Science.gov

Sample records for molecular conformational generation

  1. Cosolvent-Based Molecular Dynamics for Ensemble Docking: Practical Method for Generating Druggable Protein Conformations.

    PubMed

    Uehara, Shota; Tanaka, Shigenori

    2017-04-07

    Protein flexibility is a major hurdle in current structure-based virtual screening (VS). In spite of the recent advances in high-performance computing, protein-ligand docking methods still demand tremendous computational cost to take into account the full degree of protein flexibility. In this context, ensemble docking has proven its utility and efficiency for VS studies, but it still needs a rational and efficient method to select and/or generate multiple protein conformations. Molecular dynamics (MD) simulations are useful to produce distinct protein conformations without abundant experimental structures. In this study, we present a novel strategy that makes use of cosolvent-based molecular dynamics (CMD) simulations for ensemble docking. By mixing small organic molecules into a solvent, CMD can stimulate dynamic protein motions and induce partial conformational changes of binding pocket residues appropriate for the binding of diverse ligands. The present method has been applied to six diverse target proteins and assessed by VS experiments using many actives and decoys of DEKOIS 2.0. The simulation results have revealed that the CMD is beneficial for ensemble docking. Utilizing cosolvent simulation allows the generation of druggable protein conformations, improving the VS performance compared with the use of a single experimental structure or ensemble docking by standard MD with pure water as the solvent.

  2. Protein conformation and molecular order probed by second-harmonic-generation microscopy

    NASA Astrophysics Data System (ADS)

    Vanzi, Francesco; Sacconi, Leonardo; Cicchi, Riccardo; Pavone, Francesco S.

    2012-06-01

    Second-harmonic-generation (SHG) microscopy has emerged as a powerful tool to image unstained living tissues and probe their molecular and supramolecular organization. In this article, we review the physical basis of SHG, highlighting how coherent summation of second-harmonic response leads to the sensitivity of polarized SHG to the three-dimensional distribution of emitters within the focal volume. Based on the physical description of the process, we examine experimental applications for probing the molecular organization within a tissue and its alterations in response to different biomedically relevant conditions. We also describe the approach for obtaining information on molecular conformation based on SHG polarization anisotropy measurements and its application to the study of myosin conformation in different physiological states of muscle. The capability of coupling the advantages of nonlinear microscopy (micrometer-scale resolution in deep tissue) with tools for probing molecular structure in vivo renders SHG microscopy an extremely powerful tool for the advancement of biomedical optics, with particular regard to novel technologies for molecular diagnostic in vivo.

  3. Structural and molecular conformation of myosin in intact muscle fibers by second harmonic generation

    NASA Astrophysics Data System (ADS)

    Nucciotti, V.; Stringari, C.; Sacconi, L.; Vanzi, F.; Linari, M.; Piazzesi, G.; Lombardi, V.; Pavone, F. S.

    2009-02-01

    Recently, the use of Second Harmonic Generation (SHG) for imaging biological samples has been explored with regard to intrinsic SHG in highly ordered biological samples. As shown by fractional extraction of proteins, myosin is the source of SHG signal in skeletal muscle. SHG is highly dependent on symmetries and provides selective information on the structural order and orientation of the emitting proteins and the dynamics of myosin molecules responsible for the mechano-chemical transduction during contraction. We characterise the polarization-dependence of SHG intensity in three different physiological states: resting, rigor and isometric tetanic contraction in a sarcomere length range between 2.0 μm and 4.0 μm. The orientation of motor domains of the myosin molecules is dependent on their physiological states and modulate the SHG signal. We can discriminate the orientation of the emitting dipoles in four different molecular conformations of myosin heads in intact fibers during isometric contraction, in resting and rigor. We estimate the contribution of the myosin motor domain to the total second order bulk susceptibility from its molecular structure and its functional conformation. We demonstrate that SHG is sensitive to the fraction of ordered myosin heads by disrupting the order of myosin heads in rigor with an ATP analog. We estimate the fraction of myosin motors generating the isometric force in the active muscle fiber from the dependence of the SHG modulation on the degree of overlap between actin and myosin filaments during an isometric contraction.

  4. Generative models of conformational dynamics.

    PubMed

    Langmead, Christopher James

    2014-01-01

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

  5. Conformation, orientation and interaction in molecular monolayers: A surface second harmonic and sum frequency generation study

    SciTech Connect

    Superfine, R.; Huang, J.Y.; Shen, Y.R.

    1988-12-01

    We have used sum frequency generation (SFG) to study the order in a silane monolayer before and after the deposition of a coadsorbed liquid crystal monolayer. We observe an increase in the order of the chain of the silane molecule induced by the interpenetration of the liquid crystal molecules. By using second harmonic generation (SHG) and SFG, we have studied the orientation and conformation of the liquid crystal molecule on clean and silane coated glass surfaces. On both surfaces, the biphenyl group is tilted by 70{degree} with the alkyl chain end pointing away from the surface. The shift in the C-H stretch frequencies in the coadsorbed system indicates a significant interaction between molecules. 9 refs., 3 figs.

  6. Effect of nanoscale geometry on molecular conformation: vibrational sum-frequency generation of alkanethiols on gold nanoparticles.

    PubMed

    Weeraman, Champika; Yatawara, Achani K; Bordenyuk, Andrey N; Benderskii, Alexander V

    2006-11-08

    Vibrational sum frequency generation (VSFG) spectroscopy was used to study the nanoscale geometric effects on molecular conformation of dodecanethiol ligand on gold nanoparticles of varying size between 1.8 and 23 nm. By analyzing the CH3 and CH2 stretch transitions of dodecanethiol using the spectroscopic propensity rules for the SFG process, we observe the increase of the gauche defects in the alkyl chain of the ligand on the nanoparticle surface when the curvature approaches the size of the molecule ( approximately 1.6 nm). In contrast, linear infrared absorption and Raman spectra, governed by different selection rules, do not allow observation of the size-dependent conformational changes. The results are understood in terms of the geometric packing effect, where the curvature of the nanoparticle surface results in the increased conical volume available for the alkyl chain.

  7. Generative Models of Conformational Dynamics

    PubMed Central

    Langmead, Christopher James

    2014-01-01

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

  8. Benchmarking Commercial Conformer Ensemble Generators.

    PubMed

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

    2017-10-02

    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 (DG) 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 RMSDs 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 DG algorithm (with minimization enabled) appears to be a good free alternative since its performance is comparable to that of the mid-ranked commercial algorithms. Based on a statistical analysis, we elaborate on which algorithms to use and how to parameterize them for best performance in different application scenarios.

  9. Conformational Transitions in Molecular Systems

    NASA Astrophysics Data System (ADS)

    Bachmann, M.; Janke, W.

    2008-11-01

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

  10. 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).

  11. Molecular mechanics conformational analysis of tylosin

    NASA Astrophysics Data System (ADS)

    Ivanov, Petko M.

    1998-01-01

    The conformations of the 16-membered macrolide antibiotic tylosin were studied with molecular mechanics (AMBER∗ force field) including modelling of the effect of the solvent on the conformational preferences (GB/SA). A Monte Carlo conformational search procedure was used for finding the most probable low-energy conformations. The present study provides complementary data to recently reported analysis of the conformations of tylosin based on NMR techniques. A search for the low-energy conformations of protynolide, a 16-membered lactone containing the same aglycone as tylosin, was also carried out, and the results were compared with the observed conformation in the crystal as well as with the most probable conformations of the macrocyclic ring of tylosin. The dependence of the results on force field was also studied by utilizing the MM3 force field. Some particular conformations were computed with the semiempirical molecular orbital methods AM1 and PM3.

  12. 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.

  13. Measuring the mechanical properties of molecular conformers.

    PubMed

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

    2015-09-21

    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.

  14. Mesh generation by conformal and quasiconformal mappings

    NASA Technical Reports Server (NTRS)

    Mastin, C. W.; Thompson, J. F.

    1981-01-01

    It is pointed out that many recent advances in the finite-difference solution of elliptic equations have been limited to regions whose boundary contours coincide with coordinate lines of the Cartesian coordinate system. The reason for this is related to the fact that in the case of an arbitrary curvilinear coordinate system the original equation becomes much more complex. However, there is no added complexity if an orthogonal coordinate system is generated from a conformal mapping. In the present investigation, a finite difference method developed for the construction of conformal mappings has been generalized to construct quasi-conformal mappings. It is expected that the use of more sophisticated numerical algorithms could lead to improvements in both speed and accuracy. Quasi-conformal mappings have applications not only in the solution of elliptic equations but also in other areas such as orthogonal mesh generation on surfaces and the solution of certain fluid flow problems.

  15. Conformation effects on the molecular orbitals of serine

    NASA Astrophysics Data System (ADS)

    Wang, Ke-Dong; Ma, Peng-Fei; Shan, Xu

    2011-03-01

    This paper calculates the five most stable conformers of serine with Hartree—Fock theory, density functional theory (B3LYP), Møller—Plesset perturbation theory (MP4(SDQ)) and electron propagation theory with the 6-311++G(2d,2p) basis set. The calculated vertical ionization energies for the valence molecular orbitals of each conformer are in agreement with the experimental data, indicating that a range of molecular conformations would coexist in an equilibrium sample. Information of the five outer valence molecular orbitals for each conformer is explored in coordinate and momentum spaces using dual space analysis to investigate the conformational processes, which are generated from the global minimum conformer Ser1 by rotation of C2-C3 (Ser4), C1-C2 (Ser5) and C1-O2 (Ser2 and Ser3). Orbitals 28a, 27a and 26a are identified as the fingerprint orbitals for all the conformational processes. Project supported by the Doctoral Research Fund of Henan Normal University, China (Grant No. 525449).

  16. Measuring the mechanical properties of molecular conformers

    PubMed Central

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

    2015-01-01

    Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules. PMID:26388232

  17. Generative Topographic Mapping of Conformational Space.

    PubMed

    Horvath, Dragos; Baskin, Igor; Marcou, Gilles; Varnek, Alexandre

    2017-10-01

    Herein, Generative Topographic Mapping (GTM) was challenged to produce planar projections of the high-dimensional conformational space of complex molecules (the 1LE1 peptide). GTM is a probability-based mapping strategy, and its capacity to support property prediction models serves to objectively assess map quality (in terms of regression statistics). The properties to predict were total, non-bonded and contact energies, surface area and fingerprint darkness. Map building and selection was controlled by a previously introduced evolutionary strategy allowed to choose the best-suited conformational descriptors, options including classical terms and novel atom-centric autocorrellograms. The latter condensate interatomic distance patterns into descriptors of rather low dimensionality, yet precise enough to differentiate between close favorable contacts and atom clashes. A subset of 20 K conformers of the 1LE1 peptide, randomly selected from a pool of 2 M geometries (generated by the S4MPLE tool) was employed for map building and cross-validation of property regression models. The GTM build-up challenge reached robust three-fold cross-validated determination coefficients of Q(2) =0.7…0.8, for all modeled properties. Mapping of the full 2 M conformer set produced intuitive and information-rich property landscapes. Functional and folding subspaces appear as well-separated zones, even though RMSD with respect to the PDB structure was never used as a selection criterion of the maps. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. On probing conformation of microtubules by second-harmonic generation

    NASA Astrophysics Data System (ADS)

    Sharoukhov, Denis; Lim, Hyungsik

    2016-01-01

    Microtubule (MT) is a component of cytoskeleton playing an important role in a variety of cellular processes. Altering the structure of MT is a crucial mechanism of modulating the function, but it is difficult to measure the in vivo conformation. We present here the use of second-harmonic generation (SHG) for acquiring information about the architecture of MTs in living tissue. Axonal MTs were imaged by polarization-resolved SHG and anisotropy in the molecular structure was determined by means of the second-order tensor analysis. The feasibility of the second-order tensor analysis was tested for measuring the conformational changes induced by MT-stabilizing drug. It demonstrates that the new optical contrast may be useful for investigating the dynamics of MT cytoskeleton in vivo.

  19. Patterns and conformations in molecularly thin films

    NASA Astrophysics Data System (ADS)

    Basnet, Prem B.

    Molecularly thin films have been a subject of great interest for the last several years because of their large variety of industrial applications ranging from micro-electronics to bio-medicine. Additionally, molecularly thin films can be used as good models for biomembrane and other systems where surfaces are critical. Many different kinds of molecules can make stable films. My research has considered three such molecules: a polymerizable phospholipid, a bent-core molecules, and a polymer. One common theme of these three molecules is chirality. The phospolipid molecules studied here are strongly chiral, which can be due to intrinsically chiral centers on the molecules and also due to chiral conformations. We find that these molecules give rise to chiral patterns. Bent-core molecules are not intrinsically chiral, but individual molecules and groups of molecules can show chiral structures, which can be changed by surface interactions. One major, unconfirmed hypothesis for the polymer conformation at surface is that it forms helices, which would be chiral. Most experiments were carried out at the air/water interface, in what are called Langmuir films. Our major tools for studying these films are Brewster Angle Microscopy (BAM) coupled with the thermodynamic information that can be deduced from surface pressure isotherms. Phospholipids are one of the important constituents of liposomes -- a spherical vesicle com-posed of a bilayer membrane, typically composed of a phospholipid and cholesterol bilayer. The application of liposomes in drug delivery is well-known. Crumpling of vesicles of polymerizable phospholipids has been observed. With BAM, on Langmuir films of such phospholipids, we see novel spiral/target patterns during compression. We have found that both the patterns and the critical pressure at which they formed depend on temperature (below the transition to a i¬‘uid layer). Bent-core liquid crystals, sometimes knows as banana liquid crystals, have drawn

  20. Molecular Orbital Studies of Ethylenediamine Conformations

    PubMed Central

    Jhon, Mu Shik; Cho, Ung-Ln; Kier, Lemont B.; Eyring, Henry

    1972-01-01

    Semiempirical quantum mechanical treatments are applied to the ethylenediamine di-cation, mono-action, and neutral molecule by the use of the extended Huckel theory. The minimum energies of conformations of molecules for rotation about the CH2-CH2 axis is found. The theoretical predictions for the conformation with minimum values. The importance of the ethylenediamine conformations are discussed. PMID:16591963

  1. Conformational Analysis in 18-Membered Macrolactones Based on Molecular Modeling

    PubMed Central

    Belaidi, Salah; Harkati, Dalal

    2011-01-01

    Conformational analysis of 18-ring membered macrolactones has been carried out using molecular mechanics calculations and molecular dynamics. A high conformational flexibility of macrolactones was obtained, and an important stereoselectivity was observed for the complexed macrolides. For 18d macrolactone, which was presented by a most favored conformer with 20.1% without complex, it was populated with 50.1% in presence of Fe(CO)3. PMID:24052826

  2. Freely available conformer generation methods: how good are they?

    PubMed

    Ebejer, Jean-Paul; Morris, Garrett M; Deane, Charlotte M

    2012-05-25

    Conformer generation has important implications in cheminformatics, particularly in computational drug discovery where the quality of conformer generation software may affect the outcome of a virtual screening exercise. We examine the performance of four freely available small molecule conformer generation tools (Balloon, Confab, Frog2, and RDKit) alongside a commercial tool (MOE). The aim of this study is 3-fold: (i) to identify which tools most accurately reproduce experimentally determined structures; (ii) to examine the diversity of the generated conformational set; and (iii) to benchmark the computational time expended. These aspects were tested using a set of 708 drug-like molecules assembled from the OMEGA validation set and the Astex Diverse Set. These molecules have varying physicochemical properties and at least one known X-ray crystal structure. We found that RDKit and Confab are statistically better than other methods at generating low rmsd conformers to the known structure. RDKit is particularly suited for less flexible molecules while Confab, with its systematic approach, is able to generate conformers which are geometrically closer to the experimentally determined structure for molecules with a large number of rotatable bonds (≥10). In our tests RDKit also resulted as the second fastest method after Frog2. In order to enhance the performance of RDKit, we developed a postprocessing algorithm to build a diverse and representative set of conformers which also contains a close conformer to the known structure. Our analysis indicates that, with postprocessing, RDKit is a valid free alternative to commercial, proprietary software.

  3. Confab - Systematic generation of diverse low-energy conformers

    PubMed Central

    2011-01-01

    Background Many computational chemistry analyses require the generation of conformers, either on-the-fly, or in advance. We present Confab, an open source command-line application for the systematic generation of low-energy conformers according to a diversity criterion. Results Confab generates conformations using the 'torsion driving approach' which involves iterating systematically through a set of allowed torsion angles for each rotatable bond. Energy is assessed using the MMFF94 forcefield. Diversity is measured using the heavy-atom root-mean-square deviation (RMSD) relative to conformers already stored. We investigated the recovery of crystal structures for a dataset of 1000 ligands from the Protein Data Bank with fewer than 1 million conformations. Confab can recover 97% of the molecules to within 1.5 Å at a diversity level of 1.5 Å and an energy cutoff of 50 kcal/mol. Conclusions Confab is available from http://confab.googlecode.com. PMID:21410983

  4. Network Visualization of Conformational Sampling during Molecular Dynamics Simulation

    PubMed Central

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

    2013-01-01

    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. PMID:24211466

  5. 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

  6. 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

  7. Close intramolecular sulfur-oxygen contacts: modified force field parameters for improved conformation generation.

    PubMed

    Lupyan, Dmitry; Abramov, Yuriy A; Sherman, Woody

    2012-11-01

    The Cambridge Structural Database (CSD) offers an excellent data source to study small molecule conformations and molecular interactions. We have analyzed 130 small molecules from the CSD containing an intramolecular sulfur-oxygen distance less than the sum of their van der Waals (vdW) radii. Close S···O distances are observed in several important medicinal chemistry motifs (e.g. a carbonyl oxygen connected by a carbon or nitrogen linker to a sulfur) and are not treated well with existing parameters in the MMFFs or OPLS_2005 force fields, resulting in suboptimal geometries and energetics. In this work, we develop modified parameters for the OPLS_2005 force field to better treat this specific interaction in order to generate conformations close to those found in the CSD structures. We use a combination of refitting a force field torsional parameter, adding a specific atom pair vdW term, and attenuating the electrostatic interactions to obtain an improvement in the accuracy of geometry minimizations and conformational searches for these molecules. Specifically, in a conformational search 58 % of the cases produced a conformation less than 0.25 Å from the CSD crystal conformation with the modified OPLS force field parameters developed in this work. In contrast, 25 and 37 % produced a conformation less than 0.25 Å with the MMFFs and OPLS_2005 force fields, respectively. As an application of the new parameters, we generated conformations for the tyrosine kinase inhibitor axitinib (trade name Inlyta) that could be correctly repacked into three observed polymorphic structures, which was not possible with conformations generated using MMFFs or OPLS_2005. The improved parameters can be mapped directly onto physical characteristics of the systems that are treated inadequately with the molecular mechanics force fields used in this study and potentially other force fields as well.

  8. Close intramolecular sulfur-oxygen contacts: modified force field parameters for improved conformation generation

    NASA Astrophysics Data System (ADS)

    Lupyan, Dmitry; Abramov, Yuriy A.; Sherman, Woody

    2012-11-01

    The Cambridge Structural Database (CSD) offers an excellent data source to study small molecule conformations and molecular interactions. We have analyzed 130 small molecules from the CSD containing an intramolecular sulfur-oxygen distance less than the sum of their van der Waals (vdW) radii. Close S···O distances are observed in several important medicinal chemistry motifs (e.g. a carbonyl oxygen connected by a carbon or nitrogen linker to a sulfur) and are not treated well with existing parameters in the MMFFs or OPLS_2005 force fields, resulting in suboptimal geometries and energetics. In this work, we develop modified parameters for the OPLS_2005 force field to better treat this specific interaction in order to generate conformations close to those found in the CSD structures. We use a combination of refitting a force field torsional parameter, adding a specific atom pair vdW term, and attenuating the electrostatic interactions to obtain an improvement in the accuracy of geometry minimizations and conformational searches for these molecules. Specifically, in a conformational search 58 % of the cases produced a conformation less than 0.25 Å from the CSD crystal conformation with the modified OPLS force field parameters developed in this work. In contrast, 25 and 37 % produced a conformation less than 0.25 Å with the MMFFs and OPLS_2005 force fields, respectively. As an application of the new parameters, we generated conformations for the tyrosine kinase inhibitor axitinib (trade name Inlyta) that could be correctly repacked into three observed polymorphic structures, which was not possible with conformations generated using MMFFs or OPLS_2005. The improved parameters can be mapped directly onto physical characteristics of the systems that are treated inadequately with the molecular mechanics force fields used in this study and potentially other force fields as well.

  9. 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

  10. Xanthan hydrogel films: molecular conformation, charge density and protein carriers.

    PubMed

    Bueno, Vânia Blasques; Petri, Denise Freitas Siqueira

    2014-01-30

    In this article the molecular conformation of xanthan chains in hydrogel films was investigated by means of circular dichroism, showing substantial differences between xanthan hydrogel prepared in the absence (XNT) and in the presence of citric acid (XCA). The xanthan chains in XNT hydrogels films presented ordered conformation (helixes), while in XCA they were in the disordered conformation (coils), exposing a larger number of carboxylate groups than XNT. The large charge density in XCA hydrogels was evidenced by their behavior under variable ionic strength. Studies about the application of XNT and XCA for loading and delivering of bovine serum albumin (BSA) and lysozyme (LYZ) showed that both events are controlled by hydrogels and proteins net charge, which can be triggered by pH. The preservation of LYZ native conformation after hydrogel loading explained the substantial bactericidal activity of LYZ loaded hydrogels and enables their use as active wound dressings.

  11. 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 (Ea), 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. Ea, 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.

  12. Learning generative models of molecular dynamics

    PubMed Central

    2012-01-01

    We introduce three algorithms for learning generative models of molecular structures from molecular dynamics simulations. The first algorithm learns a Bayesian-optimal undirected probabilistic model over user-specified covariates (e.g., fluctuations, distances, angles, etc). L1 reg-ularization is used to ensure sparse models and thus reduce the risk of over-fitting the data. The topology of the resulting model reveals important couplings between different parts of the protein, thus aiding in the analysis of molecular motions. The generative nature of the model makes it well-suited to making predictions about the global effects of local structural changes (e.g., the binding of an allosteric regulator). Additionally, the model can be used to sample new conformations. The second algorithm learns a time-varying graphical model where the topology and parameters change smoothly along the trajectory, revealing the conformational sub-states. The last algorithm learns a Markov Chain over undirected graphical models which can be used to study and simulate kinetics. We demonstrate our algorithms on multiple molecular dynamics trajectories. PMID:22369071

  13. Learning generative models of molecular dynamics.

    PubMed

    Razavian, Narges Sharif; Kamisetty, Hetunandan; Langmead, Christopher J

    2012-01-01

    We introduce three algorithms for learning generative models of molecular structures from molecular dynamics simulations. The first algorithm learns a Bayesian-optimal undirected probabilistic model over user-specified covariates (e.g., fluctuations, distances, angles, etc). L1 regularization is used to ensure sparse models and thus reduce the risk of over-fitting the data. The topology of the resulting model reveals important couplings between different parts of the protein, thus aiding in the analysis of molecular motions. The generative nature of the model makes it well-suited to making predictions about the global effects of local structural changes (e.g., the binding of an allosteric regulator). Additionally, the model can be used to sample new conformations. The second algorithm learns a time-varying graphical model where the topology and parameters change smoothly along the trajectory, revealing the conformational sub-states. The last algorithm learns a Markov Chain over undirected graphical models which can be used to study and simulate kinetics. We demonstrate our algorithms on multiple molecular dynamics trajectories.

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

    NASA Astrophysics Data System (ADS)

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

    2013-12-01

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

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

    SciTech Connect

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

    2013-12-14

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

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

    PubMed

    Petridis, Loukas; Smith, Jeremy C

    2016-02-08

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

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

    DOE PAGES

    Petridis, Loukas; Smith, Jeremy C.

    2016-01-13

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

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

    SciTech Connect

    Petridis, Loukas; Smith, Jeremy C.

    2016-01-13

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

  19. Conformational statistics and molecular modeling on polybenzoxazine

    NASA Astrophysics Data System (ADS)

    Kim, Won-Kook

    A Rotational Isomeric State (RIS) model has been developed from the conformational study on a model dimer as a variables of the stereochemistry and the torsional sequence of C-O bond. Chain dimension in terms of the characteristic ratio was calculated for two ideal cases. From the RIS Monte Carlo chains whose end-to-end distances are near the average value, five independent static bulk structures were obtained by employing the cubic periodic boundary conditions at bulk density of 1.1 g/cmsp3 and the MD and energy minimization. The solubility parameter was predicted to be 8.29 (cal/cmsp3)sp{1/2} with the standard deviation of 0.71. The bulk structure was analyzed using the pair correlation function, hydrogen bonding structure, and the orientational order parameter of the phenyl rings. Free volumes were studied as a function of probe radius, and the size distribution and shape were evaluated. The diffusion of water and oxygen molecules in the PBO matrix was studied at 295 K and 450 K. The predicted diffusion coefficients are remarkably close, given their considerable size difference. The chain mobility at two different temperatures was studied from torsional auto-correlation function. The interaction of the diffusant molecules and the atoms on PBO matrix are studied from the pair correlation function. The hydrogen bonding of water and the hydroxyl groups in PBO is evident in the pair correlation function. The averaged hydrogen bonding fraction and hydrogen bonding life time were studied using hydrogen bonding auto-correlation function. In hydrogen bonding auto-correlation function, the life time of hydrogen bond between water and PBO is much shorter then the average residence time of cavity, therefore the hydrogen bond does not remarkably retard the diffusion of water in PBO matrix. The association of water is also observed at two temperatures. Thin film of thickness ˜28 A was constructed in vacuum from the bulk amorphous PBO after extending one edge (the Z-axis) of

  20. Electrostatic Swelling and Conformational Variation Observed in High-Generation Polyelectrolyte Dendrimers

    SciTech Connect

    Butler, Paul D; Chen, Wei-Ren; Herwig, Kenneth W; Hong, Kunlun; Liu, Yun; Porcar, L.; Shew, Chwen-Yang; Smith, Gregory Scott; Chen, Hsin-Lung; Chen, Chun-Yu; Li, Xin; Liu, Emily

    2010-01-01

    A coordinated study combining small angle neutron scattering (SANS) and small angle x-ray scattering (SAXS) measurements was conducted to investigate the structural characteristics of aqueous (D2O) generation 7 and 8 (G7 & G8) PAMAM dendrimer solutions as a function of molecular protonation at room temperature. The change in intra-molecular conformation was clearly exhibited in the data analysis by separating the variation in the inter-molecular correlation. Our results unambiguously demonstrate an increased molecular size and evolved intra-molecular density profile upon increasing the molecular protonation. This is contrary to the existing understanding that in higher generation polyelectrolyte dendrimers, steric crowding stiffens the local motion of dendrimer segments exploring additional available intra-dendrimer volume and therefore inhibits the electrostatic swelling. Our observation is relevant to elucidation of the general microscopic picture of polyelectrolyte dendrimer structure, as well as the development of dendrimer-based packages with based on the stimuli-responsive principle.

  1. Conformational analysis of molecular chains using nano-kinematics.

    PubMed

    Manocha, D; Zhu, Y; Wright, W

    1995-02-01

    We present algorithms for 3-D manipulation and conformational analysis of molecular chains, when bond lengths, bond angles and related dihedral angles remain fixed. These algorithms are useful for local deformations of linear molecules, exact ring closure in cyclic molecules and molecular embedding for short chains. Other possible applications include structure prediction, protein folding, conformation energy analysis and 3D molecular matching and docking. The algorithms are applicable to all serial molecular chains and make no assumptions about their geometry. We make use of results on direct and inverse kinematics from robotics and mechanics literature and show the correspondence between kinematics and conformational analysis of molecules. In particular, we pose these problems algebraically and compute all the solutions making use of the structure of these equations and matrix computations. The algorithms have been implemented and perform well in practice. In particular, they take tens of milliseconds on current workstations for local deformations and chain closures on molecular chains consisting of six or fewer rotatable dihedral angles.

  2. Probing myosin structural conformation in vivo by second-harmonic generation microscopy

    PubMed Central

    Pavone, F. S.

