data suggest that compounds AZD7545 and dichloroacetate lock PDK4 in the open and the closed conformational states, respectively. We propose that PDK4 with bound ADP exists in equilibrium between the open and the closed conformations. The favored metastable open conformation is responsible for the robust basal activity of PDK4 in the absence of the PDC core.

Can an Endplate-conformed Cervical Cage Provide a Better Biomechanical Environment than a Typical Non-conformed Cage?: A Finite Element Model and Cadaver Study.

PubMed

Zhang, Fan; Xu, Hao-Cheng; Yin, Bo; Xia, Xin-Lei; Ma, Xiao-Sheng; Wang, Hong-Li; Yin, Jun; Shao, Ming-Hao; Lyu, Fei-Zhou; Jiang, Jian-Yuan

2016-08-01

To evaluate the biomechanical characteristics of endplate-conformed cervical cages by finite element method (FEM) analysis and cadaver study. Twelve specimens (C2 -C7 ) and a finite element model (C3 -C7 ) were subjected to biomechanical evaluations. In the cadaver study, specimens were randomly assigned to intact (I), endplate-conformed (C) and non-conformed (N) groups with C4-5 discs as the treated segments. The morphologies of the endplate-conformed cages were individualized according to CT images of group C and the cages fabricated with a 3-D printer. The non-conformed cages were wedge-shaped and similar to commercially available grafts. Axial pre-compression loads of 73.6 N and moment of 1.8 Nm were used to simulate flexion (FLE), extension (EXT), lateral bending (LB) and axial rotation (AR). Range of motion (ROM) at C4-5 of each specimen was recorded and film sensors fixed between the cages and C5 superior endplates were used to detect interface stress. A finite element model was built based on the CT data of a healthy male volunteer. The morphologies of the endplate-conformed and wedge-shaped, non-conformed cervical cages were both simulated by a reverse engineering technique and implanted at the segment of C4-5 in the finite element model for biomechanical evaluation. Force loading and grouping were similar to those applied in the cadaver study. ROM of C4-5 in group I were recorded to validate the finite element model. Additionally, maximum cage-endplate interface stresses, stress distribution contours on adjoining endplates, intra-disc stresses and facet loadings at adjacent segments were measured and compared between groups. In the cadaver study, Group C showed a much lower interface stress in all directions of motion (all P < 0.05) and the ROM of C4-5 was smaller in FLE-EXT (P = 0.001) but larger in AR (P = 0.017). FEM analysis produced similar results: the model implanted with an endplate-conformed cage presented a lower interface stress with a more uniform stress distribution than that implanted with a non-conformed cage. Additionally, intra-disc stress and facet loading at the adjacent segments were obviously increased in both groups C and N, especially those at the supra-jacent segments. However, stress increase was milder in group C than in group N for all directions of motion. Endplate-conformed cages can decrease cage-endplate interface stress in all directions of motion and increase cervical stability in FLE-EXT. Additionally, adjacent segments are possibly protected because intra-disc stress and facet loading are smaller after endplate-conformed cage implantation. However, axial stability was reduced in group C, indicating that endplate-conformed cage should not be used alone and an anterior plate system is still important in anterior cervical discectomy and fusion. © 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.

Spectra and structure of silicon containing compounds. XXXII. Raman and infrared spectra, conformational stability, vibrational assignment and ab initio calculations of n-propylsilane-d0 and Si-d3.

PubMed

Durig, James R; Pan, Chunhua; Guirgis, Gamil A

2003-03-15

The infrared (3100-40 cm(-1)) and Raman (3100-20 cm(-1)) spectra of gaseous and solid n-propylsilane, CH(3)CH(2)CH(2)SiH(3) and the Si-d(3) isotopomer, CH(3)CH(2)CH(2)SiD(3), have been recorded. Additionally, the Raman spectra of the liquids have been recorded and qualitative depolarization values obtained. Both the anti and gauche conformers have been identified in the fluid phases but only the anti conformer remains in the solid. Variable temperature (-105 to -150 degrees C) studies of the infrared spectra of n-propylsilane dissolved in liquid krypton have been recorded and the enthalpy difference has been determined to be 220+/-22 cm(-1) (2.63+/-0.26 kJ mol(-1)) with the anti conformer the more stable form. A similar value of 234+/-23 cm(-1) (2.80+/-0.28 kJ mol(-1)) was obtained for deltaH for the Si-d(3) isotopomer. At ambient temperature it is estimated that there is 30+/-2% of the gauche conformer present. The potential function governing the conformation interchange has been estimated from the far infrared spectral data, the enthalpy difference, and the dihedral angle of the gauche conformer, which is compared to the one predicted from ab initio MP2/6-31G(d) calculations. The barriers to conformational interchange are: 942, 970 and 716 cm(-1) for the anti to gauche, gauche to gauche, and gauche to anti conformers, respectively. Relatively complete vibrational assignments are proposed for both the n-propylsilane-d(0) and Si-d(3) molecules based on the relative infrared and Raman spectral intensities, infrared band contours, depolarization ratios, and normal coordinate calculations. The geometrical parameters, harmonic force constants, vibrational frequencies, infrared intensities, Raman activities and depolarization ratios, and energy differences have been obtained for the anti and gauche conformers from ab initio MP2/6-31G(d) calculations. Structural parameters and energy differences have also been obtained utilizing the larger 6-311 + G(d,p) and 6-311 + G(2d,2p) basis sets. From the isolated Si-H stretching frequency from the Si-d(2) isotopomer the r(0) distances of 1.484 and 1.485 A have been determined for the SiH(s) and SiH(a) bonds, respectively, for the anti conformer, and 1.486 A for the SiH bond for the gauche conformer. Utilizing previously reported microwave rotational constants for the anti conformer and the determined SiH distances along with ab initio predicted parameters 'adjusted r(0)' parameters have been obtained for the anti conformer. The results are discussed and compared to those obtained for some similar molecules. Copyright 2002 Elsevier Science B.V.

Spectra and structure of silicon containing compounds. XXXII. Raman and infrared spectra, conformational stability, vibrational assignment and ab initio calculations of n-propylsilane-d 0 and Si-d 3

NASA Astrophysics Data System (ADS)

Durig, James R.; Pan, Chunhua; Guirgis, Gamil A.