    2010-01-01

    Understanding of complex biological processes requires knowledge of molecular structures and measurement of their dynamics in vivo. The collective chemomechanical action of myosin molecules (the molecular motors) in the muscle sarcomere represents a paradigmatic example in this respect. Here, we describe a label-free imaging method sensitive to protein conformation in vivo. We employed the order-based contrast enhancement by second-harmonic generation (SHG) for the functional imaging of muscle cells. We found that SHG polarization anisotropy (SPA) measurements report on the structural state of the actomyosin motors, with significant sensitivity to the conformation of myosin. In fact, each physiological/biochemical state we probed (relaxed, rigor, isometric contraction) produced a distinct value of polarization anisotropy. Employing a full reconstruction of the contributing elementary SHG emitters in the actomyosin motor array at atomic scale, we provide a molecular interpretation of the SPA measurements in terms of myosin conformations. We applied this method to the discrimination between attached and detached myosin heads in an isometrically contracting intact fiber. Our observations indicate that isometrically contracting muscle sustains its tetanic force by steady-state commitment of 30% of myosin heads. Applying SPA and molecular structure modeling to the imaging of unstained living tissues provides the basis for a generation of imaging and diagnostic tools capable of probing molecular structures and dynamics in vivo. PMID:20385845

  3. 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

  4. Conformational and functional analysis of molecular dynamics trajectories by self-organising maps.

    PubMed

    Fraccalvieri, Domenico; Pandini, Alessandro; Stella, Fabio; Bonati, Laura

    2011-05-14

    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. 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. 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.

  5. Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin.

    PubMed Central

    Caves, L. S.; Evanseck, J. D.; Karplus, M.

    1998-01-01

    Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory. PMID:9541397

  6. Fast Generation of body conforming grids for 3-D

    NASA Technical Reports Server (NTRS)

    Dulikravich, O.

    1980-01-01

    A fast algorithm was developed for accurately generating boundary conforming, three dimensional, consecutively refined, computational grids applicable to arbitrary axial turbomachinery geometry. The method is based on using a single analytic function to generate two dimensional grids on a number of coaxial axisymmetric surfaces positioned between the hub and the shroud. These grids are of the "O" type and are characterized by quasi-orthogonality, geometric periodicity, and an adequate resolution throughout the flowfield. Due to the built in additional nonorthogonal coordinate stretching and shearing, the grid lines leaving the trailing of the blade end at downstream infinity, thus simplifying the numerical treatment of the three dimensional trailing vortex sheet.

  7. Non-Gaussianity of scalar perturbations generated by conformal mechanisms

    SciTech Connect

    Libanov, M.; Mironov, S.; Rubakov, V.

    2011-10-15

    We consider theories which explain the flatness of the power spectrum of scalar perturbations in the Universe by conformal invariance, such as conformal rolling model and Galilean Genesis. We show that to the leading nonlinear order, perturbations in all models from this class behave in one and the same way, at least if the energy density of the relevant fields is small compared to the total energy density (spectator approximation). We then turn to the intrinsic non-Gaussianities in these models (as opposed to non-Gaussianities that may be generated during subsequent evolution). The intrinsic bispectrum vanishes, so we perform the complete calculation of the trispectrum and compare it with the trispectra of local forms in various limits. The most peculiar feature of our trispectrum is a (fairly mild) singularity in the limit where two momenta are equal in absolute value and opposite in direction (folded limit). Generically, the intrinsic non-Gaussianity can be of detectable size.

  8. Origin of molecular conformational stability: Perspectives from molecular orbital interactions and density functional reactivity theory

    SciTech Connect

    Liu, Shubin E-mail: schauer@unc.edu; Schauer, Cynthia K. E-mail: schauer@unc.edu

    2015-02-07

    To have a quantitative understanding about the origin of conformation stability for molecular systems is still an unaccomplished task. Frontier orbital interactions from molecular orbital theory and energy partition schemes from density functional reactivity theory are the two approaches available in the literature that can be used for this purpose. In this work, we compare the performance of these approaches for a total of 48 simple molecules. We also conduct studies to flexibly bend bond angles for water, carbon dioxide, borane, and ammonia molecules to obtain energy profiles for these systems over a wide range of conformations. We find that results from molecular orbital interactions using frontier occupied orbitals such as the highest occupied molecular orbital and its neighbors are only qualitatively, at most semi-qualitatively, trustworthy. To obtain quantitative insights into relative stability of different conformations, the energy partition approach from density functional reactivity theory is much more reliable. We also find that the electrostatic interaction is the dominant descriptor for conformational stability, and steric and quantum effects are smaller in contribution but their contributions are indispensable. Stable molecular conformations prefer to have a strong electrostatic interaction, small molecular size, and large exchange-correlation effect. This work should shed new light towards establishing a general theoretical framework for molecular stability.

  9. Origin of molecular conformational stability: perspectives from molecular orbital interactions and density functional reactivity theory.

    PubMed

    Liu, Shubin; Schauer, Cynthia K

    2015-02-07

    To have a quantitative understanding about the origin of conformation stability for molecular systems is still an unaccomplished task. Frontier orbital interactions from molecular orbital theory and energy partition schemes from density functional reactivity theory are the two approaches available in the literature that can be used for this purpose. In this work, we compare the performance of these approaches for a total of 48 simple molecules. We also conduct studies to flexibly bend bond angles for water, carbon dioxide, borane, and ammonia molecules to obtain energy profiles for these systems over a wide range of conformations. We find that results from molecular orbital interactions using frontier occupied orbitals such as the highest occupied molecular orbital and its neighbors are only qualitatively, at most semi-qualitatively, trustworthy. To obtain quantitative insights into relative stability of different conformations, the energy partition approach from density functional reactivity theory is much more reliable. We also find that the electrostatic interaction is the dominant descriptor for conformational stability, and steric and quantum effects are smaller in contribution but their contributions are indispensable. Stable molecular conformations prefer to have a strong electrostatic interaction, small molecular size, and large exchange-correlation effect. This work should shed new light towards establishing a general theoretical framework for molecular stability.

  10. Assessing protein conformational sampling and structural stability via de novo design and molecular dynamics simulations.

    PubMed

    Cunha, Keila C; Rusu, Victor H; Viana, Isabelle F T; Marques, Ernesto T A; Dhalia, Rafael; Lins, Roberto D

    2015-06-01

    Molecular dynamics and de novo techniques, associated to quality parameter sets, have excelled at determining the structure of small proteins with high accuracy. To achieve a detailed description of protein conformations, these methods must critically assess the thermodynamic features of the molecular ensembles. Here, a comparison of the conformational ensemble generated by molecular dynamics and de novo techniques were carried out for six Top7-based proteins carrying gp41 HIV-1 epitopes. The native Top7, a highly stable computationally designed protein, was used as benchmark. Structural stability, flexibility, and secondary structure content were assessed. The consistency of the latter was compared to experimental circular dichroism spectra for all proteins. While both methods are capable to identify the stable from unstable chimeric proteins, the sampled conformational space and flexibility differ significantly in both methods. Molecular dynamics simulations seem to better describe secondary structure content and identify regions responsible for conformational instability. The de novo method, as implemented in Rosetta-a prime tool for protein design, overestimates secondary structure content. On the other hand, its empirical energy function is capable to predict the threshold for protein stability.

  11. Sampling Molecular Conformers in Solution with Quantum Mechanical Accuracy at a Nearly Molecular-Mechanics Cost.

    PubMed

    Rosa, Marta; Micciarelli, Marco; Laio, Alessandro; Baroni, Stefano

    2016-09-13

    We introduce a method to evaluate the relative populations of different conformers of molecular species in solution, aiming at quantum mechanical accuracy, while keeping the computational cost at a nearly molecular-mechanics level. This goal is achieved by combining long classical molecular-dynamics simulations to sample the free-energy landscape of the system, advanced clustering techniques to identify the most relevant conformers, and thermodynamic perturbation theory to correct the resulting populations, using quantum-mechanical energies from density functional theory. A quantitative criterion for assessing the accuracy thus achieved is proposed. The resulting methodology is demonstrated in the specific case of cyanin (cyanidin-3-glucoside) in water solution.

  12. Complete maps of molecular-loop conformational spaces.

    PubMed

    Porta, Josep M; Ros, Lluís; Thomas, Federico; Corcho, Francesc; Cantó, Josep; Pérez, Juan Jesús

    2007-10-01

    This paper presents a numerical method to compute all possible conformations of distance-constrained molecular loops, i.e., loops where some interatomic distances are held fixed, while others can vary. The method is general (it can be applied to single or multiple intermingled loops of arbitrary topology) and complete (it isolates all solutions, even if they form positive-dimensional sets). Generality is achieved by reducing the problem to finding all embeddings of a set of points constrained by pairwise distances, which can be formulated as computing the roots of a system of Cayley-Menger determinants. Completeness is achieved by expressing these determinants in Bernstein form and using a numerical algorithm that exploits such form to bound all root locations at any desired precision. The method is readily parallelizable, and the current implementation can be run on single- or multiprocessor machines. Experiments are included that show the method's performance on rigid loops, mobile loops, and multiloop molecules. In all cases, complete maps including all possible conformations are obtained, thus allowing an exhaustive analysis and visualization of all pseudo-rotation paths between different conformations satisfying loop closure.

  13. Enthalpy-Entropy Compensation upon Molecular Conformational Changes.

    PubMed

    Ahmad, Mazen; Helms, Volkhard; Lengauer, Thomas; Kalinina, Olga V

    2015-04-14

    The change in free energy is the dominant factor in all chemical processes; it usually encompasses enthalpy-entropy compensation (EEC). Here, we use the free energy perturbation formalism to show that EEC is influenced by the molecular conformational changes (CCs) of the entire system comprising the solute and by the already known solvent reorganization. The internal changes of enthalpy and the entropy due to CCs upon modifying the interactions (perturbation) cancel each other exactly. The CCs influence the dissipation of the modified interactions and their contributions to the free energy. Using molecular simulations, we show that, for solvation of six different HIV-1 protease inhibitors, CCs in the solute cause EEC as large as 10-30 kcal/mol. Moreover, the EEC due to CCs in HIV-1 protease is shown to vary significantly upon modifying its bound ligand. These findings have important implications for understanding of EEC phenomena and for interpretation of thermodynamic measurements.

  14. Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database.

    PubMed

    Hawkins, Paul C D; Skillman, A Geoffrey; Warren, Gregory L; Ellingson, Benjamin A; Stahl, Matthew T

    2010-04-26

    Here, we present the algorithm and validation for OMEGA, a systematic, knowledge-based conformer generator. The algorithm consists of three phases: assembly of an initial 3D structure from a library of fragments; exhaustive enumeration of all rotatable torsions using values drawn from a knowledge-based list of angles, thereby generating a large set of conformations; and sampling of this set by geometric and energy criteria. Validation of conformer generators like OMEGA has often been undertaken by comparing computed conformer sets to experimental molecular conformations from crystallography, usually from the Protein Databank (PDB). Such an approach is fraught with difficulty due to the systematic problems with small molecule structures in the PDB. Methods are presented to identify a diverse set of small molecule structures from cocomplexes in the PDB that has maximal reliability. A challenging set of 197 high quality, carefully selected ligand structures from well-solved models was obtained using these methods. This set will provide a sound basis for comparison and validation of conformer generators in the future. Validation results from this set are compared to the results using structures of a set of druglike molecules extracted from the Cambridge Structural Database (CSD). OMEGA is found to perform very well in reproducing the crystallographic conformations from both these data sets using two complementary metrics of success.

  15. Adiabatic bias molecular dynamics: A method to navigate the conformational space of complex molecular systems

    NASA Astrophysics Data System (ADS)

    Marchi, Massimo; Ballone, Pietro

    1999-02-01

    This study deals with a novel molecular simulation technique, named adiabatic bias molecular dynamics (MD), which provides a simple and reasonably inexpensive route to generate MD trajectories joining points in conformational space separated by activation barriers. Because of the judicious way the biasing potential is updated during the MD runs, the technique allows with some additional effort the computation of the free energy change experienced during the trajectory. The adiabatic bias method has been applied to a nontrivial problem: The unfolding of an atomistic model of lysozyme. Here, the radius of gyration (Rg) was used as a convenient reaction coordinate. For changes in Rg between 19.7 and 28 Å, we observe a net loss of the native tertiary structure of lysozyme. At the same time, secondary structure elements such as α-helices are retained although some of the original order is diminished. The calculated free energy profile for the unfolding transition shows a monotonous increase with Rg and depends crucially on the nonbonded cutoff used in the potential model.

  16. 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.

  17. A script for automated 3-dimentional structure generation and conformer search from 2- dimentional chemical drawing.

    PubMed

    Ishikawa, Yoshinobu

    2013-01-01

    Building 3-dimensional (3D) molecules is the starting point in molecular modeling. Conformer search and identification of a global energy minimum structure are often performed computationally during spectral analysis of data from NMR, IR, and VCD or during rational drug design through ligand-based, structure-based, and QSAR approaches. I herein report a convenient script that allows for automated building of 3D structures and conformer searching from 2-dimensional (2D) drawing of chemical structures. With this Bash shell script, which runs on Mac OS X and the Linux platform, the tasks are consecutively and iteratively executed without a 3D molecule builder via the command line interface of the free (academic) software OpenBabel, Balloon, and MOPAC2012. A large number of 2D chemical drawing files can be processed simultaneously, and the script functions with stereoisomers. Semi-empirical quantum chemical calculation ensures reliable ranking of the generated conformers on the basis of energy. In addition to an energy-sorted list of file names of the conformers, their Gaussian input files are provided for ab initio and density functional theory calculations to predict rigorous electronic energies, structures, and properties. This script is freely available to all scientists.

  18. A Script for Automated 3-Dimentional Structure Generation and Conformer Search from 2- Dimentional Chemical Drawing

    PubMed Central

    Ishikawa, Yoshinobu

    2013-01-01

    Building 3-dimensional (3D) molecules is the starting point in molecular modeling. Conformer search and identification of a global energy minimum structure are often performed computationally during spectral analysis of data from NMR, IR, and VCD or during rational drug design through ligand-based, structure-based, and QSAR approaches. I herein report a convenient script that allows for automated building of 3D structures and conformer searching from 2-dimensional (2D) drawing of chemical structures. With this Bash shell script, which runs on Mac OS X and the Linux platform, the tasks are consecutively and iteratively executed without a 3D molecule builder via the command line interface of the free (academic) software OpenBabel, Balloon, and MOPAC2012. A large number of 2D chemical drawing files can be processed simultaneously, and the script functions with stereoisomers. Semi-empirical quantum chemical calculation ensures reliable ranking of the generated conformers on the basis of energy. In addition to an energy-sorted list of file names of the conformers, their Gaussian input files are provided for ab initio and density functional theory calculations to predict rigorous electronic energies, structures, and properties. This script is freely available to all scientists. PMID:24391363

  19. Temperature dependent conformation studies of Calmodulin Protein using Molecular Dynamics

    NASA Astrophysics Data System (ADS)

    Aneja, Sahil; Bhartiya, Vivek Kumar; Negi, Sunita

    2016-10-01

    Calmodulin (CaM) protein plays a very crucial role in the calcium signaling inside the eukaryotic cell structure [1, 2]. It can also bind to other proteins/targets and facilitate various activities inside the cell [3, 4]. Temperature dependent conformation changes in the CaM protein are studied with extensive molecular dynamics simulations. The quantitative comparison of simulation data with various forms of experimental results probing different aspects of the folding process can facilitate robust assessment of the accuracy of the calculations. It can also provide a detailed structural interpretation for the experimental observations as well as physical interpretation for theory behind different aspects of the experiment. Earlier these kinds of studies have been performed experimentally using fluorescence measurements as in [5]. The calcium bound form of CaM is observed to undergo a reversible conformation change in the range 295-301 K at calcium ion concentration 150 mM. The transition temperature was observed to depend on the calcium ion concentration of the protein. Leap-dynamics approach was used earlier to study the temperature dependent conformation change of CaM [6]. At 290 K, both the N- and C-lobes were stable, at 325 K, the C-lobe unfolds whereas at 360 both the lobes unfold [6]. In this work, we perform molecular dynamics simulations of 100 ns each for the temperatures 325 K and 375 K on the apo form of CaM, 3CLN and 1CFD. A remarkable dependence of the temperature is observed on the overall dynamics of both the forms of the protein as reported in our earlier study [7, 8]. 1CFD shows a much flexible linker as compared to 3CLN whereas the overall dynamics of the lobes mainly N-lobe is observed to be more in later case. Salt bridge formation between the residues 2 (ASP) and 148 (LYS) leads to a more compact form of 1CFD at 325 K. The unfolding of the protein is observed to increase with the increase in the temperature similar to the earlier reported

  20. Probing molecular conformations in momentum space: The case of n-pentane

    NASA Astrophysics Data System (ADS)

    Knippenberg, S.; Huang, Y. R.; Hajgató, B.; François, J.-P.; Deng, J. K.; Deleuze, M. S.

    2007-11-01

    A comprehensive study, throughout the valence region, of the electronic structure and electron momentum density distributions of the four conformational isomers of n-pentane is presented. Theoretical (e,2e) valence ionization spectra at high electron impact energies (1200eV+electron binding energy) and at azimuthal angles ranging from 0° to 10° in a noncoplanar symmetric kinematical setup are generated according to the results of large scale one-particle Green's function calculations of Dyson orbitals and related electron binding energies, using the third-order algebraic-diagrammatic construction [ADC(3)] scheme. The results of a focal point analysis (FPA) of relative conformer energies [A. Salam and M. S. Deleuze, J. Chem. Phys. 116, 1296 (2002)] and improved thermodynamical calculations accounting for hindered rotations are also employed in order to quantitatively evaluate the abundance of each conformer in the gas phase at room temperature and reliably predict the outcome of experiments on n-pentane employing high resolution electron momentum spectroscopy. Comparison with available photoelectron measurements confirms the suggestion that, due to entropy effects, the trans-gauche (tg) conformer strongly dominates the conformational mixture characterizing n-pentane at room temperature. Our simulations demonstrate therefore that experimental measurements of (e,2e) valence ionization spectra and electron momentum distributions would very consistently and straightforwardly image the topological changes and energy variations that molecular orbitals undergo due to torsion of the carbon backbone. The strongest fingerprints for the most stable conformer (tt) are found for the electron momentum distributions associated with ionization channels at the top of the inner-valence region, which sensitively image the development of methylenic hyperconjugation in all-staggered n-alkane chains.

  1. Conformational space exploration of Met- and Leu-enkephalin using the MOLS method, molecular dynamics, and Monte Carlo simulation--a comparative study.

    PubMed

    Ramya, L; Gautham, N

    2012-03-01

    We report here a comparative study of the molecular conformational energy landscape generated using the mutually orthogonal Latin squares (MOLS) method, molecular dynamics (MD), and Monte Carlo (MC) simulation. The MOLS method, as described earlier from our laboratory, uses an experimental design technique to rapidly and exhaustively sample the low energy conformations of a molecule. MD and MC simulations have been used to perform similar tasks. In the comparison reported here, the three methods were applied to a pair of neuropeptides, namely Met- and Leu-enkephalin. A set of 1500 conformations of these enkephalins were generated using these methods with CHARMM22 force field, and the resulting samples were analyzed to determine the extent and nature of coverage of the conformational space. The results indicate that the MOLS method samples a larger number of possible conformations and identifies conformations closer to the experimental structures than the MD and MC simulations. Copyright © 2011 Wiley Periodicals, Inc.

  2. A numerical study of hybrid optimization methods for the molecular conformation problems

    SciTech Connect

    Meza, J.C.; Martinez, M.L.

    1993-05-01

    An important area of research in computational biochemistry is the design of molecules for specific applications. The design of these molecules depends on the accurate determination of their three-dimensional structure or conformation. Under the assumption that molecules will settle into a configuration for which their energy is at a minimum, this design problem can be formulated as a global optimization problem. The solution of the molecular conformation problem can then be obtained, at least in principle, through any number of optimization algorithms. Unfortunately, it can easily be shown that there exist a large number of local minima for most molecules which makes this an extremely difficult problem for any standard optimization method. In this study, we present results for various optimization algorithms applied to a molecular conformation problem. We include results for genetic algorithms, simulated annealing, direct search methods, and several gradient methods. The major result of this study is that none of these standard methods can be used in isolation to efficiently generate minimum energy configurations. We propose instead several hybrid methods that combine properties of several local optimization algorithms. These hybrid methods have yielded better results on representative test problems than single methods.

  3. Near-infrared laser-induced generation of three rare conformers of glycolic acid.

    PubMed

    Halasa, Anna; Lapinski, Leszek; Reva, Igor; Rostkowska, Hanna; Fausto, Rui; Nowak, Maciej J

    2014-07-31

    Structural transformations were induced in conformers of glycolic acid by selective excitation with monochromatic tunable near-infrared laser light. For the compound isolated in Ar matrixes, near-IR excitation led to generation of two higher-energy conformers (GAC; AAT) differing from the most stable SSC form by 180° rotation around the C-C bond. A detailed investigation of this transformation revealed that one conformer (GAC) is produced directly from the near-IR-excited most stable conformer. The other higher-energy conformer (AAT) was effectively generated only upon excitation of the primary photoproduct (GAC) with another near-IR photon. Once these higher-energy conformers of glycolic acid were generated in an Ar matrix, they could be subsequently transformed into one another upon selective near-IR excitations. Interestingly, no repopulation of the initial most stable SSC conformer occurred upon near-IR excitation of the higher-energy forms of the compound isolated in solid Ar. A dramatically different picture of near-IR-induced conformational transformations was observed for glycolic acid isolated in N2 matrixes. In this case, upon near-IR excitation, the most stable SSC form converted solely into a new conformer (SST), where the acid OH group is rotated by 180°. This conformational transformation was found to be photoreversible. Moreover, SST conformer, photoproduced in the N2 matrix, spontaneously converted to the most stable SSC form of glycolic acid, when the matrix was kept at cryogenic temperature and in the dark.

  4. Molecular insight into protein conformational transition in hydrophobic charge induction chromatography: a molecular dynamics simulation.

    PubMed

    Zhang, Lin; Zhao, Guofeng; Sun, Yan

    2009-05-14

    Hydrophobic charge induction chromatography (HCIC) is an adsorption chromatography combining hydrophobic interaction in adsorption with electrostatic repulsion in elution. The method has been successfully applied in the separation and purification of antibodies and other proteins. However, little is understood about protein conformational transition and the dynamic process within adsorbent pores. In the present study, a pore model is established to represent the realistic porous adsorbent composed of matrix and immobilized HCIC ligands. Protein adsorption, desorption, and conformational transition in the HCIC pore and its implications to the separation performance are shown by a molecular dynamics simulation of a 46-bead beta-barrel coarse-grained model protein in the adsorbent pore. Repeated adjustment of both protein position and orientation is observed before reaching a stable adsorption. Once the protein is adsorbed, there is a dynamic equilibrium between unfolding and refolding. The effect of hydrophobic interaction strength between protein and ligands on adsorption phenomena is then examined. Strong hydrophobic interaction, representing the presence of high-concentration lyotropic salt in mobile phase, can speed up the adsorption but cause protein unfolding more significantly. On the contrary, weak hydrophobic interaction, representing the absence of a lyotropic salt or the presence of a chaotropic agent, can reserve native protein conformation but does not lead to stable adsorption. In the elution, protein unfolding occurs due to simultaneous hydrophobic adsorption and electrostatic repulsion in the opposite directions. When the protein has been desorbed, the conformational transition between unfolded and native protein is still observed due to the long-range nature of electrostatic interaction. The simulation has provided molecular insight into protein conformational transition in the whole HCIC process, and it would be beneficial to the rational design of

  5. Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

    NASA Astrophysics Data System (ADS)

    Gilbert, Kathleen M.; Skawinski, William J.; Misra, Milind; Paris, Kristina A.; Naik, Neelam H.; Buono, Ronald A.; Deutsch, Howard M.; Venanzi, Carol A.

    2004-11-01

    Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte> MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl

  6. A method for finding candidate conformations for molecular replacement using relative rotation between domains of a known structure.

    PubMed

    Jeong, Jay I; Lattman, Eaton E; Chirikjian, Gregory S

    2006-04-01

    This paper presents a methodology to obtain candidate conformations of multidomain proteins for use in molecular replacement. For each separate domain, the orientational relationship between the template and the target structure is obtained using standard molecular replacement. The orientational relationships of the domains are then used to calculate the relative rotation between the domains in the target conformation by using pose-estimation techniques from the field of robotics and computer vision. With the angle of relative rotation between the domains as a cost function, iterative normal-mode analysis is used to drive the template structure to a candidate conformation that matches the X-ray crystallographic data obtained for the target conformation. The selection of the correct intra-protein domain orientations from among the many spurious maxima in the rotation function (including orientations obtained from domains in symmetry mates rather than within the same copy of the protein) presents a challenge. This problem is resolved by checking R factors of each domain, measuring the absolute value of relative rotation between domains, and evaluating the cost value after each candidate conformation is driven to convergence with iterative NMA. As a validation, the proposed method is applied to three test proteins: ribose-binding protein, lactoferrin and calcium ATPase. In each test case, the orientation and translation of the final candidate conformation in the unit cell are generated correctly from the suggested procedure. The results show that the proposed method can yield viable candidate conformations for use in molecular replacement and can reveal the structural details and pose of the target conformation in the crystallographic unit cell.

  7. Numerical Computation of Diffusion Properties in Molecular Systems on a Topology-Conforming Grid

    NASA Astrophysics Data System (ADS)

    Teo, Ivan; Schulten, Klaus

    2012-02-01

    Multiscale problems involving diffusion in molecular systems are a mainstay of computational biophysics. Given a molecular system, the local diffusion coefficient D(r) as well as the equilibrium distribution function P(r) that characterizes the local free energy are computed to describe the kinetics of diffusing particles at each point in space through the Smoluchowski equation (SE). An irregular grid of space-varying fineness conforming to P(r) is generated via the method of topology-representing networks and a subsequent Voronoi tessellation. The discretized SE produces a rate matrix which describes the probabilities of particles hopping from point to point on the grid. We demonstrate the calculation of the rate matrix for ions diffusing through the balloon-like structure of the mechanosensitive channel of small conductance (MscS) and thence the determination of mean first-passage times that characterize conduction of ions through balloon and channel.

  8. Molecular tectonics: generation and structural studies on 1- and 2D coordination networks based on a meta-cyclophane in 1,3-alternate conformation bearing four pyrazolyl units and cobalt, zinc and copper cations.

    PubMed

    Ehrhart, Jérôme; Planeix, Jean-Marc; Kyritsakas-Gruber, Nathalie; Hosseini, Mir Wais

    2009-08-28

    The combination of a [1111] metacyclophane blocked in 1,3-alternate conformation and bearing four pyrazolyl coordinating units with MX(2) (M = Co, Zn and X = Cl or Br) leads to the formation of crystals formed by packing of 2D coordination networks. In the case of CuBr(2), the formation of a 1D network was observed. Structural studies by X-ray diffraction methods on single crystals were performed on all cases reported.

  9. Temperature-accelerated molecular dynamics gives insights into globular conformations sampled in the free state of the AC catalytic domain.

    PubMed

    Selwa, Edithe; Huynh, Tru; Ciccotti, Giovanni; Maragliano, Luca; Malliavin, Thérèse E

    2014-10-01

    The catalytic domain of the adenyl cyclase (AC) toxin from Bordetella pertussis is activated by interaction with calmodulin (CaM), resulting in cAMP overproduction in the infected cell. In the X-ray crystallographic structure of the complex between AC and the C terminal lobe of CaM, the toxin displays a markedly elongated shape. As for the structure of the isolated protein, experimental results support the hypothesis that more globular conformations are sampled, but information at atomic resolution is still lacking. Here, we use temperature-accelerated molecular dynamics (TAMD) simulations to generate putative all-atom models of globular conformations sampled by CaM-free AC. As collective variables, we use centers of mass coordinates of groups of residues selected from the analysis of standard molecular dynamics (MD) simulations. Results show that TAMD allows extended conformational sampling and generates AC conformations that are more globular than in the complexed state. These structures are then refined via energy minimization and further unrestrained MD simulations to optimize inter-domain packing interactions, thus resulting in the identification of a set of hydrogen bonds present in the globular conformations.

  10. Molecular dynamics analysis of conformational change of paramyxovirus F protein during the initial steps of membrane fusion

    SciTech Connect

    Martin-Garcia, Fernando; Mendieta-Moreno, Jesus Ignacio; Mendieta, Jesus

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Initial conformational change of paramyxovirus F protein is caused only by mechanical forces. Black-Right-Pointing-Pointer HRA region undergoes a structural change from a beta + alpha conformation to an extended coil and then to an all-alpha conformation. Black-Right-Pointing-Pointer HRS domains of F protein form three single {alpha}-helices prior to generation of the coiled coil. -- Abstract: The fusion of paramyxovirus to the cell membrane is mediated by fusion protein (F protein) present in the virus envelope, which undergoes a dramatic conformational change during the process. Unlike hemagglutinin in orthomyxovirus, this change is not mediated by an alteration of environmental pH, and its cause remains unknown. Steered molecular dynamics analysis leads us to suggest that the conformational modification is mediated only by stretching mechanical forces once the transmembrane fusion peptide of the protein is anchored to the cell membrane. Such elongating forces will generate major secondary structure rearrangement in the heptad repeat A region of the F protein; from {beta}-sheet conformation to an elongated coil and then spontaneously to an {alpha}-helix. In addition, it is proposed that the heptad repeat A region adopts a final three-helix coiled coil and that this structure appears after the formation of individual helices in each monomer.

  11. Various conformations of carbon nanocoils prepared by supported Ni-Fe/molecular sieve catalyst.

    PubMed

    Yang, Shaoming; Chen, Xiuqin; Takeuchi, K; Motojima, Seiji

    2006-01-01

    The carbon nanocoils with various kinds of conformations were prepared by the catalytic pyrolysis of acetylene using the Ni metal catalyst supported on molecular Sieves which was prepared using Fe-containing kaolin as the raw material. There are four kinds of carbon nanocoils conformations produced by this catalyst. The influences of reaction temperature and gas conditions on the conformations of the nanocoils were investigated and the reasons of forming nano-size coils were discussed by comparison with pure Ni metal catalyst.

  12. A knowledge-based approach to generating diverse but energetically representative ensembles of ligand conformers

    NASA Astrophysics Data System (ADS)

    Dorfman, Roman J.; Smith, Karl M.; Masek, Brian B.; Clark, Robert D.

    2008-09-01

    This paper describes a new and efficient stochastic conformational sampling method for generating a range of low-energy molecule conformations. Sampling can be tailored to a specific structural domain (e.g., peptides) by extracting torsional profiles from specific datasets and subsequently applying them to target molecules outside the reference set. The programs that handle creation of the knowledge-based torsional profiles and conformer generation per se are separate and so can be used independently or sequentially, depending on the task at hand. The conformational ensembles produced are contrasted with those generated using local minimization approaches. They are also quantitatively compared with a broader range of techniques in terms of speed and the ability to reproduce bound ligand conformations found in complexes with proteins.

  13. Influence of rotational energy barriers to the conformational search of protein loops in molecular dynamics and ranking the conformations.

    PubMed

    Tappura, K

    2001-08-15

    An adjustable-barrier dihedral angle potential was added as an extension to a novel, previously presented soft-core potential to study its contribution to the efficacy of the search of the conformational space in molecular dynamics. As opposed to the conventional soft-core potential functions, the leading principle in the design of the new soft-core potential, as well as of its extension, the soft-core and adjustable-barrier dihedral angle (SCADA) potential (referred as the SCADA potential), was to maintain the main equilibrium properties of the original force field. This qualifies the methods for a variety of a priori modeling problems without need for additional restraints typically required with the conventional soft-core potentials. In the present study, the different potential energy functions are applied to the problem of predicting loop conformations in proteins. Comparison of the performance of the soft-core and SCADA potential showed that the main hurdles for the efficient sampling of the conformational space of (loops in) proteins are related to the high-energy barriers caused by the Lennard-Jones and Coulombic energy terms, and not to the rotational barriers, although the conformational search can be further enhanced by lowering the rotational barriers of the dihedral angles. Finally, different evaluation methods were studied and a few promising criteria found to distinguish the near-native loop conformations from the wrong ones.

  14. 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

  15. First steps towards conformationally selective artificial lectins: the chair-boat discrimination by molecularly imprinted polymers.

    PubMed

    de Talancé, Vincent Lemau; Massinon, Olivier; Baati, Rachid; Wagner, Alain; Vincent, Stéphane P

    2012-11-07

    A series of molecularly imprinted polymers (MIPs) were prepared in the presence of a synthetic galactoside locked in a (1,4)B boat conformation. This study demonstrates that, depending on the polymerisation technique, an organic material can selectively bind a carbohydrate in a biologically relevant boat conformation.

  16. Investigation on surface molecular conformations and pervaporation performance of the poly(vinyl alcohol) (PVA) membrane.

    PubMed

    Zhang, Wei; Zhang, Zhennan; Wang, Xinping

    2009-05-01

    A simple method of changing pre-treatment temperature in the course of film formation was used to tune the surface structures of PVA membranes. Surface structure and property of the resulting membranes were characterized by X-ray photoelectron spectroscopy (XPS), sum frequency generation (SFG) vibrational spectroscopy, and contact angle measurements. The results show that PVA have different molecular conformations at the membrane surface while those membranes were prepared at different pre-treatment temperature. At higher pre-treatment temperatures, polar acetoxyl residues and hydroxyl groups of the PVA chains oriented in a more orderly fashion, as induced by the faster evaporation of water. When the membranes were in air, CH(3) groups adjacent to the acetoxyl groups covered the surface in order to minimize the surface free energy, while backbones of the PVA were rarely observed. These surfaces exhibited a hydrophilic nature upon contact with water due to rapid surface reconstruction. Conversely, at lower pre-treatment temperatures, the backbone CH(2) groups dominated the surface, forming a less hydrophilic surface. When the PVA membranes were employed to separate ethanol/water mixtures, it was found that the PVA membranes with more hydrophilic surface exhibited higher water selectivity. Our investigation indicates that molecular conformations on the membrane surface have considerable influence on pervaporation performance.

  17. Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling.

    PubMed

    Novak, Predrag; Tomisić, Zrinka Banić; Tepes, Predrag; Lazarevski, Gorjana; Plavec, Janez; Turkalj, Gordana

    2005-01-07

    Conformations of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative were determined in various solvents. The experimental NMR data--coupling constants and NOE contacts--were compared with the results of molecular modelling--molecular mechanics calculations and molecular dynamics simulations. The conformational changes, on the right-hand side of the 14-membered ring, affected mostly the 3JH2,H3 values and NOE crosspeaks H3 or H4 to H11. Oleandomycin was found to be present predominantly in the C3-C5 folded-in conformations in DMSO-d6 solution, whereas in buffered D2O, acetone-d6 and CDCl3, there was a mixture of folded-in and folded-out conformational families. The predominant conformation of the 8-methylene-oleandomycin-9-oxime derivative in solution was a folded-out one although different amounts of folded-in conformation were also present depending on the solvent. Oleandrose and desosamine sugar moieties adopted the usual and expected chair conformation. The conformation around the glycosidic bonds, governing the relative orientation of sugars vs. the lactone ring, showed a certain flexibility within two conformationally close families. We believe that by combining the experimental NMR data and the molecular modelling techniques, as reported in this paper, we have made significant progress in understanding the conformational behaviour and properties of macrolides. Our belief is based on our own current studies on oleandomycins as well as on the previously reported results and best practices concerning other macrolides. A rational for macrolide conformational studies and advances in methodology has been suggested accordingly.

  18. Multiple receptor conformers based molecular docking study of fluorine enhanced ethionamide with mycobacterium enoyl ACP reductase (InhA).

    PubMed

    Khan, Akib Mahmud; Shawon, Jakaria; Halim, Mohammad A

    2017-09-14

    A major limitation in current molecular docking method is that of failure to account for receptor flexibility. Herein we report multiple receptor conformers based molecular docking as a practical alternative to account for the receptor flexibility. Multiple (forty) conformers of Mycobacterium Enoyl ACP Reductase (InhA) are generated from Molecular Dynamics simulation and twenty crystallographic structures of InhA bound to different inhibitors are obtained from the Protein Data Bank. Fluorine directed modifications are performed to currently available anti-tuberculosis drug ethionamide. The modified drugs are optimized using B3LYP 6-31G (d,p) level of theory. Dipole moment, frontier orbital gap and thermodynamical properties such as electronic energy, enthalpy and Gibbs free energy of these optimized drugs are investigated. These drugs are subsequently docked against the conformers of InhA. Molecular docking against multiple InhA conformations show variation in ligand binding affinity and suggest that Ser94, Gly96, Lys165 and Ile194 amino acids play critical role on strong drug-InhA interaction. Modified drug N1 showed greater binding affinity compared to EN in most conformations. Structure of PDB ID: 2NSD and snapshot conformer at 5.5ns show most favorable binding with N1 compared to other conformers. Fluorine participates in forming fluorine bonds and contributes significantly in increasing binding affinity. Our study reveal that addition of trifluoromethyl group explicitly shows promise in improving thermodynamic properties and in enhancing hydrogen bonding and non-bonded interactions. Molecular dynamics (MD) simulation show that EN and N1 remained in the binding pocket similar to the docked pose of EN-InhA and E1-InhA complexes and also suggested that InhA binds to its inhibitor in inhibitor-induced folding manner. ADMET calculations predict modified drugs to have improved pharmacokinetic properties. Our study concludes that multiple receptor conformers based

  19. Singlet molecular oxygen generated by biological hydroperoxides.

    PubMed

    Miyamoto, Sayuri; Martinez, Glaucia R; Medeiros, Marisa H G; Di Mascio, Paolo

    2014-10-05

    The chemistry behind the phenomenon of ultra-weak photon emission has been subject of considerable interest for decades. Great progress has been made on the understanding of the chemical generation of electronically excited states that are involved in these processes. Proposed mechanisms implicated the production of excited carbonyl species and singlet molecular oxygen in the mechanism of generation of chemiluminescence in biological system. In particular, attention has been focused on the potential generation of singlet molecular oxygen in the recombination reaction of peroxyl radicals by the Russell mechanism. In the last ten years, our group has demonstrated the generation of singlet molecular oxygen from reactions involving the decomposition of biologically relevant hydroperoxides, especially from lipid hydroperoxides in the presence of metal ions, peroxynitrite, HOCl and cytochrome c. In this review we will discuss details on the chemical aspects related to the mechanism of singlet molecular oxygen generation from different biological hydroperoxides.

  20. A phenomenological relationship between molecular geometry change and conformational energy change

    NASA Astrophysics Data System (ADS)

    Bodi, Andras; Bjornsson, Ragnar; Arnason, Ingvar

    2010-08-01

    A linear correlation is established between the change in the axial/equatorial conformational energy difference and the change in the molecular geometry transformation during conformational inversion in substituted six-membered ring systems, namely in the 1-substituted cyclohexane/silacyclohexane, cyclohexane/ N-substituted piperidine and 1-substituted silacyclohexane/ P-substituted phosphorinane compound families, and for the analogous gauche/anti conformational isomerism in 1-substituted propanes/1-silapropanes. The nuclear repulsion energy parameterizes the molecular geometry, and changes in the conformational energy between the related compound families are linearly correlated with the changes in the nuclear repulsion energy difference based on DFT (B3LYP, M06-2X), G3B3, and CBS-QB3 calculations. This correlation reproduces the sometimes remarkable contrast between the conformational behavior of analogous compounds, e.g., the lack of a general equatorial preference in silacyclohexanes.

  1. Conformational properties of penicillins: quantum chemical calculations and molecular dynamics simulations of benzylpenicillin.

    PubMed

    Díaz, Natalia; Suárez, Dimas; Sordo, Tomás L

    2003-11-30

    Herein, we present theoretical results on the conformational properties of benzylpenicillin, which are characterized by means of quantum chemical calculations (MP2/6-31G* and B3LYP/6-31G*) and classical molecular dynamics simulations (5 ns) both in the gas phase and in aqueous solution. In the gas phase, the benzylpenicillin conformer in which the thiazolidine ring has the carboxylate group oriented axially is the most favored one. Both intramolecular CH. O and dispersion interactions contribute to stabilize the axial conformer with respect to the equatorial one. In aqueous solution, a molecular dynamics simulation predicts a relative population of the axial:equatorial conformers of 0.70:0.30 in consonance with NMR experimental data. Overall, the quantum chemical calculations as well as the simulations give insight into substituent effects, the conformational dynamics of benzylpenicillin, the frequency of ring-puckering motions, and the correlation of side chain and ring-puckering motions.

  2. De novo designed coiled-coil proteins with variable conformations as components of molecular electronic devices.

    PubMed

    Shlizerman, Clara; Atanassov, Alexander; Berkovich, Inbal; Ashkenasy, Gonen; Ashkenasy, Nurit

    2010-04-14

    Conformational changes of proteins are widely used in nature for controlling cellular functions, including ligand binding, oligomerization, and catalysis. Despite the fact that different proteins and artificial peptides have been utilized as electron-transfer mediators in electronic devices, the unique propensity of proteins to switch between different conformations has not been used as a mechanism to control device properties and performance. Toward this aim, we have designed and prepared new dimeric coiled-coil proteins that adopt different conformations due to parallel or antiparallel relative orientations of their monomers. We show here that controlling the conformation of these proteins attached as monolayers to gold, which dictates the direction and magnitude of the molecular dipole relative to the surface, results in quantitative modulation of the gold work function. Furthermore, charge transport through the proteins as molecular bridges is controlled by the different protein conformations, producing either rectifying or ohmic-like behavior.

  3. 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.

  4. High-Quality Dataset of Protein-Bound Ligand Conformations and Its Application to Benchmarking Conformer Ensemble Generators.

    PubMed

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

    2017-03-27

    We developed a cheminformatics pipeline for the fully automated selection and extraction of high-quality protein-bound ligand conformations from X-ray structural data. The pipeline evaluates the validity and accuracy of the 3D structures of small molecules according to multiple criteria, including their fit to the electron density and their physicochemical and structural properties. Using this approach, we compiled two high-quality datasets from the Protein Data Bank (PDB): a comprehensive dataset and a diversified subset of 4626 and 2912 structures, respectively. The datasets were applied to benchmarking seven freely available conformer ensemble generators: Balloon (two different algorithms), the RDKit standard conformer ensemble generator, the Experimental-Torsion basic Knowledge Distance Geometry (ETKDG) algorithm, Confab, Frog2 and Multiconf-DOCK. Substantial differences in the performance of the individual algorithms were observed, with RDKit and ETKDG generally achieving a favorable balance of accuracy, ensemble size and runtime. The Platinum datasets are available for download from http://www.zbh.uni-hamburg.de/platinum_dataset .

  5. Structural determination of molecular stereochemistry using VCD spectroscopy and a conformational code: absolute configuration and solution conformation of a chiral liquid pesticide, (R)-(+)-malathion.

    PubMed

    Izumi, Hiroshi; Ogata, Atsushi; Nafie, Laurence A; Dukor, Rina K

    2009-01-01

    The absolute configuration and solution conformation of (R)-(+)-malathion were determined by using vibrational circular dichroism spectroscopy and a fragment-conformational search with a recently published conformational code. The determination of molecular stereochemistry was carried out without a conformational search using molecular mechanics calculations. Density functional theory calculations of the fragments of (R)-malathion, ethyl propionate, (R)-ethyl 2-(methylthio)propanoate, (R)-diethyl 2-(methylthio)succinate, and O,O,S-trimethyl phosphorodithioate were carried out, and the principal conformational features of the fragments were profiled. This fragment-conformational search reduces the time needed for the selection of the predominant conformations for (R)-malathion and significantly improves the accuracy of the determination of absolute configuration.

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

    SciTech Connect

    Huang, Jingsong; Meunier, Vincent; Tian, Yong-Hui; Kertesz, Prof. Miklos

    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 involves 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.

  7. Next-generation molecular diagnostics.

    PubMed

    Aldape, Kenneth; Pfister, Stefan M

    2016-01-01

    The classification of brain tumors is based on the time-honored tradition of histologic examination, coupled with clinicopathologic correlation, and is based on the fundamental importance of microscopic morphologic interpretation. Supplementation by immunohistochemical markers is of substantial value to distinguish related entities and to confirm morphologic impressions. The use of techniques such as fluorescent in situ hybridization (FISH) is also critical in specific situations. However, with these practices, it is clear that the use of state-of-the-art molecular techniques has great promise to add to classification to (1) reduce the subjectivity inherent in interobserver discordance, particularly with specific entities; and (2) elucidate the biologic diversity of entities that are not resolvable by routine methods. In this chapter, we discuss these possibilities, focusing on several tumor types affecting the central nervous system, including diffuse glioma and ependymoma.

  8. Vibrational modes and changing molecular conformation of perfluororubrene in thin films and solution.

    PubMed

    Anger, F; Scholz, R; Gerlach, A; Schreiber, F

    2015-06-14

    We investigate the vibrational properties of perfluororubrene (PF-RUB) in thin films on silicon wafers with a native oxide layer as well as on silicon wafers covered with a self-assembled monolayer and in dichloromethane solution. In comparison with computed Raman and IR spectra, we can assign the molecular modes and identify two molecular conformations with twisted and planar tetracene backbones of the molecule. Moreover, we employ Raman imaging techniques to study the morphology and distribution of the molecular conformation in PF-RUB thin films.

  9. Probing flexible conformations in molecular junctions by inelastic electron tunneling spectroscopy

    SciTech Connect

    Deng, Mingsen; Ye, Gui; Jiang, Jun; Cai, Shaohong; Sun, Guangyu

    2015-01-15

    The probe of flexible molecular conformation is crucial for the electric application of molecular systems. We have developed a theoretical procedure to analyze the couplings of molecular local vibrations with the electron transportation process, which enables us to evaluate the structural fingerprints of some vibrational modes in the inelastic electron tunneling spectroscopy (IETS). Based on a model molecule of Bis-(4-mercaptophenyl)-ether with a flexible center angle, we have revealed and validated a simple mathematical relationship between IETS signals and molecular angles. Our results might open a route to quantitatively measure key geometrical parameters of molecular junctions, which helps to achieve precise control of molecular devices.

  10. Protein dynamics and conformational disorder in molecular recognition.

    PubMed

    Mittag, Tanja; Kay, Lewis E; Forman-Kay, Julie D

    2010-01-01

    Recognition requires protein flexibility because it facilitates conformational rearrangements and induced-fit mechanisms upon target binding. Intrinsic disorder is an extreme on the continuous spectrum of possible protein dynamics and its role in recognition may seem counterintuitive. However, conformational disorder is widely found in many eukaryotic regulatory proteins involved in processes such as signal transduction and transcription. Disordered protein regions may in fact confer advantages over folded proteins in binding. Rapidly interconverting and diverse conformers may create mean electrostatic fields instead of presenting discrete charges. The resultant "polyelectrostatic" interactions allow for the utilization of post-translational modifications as a means to change the net charge and thereby modify the electrostatic interaction of a disordered region. Plasticity of disordered protein states enables steric advantages over folded proteins and allows for unique binding configurations. Disorder may also have evolutionary advantages, as it facilitates alternative splicing, domain shuffling and protein modularity. As proteins exist in a continuous spectrum of disorder, so do their complexes. Indeed, disordered regions in complexes may control the degree of motion between domains, mask binding sites, be targets of post-translational modifications, permit overlapping binding motifs, and enable transient binding of different binding partners, making them excellent candidates for signal integrators and explaining their prevalence in eukaryotic signaling pathways. "Dynamic" complexes arise if more than two transient protein interfaces are involved in complex formation of two binding partners in a dynamic equilibrium. "Disordered" complexes, in contrast, do not involve significant ordering of interacting protein segments but rely exclusively on transient contacts. The nature of these interactions is not well understood yet but advancements in the structural

  11. Better Informed Distance Geometry: Using What We Know To Improve Conformation Generation.

    PubMed

    Riniker, Sereina; Landrum, Gregory A

    2015-12-28

    Small organic molecules are often flexible, i.e., they can adopt a variety of low-energy conformations in solution that exist in equilibrium with each other. Two main search strategies are used to generate representative conformational ensembles for molecules: systematic and stochastic. In the first approach, each rotatable bond is sampled systematically in discrete intervals, limiting its use to molecules with a small number of rotatable bonds. Stochastic methods, on the other hand, sample the conformational space of a molecule randomly and can thus be applied to more flexible molecules. Different methods employ different degrees of experimental data for conformer generation. So-called knowledge-based methods use predefined libraries of torsional angles and ring conformations. In the distance geometry approach, on the other hand, a smaller amount of empirical information is used, i.e., ideal bond lengths, ideal bond angles, and a few ideal torsional angles. Distance geometry is a computationally fast method to generate conformers, but it has the downside that purely distance-based constraints tend to lead to distorted aromatic rings and sp(2) centers. To correct this, the resulting conformations are often minimized with a force field, adding computational complexity and run time. Here we present an alternative strategy that combines the distance geometry approach with experimental torsion-angle preferences obtained from small-molecule crystallographic data. The torsional angles are described by a previously developed set of hierarchically structured SMARTS patterns. The new approach is implemented in the open-source cheminformatics library RDKit, and its performance is assessed by comparing the diversity of the generated ensemble and the ability to reproduce crystal conformations taken from the crystal structures of small molecules and protein-ligand complexes.

  12. Influence of Molecular Solvation on the Conformation of Star Polymers

    SciTech Connect

    Li, Xin; Porcar, L.; Sanchez-Diaz, Luis E; Do, Changwoo; Liu, Yun; Smith, Gregory Scott; Hong, Kunlun; Chen, Wei-Ren

    2014-01-01

    We have used neutron scattering to investigate the influence of concentration on the conformation of a star polymer. By varying the contrast between the solvent and isotopically labeled stars, we obtain the distributions of polymer and solvent within a star polymer from analysis of scattering data. A correlation between the local desolvation and the inward folding of star branches is discovered. From the perspective of thermodynamics, we find an analogy between the mechanism of polymer localization driven by solvent depletion and that of the hydrophobic collapse of polymers in solutions.

  13. Molecular structure and conformations of caramboxin, a natural neurotoxin from the star fruit: A computational study

    NASA Astrophysics Data System (ADS)

    Pichierri, Fabio

    2015-01-01

    Using density functional theory calculations we investigate the molecular structure and conformations of caramboxin, a neurotoxin recently isolated from the star fruit Averroha carambola. Among the seven conformers that exist within an energy window of ∼16.0 kcal/mol, two of them are the most favored ones with an energy difference of less than 2.0 kcal/mol. The computed chemical shifts of these two low-energy conformers are in good agreement with the experimental values determined in deuterated dimethylsulfoxide thus confirming the 2D chemical structure assigned to the neurotoxin. A topological analysis of the theoretical electronic charge density of four caramboxin conformers reveals the existence of intramolecular CH⋯O/N interactions which, in addition to the classical OH⋯O/N H-bonding interactions, contribute to decrease the conformational freedom of the neurotoxin.

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

    SciTech Connect

    Huang, Jingsong; Sumpter, Bobby G; Meunier, Vincent; Tian, Yong-Hui; Kertesz, Prof. Miklos

    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.

  15. A method for correlations analysis of coordinates: applications for molecular conformations.

    PubMed

    Chema, Doron; Becker, Oren M

    2002-01-01

    We describe a new method to analyze multiple correlations between subsets of coordinates that represent a sample. The correlation is established only between specific regions of interest at the coordinates. First, the region(s) of interest are selected at each molecular coordinate. Next, a correlation matrix is constructed for the selected regions. The matrix is subject to further analysis, illuminating the multidimensional structural characteristics that exist in the conformational space. The method's abilities are demonstrated in several examples: it is used to analyze the conformational space of complex molecules, it is successfully applied to compare related conformational spaces, and it is used to analyze a diverse set of protein folding trajectories.

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

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

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

  17. Molecular conformation of linear alkane molecules: From gas phase to bulk water through the interface

    NASA Astrophysics Data System (ADS)

    Murina, Ezequiel L.; Fernández-Prini, Roberto; Pastorino, Claudio

    2017-08-01

    We studied the behavior of long chain alkanes (LCAs) as they were transferred from gas to bulk water, through the liquid-vapor interface. These systems were studied using umbrella sampling molecular dynamics simulation and we have calculated properties like free energy profiles, molecular orientation, and radius of gyration of the LCA molecules. The results show changes in conformation of the solutes along the path. LCAs adopt pronounced molecular orientations and the larger ones extend appreciably when partially immersed in the interface. In bulk water, their conformations up to dodecane are mainly extended. However, larger alkanes like eicosane present a more stable collapsed conformation as they approach bulk water. We have characterized the more probable configurations in all interface and bulk regions. The results obtained are of interest for the study of biomatter processes requiring the transfer of hydrophobic matter, especially chain-like molecules like LCAs, from gas to bulk aqueous systems through the interface.

  18. Molecular conformation of linear alkane molecules: From gas phase to bulk water through the interface.

    PubMed

    Murina, Ezequiel L; Fernández-Prini, Roberto; Pastorino, Claudio

    2017-08-14

    We studied the behavior of long chain alkanes (LCAs) as they were transferred from gas to bulk water, through the liquid-vapor interface. These systems were studied using umbrella sampling molecular dynamics simulation and we have calculated properties like free energy profiles, molecular orientation, and radius of gyration of the LCA molecules. The results show changes in conformation of the solutes along the path. LCAs adopt pronounced molecular orientations and the larger ones extend appreciably when partially immersed in the interface. In bulk water, their conformations up to dodecane are mainly extended. However, larger alkanes like eicosane present a more stable collapsed conformation as they approach bulk water. We have characterized the more probable configurations in all interface and bulk regions. The results obtained are of interest for the study of biomatter processes requiring the transfer of hydrophobic matter, especially chain-like molecules like LCAs, from gas to bulk aqueous systems through the interface.

  19. Molecular Clustering Interrelationships and Carbohydrate Conformation in Hull and Seeds Among Barley Cultivars

    SciTech Connect

    N Liu; P Yu

    2011-12-31

    The objective of this study was to use molecular spectral analyses with the diffuse reflectance Fourier transform infrared spectroscopy (DRIFT) bioanlytical technique to study carbohydrate conformation features, molecular clustering and interrelationships in hull and seed among six barley cultivars (AC Metcalfe, CDC Dolly, McLeod, CDC Helgason, CDC Trey, CDC Cowboy), which had different degradation kinetics in rumen. The molecular structure spectral analyses in both hull and seed involved the fingerprint regions of ca. 1536-1484 cm{sup -1} (attributed mainly to aromatic lignin semicircle ring stretch), ca. 1293-1212 cm{sup -1} (attributed mainly to cellulosic compounds in the hull), ca. 1269-1217 cm{sup -1} (attributed mainly to cellulosic compound in the seeds), and ca. 1180-800 cm{sup -1} (attributed mainly to total CHO C-O stretching vibrations) together with an agglomerative hierarchical cluster (AHCA) and principal component spectral analyses (PCA). The results showed that the DRIFT technique plus AHCA and PCA molecular analyses were able to reveal carbohydrate conformation features and identify carbohydrate molecular structure differences in both hull and seeds among the barley varieties. The carbohydrate molecular spectral analyses at the region of ca. 1185-800 cm{sup -1} together with the AHCA and PCA were able to show that the barley seed inherent structures exhibited distinguishable differences among the barley varieties. CDC Helgason had differences from AC Metcalfe, MeLeod, CDC Cowboy and CDC Dolly in carbohydrate conformation in the seed. Clear molecular cluster classes could be distinguished and identified in AHCA analysis and the separate ellipses could be grouped in PCA analysis. But CDC Helgason had no distinguished differences from CDC Trey in carbohydrate conformation. These carbohydrate conformation/structure difference could partially explain why the varieties were different in digestive behaviors in animals. The molecular spectroscopy

  20. Role of Molecular Conformations in Rubrene Thin Film Growth

    SciTech Connect

    Kaefer, D.; Ruppel, L.; Witte, G.; Woell, Ch.

    2005-10-14

    A systematic analysis of the growth of rubrene (C{sub 42}H{sub 28}), an organic molecule that currently attracts considerable attention with regard to its application in molecular electronics, is carried out by using x-ray absorption spectroscopy and thermal desorption spectroscopy. The results allow us to unravel a fundamental mechanism that effectively limits organic epitaxy for a large class of organic molecules. If the structure of the free molecule differs substantially from that of the corresponding molecular structure in the bulk, the crystallization is severely hampered.