2003-03-01

The infrared (3100-40 cm -1) and Raman (3100-20 cm -1) spectra of gaseous and solid n-propylsilane, CH 3CH 2CH 2SiH 3 and the Si-d 3 isotopomer, CH 3CH 2CH 2SiD 3, have been recorded. Additionally, the Raman spectra of the liquids have been recorded and qualitative depolarization values obtained. Both the anti and gauche conformers have been identified in the fluid phases but only the anti conformer remains in the solid. Variable temperature (-105 to -150 °C) studies of the infrared spectra of n-propylsilane dissolved in liquid krypton have been recorded and the enthalpy difference has been determined to be 220±22 cm -1 (2.63±0.26 kJ mol -1) with the anti conformer the more stable form. A similar value of 234±23 cm -1 (2.80±0.28 kJ mol -1) was obtained for Δ H for the Si-d 3 isotopomer. At ambient temperature it is estimated that there is 30±2% of the gauche conformer present. The potential function governing the conformation interchange has been estimated from the far infrared spectral data, the enthalpy difference, and the dihedral angle of the gauche conformer, which is compared to the one predicted from ab initio MP2/6-31G(d) calculations. The barriers to conformational interchange are: 942, 970 and 716 cm -1 for the anti to gauche, gauche to gauche, and gauche to anti conformers, respectively. Relatively complete vibrational assignments are proposed for both the n-propylsilane-d 0 and Si-d 3 molecules based on the relative infrared and Raman spectral intensities, infrared band contours, depolarization ratios, and normal coordinate calculations. The geometrical parameters, harmonic force constants, vibrational frequencies, infrared intensities, Raman activities and depolarization ratios, and energy differences have been obtained for the anti and gauche conformers from ab initio MP2/6-31G(d) calculations. Structural parameters and energy differences have also been obtained utilizing the larger 6-311+G(d,p) and 6-311+G(2d,2p) basis sets. From the isolated SiH stretching frequency from the Si-d 2 isotopomer the r0 distances of 1.484 and 1.485 Å have been determined for the SiH s and SiH a bonds, respectively, for the anti conformer, and 1.486 Å for the SiH bond for the gauche conformer. Utilizing previously reported microwave rotational constants for the anti conformer and the determined SiH distances along with ab initio predicted parameters 'adjusted r0' parameters have been obtained for the anti conformer. The results are discussed and compared to those obtained for some similar molecules.

Gas-phase conformations of 2-methyl-1,3-dithiolane investigated by microwave spectroscopy

NASA Astrophysics Data System (ADS)

Van, Vinh; Stahl, Wolfgang; Schwell, Martin; Nguyen, Ha Vinh Lam

2018-03-01

The conformational analysis of 2-methyl-1,3-dithiolane using quantum chemical calculations at some levels of theory yielded only one stable conformer with envelope geometry. However, other levels of theory indicated two envelope conformers. Analysis of the microwave spectrum recorded using two molecular jet Fourier transform microwave spectrometers covering the frequency range from 2 to 40 GHz confirms that only one conformer exists under jet conditions. The experimental spectrum was reproduced using a rigid-rotor model with centrifugal distortion correction within the measurement accuracy of 1.5 kHz, and molecular parameters were determined with very high accuracy. The gas phase structure of the title molecule is compared with the structures of other related molecules studied under the same experimental conditions.

Downregulation of the posterior medial frontal cortex prevents social conformity.

PubMed

Klucharev, Vasily; Munneke, Moniek A M; Smidts, Ale; Fernández, Guillén

2011-08-17

We often change our behavior to conform to real or imagined group pressure. Social influence on our behavior has been extensively studied in social psychology, but its neural mechanisms have remained largely unknown. Here we demonstrate that the transient downregulation of the posterior medial frontal cortex by theta-burst transcranial magnetic stimulation reduces conformity, as indicated by reduced conformal adjustments in line with group opinion. Both the extent and probability of conformal behavioral adjustments decreased significantly relative to a sham and a control stimulation over another brain area. The posterior part of the medial frontal cortex has previously been implicated in behavioral and attitudinal adjustments. Here, we provide the first interventional evidence of its critical role in social influence on human behavior.

How and How Much Molecular Conformation Affects Electronic Circular Dichroism: The Case of 1,1-Diarylcarbinols.

PubMed

Padula, Daniele; Pescitelli, Gennaro

2018-01-09

Chiroptical spectra such as electronic circular dichroism (ECD) are said to be much more sensitive to conformation than their non-chiroptical counterparts, however, it is difficult to demonstrate such a common notion in a clear-cut way. We run DFT and TDDFT calculations on two closely related 1,1-diarylmethanols which show mirror-image ECD spectra for the same absolute configuration. We demonstrate that the main reason for the different chiroptical response of the two compounds lies in different conformational ensembles, caused by a single hydrogen-to-methyl substitution. We conclude that two compounds, having the same configuration but different conformation, may exhibit mirror-image ECD signals, stressing the importance and impact of conformational factors on ECD spectra.

Difference in dimer conformation between amyloid-β(1-42) and (1-43) proteins: Replica exchange molecular dynamics simulations in water

NASA Astrophysics Data System (ADS)

Yano, Atsushi; Okamoto, Akisumi; Nomura, Kazuya; Higai, Shin'ichi; Kurita, Noriyuki

2014-03-01

We searched stable conformations of amyloid-β (Aβ) dimers composed of Aβ(1-42) or Aβ(1-43) protein in water by replica-exchange molecular dynamics simulations and found that Thr43 of the C-terminal of Aβ(1-43) is hydrogen bonded to Arg5 of the same monomer in the Aβ(1-43) dimer, resulting in its ring-shaped conformation, while Aβ(1-42) has no such hydrogen-bond. This conformation is expected to aggregate more easily into a compact conformation of Aβ fibrils. We also investigated the binding affinity and the specific interactions between Aβ monomers by ab initio fragment molecular orbital calculations to elucidate which Aβ residues contribute to the dimerization.

Spectroscopic study of jet-cooled indole-3-carbinol by laser desorption technique: Franck-Condon simulations and anharmonic calculations

NASA Astrophysics Data System (ADS)

Ahn, Ahreum; Min, Ahreum; Moon, Cheol Joo; Lee, Ji Hoon; Lee, Seung Jun; Warashina, Taichi; Ishiuchi, Shun-ichi; Fujii, Masaaki; Choi, Myong Yong

2015-10-01

The conformational structure of indole-3-carbinol (I3C) has been investigated in the gas phase for the first time using a laser desorption technique. A UV-UV hole-burning technique revealed the presence of a single conformer of I3C in the mass-selected resonant two-photon ionization spectrum. The assignment of the observed IR spectrum of I3C is inconclusive due to almost identically predicted IR frequencies of the two lowest energy conformers from harmonic calculations. A conclusive assignment for the conformer of I3C has been reported with an aid of performing anharmonic calculations and Franck-Condon simulations on the two lowest-energy conformers.