  1. Mussel adhesion is dictated by time-regulated secretion and molecular conformation of mussel adhesive proteins.

    PubMed

    Petrone, Luigi; Kumar, Akshita; Sutanto, Clarinda N; Patil, Navinkumar J; Kannan, Srinivasaraghavan; Palaniappan, Alagappan; Amini, Shahrouz; Zappone, Bruno; Verma, Chandra; Miserez, Ali

    2015-10-28

    Interfacial water constitutes a formidable barrier to strong surface bonding, hampering the development of water-resistant synthetic adhesives. Notwithstanding this obstacle, the Asian green mussel Perna viridis attaches firmly to underwater surfaces via a proteinaceous secretion (byssus). Extending beyond the currently known design principles of mussel adhesion, here we elucidate the precise time-regulated secretion of P. viridis mussel adhesive proteins. The vanguard 3,4-dihydroxy-L-phenylalanine (Dopa)-rich protein Pvfp-5 acts as an adhesive primer, overcoming repulsive hydration forces by displacing surface-bound water and generating strong surface adhesion. Using homology modelling and molecular dynamics simulations, we find that all mussel adhesive proteins are largely unordered, with Pvfp-5 adopting a disordered structure and elongated conformation whereby all Dopa residues reside on the protein surface. Time-regulated secretion and structural disorder of mussel adhesive proteins appear essential for optimizing extended nonspecific surface interactions and byssus' assembly. Our findings reveal molecular-scale principles to help the development of wet-resistant adhesives.

  2. Mussel adhesion is dictated by time-regulated secretion and molecular conformation of mussel adhesive proteins

    PubMed Central

    Petrone, Luigi; Kumar, Akshita; Sutanto, Clarinda N.; Patil, Navinkumar J.; Kannan, Srinivasaraghavan; Palaniappan, Alagappan; Amini, Shahrouz; Zappone, Bruno; Verma, Chandra; Miserez, Ali

    2015-01-01

    Interfacial water constitutes a formidable barrier to strong surface bonding, hampering the development of water-resistant synthetic adhesives. Notwithstanding this obstacle, the Asian green mussel Perna viridis attaches firmly to underwater surfaces via a proteinaceous secretion (byssus). Extending beyond the currently known design principles of mussel adhesion, here we elucidate the precise time-regulated secretion of P. viridis mussel adhesive proteins. The vanguard 3,4-dihydroxy-L-phenylalanine (Dopa)-rich protein Pvfp-5 acts as an adhesive primer, overcoming repulsive hydration forces by displacing surface-bound water and generating strong surface adhesion. Using homology modelling and molecular dynamics simulations, we find that all mussel adhesive proteins are largely unordered, with Pvfp-5 adopting a disordered structure and elongated conformation whereby all Dopa residues reside on the protein surface. Time-regulated secretion and structural disorder of mussel adhesive proteins appear essential for optimizing extended nonspecific surface interactions and byssus' assembly. Our findings reveal molecular-scale principles to help the development of wet-resistant adhesives. PMID:26508080

  3. Mussel adhesion is dictated by time-regulated secretion and molecular conformation of mussel adhesive proteins

    NASA Astrophysics Data System (ADS)

    Petrone, Luigi; Kumar, Akshita; Sutanto, Clarinda N.; Patil, Navinkumar J.; Kannan, Srinivasaraghavan; Palaniappan, Alagappan; Amini, Shahrouz; Zappone, Bruno; Verma, Chandra; Miserez, Ali

    2015-10-01

    Interfacial water constitutes a formidable barrier to strong surface bonding, hampering the development of water-resistant synthetic adhesives. Notwithstanding this obstacle, the Asian green mussel Perna viridis attaches firmly to underwater surfaces via a proteinaceous secretion (byssus). Extending beyond the currently known design principles of mussel adhesion, here we elucidate the precise time-regulated secretion of P. viridis mussel adhesive proteins. The vanguard 3,4-dihydroxy-L-phenylalanine (Dopa)-rich protein Pvfp-5 acts as an adhesive primer, overcoming repulsive hydration forces by displacing surface-bound water and generating strong surface adhesion. Using homology modelling and molecular dynamics simulations, we find that all mussel adhesive proteins are largely unordered, with Pvfp-5 adopting a disordered structure and elongated conformation whereby all Dopa residues reside on the protein surface. Time-regulated secretion and structural disorder of mussel adhesive proteins appear essential for optimizing extended nonspecific surface interactions and byssus' assembly. Our findings reveal molecular-scale principles to help the development of wet-resistant adhesives.

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

    SciTech Connect

    Huang, Jingsong; Sumpter, Bobby G; Meunier, Vincent; Tian, Yong-Hui; Kertesz, Prof. Miklos

    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/12c 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.

  5. Molecular dynamics study of 2rotaxanes: influence of solvation and cation on co-conformation.

    PubMed

    Fradera, Xavier; Márquez, Manuel; Smith, Bradley D; Orozco, Modesto; Luque, F Javier

    2003-06-13

    The conformational preference of a [2]rotaxane system has been examined by molecular dynamics simulations. The rotaxane wheel consists of two bridged binding components: a cis-dibenzo-18-crown-6 ether and a 1,3-phenyldicarboxamide, and the penetrating axle consists of a central isophthaloyl unit with phenyltrityl capping groups. The influence of solvation on the co-conformation of the [2]rotaxane was evaluated by comparing the conformational flexibility in two solvents: chloroform and dimethyl sulfoxide. Attention was also paid to the effect of cation binding on the dynamical properties of the [2]rotaxane. The conformational stability of the [2]rotaxane was calculated using a MM/PB-SA strategy, and the occurrence of specific motions was examined by essential dynamics analysis. The changes in the co-conformational properties in the two solvents and upon cation binding are discussed in light of the available NMR data. The results indicate that in chloroform solution the [2]rotaxane system exists as a mixture of co-conformational states including some that have hydrogen bonds between axle C=O and wheel NH groups. Analysis of the simulations allow us to hypothesize that the [2]rotaxane's circumrotation motion can occur as the result of a dynamic process that combines a preliminary axle sliding step that breaks these hydrogen bonds and a conformational change in the ester group more distant from the wheel. In contrast, no hydrogen-bonded co-conformation was found in dimethyl sulfoxide, which appears to be due to the preferential formation of hydrogen bonds between the wheel NH groups with solvent molecules. Moreover, the axle experiences notable changes in anisotropic shielding, which would explain why the NMR signals are broadened in this solvent. Insertion of a sodium cation into the crown ether reduces co-conformational flexibility due to an interaction of the axle with the cation. Overall, the results reveal how both solvent and ionic atmosphere can influence the co-conformational

  6. ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs

    NASA Astrophysics Data System (ADS)

    Cleves, Ann E.; Jain, Ajay N.

    2017-03-01

    We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.

  7. ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs.

    PubMed

    Cleves, Ann E; Jain, Ajay N

    2017-03-13

    We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.

  8. ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs

    NASA Astrophysics Data System (ADS)

    Cleves, Ann E.; Jain, Ajay N.

    2017-05-01

    We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.

  9. Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions

    NASA Astrophysics Data System (ADS)

    Kumawat, Amit; Chakrabarty, Suman; Kulkarni, Kiran

    2017-04-01

    Ras superfamily of GTPases regulate myriad cellular processes through a conserved nucleotide (GTP/GDP) dependent switching mechanism. Unlike Ras family of GTPases, for the Rho GTPases, there is no clear evidence for the existence of “sub-states” such as state 1 & state 2 in the GTP bound form. To explore the nucleotide dependent conformational space of the Switch I loop and also to look for existence of state 1 like conformations in Rho GTPases, atomistic molecular dynamics and metadynamics simulations on RhoA were performed. These studies demonstrate that both the nucleotide-free state and the GDP bound “OFF” state have very similar conformations, whereas the GTP bound “ON” state has unique conformations with signatures of two intermediate states. The conformational free energy landscape for these systems suggests the presence of multiple intermediate states. Interestingly, the energetic penalty of exposing the non-polar residues in the GTP bound form is counter balanced by the favourable hydrogen bonded interactions between the γ-phosphate group of GTP with the highly conserved Tyr34 and Thr37 residues. These competing molecular interactions lead to a tuneable energy landscape of the Switch I conformation, which can undergo significant changes based on the local environment including changes upon binding to effectors.

  10. Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions

    PubMed Central

    Kumawat, Amit; Chakrabarty, Suman; Kulkarni, Kiran

    2017-01-01

    Ras superfamily of GTPases regulate myriad cellular processes through a conserved nucleotide (GTP/GDP) dependent switching mechanism. Unlike Ras family of GTPases, for the Rho GTPases, there is no clear evidence for the existence of “sub-states” such as state 1 & state 2 in the GTP bound form. To explore the nucleotide dependent conformational space of the Switch I loop and also to look for existence of state 1 like conformations in Rho GTPases, atomistic molecular dynamics and metadynamics simulations on RhoA were performed. These studies demonstrate that both the nucleotide-free state and the GDP bound “OFF” state have very similar conformations, whereas the GTP bound “ON” state has unique conformations with signatures of two intermediate states. The conformational free energy landscape for these systems suggests the presence of multiple intermediate states. Interestingly, the energetic penalty of exposing the non-polar residues in the GTP bound form is counter balanced by the favourable hydrogen bonded interactions between the γ-phosphate group of GTP with the highly conserved Tyr34 and Thr37 residues. These competing molecular interactions lead to a tuneable energy landscape of the Switch I conformation, which can undergo significant changes based on the local environment including changes upon binding to effectors. PMID:28374773

  11. Molecular Environment Modulates Conformational Differences between Crystal and Solution States of Human β-Defensin 2.

    PubMed

    Li, Jianguo; Hu, Zhongqiao; Beuerman, Roger; Verma, Chandra

    2017-04-06

    Human β-defensin 2 is a cysteine-rich antimicrobial peptide. In the crystal state, the N-terminal segment (residues 1-11) exhibits a helical conformation. However, a truncated form, with four amino acids removed from the N-terminus, adopts nonhelical conformations in solution, as shown by NMR. To explore the molecular origins of these different conformations, we performed Hamiltonian replica exchange molecular dynamics simulations of the peptide in solution and in the crystal state. It is found that backbone hydration and specific protein-protein interactions are key parameters that determine the peptide conformation. The helical conformation in the crystal state mainly arises from reduced hydration as well as a salt bridge between the peptide and a symmetry-related neighboring monomer in the crystal. When the extent of hydration is reduced and the salt bridge is reintroduced artificially, the peptide is successfully folded back to the helical conformation in solution. The findings not only shed light on the development of accurate force field parameters for protein molecules but also provide practical guidance in the design of functional proteins and peptides.

  12. Molecular simulation uncovers the conformational space of the λ Cro dimer in solution.

    PubMed

    Ahlstrom, Logan S; Miyashita, Osamu

    2011-11-16

    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 Arg(4) and Glu(53) 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. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  13. 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

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

    SciTech Connect

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

    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 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

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

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

    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

  16. Conformational space of clindamycin studied by ab initio and full-atom molecular dynamics.

    PubMed

    Kulczycka-Mierzejewska, Katarzyna; Trylska, Joanna; Sadlej, Joanna

    2016-01-01

    Molecular dynamics (MD) simulations allow determining internal flexibility of molecules at atomic level. Using ab initio Born-Oppenheimer molecular dynamics (BOMD), one can simulate in a reasonable time frame small systems with hundreds of atoms, usually in vacuum. With quantum mechanics/molecular mechanics (QM/MM) or full-atom molecular dynamics (FAMD), the influence of the environment can also be simulated. Here, we compare three types of MD calculations: ab initio BOMD, hybrid QM/MM, and classical FAMD. As a model system, we use a small antibiotic molecule, clindamycin, which is one of the lincosamide antibiotics. Clindamycin acquires two energetically stable forms and we investigated the transition between these two experimentally known conformers. We performed 60-ps BOMD simulations in vacuum, 50-ps QM/MM, and 100-ns FAMD in explicit water. The transition between two antibiotic conformers was observed using both BOMD and FAMD methods but was not noted in the QM/MM simulations.

  17. Molecular mechanics work station for protein conformational studies

    SciTech Connect

    Fine, R.; Levinthal, C.; Schoenborn, B.; Dimmier, G.; Rankowitz, C.

    1984-01-01

    Interest in computational problems in Biology has intensified over the last few years, partly due to the development of techniques for the rapid cloning, sequencing, and mutagenesis of genes from organisims ranging from E. coli to Man. The central dogma of molecular biology; that DNA codes for mRNA which codes for protein, has been understood in a linear programming sense since the genetic code was cracked. But what is not understood at present is how a protein, once assembled as a long sequence of amino acids, folds back on itself to produce a three-dimensional structure which is unique to that protein and which dictates its chemical and biological activity. This folding process is purely physics, and involves the time evolution of a system of several thousand atoms which interact with each other and with atoms from the surrounding solvent. Molecular dynamics simulations on smaller molecules suggest that approaches which treat the protein as a classical ensemble of atoms interacting with each other via an empirical Hamiltonian can yield the kind of predictive results one would like when applied to proteins.

  18. Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens.

    PubMed Central

    Duax, W L; Griffin, J F; Weeks, C M; Korach, K S

    1985-01-01

    The X-ray crystallographic structural determinations of synthetic estrogens and antiestrogens provide reliable information on the global minimum energy conformation of these molecules or a local minimum energy conformation that is within 1 or 2 kcal/mole of the global minimum. In favorable cases, state-of-the-art molecular mechanics calculations provide quantitative agreement with X-ray results and information on the relative energy of other local minimum energy conformations not observed crystallographically. Because the conformation of diethylstilbestrol (DES) observed in solvated crystals has an overall conformation and dipole moment more similar to estradiol it is the form more likely to bind to the receptor and produce hormone activity. Either phenol ring of DES can successfully mimic the estradiol A-ring in binding to the receptor. Indenestrol A (INDA) and indenestrol B (INDB) have nearly identical fully extended planar conformations. Either the alpha or gamma rings of these compounds may mimic the A ring of estradiol and compete for the estrogen receptor. Although there are eight distinct ways in which molecules of a racemic mixture of INDA or INDB can bind to the receptor, not all of them may be able to elicit a hormonal response. This may account for the reduced biological activity of the compounds despite their successful competition for receptor binding. The minimum energy conformations of Z-pseudodiethylstilbestrol (ZPD) and E-pseudodiethylstilbestrol (EPD) are bent in a fashion similar to that of indanestrol (INDC). These molecules have good binding affinity suggesting that the receptor does not require a flat molecule. Therefore these conformations would appear to be compatible with receptor binding, but only the Z isomer has an energetically allowed extended conformation that accounts for its observed biological activity relative to DES. PMID:3905370

  19. Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms☆

    PubMed Central

    Mori, Takaharu; Miyashita, Naoyuki; Im, Wonpil; Feig, Michael; Sugita, Yuji

    2016-01-01

    This paper reviews various enhanced conformational sampling methods and explicit/implicit solvent/membrane models, as well as their recent applications to the exploration of the structure and dynamics of membranes and membrane proteins. Molecular dynamics simulations have become an essential tool to investigate biological problems, and their success relies on proper molecular models together with efficient conformational sampling methods. The implicit representation of solvent/membrane environments is reasonable approximation to the explicit all-atom models, considering the balance between computational cost and simulation accuracy. Implicit models can be easily combined with replica-exchange molecular dynamics methods to explore a wider conformational space of a protein. Other molecular models and enhanced conformational sampling methods are also briefly discussed. As application examples, we introduce recent simulation studies of glycophorin A, phospholamban, amyloid precursor protein, and mixed lipid bilayers and discuss the accuracy and efficiency of each simulation model and method. This article is part of a Special Issue entitled: Membrane Proteins. Guest Editors: J.C. Gumbart and Sergei Noskov. PMID:26766517

  20. Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms.

    PubMed

    Mori, Takaharu; Miyashita, Naoyuki; Im, Wonpil; Feig, Michael; Sugita, Yuji

    2016-07-01

    This paper reviews various enhanced conformational sampling methods and explicit/implicit solvent/membrane models, as well as their recent applications to the exploration of the structure and dynamics of membranes and membrane proteins. Molecular dynamics simulations have become an essential tool to investigate biological problems, and their success relies on proper molecular models together with efficient conformational sampling methods. The implicit representation of solvent/membrane environments is reasonable approximation to the explicit all-atom models, considering the balance between computational cost and simulation accuracy. Implicit models can be easily combined with replica-exchange molecular dynamics methods to explore a wider conformational space of a protein. Other molecular models and enhanced conformational sampling methods are also briefly discussed. As application examples, we introduce recent simulation studies of glycophorin A, phospholamban, amyloid precursor protein, and mixed lipid bilayers and discuss the accuracy and efficiency of each simulation model and method. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Balanced and Bias-Corrected Computation of Conformational Entropy Differences for Molecular Trajectories.

    PubMed

    Numata, Jorge; Knapp, Ernst-Walter

    2012-04-10

    The mutual information (MI) expansion is applied to two molecular systems to probe algorithms that serve to estimate conformational entropy differences more precisely. The individual terms of the MI expansion are evaluated with a histogram method. Internal coordinates are used to avoid spurious correlations, which would require higher order terms in the MI expansion. Two approaches are applied that compensate for systematic errors that occur with a histogram method: (1) Simulation data are balanced by using the same number of coordinate sets (frames) for both conformer domains considered for the entropy difference computation. Balancing puts fluctuations of the histogram bin contents on the same level for both conformer domains, allowing efficient error cancellation. (2) Bias correction compensates for systematic deviations due to a finite number of frames per bin. Applying both corrections improves the precision of entropy differences drastically. Estimates of entropy differences are compared to thermodynamic benchmarks of a simple polymer model and trialanine, where excellent agreement was found. For trialanine, the average error for the estimated conformational entropy difference is only 0.3 J/(mol K), which is 100 times smaller than without applying the two corrections. Guidelines are provided for efficiently estimating conformational entropies. The program ENTROPICAL, used for the computations, is made available, which can be used for molecular dynamics or Monte Carlo simulation data on macromolecules like oligopeptides, polymers, proteins, and ligands.

  2. Orientation and conformation of a lipase at an interface studied by molecular dynamics simulations.

    PubMed Central

    Jensen, Morten Ø; Jensen, Torben R; Kjaer, Kristian; Bjørnholm, Thomas; Mouritsen, Ole G; Peters, Günther H

    2002-01-01

    Electron density profiles calculated from molecular dynamics trajectories are used to deduce the orientation and conformation of Thermomyces lanuginosa lipase and a mutant adsorbed at an air-water interface. It is demonstrated that the profiles display distinct fine structures, which uniquely characterize enzyme orientation and conformation. The density profiles are, on the nanosecond timescale, determined by the average enzyme conformation. We outline a computational scheme that from a single molecular dynamics trajectory allows for extraction of electron density profiles referring to different orientations of the lipase relative to an implicit interface. Profiles calculated for the inactive and active conformations of the lipase are compared with experimental electron density profiles measured by x-ray reflectivity for the lipase adsorbed at an air-water interface. The experimental profiles contain less fine structural information than the calculated profiles because the resolution of the experiment is limited by the intrinsic surface roughness of water. Least squares fits of the calculated profiles to the experimental profiles provide areas per adsorbed enzyme and suggest that Thermomyces lanuginosa lipase adsorbs to the air-water interface in a semiopen conformation with the lid oriented away from the interface. PMID:12080103

  3. Electron Momentum Spectroscopy Investigation of Molecular Conformations of Ethanol Considering Vibrational Effects.

    PubMed

    Tang, Yaguo; Shan, Xu; Niu, Shanshan; Liu, Zhaohui; Wang, Enliang; Watanabe, Noboru; Yamazaki, Masakazu; Takahashi, Masahiko; Chen, Xiangjun

    2017-01-12

    The interpretation of experimental electron momentum distributions (EMDs) of ethanol, one of the simplest molecules having conformers, has confused researchers for years. High-level calculations of Dyson orbital EMDs by thermally averaging the gauche and trans conformers as well as molecular dynamical simulations failed to quantitatively reproduce the experiments for some of the outer valence orbitals. In this work, the valence shell electron binding energy spectrum and EMDs of ethanol are revisited by the high-sensitivity electron momentum spectrometer employing symmetric noncoplanar geometry at an incident energy of 1200 eV plus binding energy, together with a detailed analysis of the influence of vibrational motions on the EMDs for the two conformers employing a harmonic analytical quantum mechanical (HAQM) approach by taking into account all of the vibrational modes. The significant discrepancies between theories and experiments in previous works have now been interpreted quantitatively, indicating that the vibrational effect plays a significant role in reproducing the experimental results, not only through the low-frequency OH and CH3 torsion modes but also through other high-frequency ones. Rational explanation of experimental momentum profiles provides solid evidence that the trans conformer is slightly more stable than the gauche conformer, in accordance with thermodynamic predictions and other experiments. The case of ethanol demonstrates the significance of considering vibrational effects when performing a conformational study on flexible molecules using electron momentum spectroscopy.

  4. Conformational changes below the Tm: Molecular dynamics studies of the thermal pretransition of ribonuclease A†

    PubMed Central

    Merkley, Eric D.; Bernard, Brady; Daggett, Valerie

    2008-01-01

    Recent work suggests that some native conformations of proteins can vary with temperature. To obtain an atomic-level description of this structural and conformational variation, we have performed all-atom, explicit-solvent molecular dynamics simulations of bovine pancreatic ribonuclease A (RNase A) up to its melting temperature (Tm ≈ 337 K). RNase A has a thermal pretransition near 320 K [Stelea, S.D, Pancoska, P., Benight, A.S., Keiderling, T.A. (2001) Prot. Sci. 10, 970—978]. Our simulations identify a conformational change that coincides with this pretransition. Between 310 and 320 K, there is a small but significant decrease in the number of native contacts, β-sheet hydrogen bonding, and deviation of backbone conformation from the starting structure, and an increase in nonnative contacts. Native contacts are lost in β-sheet regions and in α1, partially due to movement of α1 away from the β-sheet core. At 330 and 340 K, a nonnative helical segment forms at residues 15–20, corresponding to a helix observed in the N-terminal domain-swapped dimer [Liu Y.S., Hart, P.J., Schulnegger, M.P., Eisenberg, D. (1998) Proc. Natl. Acad. Sci. USA, 95, 3437—3432]. The conformations observed at the higher temperatures possess native-like topology and overall conformation, with many native contacts, but they have a disrupted active site. We propose that these conformations may represent the native state at elevated temperature, or the N′ state. These simulations show that subtle, functionally important changes in protein conformation can occur below the Tm. PMID:18161991

  5. Accurate conformation-dependent molecular electrostatic potentials for high-throughput in silico drug discovery.

    PubMed

    Puranen, J Santeri; Vainio, Mikko J; Johnson, Mark S

    2010-06-01

    The atom-centered partial charges-approximation is commonly used in current molecular modeling tools as a computationally inexpensive alternative to quantum mechanics for modeling electrostatics. Even today, the use of partial charges remains useful despite significant advances in improving the efficiency of ab initio methods. Here, we report on new parameters for the EEM and SFKEEM electronegativity equalization-based methods for rapidly determining partial charges that will accurately model the electrostatic potential of flexible molecules. The developed parameters cover most pharmaceutically relevant chemistries, and charges obtained using these parameters reproduce the B3LYP/cc-pVTZ reference electrostatic potential of a set of FDA-approved drug molecules at best to an average accuracy of 13 +/- 4 kJ mol(-1); thus, equipped with these parameters electronegativity equalization-based methods rival the current best non-quantum mechanical methods, such as AM1-BCC, in accuracy, yet incur a lower computational cost. Software implementations of EEM and SFKEEM, including the developed parameters, are included in the conformer-generation tool BALLOON, available free of charge at http://web.abo.fi/fak/mnf/bkf/research/johnson/software.php. Copyright 2009 Wiley Periodicals, Inc.

  6. Single-strand conformation polymorphism (SSCP) analysis of the molecular pathology of hemophilia B.

    PubMed

    David, D; Rosa, H A; Pemberton, S; Diniz, M J; Campos, M; Lavinha, J

    1993-01-01

    In the present study, we report the application of polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis to the screening of seven functionally important factor IX gene (FIX) regions (total length 2.66 kb) in 9 unrelated haemophilia B patients of Portuguese or African origin. In eight of the patients an altered migration pattern of single-stranded DNA was observed. Direct sequencing of the relevant DNA fragments unveiled the following sequence alterations: two novel mutations, namely FIXBarcelos Thr-380-Pro and FIXLousada 9bp insertion at position 31,309 or 31,318; five mutations previously reported in other ethnic groups (FIXPorto Arg-145-His, FIXLuanda Gly-207-Arg, FIXPenafiel Arg-248-Gln, FIXSesimbra Arg-333-Gln, FIXCascais Arg-333-Stop); and a normal variant, G-->T transvertion at position 6,596 in intron 2. We propose hypothetical models for the generation of the 9 bp duplication (FIXLousada). We have performed molecular modeling studies in order to predict the structure of the variant FIX molecules.

  7. Methods for Identifying and Averaging Variable Molecular Conformations in Tomograms of Actively Contracting Insect Flight Muscle

    PubMed Central

    Wu, Shenping; Liu, Jun; Reedy, Mary C.; Winkler, Hanspeter; Reedy, Michael K.; Taylor, Kenneth A.

    2009-01-01

    During active muscle contraction, tension is generated through many simultaneous, independent interactions between the molecular motor myosin and the actin filaments. The ensemble of myosin motors displays heterogeneous conformations reflecting different kinetic steps of the ATPase pathway. We used electron tomography of actively contracting insect flight muscle fast-frozen, freeze-substituted, Araldite embedded, thin sectioned and stained, to obtain 3-D snapshots of the multiplicity of actin-attached myosin structures. We describe procedures for alignment of the repeating lattice of sub-volumes (38.7 nm cross-bridge repeats bounded by troponin) and multivariate data analysis to identify self-similar repeats for computing class averages. Improvements in alignment and classification of repeat sub-volumes reveals (for the first time in active muscle images) the helix of actin subunits in the thin filament and the troponin density with sufficient clarity that a quasiatomic model of the thin filament can be built into the class averages independent of the myosin cross-bridges. We show how quasiatomic model building can identify both strong and weak myosin attachments to actin. We evaluate the accuracy of image classification to enumerate the different types of actin-myosin attachments. PMID:19698791

  8. Conformational diversity of bacterial FabH: Implications for molecular recognition specificity

    PubMed Central

    Mittal, Anuradha; Johnson, Michael E.

    2015-01-01

    The molecular basis of variable substrate and inhibitor specificity of the highly conserved bacterial fatty acid synthase enzyme, FabH, across different bacterial species remains poorly understood. In the current work, we explored the conformational diversity of FabH enzymes to understand the determinants of diverse interaction specificity across Gram-positive and Gram-negative bacteria. Atomistic molecular dynamics simulations reveal that FabH from E. coli and E. faecalis exhibit distinct native state conformational ensembles and dynamic behaviors. Despite strikingly similar substrate binding pockets, hot spot assessment using computational solvent mapping identified quite different favorable binding interactions between the two homologs. Our data suggest that FabH utilizes protein dynamics and seemingly minor sequence and structural differences to modulate its molecular recognition and substrate specificity across bacterial species. These insights will potentially facilitate the rational design and development of antibacterial inhibitors against FabH enzymes. PMID:25437098

  9. Conformational behaviour and molecular similarity of some β1-adrenergic ligands

    NASA Astrophysics Data System (ADS)

    Fantucci, Piercarlo; Mattioli, Elena; Villa, Anna Maria; Villa, Luigi

    1992-08-01

    The conformational behaviour of a series of aryloxypropanolamines was investigated by means of a new procedure which allows the sampling of the molecular torsional surface in a very efficient way. The combination of such a procedure with the standard molecular mechanics algorithms for the geometry optimization gives, as a result, the definition of a powerful computational scheme for the detailed analysis of the potential energy surface of complex molecules. The compounds studied show a remarkable tendency to form intramolecular hydrogen bonds, which seem to play a key role in determining the lowest energy structures. The indices of molecular similarity proposed by Carbó, computed for the most stable conformers, do not account for differences between diastereoisomers, and, as a consequence, can hardly be used to attempt a structure-activity correlation.

  10. Effect of molecular conformation on the mechanofluorochromic properties based on DDIF

    NASA Astrophysics Data System (ADS)

    Mai, Runsheng; Peng, Huojun; Meng, Yuying; Chang, Xinyue; Jiang, Yue; Gao, Jinwei; Zhou, Guofu; Liu, Jun-ming

    2017-07-01

    Mechanofluorochromic (MFC) materials are smart materials in that their absorption and/or emission can respond to mechanical stimuli. They have received much attention recently. Although there have been several new material systems designed, little work has been done regarding the influence of molecular conformation on MFC properties. Herein, to disclose the relationship between molecular conformation and MFC properties, two molecules based on a 6, 12-Dihydro-6, 12-diaza-indeno[1,2-b]fluorine (DDIF) building block with thienyl linker, BDDIF-Th and BDDIF-BTh, have been designed and synthesized. Optical and electrochemical properties have been studied by UV-vis spectrometer and cyclic voltammetry measurements. Weak aggregation-induced emission (AIE) phenomena were obtained in the tetrahydrofuran (THF)/water solution. MFC behaviors suggest that BDDIF-Th is more sensible to the external mechanical forces than BDDIF-BTh. The color change could be attributed to the appearance of new emission peak instead of a bathochromic or hypsochromic effect. Theoretical calculations reveal that MFC performance is highly related to the molecular conformation, meaning that the BDDIF-BTh with perpendicular conformation is more difficult to flatten than the comparatively planar BDDIF-Th.

  11. Theoretical studies on the molecular structure, conformational preferences, topological and vibrational analysis of allicin

    NASA Astrophysics Data System (ADS)

    Durlak, Piotr; Berski, Sławomir; Latajka, Zdzisław

    2016-01-01

    The molecular structure, conformational preferences, topological and vibrational analysis of allicin has been investigated at two different approaches. Calculations have been carried out on static (DFT and MP2) levels with an assortment of Dunning's basis sets and dynamic CPMD simulations. In this both case within the isolated molecule approximation. The results point out that at least twenty different conformers coexist on the PES as confirmed by the flexible character of this molecule. The topological analysis of ELF showed very similar nature of the Ssbnd S and Ssbnd O bonds. The infrared spectrum has been calculated, and a comparative vibrational analysis has been performed.

  12. DFT molecular modeling and NMR conformational analysis of a new longipinenetriolone diester

    NASA Astrophysics Data System (ADS)

    Cerda-García-Rojas, Carlos M.; Guerra-Ramírez, Diana; Román-Marín, Luisa U.; Hernández-Hernández, Juan D.; Joseph-Nathan, Pedro

    2006-05-01

    The structure and conformational behavior of the new natural compound (4 R,5 S,7 S,8 R,9 S,10 R,11 R)-longipin-2-en-7,8,9-triol-1-one 7-angelate-9-isovalerate (1) isolated from Stevia eupatoria, were studied by molecular modeling and NMR spectroscopy. A Monte Carlo search followed by DFT calculations at the B3LYP/6-31G* level provided the theoretical conformations of the sesquiterpene framework, which were in full agreement with results derived from the 1H- 1H coupling constant analysis.

  13. Asymmetric synthesis of first generation molecular motors.

    PubMed

    Neubauer, Thomas M; van Leeuwen, Thomas; Zhao, Depeng; Lubbe, Anouk S; Kistemaker, Jos C M; Feringa, Ben L

    2014-08-15

    A general enantioselective route to functionalized first generation molecular motors is described. An enantioselective protonation of the silyl enol ethers of indanones by a Au(I)BINAP complex sets the stage for a highly diastereoselective McMurry coupling as a second enhancement step for enantiomeric excess. In this way various functionalized overcrowded alkenes could be synthesized in good yields (up to 78%) and good to excellent enantiomeric excess (85% ee->98% ee) values.

  14. Central pattern generators deciphered by molecular genetics.

    PubMed

    Kiehn, Ole; Kullander, Klas

    2004-02-05

    Central pattern generators (CPGs) are localized neuronal networks that have the ability to produce rhythmic movements even in the absence of movement-related sensory feedback. They are found in all animals, including man, and serve as informative model systems for understanding how neuronal networks produce behavior. Traditionally, CPGs have been investigated with electrophysiological techniques. Here we review recent molecular and genetic approaches for dissecting the organization and development of CPGs.

  15. S-Shaped Conformation of the Quaterthiophene Molecular Backbone in Two-Dimensional Bisterpyridine-Derivative Self-Assembled Nanoarchitecture.

    PubMed

    Kervella, Yann; Shilova, Ekaterina; Latil, Sylvain; Jousselme, Bruno; Silly, Fabien

    2015-12-15

    The conformation and the two-dimensional self-assembly of 4'-(3',4″-dihexyloxy-5,2':5',2″:5″,2‴-quaterthien-2,5‴-diyl)-bis(2,2':6',2″-terpyridine) molecules are theoretically and experimentally investigated. This molecular building block forms a hydrogen-bonded chiral supramolecular nanoarchitecture on graphite at the solid/liquid interface. Scanning tunneling microscopy (STM) shows that the molecule adopts an S-shaped conformation in this structure. DFTB+ calculations reveal that this conformation is not the lowest-energy conformation. The molecular nanoarchitecture appears to be stabilized by hydrogen bonding as well as van der Waals interactions. I-, L-, and D-shaped molecular conformations are, however, locally observed at the domain boundary, but these conformations do not self-assemble into organized 2D structures.

  16. A uniform molecular model of δ opioid agonist and antagonist pharmacophore conformations

    NASA Astrophysics Data System (ADS)

    Brandt, Wolfgang

    1998-11-01

    On the basis of a model of the pharmacophore conformations of agonist of the δ-opioid receptor the corresponding δ-antagonist conformations were determined by means of force field calculations. The results explain the unusual behavior of several cyclic β-casomorphin analogues on the molecular level. Thus, for instance, the model helps to understand why Tyr-c[D-Orn-2-Nal-D-Pro-Gly] is a mixed μ-agonist and δ-antagonist. Furthermore, the model is consistent with low energy conformations of other δ-antagonists such as Tyr-Tic-Phe, Tyr-Tic-Phe-Phe, naltrindole and BNTX. The occupation of a special spatial area by bulky groups close to the protonated N-terminus of opioid peptides is assumed to be highly critical for the switch from agonist to antagonist behavior.

  17. Molecular modeling of the conformational dynamics of the cellular prion protein

    NASA Astrophysics Data System (ADS)

    Nguyen, Charles; Colling, Ian; Bartz, Jason; Soto, Patricia

    2014-03-01

    Prions are infectious agents responsible for transmissible spongiform encephalopathies (TSEs), a type of fatal neurodegenerative disease in mammals. Prions propagate biological information by conversion of the non-pathological version of the prion protein to the infectious conformation, PrPSc. A wealth of knowledge has shed light on the nature and mechanism of prion protein conversion. In spite of the significance of this problem, we are far from fully understanding the conformational dynamics of the cellular isoform. To remedy this situation we employ multiple biomolecular modeling techniques such as docking and molecular dynamics simulations to map the free energy landscape and determine what specific regions of the prion protein are most conductive to binding. The overall goal is to characterize the conformational dynamics of the cell form of the prion protein, PrPc, to gain insight into inhibition pathways against misfolding. NE EPSCoR FIRST Award to Patricia Soto.

  18. Finding Stable Graphene Conformations from Pull and Release Experiments with Molecular Dynamics

    PubMed Central

    Yamaletdinov, Ruslan D.; Pershin, Yuriy V.

    2017-01-01

    Here, we demonstrate that stable conformations of graphene nanoribbons can be identified using pull and release experiments, when the stretching force applied to a single-layer graphene nanoribbon is suddenly removed. As it is follows from our numerical experiments performed by means of molecular dynamics simulations, in such experiments, favorable conditions for the creation of folded structures exist. Importantly, at finite temperatures, the process of folding is probabilistic. We have calculated the transition probabilities to folded conformations for a graphene nanoribbon of a selected size. Moreover, the ground state conformation has been identified and it is shown that its type is dependent on the nanoribbon length. We anticipate that the suggested pull and release approach to graphene folding may find applications in the theoretical studies and fabrication of emergent materials and their structures. PMID:28195156

  19. Finding Stable Graphene Conformations from Pull and Release Experiments with Molecular Dynamics

    NASA Astrophysics Data System (ADS)

    Yamaletdinov, Ruslan D.; Pershin, Yuriy V.

    2017-02-01

    Here, we demonstrate that stable conformations of graphene nanoribbons can be identified using pull and release experiments, when the stretching force applied to a single-layer graphene nanoribbon is suddenly removed. As it is follows from our numerical experiments performed by means of molecular dynamics simulations, in such experiments, favorable conditions for the creation of folded structures exist. Importantly, at finite temperatures, the process of folding is probabilistic. We have calculated the transition probabilities to folded conformations for a graphene nanoribbon of a selected size. Moreover, the ground state conformation has been identified and it is shown that its type is dependent on the nanoribbon length. We anticipate that the suggested pull and release approach to graphene folding may find applications in the theoretical studies and fabrication of emergent materials and their structures.

  20. Dynamic control of protein conformation transition in chromatographic separation based on hydrophobic interactions: molecular dynamics simulation.

    PubMed

    Zhang, Lin; Lu, Diannan; Liu, Zheng

    2009-03-20

    Conformational transitions of a protein in hydrophobic interaction based chromatography, including hydrophobic interaction chromatography (HIC) and reversed-phase liquid chromatography (RPLC), and their impact on the separation process and performance were probed by molecular dynamics simulation of a 46-bead beta-barrel coarse-grained model protein in a confined pore, which represents the porous adsorbent. The transition of the adsorbed protein from the native conformation to an unfolded one occurred as a result of strong hydrophobic interactions with the pore surface, which reduced the formation of protein aggregates. The conformational transition was also displayed in the simulation once an elution buffer characterized by weaker hydrophobicity was introduced to strip protein from pore surface. The discharged proteins that underwent conformational transition were prone to aggregation; thus, an unsatisfactory yield of the native protein was obtained. An orthogonal experiment revealed that in addition to the strengths of the protein-protein and protein-adsorbent hydrophobic interactions, the elution time required to reduce the above-mentioned interactions also determined the yield of native protein by HIC and RPLC. Stepwise elution, characterized by sequential reduction of the hydrophobic interactions between the protein and adsorbent, was presented as a dynamic strategy for tuning conformational transitions to favor the native conformation and reduce the formation of protein aggregates during the elution process. The yield of the native protein obtained by this dynamic operation strategy was higher than that obtained by steady-state elution. The simulation study qualitatively reproduced the experimental observations and provided molecular insight that would be helpful for designing and optimizing HIC and RPLC separation of proteins.

  1. Molecular mechanics approach for design and conformational studies of macrocyclic ligands

    SciTech Connect

    Rohini,; Akbar, Rifat; Kanungo, B. K.

    2015-08-28

    Computational Chemistry has revolutionized way of viewing molecules at the quantum mechanical scale by allowing simulating various chemical scenarios that are not possible to study in a laboratory. The remarkable applications of computational chemistry have promoted to design and test of the effectiveness of various methods for searching the conformational space of highly flexible molecules. In this context, we conducted a series of optimization and conformational searches on macrocyclic based ligands, 9N3Me5Ox, (1,4,7-tris(5-methyl-8-hydroxyquinoline)-1,4,7-triazacyclononane) and 12N3Me5Ox, (1,5,9-tris(5-methyl-8-hydroxyquinoline)-1,5,9-triazacyclododecane) and studied their selectivity and coordination behavior with some lanthanide metal ions in molecular mechanics and semiempirical methods. The methods include both systematic and random conformational searches for dihedral angles, torsion angles and Cartesian coordinates. Structural studies were carried out by using geometry optimization, coordination scans and electronic properties were evaluated. The results clearly show that chair-boat conformational isomer of 9N3Me5Ox ligand is more stable due to lower eclipsing ethane interaction and form stronger adduct complexes with lanthanide metal ion. This is because of the fact that, in a central unit of 9N3 of the ligand form six endo type bonds out of nine. The rest of bonds have trans conformation. In contrast, for the adduct of 12N3Me5Ox, two C-C bonds have on eclipsed conformation, and others have synclinal and antiperiplanar confirmations. The distortion of the two eclipsed conformations may affect the yields and the stability of the complexes.

  2. Molecular mechanics approach for design and conformational studies of macrocyclic ligands

    NASA Astrophysics Data System (ADS)

    Rohini, Akbar, Rifat; Kanungo, B. K.

    2015-08-01

    Computational Chemistry has revolutionized way of viewing molecules at the quantum mechanical scale by allowing simulating various chemical scenarios that are not possible to study in a laboratory. The remarkable applications of computational chemistry have promoted to design and test of the effectiveness of various methods for searching the conformational space of highly flexible molecules. In this context, we conducted a series of optimization and conformational searches on macrocyclic based ligands, 9N3Me5Ox, (1,4,7-tris(5-methyl-8-hydroxyquinoline)-1,4,7-triazacyclononane) and 12N3Me5Ox, (1,5,9-tris(5-methyl-8-hydroxyquinoline)-1,5,9-triazacyclododecane) and studied their selectivity and coordination behavior with some lanthanide metal ions in molecular mechanics and semiempirical methods. The methods include both systematic and random conformational searches for dihedral angles, torsion angles and Cartesian coordinates. Structural studies were carried out by using geometry optimization, coordination scans and electronic properties were evaluated. The results clearly show that chair-boat conformational isomer of 9N3Me5Ox ligand is more stable due to lower eclipsing ethane interaction and form stronger adduct complexes with lanthanide metal ion. This is because of the fact that, in a central unit of 9N3 of the ligand form six endo type bonds out of nine. The rest of bonds have trans conformation. In contrast, for the adduct of 12N3Me5Ox, two C-C bonds have on eclipsed conformation, and others have synclinal and antiperiplanar confirmations. The distortion of the two eclipsed conformations may affect the yields and the stability of the complexes.

  3. A Triad of Molecular Regions Contribute to the Formation of Two Distinct MHC Class II Conformers

    PubMed Central

    Drake, Lisa A.; Drake, James R.

    2016-01-01

    MHC class II molecules present antigen-derived peptides to CD4 T cells to drive the adaptive immune response. Previous work has established that class II αβ dimers can adopt two distinct conformations, driven by the differential pairing of transmembrane domain GxxxG dimerization motifs. These class II conformers differ in their ability to be loaded with antigen-derived peptide and to effectively engage CD4 T cells. Motif 1 (M1) paired I-Ak class II molecules are efficiently loaded with peptides derived from the processing of B cell receptor-bound antigen, have unique B cell signaling properties and high T cell stimulation activity. The 11-5.2 mAb selectively binds M1 paired I-Ak class II molecules. However, the molecular determinants of 11-5.2 binding are currently unclear. Here, we report the ability of a human class II transmembrane domain to drive both M1 and M2 class II conformer formation. Protease sensitivity analysis further strengthens the idea that there are conformational differences between the extracellular domains of M1 and M2 paired class II. Finally, MHC class II chain alignments and site directed mutagenesis reveals a triad of molecular regions that contributes to 11-5.2 mAb binding. In addition to transmembrane GxxxG motif domain pairing, 11-5.2 binding is influenced directly by α chain residue Glu-71 and indirectly by the region around the inter-chain salt bridge formed by α chain Arg-52 and β chain Glu-86. These findings provide insight into the complexity of 11-5.2 mAb recognition of the M1 paired I-Ak class II conformer and further highlight the molecular heterogeneity of peptide-MHC class II complexes that drive T cell antigen recognition. PMID:27148821

  4. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability.

    PubMed

    Gersting, Søren W; Kemter, Kristina F; Staudigl, Michael; Messing, Dunja D; Danecka, Marta K; Lagler, Florian B; Sommerhoff, Christian P; Roscher, Adelbert A; Muntau, Ania C

    2008-07-01

    A significant share of patients with phenylalanine hydroxylase (PAH) deficiency benefits from pharmacological doses of tetrahydrobiopterin (BH(4)), the natural PAH cofactor. Phenylketonuria (PKU) is hypothesized to be a conformational disease, with loss of function due to protein destabilization, and the restoration of enzyme function that is observed in BH(4) treatment might be transmitted by correction of protein misfolding. To elucidate the molecular basis of functional impairment in PAH deficiency, we investigated the impact of ten PAH gene mutations identified in patients with BH(4)-responsiveness on enzyme kinetics, stability, and conformation of the protein (F55L, I65S, H170Q, P275L, A300S, S310Y, P314S, R408W, Y414C, Y417H). Residual enzyme activity was generally high, but allostery was disturbed in almost all cases and pointed to altered protein conformation. This was confirmed by reduced proteolytic stability, impaired tetramer assembly or aggregation, increased hydrophobicity, and accelerated thermal unfolding--with particular impact on the regulatory domain--observed in most variants. Three-dimensional modeling revealed the involvement of functionally relevant amino acid networks that may communicate misfolding throughout the protein. Our results substantiate the view that PAH deficiency is a protein-misfolding disease in which global conformational changes hinder molecular motions essential for physiological enzyme function. Thus, PKU has evolved from a model of a genetic disease that leads to severe neurological impairment to a model of a treatable protein-folding disease with loss of function.

  5. Conformational studies of immunodominant myelin basic protein 1-11 analogues using NMR and molecular modeling.

    PubMed

    Laimou, Despina; Lazoura, Eliada; Troganis, Anastassios N; Matsoukas, Minos-Timotheos; Deraos, Spyros N; Katsara, Maria; Matsoukas, John; Apostolopoulos, Vasso; Tselios, Theodore V

    2011-11-01

    Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP(1-11)) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP(1-11)[4A]) or a tyrosine residue (Ac-MBP(1-11)[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-A(u) was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln(3) residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-A(u) complex, has a different orientation in the mutated analogues especially in the Ac-MBP(1-11)[4A] peptide. In particular the side chain of Gln(3) is not solvent exposed as for the native Ac-MBP(1-11) and it is not available for interaction with the TCR.

  6. Conformational studies of immunodominant myelin basic protein 1-11 analogues using NMR and molecular modeling

    NASA Astrophysics Data System (ADS)

    Laimou, Despina; Lazoura, Eliada; Troganis, Anastassios N.; Matsoukas, Minos-Timotheos; Deraos, Spyros N.; Katsara, Maria; Matsoukas, John; Apostolopoulos, Vasso; Tselios, Theodore V.

    2011-11-01

    Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP1-11) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP1-11[4A]) or a tyrosine residue (Ac-MBP1-11[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-Au was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln3 residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-Au complex, has a different orientation in the mutated analogues especially in the Ac-MBP1-11[4A] peptide. In particular the side chain of Gln3 is not solvent exposed as for the native Ac-MBP1-11 and it is not available for interaction with the TCR.

  7. Conformation of the umifenovir cation in the molecular and crystal structures of four carboxylic acid salts

    NASA Astrophysics Data System (ADS)

    Orola, Liana; Sarcevica, Inese; Kons, Artis; Actins, Andris; Veidis, Mikelis V.

    2014-01-01

    The umifenovir salts of maleic, salicylic, glutaric, and gentisic acid as well as the chloroform solvate of the salicylate were prepared. Single crystals of the five compounds were obtained and their molecular and crystal structures determined by X-ray diffraction. In each structure the conformation of phenyl ring with respect to the indole group of the umifenovir moiety is different. The water solubility and melting points of the studied umifenovir salts have been determined.

  8. Protein Conformational Changes Are Detected and Resolved Site Specifically by Second-Harmonic Generation.

    PubMed

    Moree, Ben; Connell, Katelyn; Mortensen, Richard B; Liu, C Tony; Benkovic, Stephen J; Salafsky, Joshua

    2015-08-18

    We present here a straightforward, broadly applicable technique for real-time detection and measurement of protein conformational changes in solution. This method is based on tethering proteins labeled with a second-harmonic generation (SHG) active dye to supported lipid bilayers. We demonstrate our method by measuring the conformational changes that occur upon ligand binding with three well-characterized proteins labeled at lysine residues: calmodulin (CaM), maltose-binding protein (MBP), and dihydrofolate reductase (DHFR). We also create a single-site cysteine mutant of DHFR engineered within the Met20 catalytic loop region and study the protein's structural motion at this site. Using published x-ray crystal structures, we show that the changes in the SHG signals upon ligand binding are the result of structural motions that occur at the labeled sites between the apo and ligand-bound forms of the proteins, which are easily distinguished from each other. In addition, we demonstrate that different magnitudes of the SHG signal changes are due to different and specific ligand-induced conformational changes. Taken together, these data illustrate the potential of the SHG approach for detecting and measuring protein conformational changes for a wide range of biological applications.

  9. Protein Conformational Changes Are Detected and Resolved Site Specifically by Second-Harmonic Generation

    PubMed Central

    Moree, Ben; Connell, Katelyn; Mortensen, Richard B.; Liu, C. Tony; Benkovic, Stephen J.; Salafsky, Joshua

    2015-01-01

    We present here a straightforward, broadly applicable technique for real-time detection and measurement of protein conformational changes in solution. This method is based on tethering proteins labeled with a second-harmonic generation (SHG) active dye to supported lipid bilayers. We demonstrate our method by measuring the conformational changes that occur upon ligand binding with three well-characterized proteins labeled at lysine residues: calmodulin (CaM), maltose-binding protein (MBP), and dihydrofolate reductase (DHFR). We also create a single-site cysteine mutant of DHFR engineered within the Met20 catalytic loop region and study the protein’s structural motion at this site. Using published x-ray crystal structures, we show that the changes in the SHG signals upon ligand binding are the result of structural motions that occur at the labeled sites between the apo and ligand-bound forms of the proteins, which are easily distinguished from each other. In addition, we demonstrate that different magnitudes of the SHG signal changes are due to different and specific ligand-induced conformational changes. Taken together, these data illustrate the potential of the SHG approach for detecting and measuring protein conformational changes for a wide range of biological applications. PMID:26287632

  10. Conformational properties, chiroptical spectra, and molecular self-assembly of 2,3-piperazinodiones and their dithiono analogues.

    PubMed

    Piotrkowska, Barbara; Myślińska, Małgorzata; Gdaniec, Maria; Herman, Aleksander; Połoński, Tadeusz

    2008-04-04

    A family of chiral cyclic oxamides was prepared by the condensation of optically active 1,2-diamines with diethyl oxalate. Thionation of the products with Lawesson's reagent afforded a series of chiral 2,3-piperazinedithiones. Molecular geometries of the title compounds were studied with the use of quantum mechanical DFT calculations and were compared to the X-ray crystallographic results. The heterocyclic six-membered ring adopted a half-chair conformation with the C-5 substituent preferably at the equatorial position, whereas a substitution at the nitrogen atoms resulted in domination of the axial form in the conformational equilibrium. The opposite helicity of the twisted oxamide chromophore in the axial and equatorial conformers led to the opposite signs of the Cotton effects corresponding to two pi-pi* electronic transitions. The CD signs can be predicted by a simple helicity rule. The same rule is valid for 2,3-piperazinodithiones, where a substitution of sulfur for oxygen in the carbonyl groups results in bathochromic shifts of the absorption and CD bands. The crystal packing analysis of several 2,3-piperazinodiones revealed that strong NH...O=C intermolecular hydrogen-bonding interactions generating the chain motif resulted in the formation of 3-D networks as well as with the use of the cyclic hydrogen-bond motif tape structures.

  11. [Protein conformational dynamics of crambin in crystal, solution and in the trajectories of molecular dynamics simulations].

    PubMed

    Abaturov, L V; Nosova, N G

    2013-01-01

    Atomic displacement parameters--B factors of the eight crambin crystal structures obtained at 0.54-1.5 angstroms resolution and temperatures of 100-293K have been analyzed. The comparable contributions to the B factor values are the intramolecular motions which are modeled by the harmonic vibration calculations and derived from the molecular dynamics simulation (MD) as well as rigid body changes in the position of a protein molecule as a whole. In solution for the average NMR structure of crambin the amplitudes of the backbone atomic fluctuations of the most residues of the segments with the regular backbone conformations are close to the amplitudes of the small scale harmonic vibrations. For the same residues the probability of the medium scale fluctuations fixed by the hydrogen exchange method is very low. The restricted conformational mobility of those segments is coupled with the depressed amplitudes of the fluctuation changes of the tertiary structure registered by the residue accessibility changes in an ensemble of NMR structures that forms the average NMR structure of crambin. The amplitudes of temperature fluctuations of backbone atoms and the tertiary structure raise in the segment with the irregular conformations, turn and loops. In the same segments the amplitudes of the calculated harmonic vibrations also increase, but to a lesser extent and especially in the interhelical loop with the most strong and complicated fluctuation changes of the backbone conformation. In solution for the NMR structure in this loop the conformational transitions occur between the conformational substates separated by the energy barriers, but they are not observed even in the long 100 ns trajectories from the MD simulation of crambin. These strong local fluctuation changes of the structure may play a key role in the protein functioning and modern performance improvements in the MD simulation techniques are oriented to increase the probability of protein appearance in the

  12. Molecular dynamics simulation and conformational analysis of some catalytically active peptides.

    PubMed

    Honarparvar, Bahareh; Skelton, Adam A

    2015-04-01

    The design of stable and inexpensive artificial enzymes with potent catalytic activity is a growing field in peptide science. The first step in this design process is to understand the key factors that can affect the conformational preference of an enzyme and correlate them with its catalytic activity. In this work, molecular dynamics simulations in explicit water of two catalytically active peptides (peptide 1: Fmoc-Phe1-Phe2-His-CONH2; peptide 2: Fmoc-Phe1-Phe2-Arg-CONH2) were performed at temperatures of 300, 400, and 500 K. Conformational analysis of these peptides using Ramachandran plots identified the secondary structures of the amino acid residues involved (Phe1, Phe2, His, Arg) and confirmed their conformational flexibility in solution. Furthermore, Ramachandran maps revealed the intrinsic preference of the constituent residues of these compounds for a helical conformation. Long-range interaction distances and radius of gyration (R g) values obtained during 20 ns MD simulations confirmed their tendency to form folded conformations. Results showed a decrease in side-chain (Phe1, Phe2, His ring, and Arg) contacts as the temperature was raised from 300 to 400 K and then to 500 K. Finally, the radial distribution functions (RDF) of the water molecules around the nitrogen atoms in the catalytically active His and Arg residues of peptide 1 and peptide 2 revealed that the strongest water-peptide interaction occurred with the arginine nitrogen atoms in peptide 2. Our results highlight differences in the secondary structures of the two peptides that can be explained by the different arrangement of water molecules around the nitrogen atoms of Arg in peptide 2 as compared to the arrangement of water molecules around the nitrogen atoms of His in peptide 1. The results of this work thus provide detailed insight into peptide conformations which can be exploited in the future design of peptide analogs.

  13. Molecular Neuroanatomy: A Generation of Progress

    PubMed Central

    Pollock, Jonathan D.; Wu, Da-Yu; Satterlee, John

    2014-01-01

    The neuroscience research landscape has changed dramatically over the past decade. An impressive array of neuroscience tools and technologies have been generated, including brain gene expression atlases, genetically encoded proteins to monitor and manipulate neuronal activity and function, cost effective genome sequencing, new technologies enabling genome manipulation, new imaging methods and new tools for mapping neuronal circuits. However, despite these technological advances, several significant scientific challenges must be overcome in the coming decade to enable a better understanding of brain function and to develop next generation cell type-targeted therapeutics to treat brain disorders. For example, we do not have an inventory of the different types of cells that exist in the brain, nor do we know how to molecularly phenotype them. We also lack robust technologies to map connections between cells. This review will provide an overview of some of the tools and technologies neuroscientists are currently using to move the field of molecular neuroanatomy forward and also discuss emerging technologies that may enable neuroscientists to address these critical scientific challenges over the coming decade. PMID:24388609

  14. Generation of prion transmission barriers by mutational control of amyloid conformations.

    PubMed

    Chien, Peter; DePace, Angela H; Collins, Sean R; Weissman, Jonathan S

    2003-08-21

    Self-propagating beta-sheet-rich protein aggregates are implicated in a wide range of protein-misfolding phenomena, including amyloid diseases and prion-based inheritance. Two properties have emerged as common features of amyloids. Amyloid formation is ubiquitous: many unrelated proteins form such aggregates and even a single polypeptide can misfold into multiple forms--a process that is thought to underlie prion strain variation. Despite this promiscuity, amyloid propagation can be highly sequence specific: amyloid fibres often fail to catalyse the aggregation of other amyloidogenic proteins. In prions, this specificity leads to barriers that limit transmission between species. Using the yeast prion [PSI+], we show in vitro that point mutations in Sup35p, the protein determinant of [PSI+], alter the range of 'infectious' conformations, which in turn changes amyloid seeding specificity. We generate a new transmission barrier in vivo by using these mutations to specifically disfavour subsets of prion strains. The ability of mutations to alter the conformations of amyloid states without preventing amyloid formation altogether provides a general mechanism for the generation of prion transmission barriers and may help to explain how mutations alter toxicity in conformational diseases.