Food as a way to convey masculinities: How conformity to hegemonic masculinity norms influences men's and women's food consumption.

PubMed

Campos, Lúcia; Bernardes, Sónia; Godinho, Cristina

2018-05-01

This study investigated how conformity to hegemonic masculinity norms affects men's and women's food consumption and whether such influence was contextually modulated. A total of 519 individuals (65% women; M = 44 years old) participated in a 2 (gender salience: low vs high) × 2 (participants' sex: male vs female) quasi-experimental between-subjects design, completing the Conformity to Masculinity Norms Inventory (Portuguese version) and reporting their past week's food consumption. Gender salience moderated the relation between men's conformity to masculinity norms and food consumption; sex-related differences in food consumption were partially mediated by conformity to masculinity norms. Implications for food consumption interventions are discussed.

Analysis of calcium-induced effects on the conformation of fengycin.

PubMed

Nasir, Mehmet Nail; Laurent, Pascal; Flore, Christelle; Lins, Laurence; Ongena, Marc; Deleu, Magali

2013-06-01

Fengycin is a natural lipopeptide with antifungal and eliciting properties and able to inhibit the activity of phospholipase A2. A combination of CD, FT-IR, NMR and fluorescence spectroscopic techniques was applied to elucidate its conformation in a membrane-mimicking environment and to investigate the effect of calcium ions on it. We mainly observed that fengycin adopts a turn conformation. Our results showed that calcium ions are bound by the two charged glutamates. The calcium binding has an influence on the fengycin conformation and more particularly, on the environment of the tyrosine residues. The modulation of the fengycin conformation by the environmental conditions may influence its biological properties. Copyright © 2013 Elsevier B.V. All rights reserved.

Conformal correlation functions in the Brownian loop soup

NASA Astrophysics Data System (ADS)

Camia, Federico; Gandolfi, Alberto; Kleban, Matthew

2016-01-01

We define and study a set of operators that compute statistical properties of the Brownian loop soup, a conformally invariant gas of random Brownian loops (Brownian paths constrained to begin and end at the same point) in two dimensions. We prove that the correlation functions of these operators have many of the properties of conformal primaries in a conformal field theory, and compute their conformal dimension. The dimensions are real and positive, but have the novel feature that they vary continuously as a periodic function of a real parameter. We comment on the relation of the Brownian loop soup to the free field, and use this relation to establish that the central charge of the loop soup is twice its intensity.

[Interconnection between architecture of protein globule and disposition of conformational conservative oligopeptides in proteins from one protein family].

PubMed

Batianovskiĭ, A V; Filatov, I V; Namiot, V A; Esipova, N G; Volotovskiĭ, I D

2012-01-01

It was shown that selective interactions between helical segments of macromolecules can realize in globular proteins in the segments characterized by the same periodicities of charge distribution i.e. between conformationally conservative oligopeptides. It was found that in the macromolecules of alpha-helical proteins conformationally conservative oligopeptides are disposed at a distance being characteristic of direct interactions. For representatives of many structural families of alpha-type proteins specific disposition of conformationally conservative segments is observed. This disposition is inherent to a particular structural family. Disposition of conformationally conservative segments is not related to homology of the amino acid sequence but reflects peculiarities of native 3D-architectures of protein globules.

Conformal Killing horizons and their thermodynamics

NASA Astrophysics Data System (ADS)

Nielsen, Alex B.; Shoom, Andrey A.

2018-05-01

Certain dynamical black hole solutions can be mapped to static spacetimes by conformal metric transformations. This mapping provides a physical link between the conformal Killing horizon of the dynamical black hole and the Killing horizon of the static spacetime. Using the Vaidya spacetime as an example, we show how this conformal relation can be used to derive thermodynamic properties of such dynamical black holes. Although these horizons are defined quasi-locally and can be located by local experiments, they are distinct from other popular notions of quasi-local horizons such as apparent horizons. Thus in the dynamical Vaidya spacetime describing constant accretion of null dust, the conformal Killing horizon, which is null by construction, is the natural horizon to describe the black hole.

Real-space visualization of conformation-independent oligothiophene electronic structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taber, Benjamen N.; Kislitsyn, Dmitry A.; Gervasi, Christian F.

2016-05-21

We present scanning tunneling microscopy and spectroscopy (STM/STS) investigations of the electronic structures of different alkyl-substituted oligothiophenes on the Au(111) surface. STM imaging showed that on Au(111), oligothiophenes adopted distinct straight and bent conformations. By combining STS maps with STM images, we visualize, in real space, particle-in-a-box-like oligothiophene molecular orbitals. We demonstrate that different planar conformers with significant geometrical distortions of oligothiophene backbones surprisingly exhibit very similar electronic structures, indicating a low degree of conformation-induced electronic disorder. The agreement of these results with gas-phase density functional theory calculations implies that the oligothiophene interaction with the Au(111) surface is generally insensitivemore » to molecular conformation.« less

Dimensionality of Social Influence.

ERIC Educational Resources Information Center

Stricker, Lawrence J.; Jackson, Douglas N.

The research reported in this study explores two problematic avenues of conformity research: (1) the widely assumed generality of diverse measures of group pressure, and (2) the dimensionality of conformity, anticonformity, and independence. These two conformity situations, present and nonpresent norm groups, used two tasks (an objective counting…

75 FR 54773 - Approval and Promulgation of Air Quality Implementation Plans; Minnesota; Carbon Monoxide (CO...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

.... Monitoring Network and Verification of Continued Attainment 4. Contingency Plan 5. Conformity Determination... Continued Attainment, Contingency Plan, and Conformity Determinations Under Limited Maintenance Plans. These.../Verification of Continued Attainment, Contingency Plan, and Conformity Determination Under Limited Maintenance...

Sex Differences in Influenceability

ERIC Educational Resources Information Center

Eagly, Alice H.

1978-01-01

Examines the hypothesis that women are more easily influenced than men by reviewing the literature on persuasion and conformity research. Persuasion research and conformity studies not involving group pressure show scant empirical support for sex differences. For group pressure conformity research, a substantial minority of studies support the…

Residue-Specific Side-Chain Polymorphisms via Particle Belief Propagation.