  15. Comparison of Implicit and Explicit Solvation Models for Iota-Cyclodextrin Conformation Analysis from Replica Exchange Molecular Dynamics.

    PubMed

    Khuntawee, Wasinee; Kunaseth, Manaschai; Rungnim, Chompoonut; Intagorn, Suradej; Wolschann, Peter; Kungwan, Nawee; Rungrotmongkol, Thanyada; Hannongbua, Supot

    2017-04-24

    Large ring cyclodextrins have become increasingly important for drug delivery applications. In this work, we have performed replica-exchange molecular dynamics simulations using both implicit and explicit water solvation models to study the conformational diversity of iota-cyclodextrin containing 14 α-1,4 glycosidic linked d-glucopyranose units (CD14). The new quantifiable calculation methods are proposed to analyze the openness, bending, and twisted conformation of CD14 in terms of circularity, biplanar angle, and one-directional conformation (ODC). CD14 in GB implicit water model (Igb5) was found mostly in an opened conformation with average circularity of 0.39 ± 0.16 and a slight bend with average biplanar angle of 145.5 ± 16.0°. In contrast, CD14 in TIP3P explicit water solvation is significantly twisted with average circularity of 0.16 ± 0.10, while 29.1% are ODCs. In addition, classification of CD14 conformations using a Gaussian mixture model (GMM) shows that 85.0% of all CD14 in implicit water at 300 K correspond to the elliptical conformation, in contrast to 82.3% in twisted form in explicit water. GMM clustering also reveals minority conformations of CD14 such as the 8-shape, boat-form, and twisted conformations. This work provides fundamental insights into CD14 conformation, influence of solvation models, and also proposes new quantifiable analysis techniques for molecular conformation studies in the future.

  16. Thermal behaviour, biological activity and conformational study of a [methoprene/beta-cyclodextrin] complex in a smoke generating formulation.

    PubMed

    Audino, Paola González; Masuh, Hector; Zerba, Eduardo

    2005-05-13

    Methoprene, an insect growth regulator, was complexed with beta-cyclodextrin, yielding a stable inclusion complex. TGA, X-ray powder diffraction and conformational analysis have been used to confirm the nature of this inclusion complex. The interaction between methoprene and beta-cyclodextrin was investigated by means of Molecular Mechanics. The results account for the formation of a 1:1 inclusion complex stabilised by Van der Waals forces and hydrogen bonds. The [methoprene-beta-cyclodextrin] complex included in smoke generating formulations and protected from thermal decomposition by the foaming agent azodicarbonamide was shown to be stable enough to release methoprene in fumes with good yields. The improved stabilty of the methoprene complex showed a correlation with increased biological activity against Musca domestica.

  17. Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding

    PubMed Central

    Papaioannou, Anastasios; Kuyucak, Serdar; Kuncic, Zdenka

    2015-01-01

    A sequence of complex conformational changes is required for insulin to bind to the insulin receptor. Recent experimental evidence points to the B chain C-terminal (BC-CT) as the location of these changes in insulin. Here, we present molecular dynamics simulations of insulin that reveal new insights into the structural changes occurring in the BC-CT. We find three key results: 1) The opening of the BC-CT is inherently stochastic and progresses through an open and then a “wide-open” conformation—the wide-open conformation is essential for receptor binding, but occurs only rarely. 2) The BC-CT opens with a zipper-like mechanism, with a hinge at the Phe24 residue, and is maintained in the dominant closed/inactive state by hydrophobic interactions of the neighboring Tyr26, the critical residue where opening of the BC-CT (activation of insulin) is initiated. 3) The mutation Y26N is a potential candidate as a therapeutic insulin analogue. Overall, our results suggest that the binding of insulin to its receptor is a highly dynamic and stochastic process, where initial docking occurs in an open conformation and full binding is facilitated through interactions of insulin receptor residues with insulin in its wide-open conformation. PMID:26629689

  18. Converting conformational changes to electrostatic energy in molecular motors: The energetics of ATP synthase.

    PubMed

    Strajbl, Marek; Shurki, Avital; Warshel, Arieh

    2003-12-09

    F1-ATPase is the catalytic component of the ATP synthase molecular machine responsible for most of the uphill synthesis of ATP in living systems. The enormous advances in biochemical and structural studies of this machine provide an opportunity for detailed understanding of the nature of its rotary mechanism. However, further quantitative progress in this direction requires development of reliable ways of translating the observed structural changes to the corresponding energies. This requirement is particularly challenging because we are dealing with a large system that couples major structural changes with a chemical process. The present work provides such a structure-function correlation by using the linear response approximation to describe the rotary mechanism. This approach allows one to evaluate the energy of transitions between different conformational states by considering only the changes in the corresponding electrostatic energies of the ligands. The relevant energetics are also obtained by calculating the linear response approximation-based free energies of transferring the ligands from water to the different sites of F1-ATPase in their different conformational states. We also use the empirical valence bond approach to evaluate the actual free-energy profile for the ATP synthesis in the different conformational states of the system. Integrating the information from the different approaches provides a semiquantitative structure-function correlation for F1-ATPase. It is found that the conformational changes are converted to changes in the electrostatic interaction between the protein and its ligands, which drives the ATP synthesis.

  19. Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology.

    PubMed

    Vaikath, Nishant N; Majbour, Nour K; Paleologou, Katerina E; Ardah, Mustafa T; van Dam, Esther; van de Berg, Wilma D J; Forrest, Shelley L; Parkkinen, Laura; Gai, Wei-Ping; Hattori, Nobutaka; Takanashi, Masashi; Lee, Seung-Jae; Mann, David M A; Imai, Yuzuru; Halliday, Glenda M; Li, Jia-Yi; El-Agnaf, Omar M A

    2015-07-01

    α-Synuclein (α-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that α-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of α-syn. We describe here the generation and characterization of six novel conformation-specific monoclonal antibodies that recognize specifically α-syn aggregates but not the soluble, monomeric form of the protein. The antibodies described herein did not recognize monomers or fibrils generated from other amyloidogenic proteins including β-syn, γ-syn, β-amyloid, tau protein, islet amyloid polypeptide and ABri. Interestingly, the antibodies did not react to overlapping linear peptides spanning the entire sequence of α-syn, confirming further that they only detect α-syn aggregates. In immunohistochemical studies, the new conformation-specific monoclonal antibodies showed underappreciated small micro-aggregates and very thin neurites in PD and DLB cases that were not observed with generic pan antibodies that recognize linear epitope. Furthermore, employing one of our conformation-specific antibodies in a sandwich based ELISA, we observed an increase in levels of α-syn oligomers in brain lysates from DLB compared to Alzheimer's disease and control samples. Therefore, the conformation-specific antibodies portrayed herein represent useful tools for research, biomarkers development, diagnosis and even immunotherapy for PD and related pathologies.

  20. Quantitative Sum-Frequency Generation Vibrational Spectroscopy of Molecular Surfaces and Interfaces: Lineshape, Polarization and Orientation

    SciTech Connect

    Wang, Hongfei; Velarde, Luis; Gan, Wei; Fu, Li

    2015-04-01

    Sum-frequency generation vibrational spectroscopy (SFG) can provide detailed information and understanding of molecular vibrational spectroscopy, orientational and conformational structure, and interactions of molecular surfaces and interfaces, through quantitative measurement and analysis. In this review, we present the current status and discuss the main developments on the measurement of intrinsic SFG spectral lineshape, formulations for polarization measurement and orientation analysis of the SFG-VS spectra. The main focus is to present a coherent formulation and discuss the main concepts or issues that can help to make SFG-VS a quantitative analytical and research tool in revealing the chemistry and physics of complex molecular surface and interface.

  1. Major Ampullate Spider Silk with Indistinguishable Spidroin Dope Conformations Leads to Different Fiber Molecular Structures.

    PubMed

    Dionne, Justine; Lefèvre, Thierry; Auger, Michèle

    2016-08-18

    To plentifully benefit from its properties (mechanical, optical, biological) and its potential to manufacture green materials, the structure of spider silk has to be known accurately. To this aim, the major ampullate (MA) silk of Araneus diadematus (AD) and Nephila clavipes (NC) has been compared quantitatively in the liquid and fiber states using Raman spectromicroscopy. The data show that the spidroin conformations of the two dopes are indistinguishable despite their specific amino acid composition. This result suggests that GlyGlyX and GlyProGlyXX amino acid motifs (X = Leu, Glu, Tyr, Ser, etc.) are conformationally equivalent due to the chain flexibility in the aqueous environment. Species-related sequence specificity is expressed more extensively in the fiber: the β-sheet content is lower and width of the orientation distribution of the carbonyl groups is broader for AD (29% and 58°, respectively) as compared to NC (37% and 51°, respectively). β-Sheet content values are close to the proportion of polyalanine segments, suggesting that β-sheet formation is mainly dictated by the spidroin sequence. The extent of molecular alignment seems to be related to the presence of proline (Pro) that may decrease conformational flexibility and inhibit chain extension and alignment upon drawing. It appears that besides the presence of Pro, secondary structure and molecular orientation contribute to the different mechanical properties of MA threads.

  2. Major Ampullate Spider Silk with Indistinguishable Spidroin Dope Conformations Leads to Different Fiber Molecular Structures

    PubMed Central

    Dionne, Justine; Lefèvre, Thierry; Auger, Michèle

    2016-01-01

    To plentifully benefit from its properties (mechanical, optical, biological) and its potential to manufacture green materials, the structure of spider silk has to be known accurately. To this aim, the major ampullate (MA) silk of Araneus diadematus (AD) and Nephila clavipes (NC) has been compared quantitatively in the liquid and fiber states using Raman spectromicroscopy. The data show that the spidroin conformations of the two dopes are indistinguishable despite their specific amino acid composition. This result suggests that GlyGlyX and GlyProGlyXX amino acid motifs (X = Leu, Glu, Tyr, Ser, etc.) are conformationally equivalent due to the chain flexibility in the aqueous environment. Species-related sequence specificity is expressed more extensively in the fiber: the β-sheet content is lower and width of the orientation distribution of the carbonyl groups is broader for AD (29% and 58°, respectively) as compared to NC (37% and 51°, respectively). β-Sheet content values are close to the proportion of polyalanine segments, suggesting that β-sheet formation is mainly dictated by the spidroin sequence. The extent of molecular alignment seems to be related to the presence of proline (Pro) that may decrease conformational flexibility and inhibit chain extension and alignment upon drawing. It appears that besides the presence of Pro, secondary structure and molecular orientation contribute to the different mechanical properties of MA threads. PMID:27548146

  3. Conformation of receptor-associated PGI2: An investigation by molecular modeling

    NASA Astrophysics Data System (ADS)

    Tsai, Ah-lim; Strobel-Jager, Eva; Wu, Kenneth K.

    1991-04-01

    To elucidate the conformation of receptor-associated prostacyclin (PGI2), we first performed structure-activity correlation analysis of over 200 PGI2 analogues and derived from this analysis several crucial features pertaining to structural requirements for PGI2 activity [Ah-lim Tsai and Kenneth K. Wu, Eicosanoids, 2 (1989) 131-143]. These structural features proved to be useful guidelines for selecting `model molecules' for further investigations by molecular mechanics. By properly selecting four analogues with either rigid or uniquely oriented α-side chain structure for geometric fitting, we succeeded in maximally minimizing the degree of freedom of the carboxylate terminus of PGI2. We were able to define the spatial relationship among the four critical functional groups, i.e., C1-COOH, C6a-O, C11-OH and C15-OH. More information is needed, however, to define the geometry of the ω-side chain, particularly for the moiety beyond C15. Nevertheless, results from structure-activity correlation analysis and molecular modeling provide useful information regarding the conformation of receptor-associated PGI2, which assumes an `elongated' conformation instead of the traditional `hairpin' structure.

  4. MED-3DMC: a new tool to generate 3D conformation ensembles of small molecules with a Monte Carlo sampling of the conformational space.

    PubMed

    Sperandio, Olivier; Souaille, Marc; Delfaud, François; Miteva, Maria A; Villoutreix, Bruno O

    2009-04-01

    Obtaining an efficient sampling of the low to medium energy regions of a ligand conformational space is of primary importance for getting insight into relevant binding modes of drug candidates, or for the screening of rigid molecular entities on the basis of a predefined pharmacophore or for rigid body docking. Here, we report the development of a new computer tool that samples the conformational space by using the Metropolis Monte Carlo algorithm combined with the MMFF94 van der Waals energy term. The performances of the program have been assessed on 86 drug-like molecules that resulted from an ADME/tox profiling applied on cocrystalized small molecules and were compared with the program Omega on the same dataset. Our program has also been assessed on the 85 molecules of the Astex diverse set. Both test sets show convincing performance of our program at sampling the conformational space.

  5. Molecular structure and conformational composition of methyl chloroacetate: An electron-diffraction and ab initio molecular orbital investigation

    NASA Astrophysics Data System (ADS)

    Aarset, Kirsten; Boldermo, Kjell Gunnar; Hagen, Kolbjørn

    2010-08-01

    The molecular structure and conformational composition of methyl chloroacetate, H 2ClC sbnd C( dbnd O) sbnd O sbnd CH 3, have been determined by gas-phase electron-diffraction (GED), using results from ab initio molecular orbital calculations (HF, MP2 and MP3/6-311+G(d,p)) to obtain constraints on some of the structural parameters. The molecules exist in the gas-phase at 25 °C as a mixture of two stable conformers: syn with C sbnd Cl eclipsing C dbnd O and gauche with C sbnd H approximately eclipsing C dbnd O. In both of these conformers O sbnd CH 3 is also eclipsing C dbnd O. The experimentally observed conformational composition at 25 °C was 36(8)% syn and 64(8)% gauche (parenthesised values are 2 σ), corresponding to a free energy difference between conformers of ΔGexp° = 1.4(9) kJ/mol. The corresponding theoretical values obtained for Δ G° are 1.1 kJ/mol (HF), 2.3 kJ/mol (MP2), and 2.4 kJ/mol (MP3). The results for the principal distances ( rh1) and angles ( ∠h1) for the major gauche conformer obtained from the combined GED/ ab initio study (2 σ uncertainties) are r(CO sbnd CCl) = 1.502(9) Å, r(C sbnd H) = 1.084(6) Å (average value), r(C sbnd Cl) = 1.782(4) Å, r(C dbnd O) = 1.213(4) Å, r(CO sbnd O) = 1.346(4) Å, r(CH 3sbnd O) = 1.468(10) Å, ∠C sbnd C sbnd Cl = 110.0(6)°, ∠C sbnd C dbnd O = 124.7(6)°, ∠C sbnd C sbnd O = 108.3(10)°, ∠C sbnd O sbnd C = 115.9(8)°, ϕ(Cl sbnd C sbnd C dbnd O) = 111(2)°, ϕ(C sbnd O sbnd C dbnd O) = 3(3)°.

  6. Membrane-induced conformational changes of kyotorphin revealed by molecular dynamics simulations.

    PubMed

    Machuqueiro, Miguel; Campos, Sara R R; Soares, Cláudio M; Baptista, António M

    2010-09-09

    The analgesic dipeptide kyotorphin (l-Tyr-l-Arg) was studied in the two most relevant protonation states at physiological pH, both in water and in a membrane model, using molecular dynamics simulations. Kyotorphin is found to exhibit a remarkable conformational freedom even when strongly interacting with the bilayer. Nevertheless, we observe a strong decrease in the population of the tyrosine's chi(1) torsion angle around 60 degrees that could be correlated with the dipeptide biological function. We employed a linear response approximation methodology to determine the N-terminus pK(a) values of kyotorphin and obtained 7.80 and 7.94 for aqueous and lipidic systems, respectively. Our results also indicate that the interaction of kyotorphin with a biological membrane model is consistent with the "membrane catalyst" hypothesis, and that even after the reduction of conformational freedom due to membrane insertion, this peptide fulfils most of the known constraints present in the opioid-like receptors.

  7. Effect of pressure on the conformation of proteins. A molecular dynamics simulation of lysozyme.

    PubMed

    McCarthy, Andrés N; Grigera, J Raúl

    2006-01-01

    The effect of pressure on the structure and mobility of lysozyme was studied by molecular dynamics computer simulation at 1 and 3 kbar (1 atm = 1.01325 bar = 101.325 kPa). The results have good agreement with the available experimental data, allowing the analysis of other features of the effect of pressure on the protein solution. The studies of mobility show that although the general mobility is restricted under pressure this is not true for some particular residues. From the analysis of secondary structure along the trajectories it is observed that the conformation under pressure is more stable, suggesting that pressure acts as a 'conformer selector' on the protein. The difference in solvent-accessed surface (SAS) with pressure shows a clear inversion of the hydrophilic/hydrophobic SAS ratio, which consequently shows that the hydrophobic interaction is considerably weaker under high hydrostatic pressure conditions.

  8. Molecular neuroanatomy: a generation of progress.

    PubMed

    Pollock, Jonathan D; Wu, Da-Yu; Satterlee, John S

    2014-02-01

    The neuroscience research landscape has changed dramatically over the past decade. Specifically, an impressive array of new tools and technologies have been generated, including but not limited to: brain gene expression atlases, genetically encoded proteins to monitor and manipulate neuronal activity, and new methods for imaging and mapping circuits. However, despite these technological advances, several significant challenges must be overcome to enable a better understanding of brain function and to develop cell type-targeted therapeutics to treat brain disorders. This review provides an overview of some of the tools and technologies currently being used to advance the field of molecular neuroanatomy, and also discusses emerging technologies that may enable neuroscientists to address these crucial scientific challenges over the coming decade.

  9. Conformational Dynamics of Mechanically Compliant DNA Nanostructures from Coarse-Grained Molecular Dynamics Simulations.

    PubMed

    Shi, Ze; Castro, Carlos E; Arya, Gaurav

    2017-05-23

    Structural DNA nanotechnology, the assembly of rigid 3D structures of complex yet precise geometries, has recently been used to design dynamic, mechanically compliant nanostructures with tunable equilibrium conformations and conformational distributions. Here we use coarse-grained molecular dynamics simulations to provide insights into the conformational dynamics of a set of mechanically compliant DNA nanostructures-DNA hinges that use single-stranded DNA "springs" to tune the equilibrium conformation of a layered double-stranded DNA "joint" connecting two stiff "arms" constructed from DNA helix bundles. The simulations reproduce the experimentally measured equilibrium angles between hinge arms for a range of hinge designs. The hinges are found to be structurally stable, except for some fraying of the open ends of the DNA helices comprising the hinge arms and some loss of base-pairing interactions in the joint regions coinciding with the crossover junctions, especially in hinges designed to exhibit a small bending angle that exhibit large local stresses resulting in strong kinks in their joints. Principal component analysis reveals that while the hinge dynamics are dominated by bending motion, some twisting and sliding of hinge arms relative to each other also exists. Forced deformation of the hinges reveals distinct bending mechanisms for hinges with short, inextensible springs versus those with longer, more extensible springs. Lastly, we introduce an approach for rapidly predicting equilibrium hinge angles from individual force-deformation behaviors of its single- and double-stranded DNA components. Taken together, these results demonstrate that coarse-grained modeling is a promising approach for designing, predicting, and studying the dynamics of compliant DNA nanostructures, where conformational fluctuations become important, multiple deformation mechanisms exist, and continuum approaches may not yield accurate properties.

  10. Accelerated molecular dynamics and protein conformational change: a theoretical and practical guide using a membrane embedded model neurotransmitter transporter.

    PubMed

    Gedeon, Patrick C; Thomas, James R; Madura, Jeffry D

    2015-01-01

    Molecular dynamics simulation provides a powerful and accurate method to model protein conformational change, yet timescale limitations often prevent direct assessment of the kinetic properties of interest. A large number of molecular dynamic steps are necessary for rare events to occur, which allow a system to overcome energy barriers and conformationally transition from one potential energy minimum to another. For many proteins, the energy landscape is further complicated by a multitude of potential energy wells, each separated by high free-energy barriers and each potentially representative of a functionally important protein conformation. To overcome these obstacles, accelerated molecular dynamics utilizes a robust bias potential function to simulate the transition between different potential energy minima. This straightforward approach more efficiently samples conformational space in comparison to classical molecular dynamics simulation, does not require advanced knowledge of the potential energy landscape and converges to the proper canonical distribution. Here, we review the theory behind accelerated molecular dynamics and discuss the approach in the context of modeling protein conformational change. As a practical example, we provide a detailed, step-by-step explanation of how to perform an accelerated molecular dynamics simulation using a model neurotransmitter transporter embedded in a lipid cell membrane. Changes in protein conformation of relevance to the substrate transport cycle are then examined using principle component analysis.

  11. myPresto/omegagene: a GPU-accelerated molecular dynamics simulator tailored for enhanced conformational sampling methods with a non-Ewald electrostatic scheme

    PubMed Central

    Kasahara, Kota; Ma, Benson; Goto, Kota; Dasgupta, Bhaskar; Higo, Junichi; Fukuda, Ikuo; Mashimo, Tadaaki; Akiyama, Yutaka; Nakamura, Haruki

    2016-01-01

    Molecular dynamics (MD) is a promising computational approach to investigate dynamical behavior of molecular systems at the atomic level. Here, we present a new MD simulation engine named “myPresto/omegagene” that is tailored for enhanced conformational sampling methods with a non-Ewald electrostatic potential scheme. Our enhanced conformational sampling methods, e.g., the virtual-system-coupled multi-canonical MD (V-McMD) method, replace a multi-process parallelized run with multiple independent runs to avoid inter-node communication overhead. In addition, adopting the non-Ewald-based zero-multipole summation method (ZMM) makes it possible to eliminate the Fourier space calculations altogether. The combination of these state-of-the-art techniques realizes efficient and accurate calculations of the conformational ensemble at an equilibrium state. By taking these advantages, myPresto/omegagene is specialized for the single process execution with Graphics Processing Unit (GPU). We performed benchmark simulations for the 20-mer peptide, Trp-cage, with explicit solvent. One of the most thermodynamically stable conformations generated by the V-McMD simulation is very similar to an experimentally solved native conformation. Furthermore, the computation speed is four-times faster than that of our previous simulation engine, myPresto/psygene-G. The new simulator, myPresto/omegagene, is freely available at the following URLs: http://www.protein.osaka-u.ac.jp/rcsfp/pi/omegagene/ and http://presto.protein.osaka-u.ac.jp/myPresto4/. PMID:27924276

  12. myPresto/omegagene: a GPU-accelerated molecular dynamics simulator tailored for enhanced conformational sampling methods with a non-Ewald electrostatic scheme.

    PubMed

    Kasahara, Kota; Ma, Benson; Goto, Kota; Dasgupta, Bhaskar; Higo, Junichi; Fukuda, Ikuo; Mashimo, Tadaaki; Akiyama, Yutaka; Nakamura, Haruki

    2016-01-01

    Molecular dynamics (MD) is a promising computational approach to investigate dynamical behavior of molecular systems at the atomic level. Here, we present a new MD simulation engine named "myPresto/omegagene" that is tailored for enhanced conformational sampling methods with a non-Ewald electrostatic potential scheme. Our enhanced conformational sampling methods, e.g., the virtual-system-coupled multi-canonical MD (V-McMD) method, replace a multi-process parallelized run with multiple independent runs to avoid inter-node communication overhead. In addition, adopting the non-Ewald-based zero-multipole summation method (ZMM) makes it possible to eliminate the Fourier space calculations altogether. The combination of these state-of-the-art techniques realizes efficient and accurate calculations of the conformational ensemble at an equilibrium state. By taking these advantages, myPresto/omegagene is specialized for the single process execution with Graphics Processing Unit (GPU). We performed benchmark simulations for the 20-mer peptide, Trp-cage, with explicit solvent. One of the most thermodynamically stable conformations generated by the V-McMD simulation is very similar to an experimentally solved native conformation. Furthermore, the computation speed is four-times faster than that of our previous simulation engine, myPresto/psygene-G. The new simulator, myPresto/omegagene, is freely available at the following URLs: http://www.protein.osaka-u.ac.jp/rcsfp/pi/omegagene/ and http://presto.protein.osaka-u.ac.jp/myPresto4/.

  13. Adsorption mechanisms of microcystin variant conformations at water-mineral interfaces: A molecular modeling investigation.

    PubMed

    Pochodylo, Amy L; Aoki, Thalia G; Aristilde, Ludmilla

    2016-10-15

    Microcystins (MCs) are potent toxins released during cyanobacterial blooms. Clay minerals are implicated in trapping MCs within soil particles in surface waters and sediments. In the absence of molecular characterization, the relevance of previously proposed adsorption mechanisms is lacking. Towards obtaining this characterization, we conducted Monte Carlo simulations combined with molecular dynamics relaxation of two MC variants, MC-leucine-arginine (MC-LR) and MC-leucine-alanine (MC-LA), adsorbed on hydrated montmorillonite with different electrolytes. The resulting adsorbate structures revealed how MC conformations and aqueous conditions dictate binding interactions at the mineral surface. Electrostatic coupling between the arginine residue and a carboxylate in MC-LR excluded the participation of arginine in mediating adsorption on montmorillonite in a NaCl solution. However, in a CaCl2 solution, the complexation of Ca by two carboxylate moieties in MC-LR changed the MC conformation, which allowed arginine to mediate electrostatic interaction with the mineral. By contrast, due to the lack of arginine in MC-LA, complexation of Ca by only one carboxylate in MC-LA was required to favor Ca-bridging interaction with the mineral. Multiple water-bridged H-bonding interactions were also important in anchoring MCs at the mineral surface. Our modeling results offer molecular insights into the structural and chemical factors that can control the fate of MCs at water-mineral interfaces.

  14. Conformation Analysis of Peptides Derived from Laminin Alpha 1-2 Chain Using Molecular Dynamics Simulation

    NASA Astrophysics Data System (ADS)

    Yamada, Hironao; Fukuda, Masaki; Miyakawa, Takeshi; Morikawa, Ryota; Takasu, Masako

    Laminin is one of the components of the basement membrane and has diverse biological activities. Several functional peptides (EF1-EF5) are identified from LG4 modules of laminin alpha 1-5 chains. Thus, we perform conformation analysis of EF1 and EF2 using molecular dynamics simulations. In this study, we perform structure sampling with NPT ensemble (300 K, 1 bar). Our results show that EF1 peptide has β-sheet structure in water, and EF2 peptide does not have. Likewise, the EF2 peptide has unstable structure compared with the EF1 peptide in water.

  15. Divalent Ion Dependent Conformational Changes in an RNA Stem-Loop Observed by Molecular Dynamics

    PubMed Central

    2016-01-01

    We compare the performance of five magnesium (Mg2+) ion models in simulations of an RNA stem loop which has an experimentally determined divalent ion dependent conformational shift. We show that despite their differences in parametrization and resulting van der Waals terms, including differences in the functional form of the nonbonded potential, when the RNA adopts its folded conformation, all models behave similarly across ten independent microsecond length simulations with each ion model. However, when the entire structure ensemble is accounted for, chelation of Mg2+ to RNA is seen in three of the five models, most egregiously and likely artifactual in simulations using a 12-6-4 model for the Lennard-Jones potential. Despite the simple nature of the fixed point-charge and van der Waals sphere models employed, and with the exception of the likely oversampled directed chelation of the 12-6-4 potential models, RNA–Mg2+ interactions via first shell water molecules are surprisingly well described by modern parameters, allowing us to observe the spontaneous conformational shift from Mg2+ free RNA to Mg2+ associated RNA structure in unrestrained molecular dynamics simulations. PMID:27294370

  16. Small-molecule G-quadruplex interactions: Systematic exploration of conformational space using multiple molecular dynamics.

    PubMed

    Husby, Jarmila; Todd, Alan K; Platts, James A; Neidle, Stephen

    2013-12-01

    G-quadruplexes are higher-order four-stranded structures formed from repetitive guanine-containing tracts in nucleic acids. They comprise a core of stacked guanine-quartets linked by loops of length and sequence that vary with the context in which the quadruplex sequence occurs. Such sequences can be found in a number of genomic environments; at the telomeric ends of eukaryotic chromosomes, in promoter regions, in untranslated sequences and in open reading frames. Quadruplex formation can inhibit telomere maintenance, transcription and translation, especially when enhanced by quadruplex-binding small molecules, and quadruplex targeting is currently of considerable interest. The available experimental structural data shows that quadruplexes can have high conformational flexibility, especially in loop regions, which has hampered attempts to use high-throughput docking to find quadruplex-binding small-molecules with new scaffolds or to optimize existing ones with structure-based design methods. An approach to overcome the challenge of quadruplex conformational flexibility is presented here, which uses a combined multiple molecular dynamics and sampling approach. Two test small molecules have been used, RHPS4 and pyridostatin, which themselves have contrasting degrees of conformational flexibility. Copyright © 2013 Wiley Periodicals, Inc.

  17. Conformational analysis of dehydrodidemnin B (aplidine) by NMR spectroscopy and molecular mechanics/dynamics calculations.

    PubMed

    Cárdenas, F; Thormann, M; Feliz, M; Caba, J M; Lloyd-Williams, P; Giralt, E

    2001-06-29

    Dehydrodidemnin B (DDB or aplidine), a potent antitumoral natural product currently in phase II clinical trials, exists as an approximately 1:1 mixture of two slowly interconverting conformations. These are sufficiently long-lived so as to allow their resolution by HPLC. NMR spectroscopy shows that this phenomenon is a consequence of restricted rotation about the Pyr-Pro(8) terminal amide bond of the molecule's side chain. The same technique also indicates that the overall three-dimensional structures of both the cis and trans isomers of DDB are similar despite the conformational change. Molecular dynamics simulations with different implicit and explicit solvent models show that the ensembles of three-dimensional structures produced are indeed similar for both the cis and trans isomers. These studies also show that hydrogen bonding patterns in both isomers are alike and that each one is stabilized by a hydrogen bond between the pyruvyl unit at the terminus of the molecule's side chain and the Thr(6) residue situated at the junction betwen the macrocycle and the molecule's side chain. Nevertheless, each conformational isomer forms this hydrogen bond using a different pyruvyl carbonyl group: CO(2) in the case of the cis isomer and CO(1) in the case of the trans isomer.

  18. Molecular modelling of the three-dimensional structure and conformational flexibility of bacterial lipopolysaccharide.

    PubMed Central

    Kastowsky, M; Gutberlet, T; Bradaczek, H

    1992-01-01

    Molecular modelling techniques have been applied to calculate the three-dimensional architecture and the conformational flexibility of a complete bacterial S-form lipopolysaccharide (LPS) consisting of a hexaacyl lipid A identical to Escherichia coli lipid A, a complete Salmonella typhimurium core oligosaccharide portion, and four repeating units of the Salmonella serogroup B O-specific chain. X-ray powder diffraction experiments on dried samples of LPS were carried out to obtain information on the dimensions of the various LPS partial structures. Up to the Ra-LPS structure, the calculated model dimensions were in good agreement with experimental data and were 2.4 nm for lipid A, 2.8 nm for Re-LPS, 3.5 nm for Rd-LPS, and 4.4 nm for Ra-LPS. The maximum length of a stretched S-form LPS model bearing four repeating units was evaluated to be 9.6 nm; however, energetically favored LPS conformations showed the O-specific chain bent with respect to the Ra-LPS portion and significantly smaller dimensions (about 5.0 to 5.5 nm). According to the calculations, the Ra-LPS moiety has an approximately cylindrical shape and is conformationally well defined, in contrast to the O-specific chain, which was found to be the most flexible portion within the molecule. PMID:1624466

  19. Conformational changes in calcium-sensor proteins under molecular crowding conditions.

    PubMed

    Sulmann, Stefan; Dell'Orco, Daniele; Marino, Valerio; Behnen, Petra; Koch, Karl-Wilhelm

    2014-05-26

    Fundamental components of signaling pathways are switch modes in key proteins that control start, duration, and ending of diverse signal transduction events. A large group of switch proteins are Ca(2+) sensors, which undergo conformational changes in response to oscillating intracellular Ca(2+) concentrations. Here we use dynamic light scattering and a recently developed approach based on surface plasmon resonance to compare the protein dynamics of a diverse set of prototypical Ca(2+)-binding proteins including calmodulin, troponin C, recoverin, and guanylate cyclase-activating protein. Surface plasmon resonance biosensor technology allows monitoring conformational changes under molecular crowding conditions, yielding for each Ca(2+)-sensor protein a fingerprint profile that reflects different hydrodynamic properties under changing Ca(2+) conditions and is extremely sensitive to even fine alterations induced by point mutations. We see, for example, a correlation between surface plasmon resonance, dynamic light scattering, and size-exclusion chromatography data. Thus, changes in protein conformation correlate not only with the hydrodynamic size, but also with a rearrangement of the protein hydration shell and a change of the dielectric constant of water or of the protein-water interface. Our study provides insight into how rather small signaling proteins that have very similar three-dimensional folding patterns differ in their Ca(2+)-occupied functional state under crowding conditions. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Conformational Analysis of a High-Mannose-Type Oligosaccharide Displaying Glucosyl Determinant Recognised by Molecular Chaperones Using NMR-Validated Molecular Dynamics Simulation.

    PubMed

    Suzuki, Tatsuya; Kajino, Megumi; Yanaka, Saeko; Zhu, Tong; Yagi, Hirokazu; Satoh, Tadashi; Yamaguchi, Takumi; Kato, Koichi

    2017-02-16

    Exploration of the conformational spaces of flexible oligosaccharides is essential to gain deeper insights into their functional mechanisms. Here we characterised dynamic conformation of a high-mannose-type dodecasaccharide with a terminal glucose residue, a critical determinant recognised by molecular chaperones. The dodecasaccharide was prepared by our developed chemoenzymatic technique, which uses (13) C labelling and lanthanide tagging to detect conformation-dependent paramagnetic effects by NMR spectroscopy. The NMR-validated molecular dynamics simulation produced the dynamic conformational ensemble of the dodecasaccharide. This determined its spatial distribution as well as the glycosidic linkage conformation of the terminal glucose determinant. Moreover, comparison of our results with previously reported crystallographic data indicates that the chaperone binding to its target oligosaccharides involves an induced-fit mechanism. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. New binding site conformations of the dengue virus NS3 protease accessed by molecular dynamics simulation.

    PubMed

    de Almeida, Hugo; Bastos, Izabela M D; Ribeiro, Bergmann M; Maigret, Bernard; Santana, Jaime M

    2013-01-01

    Dengue fever is caused by four distinct serotypes of the dengue virus (DENV1-4), and is estimated to affect over 500 million people every year. Presently, there are no vaccines or antiviral treatments for this disease. Among the possible targets to fight dengue fever is the viral NS3 protease (NS3PRO), which is in part responsible for viral processing and replication. It is now widely recognized that virtual screening campaigns should consider the flexibility of target protein by using multiple active conformational states. The flexibility of the DENV NS3PRO could explain the relatively low success of previous virtual screening studies. In this first work, we explore the DENV NS3PRO conformational states obtained from molecular dynamics (MD) simulations to take into account protease flexibility during the virtual screening/docking process. To do so, we built a full NS3PRO model by multiple template homology modeling. The model comprised the NS2B cofactor (essential to the NS3PRO activation), a glycine flexible link and the proteolytic domain. MD simulations had the purpose to sample, as closely as possible, the ligand binding site conformational landscape prior to inhibitor binding. The obtained conformational MD sample was clustered into four families that, together with principal component analysis of the trajectory, demonstrated protein flexibility. These results allowed the description of multiple binding modes for the Bz-Nle-Lys-Arg-Arg-H inhibitor, as verified by binding plots and pair interaction analysis. This study allowed us to tackle protein flexibility in our virtual screening campaign against the dengue virus NS3 protease.

  2. Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

    PubMed Central

    Rodrigues, J Rui; Simões, Carlos J V; Silva, Cândida G; Brito, Rui M M

    2010-01-01

    Protein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimer's, Huntington's and Creutzfeldt-Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT-TTR and L55P-TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P-TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single α-helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation-prone conformations characterized by full displacement of strands C and D from the main β-sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H-bond network and consequent destabilization of the CBEF β-sheet of the β-sandwich; (v) WT forms aggregation-compatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P-TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation. PMID:19937650

  3. Conformational and Cs+ complexation properties of norbadione-A: a molecular modeling study.

    PubMed

    Schurhammer, R; Diss, R; Spiess, B; Wipff, G

    2008-01-28

    We report a quantum mechanical (QM) and classical molecular dynamics (MD) study of the conformational and complexation properties of norbadione-A (NBA), a key pigment involved in the Cs+ complexation by mushrooms. The Z versus E isomers of its pulvinic moieties are compared in their neutral (Pulv0), mono- (Pulv(-1)) and di-deprotonated (Pulv(-2)) states, and the 1H chemical shifts are calculated ab initio. Pulv(-1) is found to be stabilized in the E form by an internal COOH(-)O(enolate) hydrogen-bond. No energy minimum is found for the corresponding COO(-)HO(enol) state, indicating that the conjugated enol function of Pulv0 is more acidic than the COOH function. Further deprotonation leads to the Z and E forms of Pulv(-2) that are close in energy and both account for a marked downfield shift delta of ortho-H8 protons. A similar shift is found upon deprotonation of the enol function of an ester analogue of Pulv0. Therefore, contrary to previous assumptions (ref. 7: P. Kuad, et al., J. Am. Chem. Soc., 2005, 127, 1323), the large shift of delta(H8) around pH 9.5 upon deprotonation of NBA or of pulvinic acid cannot be taken as an indicator of an E-to-Z conformational switch, but merely reflects the pH-induced conformational change of the carboxylate group adjacent to the (H8)-ring. The QM and MD studies on NBA(2-) and NBA(4-) support the view that both species prefer the E/E form with two intramolecular COOH(-)O(enolate) hydrogen-bonds in the gas phase and in solution. Finally, we simulated mono- and di-nuclear complexes of Cs+ with NBA(2-) and NBA(4-) by MD, showing that only the NBA(4-) state populated at high pH values can bind two Cs+ cations, with both E and Z conformations of the pulvinic arms.

  4. Single-strand conformation polymorphism for molecular variability studies of six viroid species.

    PubMed

    Elleuch, Amine; Hamdi, Imen; Bessaies, Nabiha; Fakhfakh, Hatem

    2013-01-01

    Molecular diversity within six viroid species and different molecular variants, in each species infecting fruit trees was first estimated by the single-strand conformation polymorphism (SSCP) technique and then by direct sequencing analysis. The different variants studied are to three Australian grapevine viroids(AGVd), four citrus dwarfing viroids (CDVd), eleven grapevine yellow speckle viroids type-1 (GYSVd-1), four hop stunt viroids (HSVd), seven peach latent mosaic viroids (PLMVd), and eight pear blister canker viroids (PBCVd). Polyacrylamide gel electrophoresis (PAGE) conditions were compared and optimized to improve the sensitivity of the existing SSCP parameters. The relationships among the various SSCP profiles observed and the variation in nucleotide sequences was studied. The results indicate that the variations of some parameters of electrophoresis for each species allowed higher resolution and hence detection of single nucleotide variations among clones initially clustered into the same group.

  5. Retrieving transient conformational molecular structure information from inner-shell photoionization of laser-aligned molecules

    SciTech Connect

    Wang, Xu; Le, Anh -Thu; Yu, Chao; Lucchese, R. R.; Lin, C. D.

    2016-03-30

    We discuss a scheme to retrieve transient conformational molecular structure information using photoelectron angular distributions (PADs) that have averaged over partial alignments of isolated molecules. The photoelectron is pulled out from a localized inner-shell molecular orbital by an X-ray photon. We show that a transient change in the atomic positions from their equilibrium will lead to a sensitive change in the alignment-averaged PADs, which can be measured and used to retrieve the former. Exploiting the experimental convenience of changing the photon polarization direction, we show that it is advantageous to use PADs obtained from multiple photon polarization directions. Lastly, a simple single-scattering model is proposed and benchmarked to describe the photoionization process and to do the retrieval using a multiple-parameter fitting method.

  6. Retrieving transient conformational molecular structure information from inner-shell photoionization of laser-aligned molecules

    DOE PAGES

    Wang, Xu; Le, Anh -Thu; Yu, Chao; ...

    2016-03-30

    We discuss a scheme to retrieve transient conformational molecular structure information using photoelectron angular distributions (PADs) that have averaged over partial alignments of isolated molecules. The photoelectron is pulled out from a localized inner-shell molecular orbital by an X-ray photon. We show that a transient change in the atomic positions from their equilibrium will lead to a sensitive change in the alignment-averaged PADs, which can be measured and used to retrieve the former. Exploiting the experimental convenience of changing the photon polarization direction, we show that it is advantageous to use PADs obtained from multiple photon polarization directions. Lastly, amore » simple single-scattering model is proposed and benchmarked to describe the photoionization process and to do the retrieval using a multiple-parameter fitting method.« less

  7. Retrieving transient conformational molecular structure information from inner-shell photoionization of laser-aligned molecules

    PubMed Central

    Wang, Xu; Le, Anh-Thu; Yu, Chao; Lucchese, R. R.; Lin, C. D.

    2016-01-01

    We discuss a scheme to retrieve transient conformational molecular structure information using photoelectron angular distributions (PADs) that have averaged over partial alignments of isolated molecules. The photoelectron is pulled out from a localized inner-shell molecular orbital by an X-ray photon. We show that a transient change in the atomic positions from their equilibrium will lead to a sensitive change in the alignment-averaged PADs, which can be measured and used to retrieve the former. Exploiting the experimental convenience of changing the photon polarization direction, we show that it is advantageous to use PADs obtained from multiple photon polarization directions. A simple single-scattering model is proposed and benchmarked to describe the photoionization process and to do the retrieval using a multiple-parameter fitting method. PMID:27025410

  8. Molecular Dynamics Simulation of Tau Peptides for the Investigation of Conformational Changes Induced by Specific Phosphorylation Patterns.

    PubMed

    Gandhi, Neha S; Kukic, Predrag; Lippens, Guy; Mancera, Ricardo L

    2017-01-01

    The Tau protein plays an important role due to its biomolecular interactions in neurodegenerative diseases. The lack of stable structure and various posttranslational modifications such as phosphorylation at various sites in the Tau protein pose a challenge for many experimental methods that are traditionally used to study protein folding and aggregation. Atomistic molecular dynamics (MD) simulations can help around deciphering relationship between phosphorylation and various intermediate and stable conformations of the Tau protein which occur on longer timescales. This chapter outlines protocols for the preparation, execution, and analysis of all-atom MD simulations of a 21-amino acid-long phosphorylated Tau peptide with the aim of generating biologically relevant structural and dynamic information. The simulations are done in explicit solvent and starting from nearly extended configurations of the peptide. The scaled MD method implemented in AMBER14 was chosen to achieve enhanced conformational sampling in addition to a conventional MD approach, thereby allowing the characterization of folding for such an intrinsically disordered peptide at 293 K. Emphasis is placed on the analysis of the simulation trajectories to establish correlations with NMR data (i.e., chemical shifts and NOEs). Finally, in-depth discussions are provided for commonly encountered problems.

  9. Peptoid conformational free energy landscapes from implicit-solvent molecular simulations in AMBER.

    PubMed

    Voelz, Vincent A; Dill, Ken A; Chorny, Ilya

    2011-01-01

    To test the accuracy of existing AMBER force field models in predicting peptoid conformation and dynamics, we simulated a set of model peptoid molecules recently examined by Butterfoss et al. (JACS 2009, 131, 16798-16807) using QM methods as well as three peptoid sequences with experimentally determined structures. We found that AMBER force fields, when used with a Generalized Born/Surface Area (GBSA) implicit solvation model, could accurately reproduce the peptoid torsional landscape as well as the major conformers of known peptoid structures. Enhanced sampling by replica exchange molecular dynamics (REMD) using temperatures from 300 to 800 K was used to sample over cis-trans isomerization barriers. Compared to (Nrch)5 and cyclo-octasarcosyl, the free energy of N-(2-nitro-3-hydroxyl phenyl)glycine-N-(phenyl)glycine has the most "foldable" free energy landscape, due to deep trans-amide minima dictated by N-aryl sidechains. For peptoids with (S)-N (1-phenylethyl) (Nspe) side chains, we observe a discrepancy in backbone dihedral propensities between molecular simulations and QM calculations, which may be due to force field effects or the inability to capture n --> n* interactions. For these residues, an empirical phi-angle biasing potential can "rescue" the backbone propensities seen in QM. This approach can serve as a general strategy for addressing force fields without resorting to a complete reparameterization. Overall, this study demonstrates the utility of implicit-solvent REMD simulations for efficient sampling to predict peptoid conformational landscapes, providing a potential tool for first-principles design of sequences with specific folding properties.

  10. Conformational Dynamics of RNA-Peptide Binding: A Molecular Dynamics Simulation Study

    PubMed Central

    Mu, Yuguang; Stock, Gerhard

    2006-01-01

    Molecular dynamics simulations of the binding of the heterochiral tripeptide KkN to the transactivation responsive (TAR) RNA of HIV-1 is presented, using an all-atom force field with explicit water. To obtain starting structures for the TAR-KkN complex, semirigid docking calculations were performed that employ an NMR structure of free TAR RNA. The molecular dynamics simulations show that the starting structures in which KkN binds to the major groove of TAR (as it is the case for the Tat-TAR complex of HIV-1) are unstable. On the other hand, the minor-groove starting structures are found to lead to several binding modes, which are stabilized by a complex interplay of stacking, hydrogen bonding, and electrostatic interactions. Although the ligand does not occupy the binding position of Tat protein, it is shown to hinder the interhelical motion of free TAR RNA. The latter is presumably necessary to achieve the conformational change of TAR RNA to bind Tat protein. Considering the time evolution of the trajectories, the binding process is found to be ligand-induced and cooperative. That is, the conformational rearrangement only occurs in the presence of the ligand and the concerted motion of the ligand and a large part of the RNA binding site is necessary to achieve the final low-energy binding state. PMID:16239331

  11. Allosteric conformational change cascade in cytoplasmic dynein revealed by structure-based molecular simulations.

    PubMed

    Kubo, Shintaroh; Li, Wenfei; Takada, Shoji

    2017-09-01

    Cytoplasmic dynein is a giant ATP-driven molecular motor that proceeds to the minus end of the microtubule (MT). Dynein hydrolyzes ATP in a ring-like structure, containing 6 AAA+ (ATPases associated with diverse cellular activities) modules, which is ~15 nm away from the MT binding domain (MTBD). This architecture implies that long-distance allosteric couplings exist between the AAA+ ring and the MTBD in order for dynein to move on the MT, although little is known about the mechanisms involved. Here, we have performed comprehensive molecular simulations of the dynein motor domain based on pre- and post- power-stroke structural information and in doing so we address the allosteric conformational changes that occur during the power-stroke and recovery-stroke processes. In the power-stroke process, the N-terminal linker movement was the prerequisite to the nucleotide-dependent AAA1 transition, from which a transition cascade propagated, on average, in a circular manner on the AAA+ ring until it reached the AAA6/C-terminal module. The recovery-stroke process was initiated by the transition of the AAA6/C-terminal, from which the transition cascade split into the two directions of the AAA+ ring, occurring both clockwise and anti-clockwise. In both processes, the MTBD conformational change was regulated by the AAA4 module and the AAA5/Strut module.

  12. Molecular weight and helix conformation determine intestinal anti-inflammatory effects of exopolysaccharide from Schizophyllum commune.

    PubMed

    Du, Bin; Yang, Yuedong; Bian, Zhaoxiang; Xu, Baojun

    2017-09-15

    Intestinal anti-inflammatory activities of exopolysaccharide from S. commune were assessed using dextran sulfate sodium (DSS)-induced colitis in mice model. The changes of molecular weight (MW), atomic force microscope morphology, X-ray diffraction, particle size distribution, and viscosity were recorded after sonication treatment. The results indicated that the triple helical structure of exopolysaccharide was dissociated into single helical structure and random coiled structure by ultrasonication via breaking of inter- and intramolecular hydrogen bonds. The medium (936kDa) and high MW (1437kDa) exopolysaccharide had the mixture of triple helix and single helix conformation, while the low MW (197kDa) exopolysaccharide exhibit random coiled conformation. The intestinal anti-inflammatory activity study showed that oral administration of medium and high MW (1437kDa) exopolysaccharide significantly recovered DSS-induced colitis in inflamed tissues and reduced inflammation induced infiltration of macrophages. These results showed that medium (936kDa) and high MW (1437kDa) exopolysaccharide had intestinal anti-inflammatory activity. The intestinal anti-inflammatory activity of exopolysaccharide was related to helical structure and molecular weight. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Quantum/molecular mechanics study of firefly bioluminescence on luciferase oxidative conformation

    NASA Astrophysics Data System (ADS)

    Pinto da Silva, Luís; Esteves da Silva, Joaquim C. G.

    2014-07-01

    This is the first report of a computational study of the color tuning mechanism of firefly bioluminescence, using the oxidative conformation of luciferase. The results of these calculations demonstrated that the electrostatic field generated by luciferase is fundamental both for the emission shift and efficiency. Further calculations indicated that a shift in emission is achieved by modulating the energy, at different degrees, of the emissive and ground states. These differences in energy modulation will then lead to changes in the energy gap between the states.

  14. Sampling small-scale and large-scale conformational changes in proteins and molecular complexes

    NASA Astrophysics Data System (ADS)

    Yun, Mi-Ran; Mousseau, N.; Derreumaux, P.

    2007-03-01

    Sampling of small-scale and large-scale motions is important in various computational tasks, such as protein-protein docking and ligand binding. Here, we report further development and applications of the activation-relaxation technique for internal coordinate space trajectories (ARTIST). This method generates conformational moves of any complexity and size by identifying and crossing well-defined saddle points connecting energy minima. Simulations on two all-atom proteins and three protein complexes containing between 70 and 300 amino acids indicate that ARTIST opens the door to the full treatment of all degrees of freedom in dense systems such as protein-protein complexes.

  15. Design of a wind turbine-generator system considering the conformability to wind velocity fluctuations

    SciTech Connect

    Wakui, Tetsuya; Hashizume, Takumi; Outa, Eisuke

    1999-07-01

    The conformability of the rated power output of the wind turbine-generator system and of the wind turbine type to wind velocity fluctuations are investigated with a simulation model. The authors examine three types of wind turbines: the Darrieus-Savonius hybrid, the Darrieus proper and the Propeller. These systems are mainly operated at a constant tip speed ratio, which refers to a maximum power coefficient points. As a computed result of the net extracting power, the Darrieus turbine proper has little conformability to wind velocity fluctuations because of its output characteristics. As for the other turbines, large-scale systems do not always have an advantage over small-scale systems as the effect of its dynamic characteristics. Furthermore, it is confirmed that the net extracting power of the Propeller turbine, under wind direction fluctuation, is much reduced when compared with the hybrid wind turbine. Thus, the authors conclude that the appropriate rated power output of the system exists with relation to the wind turbine type for each wind condition.

  16. A coupling of homology modeling with multiple molecular dynamics simulation for identifying representative conformation of GPCR structures: a case study on human bombesin receptor subtype-3.

    PubMed

    Nowroozi, Amin; Shahlaei, Mohsen

    2017-02-01

    In this study, a computational pipeline was therefore devised to overcome homology modeling (HM) bottlenecks. The coupling of HM with molecular dynamics (MD) simulation is useful in that it tackles the sampling deficiency of dynamics simulations by providing good-quality initial guesses for the native structure. Indeed, HM also relaxes the severe requirement of force fields to explore the huge conformational space of protein structures. In this study, the interaction between the human bombesin receptor subtype-3 and MK-5046 was investigated integrating HM, molecular docking, and MD simulations. To improve conformational sampling in typical MD simulations of GPCRs, as in other biomolecules, multiple trajectories with different initial conditions can be employed rather than a single long trajectory. Multiple MD simulations of human bombesin receptor subtype-3 with different initial atomic velocities are applied to sample conformations in the vicinity of the structure generated by HM. The backbone atom conformational space distribution of replicates is analyzed employing principal components analysis. As a result, the averages of structural and dynamic properties over the twenty-one trajectories differ significantly from those obtained from individual trajectories.

  17. Towards fast, rigorous and efficient conformational sampling of biomolecules: Advances in accelerated molecular dynamics.

    PubMed

    Doshi, Urmi; Hamelberg, Donald

    2015-05-01

    Accelerated molecular dynamics (aMD) has been proven to be a powerful biasing method for enhanced sampling of biomolecular conformations on general-purpose computational platforms. Biologically important long timescale events that are beyond the reach of standard molecular dynamics can be accessed without losing the detailed atomistic description of the system in aMD. Over other biasing methods, aMD offers the advantages of tuning the level of acceleration to access the desired timescale without any advance knowledge of the reaction coordinate. Recent advances in the implementation of aMD and its applications to small peptides and biological macromolecules are reviewed here along with a brief account of all the aMD variants introduced in the last decade. In comparison to the original implementation of aMD, the recent variant in which all the rotatable dihedral angles are accelerated (RaMD) exhibits faster convergence rates and significant improvement in statistical accuracy of retrieved thermodynamic properties. RaMD in conjunction with accelerating diffusive degrees of freedom, i.e. dual boosting, has been rigorously tested for the most difficult conformational sampling problem, protein folding. It has been shown that RaMD with dual boosting is capable of efficiently sampling multiple folding and unfolding events in small fast folding proteins. RaMD with the dual boost approach opens exciting possibilities for sampling multiple timescales in biomolecules. While equilibrium properties can be recovered satisfactorily from aMD-based methods, directly obtaining dynamics and kinetic rates for larger systems presents a future challenge. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion.

    PubMed

    Srikantha, Nishanthan; Mourad, Fatma; Suhling, Klaus; Elsaid, Naba; Levitt, James; Chung, Pei Hua; Somavarapu, Satyanarayana; Jackson, Timothy L

    2012-09-01

    The purpose of this study was to investigate the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion. Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore-labelled neutral albumin, neutral dextran, or neutral ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 h using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive or negative net surface charges. Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution. All molecules were 70 kDa. With FRAP, the diffusion coefficient (D) of neutral molecules was highest for albumin, followed by ficoll, then dextran (p < 0.0001). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0004). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.5865). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021). In conclusion, diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but their effects may be diametrically opposed in different molecules, and their influence on diffusion is more complex than previously thought. Each variable cannot be considered in isolation, and the interplay of all these variables needs to be tested, when selecting or designing drugs for transscleral delivery.

  19. NMR and molecular dynamics studies of the conformational epitope of the type III group B Streptococcus capsular polysaccharide and derivatives.

    PubMed

    Brisson, J R; Uhrinova, S; Woods, R J; van der Zwan, M; Jarrell, H C; Paoletti, L C; Kasper, D L; Jennings, H J

    1997-03-18

    The conformational epitope of the type III group B Streptococcus capsular polysaccharide (GBSP III) exhibits unique properties which can be ascribed to the presence of sialic acid in its structure and the requirement for an extended binding site. By means of NMR and molecular dynamics studies on GBSP III and its fragments, the extended epitope of GBSP III was further defined. The influence of sialic acid on the conformational properties of GBSP III was examined by performing conformational analysis on desialylated GBSP III, which is identical to the polysaccharide of Streptococcus pneumoniae type 14, and also on oxidized and reduced GBSP III. Conformational changes were gauged by 1H and 13C chemical shift analysis, NOE, 1D selective TOCSY-NOESY experiments, J(HH) and J(CH) variations, and NOE of OH resonances. Changes in mobility were examined by 13C T1 and T2 measurements. Unrestrained molecular dynamics simulations with explicit water using the AMBER force field and the GLYCAM parameter set were used to assess static and dynamic conformational models, simulate the observable NMR parameters and calculate helical parameters. GBSP III was found to be capable of forming extended helices. Hence, the length dependence of the conformational epitope could be explained by its location on extended helices within the random coil structure of GBSP III. The interaction of sialic acid with the backbone of the PS was also found to be important in defining the conformational epitope of GBSP III.