PubMed

Ghoraie, Laleh Soltan; Burkowski, Forbes; Li, Shuai Cheng; Zhu, Mu

2014-01-01

Protein side chains populate diverse conformational ensembles in crystals. Despite much evidence that there is widespread conformational polymorphism in protein side chains, most of the X-ray crystallography data are modeled by single conformations in the Protein Data Bank. The ability to extract or to predict these conformational polymorphisms is of crucial importance, as it facilitates deeper understanding of protein dynamics and functionality. In this paper, we describe a computational strategy capable of predicting side-chain polymorphisms. Our approach extends a particular class of algorithms for side-chain prediction by modeling the side-chain dihedral angles more appropriately as continuous rather than discrete variables. Employing a new inferential technique known as particle belief propagation, we predict residue-specific distributions that encode information about side-chain polymorphisms. Our predicted polymorphisms are in relatively close agreement with results from a state-of-the-art approach based on X-ray crystallography data, which characterizes the conformational polymorphisms of side chains using electron density information, and has successfully discovered previously unmodeled conformations.

Multiple Conformational States Contribute to the 3D Structure of a Glucan Decasaccharide: A Combined SAXS and MD Simulation Study.

PubMed

Jo, Sunhwan; Myatt, Daniel; Qi, Yifei; Doutch, James; Clifton, Luke A; Im, Wonpil; Widmalm, Göran

2018-01-25

The inherent flexibility of carbohydrates is dependent on stereochemical arrangements, and characterization of their influence and importance will give insight into the three-dimensional structure and dynamics. In this study, a β-(1→4)/β-(1→3)-linked glucosyl decasaccharide is experimentally investigated by synchrotron small-angle X-ray scattering from which its radius of gyration (R g ) is obtained. Molecular dynamics (MD) simulations of the decasaccharide show four populated states at each glycosidic linkage, namely, syn- and anti-conformations. The calculated R g values from the MD simulation reveal that in addition to syn-conformers the presence of anti-ψ conformational states is required to reproduce experimental scattering data, unveiling inherent glycosidic linkage flexibility. The CHARMM36 force field for carbohydrates thus describes the conformational flexibility of the decasaccharide very well and captures the conceptual importance that anti-conformers are to be anticipated at glycosidic linkages of carbohydrates.

Conformational landscape of isolated capped amino acids: on the nature of non-covalent interactions*

NASA Astrophysics Data System (ADS)

González, Jorge; Martínez, Rodrigo; Fernández, José A.; Millan, Judith

2017-08-01

The intramolecular interactions for isolated capped amino acids were investigated computationally by characterizing the conformers for selected amino acids with charged (arginine), polar (asparagine and glutamine), non-polar (alanine, valine and isoleucine), and aromatic (phenylalanine, tryptophan and tyrosine) side chains. The computational method applied combined a molecular mechanics conformational search (with an MMFFs forced field) followed by structural and vibrational density-functional calculations (M06-2X with a triple- ζ Pople's basis set). The intramolecular forces in each amino acid were analyzed with the Non-Covalent Interactions (NCI) analysis. The results for the 15 most stable conformers studied showed that the structure of isolated capped amino acids resembles those found in proteins. In particular, the two most stable conformers of the nine amino acids investigated exhibit γ L and β L conformations with 7- and 5-membered rings, respectively, as a result of the balance between non-covalent interactions (hydrogen bonds and van der Waals).

Conformal anomaly of generalized form factors and finite loop integrals

NASA Astrophysics Data System (ADS)

Chicherin, Dmitry; Sokatchev, Emery

2018-04-01

We reveal a new mechanism of conformal symmetry breaking at Born level. It occurs in generalized form factors with several local operators and an on-shell state of massless particles. The effect is due to hidden singularities on collinear configurations of the momenta. This conformal anomaly is different from the holomorphic anomaly of amplitudes. We present a number of examples in four and six dimensions. We find an application of the new conformal anomaly to finite loop momentum integrals with one or more massless legs. The collinear region around a massless leg creates a contact anomaly, made visible by the loop integration. The anomalous conformal Ward identity for an ℓ-loop integral is a 2nd-order differential equation whose right-hand side is an (ℓ - 1)-loop integral. It could serve as a new useful tool to find/test analytic expressions for conformal integrals. We illustrate this point with several examples of known integrals. We propose a new differential equation for the four-dimensional scalar double box.

Pyranopterin conformation defines the function of molybdenum and tungsten enzymes.

PubMed

Rothery, Richard A; Stein, Benjamin; Solomonson, Matthew; Kirk, Martin L; Weiner, Joel H

2012-09-11

We have analyzed the conformations of 319 pyranopterins in 102 protein structures of mononuclear molybdenum and tungsten enzymes. These span a continuum between geometries anticipated for quinonoid dihydro, tetrahydro, and dihydro oxidation states. We demonstrate that pyranopterin conformation is correlated with the protein folds defining the three major mononuclear molybdenum and tungsten enzyme families, and that binding-site micro-tuning controls pyranopterin oxidation state. Enzymes belonging to the bacterial dimethyl sulfoxide reductase (DMSOR) family contain a metal-bis-pyranopterin cofactor, the two pyranopterins of which have distinct conformations, with one similar to the predicted tetrahydro form, and the other similar to the predicted dihydro form. Enzymes containing a single pyranopterin belong to either the xanthine dehydrogenase (XDH) or sulfite oxidase (SUOX) families, and these have pyranopterin conformations similar to those predicted for tetrahydro and dihydro forms, respectively. This work provides keen insight into the roles of pyranopterin conformation and oxidation state in catalysis, redox potential modulation of the metal site, and catalytic function.

A Comparison of the ab Initio Calculated and Experimental Conformational Energies of Alkylcyclohexanes

NASA Astrophysics Data System (ADS)

Freeman, Fillmore; Tsegai, Zufan M.; Kasner, Marc L.; Hehre, Warren J.

2000-05-01

Ab initio 6-31G(d) and MP2/6-31G(d)//6-31G(d) methods were used to calculate the energies of the rotamers of the chair conformers of alkylcyclohexanes and trimethylsilylcyclohexane. The MP2/6-31G(d)//6-31G(d) calculated conformational energies ( ? or A values, in kcal/mol) of the alkylcyclohexanes (Me = 1.96; Et = 1.80; Pr = 1.73 iso-Pr = 1.60; t-Bu = 5.45; neo-pent = 1.32) and trimethylsilylcyclohexane (SiMe3 = 2.69) are similar to the experimental values. Plots of the calculated conformational energies for the alkylcyclohexanes and trimethylsilylcyclohexane versus their experimental values are linear (slope = 1.253 and r = .993 for 6-31G(d) and slope = 1.114 and r = .982 for MP2/6-31G(d)//6-31G(d)). The conformational energies are determined primarily by steric effects which include gauche (synclinal) interactions and repulsive nonbonded interactions in both the axial and equatorial conformers.

Synthesis of Conformal Phased Antenna Arrays With A Novel Multiobjective Invasive Weed Optimization Algorithm

NASA Astrophysics Data System (ADS)

Li, Wen Tao; Hei, Yong Qiang; Shi, Xiao Wei

2018-04-01

By virtue of the excellent aerodynamic performances, conformal phased arrays have been attracting considerable attention. However, for the synthesis of patterns with low/ultra-low sidelobes of the conventional conformal arrays, the obtained dynamic range ratios of amplitude excitations could be quite high, which results in stringent requirements on various error tolerances for practical implementation. Time-modulated array (TMA) has the advantages of low sidelobe and reduced dynamic range ratio requirement of amplitude excitations. This paper takes full advantages of conformal antenna arrays and time-modulated arrays. The active-element-pattern, including element mutual coupling and platform effects, is employed in the whole design process. To optimize the pulse durations and the switch-on instants of the time-modulated elements, multiobjective invasive weed optimization (MOIWO) algorithm based on the nondominated sorting of the solutions is proposed. A S-band 8-element cylindrical conformal array is designed and a S-band 16-element cylindrical-parabolic conformal array is constructed and tested at two different steering angles.

Conformational distribution of baclofen analogues by 1H and 13C NMR analysis and ab initio HF MO STO-3G or STO-3G* calculations

NASA Astrophysics Data System (ADS)

Vaccher, Claude; Berthelot, Pascal; Debaert, Michel; Vermeersch, Gaston; Guyon, René; Pirard, Bernard; Vercauteren, Daniel P.; Dory, Magdalena; Evrard, Guy; Durant, François

1993-12-01

The conformations of 3-(substituted furan-2-yl) and 3-(substituted thien-2-yl)-γ-aminobutyric acid 1-9 in solution (D 2O) are estimated from high-resolution (300 MHz) 1H NMR coupling data. Conformations and populations of conformers are calculated by means of a modified Karplus-like relationship for the vicinal coupling constants. The results are compared with X-ray crystallographic investigations (torsion angles) and ab initio HF MO ST-3G or STO-3G* calculations. 1H NMR spectral analysis shows how 1-9 in solution retain the preferred g- conformation around the C3C4 bond, as found in the solid state, while a partial rotation is set up around the C2C3 bond: the conformations about C2C3 are all highly populated in solution. The 13C spin-lattice relaxation times are also discussed.

Molecular structure and conformational preferences of gaseous 1-iodo-1-silacyclohexane

NASA Astrophysics Data System (ADS)

Belyakov, A. V.; Baskakov, A. A.; Berger, R. J. F.; Mitzel, N. W.; Oberhammer, H.; Arnason, I.; Wallevik, S. Ò.

2012-03-01

The molecular structure of the axial and equatorial conformers of 1-iodo-1-silacyclohexane, CH2(CH2CH2)2SiH-I, as well as thermodynamic equilibrium between these species were investigated by means of gas-phase electron diffraction (GED) and quantum chemical calculations up to MP2(full)/SDB-AUG-CC-pVTZ level of theory (MP2). According to electron diffraction data, the vapor of this compound comprises a mixture of conformers with chair conformation and Cs symmetry differing in the axial and equatorial position of the Si-I bond (axial = 73(7) mol%/equatorial = 27(7) mol%) at T = 352 K. This corresponds to a free energy difference of A = -0.59(22) kcal mol-1. The observed gas-phase electron diffraction parameters are in good agreement with those obtained from theory. NBO analysis revealed that axial conformer of 1-iodo-1-silacyclohexane is an example for electrostatic stabilization of a conformer which is unfavorable in terms of steric and conjugation interaction.

The rotational barrier in ethane: a molecular orbital study.

PubMed

Quijano-Quiñones, Ramiro F; Quesadas-Rojas, Mariana; Cuevas, Gabriel; Mena-Rejón, Gonzalo J

2012-04-20

The energy change on each Occupied Molecular Orbital as a function of rotation about the C-C bond in ethane was studied using the B3LYP, mPWB95 functional and MP2 methods with different basis sets. Also, the effect of the ZPE on rotational barrier was analyzed. We have found that σ and π energies contribution stabilize a staggered conformation. The σ(s) molecular orbital stabilizes the staggered conformation while the stabilizes the eclipsed conformation and destabilize the staggered conformation. The π(z) and molecular orbitals stabilize both the eclipsed and staggered conformations, which are destabilized by the π(v) and molecular orbitals. The results show that the method of calculation has the effect of changing the behavior of the energy change in each Occupied Molecular Orbital energy as a function of the angle of rotation about the C-C bond in ethane. Finally, we found that if the molecular orbital energy contribution is deleted from the rotational energy, an inversion in conformational preference occurs.

From conformal blocks to path integrals in the Vaidya geometry

NASA Astrophysics Data System (ADS)

Anous, Tarek; Hartman, Thomas; Rovai, Antonin; Sonner, Julian

2017-09-01

Correlators in conformal field theory are naturally organized as a sum over conformal blocks. In holographic theories, this sum must reorganize into a path integral over bulk fields and geometries. We explore how these two sums are related in the case of a point particle moving in the background of a 3d collapsing black hole. The conformal block expansion is recast as a sum over paths of the first-quantized particle moving in the bulk geometry. Off-shell worldlines of the particle correspond to subdominant contributions in the Euclidean conformal block expansion, but these same operators must be included in order to correctly reproduce complex saddles in the Lorentzian theory. During thermalization, a complex saddle dominates under certain circumstances; in this case, the CFT correlator is not given by the Virasoro identity block in any channel, but can be recovered by summing heavy operators. This effectively converts the conformal block expansion in CFT from a sum over intermediate states to a sum over channels that mimics the bulk path integral.

Performance of Conformable Phenolic Impregnated Carbon Ablator in Aerothermal Environments

NASA Technical Reports Server (NTRS)

Thornton, Jeremy; Fan, Wendy; Stackpoole, Mairead; Kao, David; Skokova, Kristina; Chavez-Garcia, Jose

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 PICA's 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.

Synthesis and stereochemical analysis of β-nitromethane substituted γ-amino acids and peptides.

PubMed

Ganesh Kumar, Mothukuri; Mali, Sachitanand M; Gopi, Hosahudya N

2013-02-07

The high diastereoselectivity in the Michael addition of nitromethane to α,β-unsaturated γ-amino esters, crystal conformations of β-nitromethane substituted γ-amino acids and peptides are studied. Results suggest that the N-Boc protected amide NH, conformations of α,β-unsaturated γ-amino esters and alkyl side chains play a crucial role in dictating the high diastereoselectivity of nitromethane addition to E-vinylogous amino esters. Investigation of the crystal conformations of both α,β-unsaturated γ-amino esters and the Michael addition products suggests that an H-C(γ)-C(β)=C(α) eclipsed conformer of the unsaturated amino ester leads to the major (anti) product compared to that of an N-C(γ)-C(β)=C(α) eclipsed conformer. The major diastereomers were separated and subjected to the peptide synthesis. The single crystal analysis of the dipeptide containing β-nitromethane substituted γ-amino acids reveals a helical type of folded conformation with an isolated H-bond involving a nine-atom pseudocycle.

Correlation functions of warped CFT

NASA Astrophysics Data System (ADS)

Song, Wei; Xu, Jianfei

2018-04-01

Warped conformal field theory (WCFT) is a two dimensional quantum field theory whose local symmetry algebra consists of a Virasoro algebra and a U(1) Kac-Moody algebra. In this paper, we study correlation functions for primary operators in WCFT. Similar to conformal symmetry, warped conformal symmetry is very constraining. The form of the two and three point functions are determined by the global warped conformal symmetry while the four point functions can be determined up to an arbitrary function of the cross ratio. The warped conformal bootstrap equation are constructed by formulating the notion of crossing symmetry. In the large central charge limit, four point functions can be decomposed into global warped conformal blocks, which can be solved exactly. Furthermore, we revisit the scattering problem in warped AdS spacetime (WAdS), and give a prescription on how to match the bulk result to a WCFT retarded Green's function. Our result is consistent with the conjectured holographic dualities between WCFT and WAdS.

Mapping transiently formed and sparsely populated conformations on a complex energy landscape

PubMed Central

Wang, Yong; Papaleo, Elena; Lindorff-Larsen, Kresten

2016-01-01

Determining the structures, kinetics, thermodynamics and mechanisms that underlie conformational exchange processes in proteins remains extremely difficult. Only in favourable cases is it possible to provide atomic-level descriptions of sparsely populated and transiently formed alternative conformations. Here we benchmark the ability of enhanced-sampling molecular dynamics simulations to determine the free energy landscape of the L99A cavity mutant of T4 lysozyme. We find that the simulations capture key properties previously measured by NMR relaxation dispersion methods including the structure of a minor conformation, the kinetics and thermodynamics of conformational exchange, and the effect of mutations. We discover a new tunnel that involves the transient exposure towards the solvent of an internal cavity, and show it to be relevant for ligand escape. Together, our results provide a comprehensive view of the structural landscape of a protein, and point forward to studies of conformational exchange in systems that are less characterized experimentally. DOI: http://dx.doi.org/10.7554/eLife.17505.001 PMID:27552057

Microwave Spectroscopy of Seven Conformers of 1,2-PROPANEDIOL

NASA Astrophysics Data System (ADS)

Neill, Justin L.; Muckle, Matt T.; Pate, Brooks H.; Lovas, F. J.; Plusquellic, D. F.; Remijan, A. J.

2009-06-01

Previously, two conformations of 1,2-propanediol have been identified by microwave spectroscopy by Caminati. Here we report the assignment of five additional conformers, two from work on a Balle-Flygare type cavity FTMW spectrometer at NIST, operating between 8 and 26 GHz, and three from a deep average scan on the chirped pulse Fourier transform microwave (CP-FTMW) spectrometer at the University of Virginia, operating between 6.5 and 18.5 GHz. All seven of the assigned conformers contain an intramolecular hydrogen bond between the two hydroxyl groups. Stark effect measurements have been performed on the cavity FTMW spectrometer to determine the dipole moments of the three lowest energy conformers. Relative abundances of the conformers have also been determined from the CP-FTMW spectrum. A subsequent interstellar search toward Sgr B2(N) yielded negative results with an upper limit to the total column density that is less than those of glycolaldehyde and ethylene glycol. W.Caminati, J. Mol. Spectrosc. 86 (1981) 193-201.

Different Conformations of Surface Cellulose Molecules in Native Cellulose Microfibrils Revealed by Layer-by-Layer Peeling.

PubMed

Funahashi, Ryunosuke; Okita, Yusuke; Hondo, Hiromasa; Zhao, Mengchen; Saito, Tsuguyuki; Isogai, Akira

2017-11-13

Layer-by-layer peeling of surface molecules of native cellulose microfibrils was performed using a repeated sequential process of 2,2,6,6-tetramethylpiperidine-1-oxyl radical-mediated oxidation followed by hot alkali extraction. Both highly crystalline algal and tunicate celluloses and low-crystalline cotton and wood celluloses were investigated. Initially, the C6-hydroxy groups of the outermost surface molecules of each algal cellulose microfibril facing the exterior had the gauche-gauche (gg) conformation, whereas those facing the interior had the gauche-trans (gt) conformation. All the other C6-hydroxy groups of the cellulose molecules inside the microfibrils contributing to crystalline cellulose I had the trans-gauche (tg) conformation. After surface peeling, the originally second-layer molecules from the microfibril surface became the outermost surface molecules, and the original tg conformation changed to gg and gt conformations. The plant cellulose microfibrils likely had disordered structures for both the outermost surface and second-layer molecules, as demonstrated using the same layer-by-layer peeling technique.

Residues with similar hexagon neighborhoods share similar side-chain conformations.

PubMed

Li, Shuai Cheng; Bu, Dongbo; Li, Ming

2012-01-01

We present in this study a new approach to code protein side-chain conformations into hexagon substructures. Classical side-chain packing methods consist of two steps: first, side-chain conformations, known as rotamers, are extracted from known protein structures as candidates for each residue; second, a searching method along with an energy function is used to resolve conflicts among residues and to optimize the combinations of side chain conformations for all residues. These methods benefit from the fact that the number of possible side-chain conformations is limited, and the rotamer candidates are readily extracted; however, these methods also suffer from the inaccuracy of energy functions. Inspired by threading and Ab Initio approaches to protein structure prediction, we propose to use hexagon substructures to implicitly capture subtle issues of energy functions. Our initial results indicate that even without guidance from an energy function, hexagon structures alone can capture side-chain conformations at an accuracy of 83.8 percent, higher than 82.6 percent by the state-of-art side-chain packing methods.

Exploration of the kinetic and thermochemical abilities for the free radical scavenging of two quercetin conformers

NASA Astrophysics Data System (ADS)

Mendoza-Wilson, Ana María; Sotelo-Mundo, Rogerio R.; Balandrán-Quintana, René R.; Glossman-Mitnik, Daniel; Sántiz-gómez, Marco a.; García-orozco, karina D.

2010-09-01

Quercetin has a great antioxidant potential due to its large capacity for free radical scavenging. Although it has been found that conformational changes have a profound effect on its chemical properties, there are few studies where conformation is associated with the antioxidant activity. The aim of this investigation was to explore the kinetic and the thermochemical abilities of two quercetin conformers for the free radical scavenging. Quercetin unhydrate (QUH) and quercetin dihydrate (QDH) conformers were studied employing 2,2-diphenyl-1-picrylhydrazyl (DPPH rad ) as in vitro radical model, and catechol and 4-hexyl-resorcinol as reference systems, for identifying the oxidation products. QDH showed to be most effective under conditions of free radical excess, while QUH was most effective when the flavonoid far exceeds the concentration of free radical. It was found, by means of experimental and computational methods, that 4'-OH, 3-OH and 3'-OH are the main reactive sites of both conformers.

Conformational switching in the coiled-coil domains of a proteasomal ATPase regulates substrate processing.

PubMed

Snoberger, Aaron; Brettrager, Evan J; Smith, David M

2018-06-18

Protein degradation in all domains of life requires ATPases that unfold and inject proteins into compartmentalized proteolytic chambers. Proteasomal ATPases in eukaryotes and archaea contain poorly understood N-terminally conserved coiled-coil domains. In this study, we engineer disulfide crosslinks in the coiled-coils of the archaeal proteasomal ATPase (PAN) and report that its three identical coiled-coil domains can adopt three different conformations: (1) in-register and zipped, (2) in-register and partially unzipped, and (3) out-of-register. This conformational heterogeneity conflicts with PAN's symmetrical OB-coiled-coil crystal structure but resembles the conformational heterogeneity of the 26S proteasomal ATPases' coiled-coils. Furthermore, we find that one coiled-coil can be conformationally constrained even while unfolding substrates, and conformational changes in two of the coiled-coils regulate PAN switching between resting and active states. This switching functionally mimics similar states proposed for the 26S proteasome from cryo-EM. These findings thus build a mechanistic framework to understand regulation of proteasome activity.

Parallel cascade selection molecular dynamics for efficient conformational sampling and free energy calculation of proteins

NASA Astrophysics Data System (ADS)

Kitao, Akio; Harada, Ryuhei; Nishihara, Yasutaka; Tran, Duy Phuoc

2016-12-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) was proposed as an efficient conformational sampling method to investigate conformational transition pathway of proteins. In PaCS-MD, cycles of (i) selection of initial structures for multiple independent MD simulations and (ii) conformational sampling by independent MD simulations are repeated until the convergence of the sampling. The selection is conducted so that protein conformation gradually approaches a target. The selection of snapshots is a key to enhance conformational changes by increasing the probability of rare event occurrence. Since the procedure of PaCS-MD is simple, no modification of MD programs is required; the selections of initial structures and the restart of the next cycle in the MD simulations can be handled with relatively simple scripts with straightforward implementation. Trajectories generated by PaCS-MD were further analyzed by the Markov state model (MSM), which enables calculation of free energy landscape. The combination of PaCS-MD and MSM is reported in this work.

Higher spin conformal geometry in three dimensions and prepotentials for higher spin gauge fields

NASA Astrophysics Data System (ADS)

Henneaux, Marc; Hörtner, Sergio; Leonard, Amaury

2016-01-01

We study systematically the conformal geometry of higher spin bosonic gauge fields in three spacetime dimensions. We recall the definition of the Cotton tensor for higher spins and establish a number of its properties that turn out to be key in solving in terms of prepotentials the constraint equations of the Hamiltonian (3 + 1) formulation of four-dimensional higher spin gauge fields. The prepotentials are shown to exhibit higher spin conformal symmetry. Just as for spins 1 and 2, they provide a remarkably simple, manifestly duality invariant formulation of the theory. While the higher spin conformal geometry is developed for arbitrary bosonic spin, we explicitly perform the Hamiltonian analysis and derive the solution of the constraints only in the illustrative case of spin 3. In a separate publication, the Hamiltonian analysis in terms of prepotentials is extended to all bosonic higher spins using the conformal tools of this paper, and the same emergence of higher spin conformal symmetry is confirmed.

Generalized conformal structure, dilaton gravity and SYK

NASA Astrophysics Data System (ADS)

Taylor, Marika

2018-01-01

A theory admits generalized conformal structure if the only scale in the quantum theory is set by a dimensionful coupling. SYK is an example of a theory with generalized conformal structure and in this paper we investigate the consequences of this structure for correlation functions and for the holographic realization of SYK. The Ward identities associated with the generalized conformal structure of SYK are implemented holographically in gravity/multiple scalar theories, which always have a parent AdS3 origin. For questions involving only the graviton/running scalar sector, one can always describe the bulk running in terms of a single scalar but multiple running scalars are in general needed once one includes the bulk fields corresponding to all SYK operators. We then explore chaos in holographic theories with generalized conformal structure. The four point function explored by Maldacena, Shenker and Stanford exhibits exactly the same chaotic behaviour in any such theory as in holographic realizations of conformal theories i.e. the dimensionful coupling scale does not affect the chaotic exponential growth.

Probing the Conformational Landscape of Polyether Building Blocks in Supersonic Jets

NASA Astrophysics Data System (ADS)

Bocklitz, Sebastian; Hewett, Daniel M.; Zwier, Timothy S.; Suhm, Martin A.

2016-06-01

Polyethylene oxides (Polyethylene glycoles) and their phenoxy-capped analogs represent a prominent class of important polymers that are highly used as precursor molecules in supramolecular reactions. After a detailed study on the simplest representative (1,2-dimethoxyethane) [1], we present results on oligoethylene oxides with increasing chain lengths obtained by spontaneous Raman scattering in a supersonic jet. Through variation of stagnation pressure, carrier gas, nozzle distance and temperature we gain information on the conformational landscape as well as the mutual interconversion of low energy conformers. The obtained results are compared to state-of-the-art quantum chemical calculations. Additionally, we present UV as well as IR-UV and UV-UV double resonance studies on 1-methoxy-2-phenoxyethane in a supersonic jet. These complementary techniques allow for conformationally selective electronic and vibrational spectra in a closely related conformational landscape. [1] S. Bocklitz, M. A. Suhm, Constraining the Conformational Landscape of a Polyether Building Block by Raman Jet Spectroscopy, Z. Phys. Chem. 2015, 229, 1625-1648.

The detection of conformational disorder by thermal analysis

NASA Astrophysics Data System (ADS)

Wunderlich, B.

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).

The detection of conformational disorder by thermal analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 tomore » 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.« less

Conformational states of the full-length glucagon receptor

PubMed Central

Yang, Linlin; Yang, Dehua; de Graaf, Chris; Moeller, Arne; West, Graham M.; Dharmarajan, Venkatasubramanian; Wang, Chong; Siu, Fai Y.; Song, Gaojie; Reedtz-Runge, Steffen; Pascal, Bruce D.; Wu, Beili; Potter, Clinton S.; Zhou, Hu; Griffin, Patrick R.; Carragher, Bridget; Yang, Huaiyu; Wang, Ming-Wei; Stevens, Raymond C.; Jiang, Hualiang

2015-01-01

Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism. PMID:26227798

tRNA Shifts the G-quadruplex-Hairpin Conformational Equilibrium in RNA towards the Hairpin Conformer.

PubMed

Rode, Ambadas B; Endoh, Tamaki; Sugimoto, Naoki

2016-11-07

Non-coding RNAs play important roles in cellular homeostasis and are involved in many human diseases including cancer. Intermolecular RNA-RNA interactions are the basis for the diverse functions of many non-coding RNAs. Herein, we show how the presence of tRNA influences the equilibrium between hairpin and G-quadruplex conformations in the 5' untranslated regions of oncogenes and model sequences. Kinetic and equilibrium analyses of the hairpin to G-quadruplex conformational transition of purified RNA as well as during co-transcriptional folding indicate that tRNA significantly shifts the equilibrium toward the hairpin conformer. The enhancement of relative translation efficiency in a reporter gene assay is shown to be due to the tRNA-mediated shift in hairpin-G-quadruplex equilibrium of oncogenic mRNAs. Our findings suggest that tRNA is a possible therapeutic target in diseases in which RNA conformational equilibria is dysregulated. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Guiding Conformation Space Search with an All-Atom Energy Potential

PubMed Central

Brunette, TJ; Brock, Oliver

2009-01-01

The most significant impediment for protein structure prediction is the inadequacy of conformation space search. Conformation space is too large and the energy landscape too rugged for existing search methods to consistently find near-optimal minima. To alleviate this problem, we present model-based search, a novel conformation space search method. Model-based search uses highly accurate information obtained during search to build an approximate, partial model of the energy landscape. Model-based search aggregates information in the model as it progresses, and in turn uses this information to guide exploration towards regions most likely to contain a near-optimal minimum. We validate our method by predicting the structure of 32 proteins, ranging in length from 49 to 213 amino acids. Our results demonstrate that model-based search is more effective at finding low-energy conformations in high-dimensional conformation spaces than existing search methods. The reduction in energy translates into structure predictions of increased accuracy. PMID:18536015

Similarity Measures for Protein Ensembles

PubMed Central

Lindorff-Larsen, Kresten; Ferkinghoff-Borg, Jesper

2009-01-01

Analyses of similarities and changes in protein conformation can provide important information regarding protein function and evolution. Many scores, including the commonly used root mean square deviation, have therefore been developed to quantify the similarities of different protein conformations. However, instead of examining individual conformations it is in many cases more relevant to analyse ensembles of conformations that have been obtained either through experiments or from methods such as molecular dynamics simulations. We here present three approaches that can be used to compare conformational ensembles in the same way as the root mean square deviation is used to compare individual pairs of structures. The methods are based on the estimation of the probability distributions underlying the ensembles and subsequent comparison of these distributions. We first validate the methods using a synthetic example from molecular dynamics simulations. We then apply the algorithms to revisit the problem of ensemble averaging during structure determination of proteins, and find that an ensemble refinement method is able to recover the correct distribution of conformations better than standard single-molecule refinement. PMID:19145244

Solvent history dependence of gramicidin A conformations in hydrated lipid bilayers.

PubMed Central

LoGrasso, P V; Moll, F; Cross, T A

1988-01-01

Reconstituted lipid bilayers of dimyristoylphosphatidylcholine (DMPC) and gramicidin A' have been prepared by cosolubilizing gramicidin and DMPC in one of three organic solvent systems followed by vacuum drying and hydration. The conformational state of gramicidin as characterized by 23Na NMR, circular dichroism, and solid state 15N NMR is dependent upon the cosolubilizing solvent system. In particular, two conformational states are described; a state in which Na+ has minimal interactions with the polypeptide, referred to as a nonchannel state, and a state in which Na+ interacts very strongly with the polypeptide, referred to as the channel state. Both of these conformations are intimately associated with the hydrophobic core of the lipid bilayer. Furthermore, both of these states are stable in the bilayer at neutral pH and at a temperature above the bilayer phase transition temperature. These results with gramicidin suggest that the conformation of membrane proteins may be dictated by the conformation before membrane insertion and may be dependent upon the mechanism by which the insertion is accomplished. PMID:2462923

Interactions in the ionic liquid [EMIM][FAP]: a coupled experimental and computational analysis.

PubMed

Voroshylova, Iuliia V; Teixeira, Filipe; Costa, Renata; Pereira, Carlos M; Cordeiro, M Natália D S

2016-01-28

Gas-phase electronic and structural properties of the room temperature ionic liquid 1-ethyl-3-methylimidazolium tris(perfluoroethyl)trifluorophosphate ([EMIM][FAP]) were studied using density functional theory, and confirmed with results from infrared spectroscopy. A conformational analysis allowed the identification of several plausible conformers of the ion pairs. For the detected conformers, the infrared spectra were predicted and their thermodynamic properties were evaluated. The topology of the electronic density of the most stable conformers of [EMIM][FAP] ion pairs were characterised using the quantum theory of atoms in molecules. A number of possible hydrogen bonds between the cations and anions of the ionic liquid were identified. Excellent correspondence was found between the predicted spectra of gas-phase [EMIM][FAP] conformers and the experimental infrared spectrum, which in turn allowed a clear attribution of the vibration modes of [EMIM][FAP]. Finally, the contribution of the various conformers of both isomers of the [FAP](-) anion to the ionic liquid macro-properties is shown.