  20. Probing conformational disorder in neurotensin by two-dimensional solid-state NMR and comparison to molecular dynamics simulations.

    PubMed

    Heise, Henrike; Luca, Sorin; de Groot, Bert L; Grubmüller, Helmut; Baldus, Marc

    2005-09-01

    An approach is introduced to characterize conformational ensembles of intrinsically unstructured peptides on the atomic level using two-dimensional solid-state NMR data and their combination with molecular dynamics simulations. For neurotensin, a peptide that binds with high affinity to a G-protein coupled receptor, this method permits the investigation of the changes in conformational preferences of a neurotransmitter transferred from a frozen aqueous solution via a lipid model phase to the receptor-bound form. The results speak against a conformational pre-organization of the ligand in detergents in which the receptor has been shown to be functional. Further extensions to the study of protein folding are possible.

  1. A New Efficient Method for Generating Conformations of Unfolded Proteins with Diverse Main-Chain Dihedral-Angle Distributions.

    PubMed

    Seki, Yasutaka; Shimbo, Yudai; Nonaka, Takamasa; Soda, Kunitsugu

    2011-07-12

    A new method for generating polypeptide-chain conformations has been developed for studying structural characteristics of unfolded proteins. It enables us to generate a large number of conformations very rapidly by avoiding atomic collisions efficiently with the use of main-chain dihedral-angle distributions derived from a crystal-structure database of proteins. In addition, combining main-chain dihedral-angle distributions for the amino acid residues incorporated in different secondary structures, we can obtain diverse conformational ensembles with different structural features. Structural characteristics of proteins denatured in high-concentration denaturant solution were analyzed by comparing predictions from this method with results from solution X-ray scattering (SXS) measurement. Analysis of the dependence of the mean square radius (Rsq) of protein on the number of residues and the shape of its Kratky profile has confirmed that the highly denaturing solvent serves as a good solvent in accordance with previous reports. It was also found that, in order for a conformational ensemble to reproduce experimental data, the percentage in which main-chain dihedral angles are found in the α region must be in the range of 20-40%. It agrees with studies on the (3)JHNα coupling constant using the multidimensional NMR method. These results confirm that our method for generating diverse conformations of polypeptide chains is very useful to the conformational analysis of unfolded protein, because it enables us to analyze comprehensively both of the local structural features obtained from NMR and the global ones obtained from SXS.

  2. Mass generation, the cosmological constant problem, conformal symmetry, and the Higgs boson

    NASA Astrophysics Data System (ADS)

    Mannheim, Philip D.

    2017-05-01

    In 2013 the Nobel Prize in Physics was awarded to Francois Englert and Peter Higgs for their work in 1964 along with the late Robert Brout on the mass generation mechanism (the Higgs mechanism) in local gauge theories. This mechanism requires the existence of a massive scalar particle, the Higgs boson, and in 2012 the Higgs boson was finally discovered at the Large Hadron Collider after being sought for almost half a century. In this article we review the work that led to the discovery of the Higgs boson and discuss its implications. We approach the topic from the perspective of a dynamically generated Higgs boson that is a fermion-antifermion bound state rather than an elementary field that appears in an input Lagrangian. In particular, we emphasize the connection with the Bardeen-Cooper-Schrieffer theory of superconductivity. We identify the double-well Higgs potential not as a fundamental potential but as a mean-field effective Lagrangian with a dynamical Higgs boson being generated through a residual interaction that accompanies the mean-field Lagrangian. We discuss what we believe to be the key challenge raised by the discovery of the Higgs boson, namely determining whether it is elementary or composite, and through study of a conformal invariant field theory model as realized with critical scaling and anomalous dimensions, suggest that the width of the Higgs boson might serve as a suitable diagnostic for discriminating between an elementary Higgs boson and a composite one. We discuss the implications of Higgs boson mass generation for the cosmological constant problem, as the cosmological constant receives contributions from the very mechanism that generates the Higgs boson mass in the first place. We show that the contribution to the cosmological constant due to a composite Higgs boson is more tractable and under control than the contribution due to an elementary Higgs boson, and is potentially completely under control if there is an underlying conformal

  3. Stable conformation of full-length amyloid-β (1-42) monomer in water: Replica exchange molecular dynamics and ab initio molecular orbital simulations

    NASA Astrophysics Data System (ADS)

    Okamoto, Akisumi; Yano, Atsushi; Nomura, Kazuya; Higai, Shin'ichi; Kurita, Noriyuki

    2013-07-01

    Aggregation of amyloid β-proteins (Aβ) plays a key role in the mechanism of molecular pathogenesis of Alzheimer’s disease (AD). It is known that full-length Aβ(1-42) is more prone to aggregation than Aβ(1-40). We here search stable conformations of solvated Aβ(1-42) monomer by replica exchange molecular dynamics simulations based on classical force fields, and the most stable conformation is determined from the total energies evaluated by the ab initio fragment molecular orbital (FMO) calculations. In addition, based on the FMO results, the amino acid residues of Aβ(1-42) contributing to the stabilization of the monomer are highlighted.

  4. 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

  5. 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.

  6. Molecularly Imprinted Materials: Towards the Next Generation

    DTIC Science & Technology

    2002-04-05

    SCINTILLATION POLYMERS : A NEW SENSOR CONCEPT Although molecularly imprinted polymers ( MIPs ) often display high binding affinity and specificity mimicking... sensors have been demonstrated over the past years. In general, molecular imprinting can be defined as a process of target directed synthesis of...efficiency. For these reasons imprinted polymer beads are preferable. Although the well-established suspension and dispersion polymerization methods

  7. Combinatorial selection of molecular conformations and supramolecular synthons in quercetin cocrystal landscapes: a route to ternary solids

    PubMed Central

    Dubey, Ritesh; Desiraju, Gautam R.

    2015-01-01

    The crystallization of 28 binary and ternary cocrystals of quercetin with dibasic coformers is analyzed in terms of a combinatorial selection from a solution of preferred molecular conformations and supramolecular synthons. The crystal structures are characterized by distinctive O—H⋯N and O—H⋯O based synthons and are classified as nonporous, porous and helical. Variability in molecular conformation and synthon structure led to an increase in the energetic and structural space around the crystallization event. This space is the crystal structure landscape of the compound and is explored by fine-tuning the experimental conditions of crystallization. In the landscape context, we develop a strategy for the isolation of ternary cocrystals with the use of auxiliary template molecules to reduce the molecular and supramolecular ‘confusion’ that is inherent in a molecule like quercetin. The absence of concomitant polymorphism in this study highlights the selectivity in conformation and synthon choice from the virtual combinatorial library in solution. PMID:26175900

  8. Energy level alignment and molecular conformation at rubrene/Ag interfaces: Impact of contact contaminations on the interfaces

    NASA Astrophysics Data System (ADS)

    Sinha, Sumona; Wang, C.-H.; Mukherjee, M.

    2017-07-01

    This paper addresses the impact of electrode contaminations on the interfacial energy level alignment, the molecular conformation, orientation and surface morphology deposited organic film at organic semiconductor/noble metal interfaces by varying of film thickness from sub-monolayer to multilayer, which currently draws significant attention with regard to its application in organic electronics. The UHV clean Ag and unclean Ag were employed as substrate whereas rubrene was used as an organic semiconducting material. The photoelectron spectroscopy (XPS and UPS) was engaged to investigate the evolution of interfacial energetics; polarization dependent near edge x-ray absorption fine structure spectroscopy (NEXAFS) was employed to understand the molecular conformation as well as orientation whereas atomic force microscopy (AFM) was used to investigate the surface morphologies of the films. The adventitious contamination layer was acted as a spacer layer between clean Ag substrate surface and rubrene molecular layer. As a consequence, hole injection barrier height, interface dipole as well as molecular-conformation, molecular-orientation and surface morphology of rubrene thin films were found to depend on the cleanliness of Ag substrate. The results have important inferences about the understanding of the impact of substrate contamination on the energy level alignment, the molecular conformation as well as orientation and surface morphology of deposited rubrene thin film at rubrene/Ag interfaces and are beneficial for the improvement of the device performance.

  9. Molecular conformation-controlled vesicle/micelle transition of cationic trimeric surfactants in aqueous solution.

    PubMed

    Wu, Chunxian; Hou, Yanbo; Deng, Manli; Huang, Xu; Yu, Defeng; Xiang, Junfeng; Liu, Yu; Li, Zhibo; Wang, Yilin

    2010-06-01

    Two star-like trimeric cationic surfactants with amide groups in spacers, tri(dodecyldimethylammonioacetoxy)diethyltriamine trichloride (DTAD) and tri(dodecyldimethylammonioacetoxy)tris(2-aminoethyl)amine trichloride (DDAD), have been synthesized, and the aggregation behavior of the surfactants in aqueous solution has been investigated by surface tension, electrical conductivity, isothermal titration microcalorimetry, dynamic light scattering, cryogenic transmission electron microscopy, and NMR techniques. Typically, both the surfactants form vesicles just above critical aggregation concentration (CAC), and then the vesicles transfer to micelles gradually with an increase of the surfactant concentration. It is approved that the conformation of the surfactant molecules changes in this transition process. Just above the CAC, the hydrophobic chains of the surfactant molecules pack more loosely because of the rigid spacer and intramolecular electrostatic repulsion in the three-charged headgroup. With the increase of the surfactant concentration, hydrophobic interaction becomes strong enough to pack the hydrophobic tails tightly and turn the molecular conformation into a pyramid-like shape, thus leading to the vesicle to micelle transition.

  10. Allosteric Regulation Points Control the Conformational Dynamics of the Molecular Chaperone Hsp90.

    PubMed

    Rehn, Alexandra; Moroni, Elisabetta; Zierer, Bettina K; Tippel, Franziska; Morra, Giulia; John, Christine; Richter, Klaus; Colombo, Giorgio; Buchner, Johannes

    2016-11-06

    Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone responsible for the activation, maturation, and trafficking of several hundred client proteins in the cell. It is well known that (but not understood how) residues far away from Hsp90's nucleotide binding pocket can regulate its ATPase activity, a phenomenon called allosteric regulation. Here, the computational design of allosteric mutations was combined with in vitro and in vivo experiments to unravel nucleotide-responsive hot spots in the regulation of Hsp90. With this approach, we identified both activating and inhibiting regulation points and show that changes in those amino acids affect the conformational dynamics and ATPase activity of Hsp90 in vitro. Our observations that activating mutations loosen and inhibiting mutations rigidify the protein explain for the first time how Hsp90 changes in response to allosteric mutations. Additionally, mutations of these allosteric regulation points can be controlled by the interplay with Hsp90 co-chaperones, thus providing cells with an efficient mechanism of modifying Hsp90's intrinsic properties via different layers of regulation. Altogether, our results show that a framework for transmitting conformational information exists in the Hsp90 structure. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations.

    PubMed

    Miettinen, Markus S; Knecht, Volker; Monticelli, Luca; Ignatova, Zoya

    2012-08-30

    Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form β-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q40) revealed that steric zipper or nanotube-like structures (β-nanotube or β-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to β-hairpin-based (β-sheet and β-sheetstack) or α-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism.

  12. The molecular structure and conformational composition of epichlorohydrin as determined by gas phase electron diffraction

    NASA Astrophysics Data System (ADS)

    Shen, Quang

    1985-09-01

    The molecular structure of gaseous epichlorohydrin has been investigated using electron diffraction data obtained at 67°C. The conformational composition at this temperature is such that the molecules exist predominantly in a gauche-2 conformer (where the CCl bond is 160° away from the CO) bond). Refinements showed that 33% (σ = 4) of the molecule exist in the gauche-1 form. The important distances ( rg) and angle (∠α) with the associated uncertainties are r(CH) = 1.095(5) Å, r(CO) = 1.442(3) Å, r(CC) = 1.475(8) Å, r(CC M) = 1.523(7) Å, r(CCl) = 1.788(2) Å, ∠CCO = 114° (1), ∠CCC M = 119°(1), ∠ClCC = 108.9° (7), and Tau(ClCCO) = -150°(10) ( gauche-2) and Tau(ClCCO) = 78° (10) ( gauche-1).

  13. Molecular conformation of a peptide fragment of transthyretin in an amyloid fibril

    PubMed Central

    Jaroniec, Christopher P.; MacPhee, Cait E.; Astrof, Nathan S.; Dobson, Christopher M.; Griffin, Robert G.

    2002-01-01

    The molecular conformation of peptide fragment 105–115 of transthyretin, TTR(105–115), previously shown to form amyloid fibrils in vitro, has been determined by magic-angle spinning solid-state NMR spectroscopy. 13C and 15N linewidth measurements indicate that TTR(105–115) forms a highly ordered structure with each amino acid in a unique environment. 2D 13C-13C and 15N-13C-13C chemical shift correlation experiments, performed on three fibril samples uniformly 13C,15N-labeled in consecutive stretches of 4 aa, allowed the complete sequence-specific backbone and side-chain 13C and 15N resonance assignments to be obtained for residues 105–114. Analysis of the 15N, 13CO, 13Cα, and 13Cβ chemical shifts allowed quantitative predictions to be made for the backbone torsion angles φ and ψ. Furthermore, four backbone 13C–15N distances were determined in two selectively 13C,15N-labeled fibril samples by using rotational-echo double-resonance NMR. The results show that TTR(105–115) adopts an extended β-strand conformation that is similar to that found in the native protein except for substantial differences in the vicinity of the proline residue. PMID:12481032

  14. A molecular modeling approach to understand the structure and conformation relationship of (GlcpA)Xylan.

    PubMed

    Guo, Qingbin; Kang, Ji; Wu, Yan; Cui, Steve W; Hu, Xinzhong; Yada, Rickey Y

    2015-12-10

    The structure and conformation relationships of a heteropolysaccharide (GlcpA)Xylan in terms of various molecular weights, Xylp/GlcpA ratio and the distribution of GlcpA along xylan chain were investigated using computer modeling. The adiabatic contour maps of xylobiose, XylpXylp(GlcpA) and (GlcpA)XylpXylp(GlcpA) indicated that the insertion of the side group (GlcpA) influenced the accessible conformational space of xylobiose molecule. RIS-Metropolis Monte Carlo method indicated that insertion of GlcpA side chain induced a lowering effect of the calculated chain extension at low GlcpA:Xylp ratio (GlcpA:Xylp = 1:3). The chain, however, became extended when the ratio of GlcpA:Xylp above 2/3. It was also shown that the spatial extension of the polymer chains was dependent on the distribution of side chain: the random distribution demonstrated the most flexible structure compared to block and alternative distribution. The present studies provide a unique insight into the dependence of both side chain ratio and distribution on the stiffness and flexibility of various (GlcpA)Xylan molecules.

  15. Unravelling the conformational dynamics of the aqueous alanine dipeptide with first-principle molecular dynamics.

    PubMed

    Gaigeot, M-P

    2009-07-30

    First principle DFT-based molecular dynamics simulations are performed in order to bring new insights into the conformational dynamics of the alanine dipeptide analogue Ac-Ala-NHMe (with methyl group caps at the extremities) immersed in liquid water at ambient temperature. Two simulations have been run for a total of 100 ps, which allows for a relevant statistical sampling of the phase space, at the ab initio level. PII-beta equilibrium and (PII-beta)-alphaR conformational interconversions are obtained, without a free-energy barrier for the Phi angle and with a rather low barrier of 2-3 kcal/mol for the Psi angle, easily overcome from solute-solvent energy transfers. We furthermore give first insights into the rather strong zwitterionic character of the peptide bonds of the dipeptide when immersed in the liquid. The structural and zwitterionic properties extracted from first-principle dynamics in the liquid phase will be useful as benchmarks for force field developments.

  16. Molecular modeling of sigma 1 receptor ligands: a model of binding conformational and electrostatic considerations.

    PubMed

    Gund, Tamara M; Floyd, Jie; Jung, Dawoon

    2004-01-01

    We have performed molecular modeling studies on several sigma 1 specific ligands, including PD144418, spipethiane, haloperidol, pentazocine, and others to develop a pharmacophore for sigma 1 receptor-ligand binding, under the assumption that all the compounds interact at the same receptor binding site. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Superposition of active molecules gave the coordinates of the hypothetical 5-point sigma 1 pharmacophore, as follows: R1 (0.85, 7.26, 0.30); R2 (5.47, 2.40, -1.51); R3 (-2.57, 4.82, -7.10); N (-0.71, 3.29, -6.40); carbon centroid (3.16, 4.83, -0.60), where R1, R2 were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor; and R3 represents a hydrogen bond between the nitrogen atom and the receptor. Additional analyses were used to describe secondary binding sites to electronegative groups such as oxygen or sulfur atom. Those coordinates are (2.34, 5.08, -4.18). The model was verified by fitting other sigma 1 receptor ligands. This model may be used to search conformational databases for other possibly active ligands. In conjunction with rational drug design techniques the model may be useful in design and synthesis of novel sigma 1 ligands of high selectivity and potency. Calculations were performed using Sybyl 6.5.

  17. Brownian molecular dynamics simulation on self-assembly behavior of diblock copolymers: influence of chain conformation.

    PubMed

    Lin, Shaoliang; He, Xiaohua; Li, Yongliang; Lin, Jiaping; Nose, Takuhei

    2009-10-22

    Brownian molecular dynamic simulations are applied on the self-assembly behavior of AB-type diblock copolymers. The influence of chain conformation of core-forming A-block changing from rigid to flexible on the aggregation structure formed by AB copolymers is investigated. It is found that at a high rigid fraction f(R) of A-block, a disk structure can be formed at a high aggregation interaction epsilon(AA) of A-bead pairs because of the tendency of orientational packing of rigid portion within the aggregate core. Transitions of aggregation structure from disk to string, further to small aggregates, and to unimers are observed with decreasing epsilon(AA). The packing of A-blocks becomes more random at relatively lower values of f(R), resulting in the formation of spherical structure. The region of string becomes narrower while the regions of the small aggregates and sphere become wider as decreasing f(R). Meanwhile, the onsets of string, disk, and sphere formation move to higher epsilon(AA). The phase diagrams for the influences of rigid potion location within the A-block and the chain rigidity of the A-block are mapped. The comparison of simulation results with existing experimental observations is also presented. Our simulation results tend to bridge a gap of different micellization behaviors between rod-coil block copolymers and coil-coil block copolymers and extend to investigate chain conformation influence on phase diagram.

  18. FAST TRACK COMMUNICATION: Conformation dependence of molecular conductance: chemistry versus geometry

    NASA Astrophysics Data System (ADS)

    Finch, Christopher M.; Sirichantaropass, Skon; Bailey, Steven W.; Grace, Iain M.; García-Suárez, Víctor M.; Lambert, Colin J.

    2008-01-01

    Recent experiments by Venkataraman et al (2006 Nature 442 904) on a series of molecular wires with varying chemical compositions revealed a linear dependence of the conductance on cos2 θ, where θ is the angle of twist between neighbouring aromatic rings. To investigate whether or not this dependence has a more general applicability, we present a first-principles theoretical study of the transport properties of this family of molecules as a function of the chemical composition, conformation and the contact atom and geometry. If the Fermi energy EF lies within the HOMO-LUMO (highest occupied molecular orbital-lowest unoccupied molecular orbital) gap, then we reproduce the above experimental results. More generally, however, if EF is located within either the LUMO or the HOMO states, the presence of resonances destroys the linear dependence of the conductance on cos2 θ and gives rise to non-monotonic behaviour associated with the level structure of the different molecules. Our results suggest that the above experiments provide a novel method for extracting spectroscopic information about molecules contacted to electrodes.

  19. Molecular identification of Amazonian stingless bees using polymerase chain reaction single-strand conformation polymorphism.

    PubMed

    Souza, M T; Carvalho-Zilse, G A

    2014-07-25

    In countries containing a mega diversity of wildlife, such as Brazil, identifying and characterizing biological diversity is a continuous process for the scientific community, even in face of technological and scientific advances. This activity demands initiatives for the taxonomic identification of highly diverse groups, such as stingless bees, including molecular analysis strategies. This type of bee is distributed in all of the Brazilian states, with the highest species diversity being found in the State of Amazônia. However, the estimated number of species diverges among taxonomists. These bees are considered the main pollinators in the Amazon rainforest, in which they obtain food and shelter; however, their persistence is constantly threatened by deforestation pressure. Hence, it is important to classify the number and abundance of bee specie, to measure their decline and implement meaningful, priority conservation strategies. This study aims to maximize the implementation of more direct, economic and successful techniques for the taxonomic identification of stingless bees. Specifically, the genes 16S rRNA and COI from mitochondrial DNA were used as molecular markers to differentiate 9 species of Amazonian stingless bees based on DNA polymorphism, using the polymerase chain reaction-single-strand conformation polymorphism technique. We registered different, exclusive SSCP haplotypes for both genes in all species analyzed. These results demonstrate that SSCP is a simple and cost-effective technique that is applicable to the molecular identification of stingless bee species.

  20. Water-mediated conformational transitions in nicotinic receptor M2 helix bundles: a molecular dynamics study.

    PubMed

    Sankararamakrishnan, R; Sansom, M S

    1995-12-27

    The ion channel of the nicotinic acetylcholine receptor is a water-filled pore formed by five M2 helix segments, one from each subunit. Molecular dynamics simulations on bundles of five M2 alpha 7 helices surrounding a central column of water and with caps of water molecules at either end of the pore have been used to explore the effects of intrapore water on helix packing. Interactions of water molecules with the N-terminal polar sidechains lead to a conformational transition from right- to left-handed supercoils during these stimulations. These studies reveal that the pore formed by the bundle of M2 helices is flexible. A structural role is proposed for water molecules in determining the geometry of bundles of isolated pore-forming helices.

  1. Influence of Molecular Conformations and Microstructure on the Optoelectronic Properties of Conjugated Polymers

    PubMed Central

    Botiz, Ioan; Stingelin, Natalie

    2014-01-01

    It is increasingly obvious that the molecular conformations and the long-range arrangement that conjugated polymers can adopt under various experimental conditions in bulk, solutions or thin films, significantly impact their resulting optoelectronic properties. As a consequence, the functionalities and efficiencies of resulting organic devices, such as field-effect transistors, light-emitting diodes, or photovoltaic cells, also dramatically change due to the close structure/property relationship. A range of structure/optoelectronic properties relationships have been investigated over the last few years using various experimental and theoretical methods, and, further, interesting correlations are continuously revealed by the scientific community. In this review, we discuss the latest findings related to the structure/optoelectronic properties interrelationships that exist in organic devices fabricated with conjugated polymers in terms of charge mobility, absorption, photoluminescence, as well as photovoltaic properties. PMID:28788568

  2. Generation and enumeration of compact conformations on the two-dimensional triangular and three-dimensional fcc lattices

    NASA Astrophysics Data System (ADS)

    Peto, Myron; Sen, Taner Z.; Jernigan, Robert L.; Kloczkowski, Andrzej

    2007-07-01

    We enumerated all compact conformations within simple geometries on the two-dimensional (2D) triangular and three-dimensional (3D) face centered cubic (fcc) lattice. These compact conformations correspond mathematically to Hamiltonian paths and Hamiltonian circuits and are frequently used as simple models of proteins. The shapes that were studied for the 2D triangular lattice included m ×n parallelograms, regular equilateral triangles, and various hexagons. On the 3D fcc lattice we generated conformations for a limited class of skewed parallelepipeds. Symmetries of the shape were exploited to reduce the number of conformations. We compared surface to volume ratios against protein length for compact conformations on the 3D cubic lattice and for a selected set of real proteins. We also show preliminary work in extending the transfer matrix method, previously developed by us for the 2D square and the 3D cubic lattices, to the 2D triangular lattice. The transfer matrix method offers a superior way of generating all conformations within a given geometry on a lattice by completely avoiding attrition and reducing this highly complicated geometrical problem to a simple algebraic problem of matrix multiplication.

  3. Generation and enumeration of compact conformations on the two-dimensional triangular and three-dimensional fcc lattices.

    PubMed

    Peto, Myron; Sen, Taner Z; Jernigan, Robert L; Kloczkowski, Andrzej

    2007-07-28

    We enumerated all compact conformations within simple geometries on the two-dimensional (2D) triangular and three-dimensional (3D) face centered cubic (fcc) lattice. These compact conformations correspond mathematically to Hamiltonian paths and Hamiltonian circuits and are frequently used as simple models of proteins. The shapes that were studied for the 2D triangular lattice included mxn parallelograms, regular equilateral triangles, and various hexagons. On the 3D fcc lattice we generated conformations for a limited class of skewed parallelepipeds. Symmetries of the shape were exploited to reduce the number of conformations. We compared surface to volume ratios against protein length for compact conformations on the 3D cubic lattice and for a selected set of real proteins. We also show preliminary work in extending the transfer matrix method, previously developed by us for the 2D square and the 3D cubic lattices, to the 2D triangular lattice. The transfer matrix method offers a superior way of generating all conformations within a given geometry on a lattice by completely avoiding attrition and reducing this highly complicated geometrical problem to a simple algebraic problem of matrix multiplication.

  4. Conformational Melding Permits a Conserved Binding Geometry in TCR Recognition of Foreign and Self Molecular Mimics

    SciTech Connect

    Borbulevych, Oleg Y.; Piepenbrink, Kurt H.; Baker, Brian M.

    2012-03-16

    Molecular mimicry between foreign and self Ags is a mechanism of TCR cross-reactivity and is thought to contribute to the development of autoimmunity. The {alpha}{beta} TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found in our study that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics and that in contrast with other recent structures of TCRs with self Ags, A6 engages the HuD Ag with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity toward HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD-HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/nonself cross-reactivity and illustrate how low peptide-MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.

  5. Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations.

    PubMed

    Sixto-López, Yudibeth; Bello, Martiniano; Rodríguez-Fonseca, Rolando Alberto; Rosales-Hernández, Martha Cecilia; Martínez-Archundia, Marlet; Gómez-Vidal, José Antonio; Correa-Basurto, José

    2016-09-23

    Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported. Clustering analysis allowed identifying the most populated conformers present during the MD simulation, which were used as starting models to perform docking calculations with five DD2-HDAC6 inhibitors: Cay10603 (CAY), Rocilinostat (RCT), Tubastatin A (TBA), Tubacin (TBC), and Nexturastat (NXT), and then were also submitted to 100-ns-long MD simulations. Docking calculations revealed that the five inhibitors bind at the DD2-HDAC6 binding site with the lowest binding free energy, the same binding mode is maintained along the 100-ns-long MD simulations. Overall, our results provide structural information about the molecular flexibility of apo and holo DD2-HDAC6 states as well as insight of the map of interactions between DD2-HDAC6 and five well-known DD2-HDAC6 inhibitors allowing structural details to guide the drug design. Finally, we highlight the importance of combining different theoretical approaches to provide suitable structural models for structure-based drug design.

  6. Molecular Dynamics Simulations Show That Conformational Selection Governs the Binding Preferences of Imatinib for Several Tyrosine Kinases*

    PubMed Central

    Aleksandrov, Alexey; Simonson, Thomas

    2010-01-01

    Tyrosine kinases transmit cellular signals through a complex mechanism, involving their phosphorylation and switching between inactive and active conformations. The cancer drug imatinib binds tightly to several homologous kinases, including Abl, but weakly to others, including Src. Imatinib specifically targets the inactive, so-called “DFG-out” conformation of Abl, which differs from the preferred, “DFG-in” conformation of Src in the orientation of a conserved Asp-Phe-Gly (DFG) activation loop. However, recent x-ray structures showed that Src can also adopt the DFG-out conformation and uses it to bind imatinib. The Src/Abl-binding free energy difference can thus be decomposed into two contributions. Contribution i measures the different protein-imatinib interactions when either kinase is in its DFG-out conformation. Contribution ii depends on the ability of imatinib to select or induce this conformation, i.e. on the relative stabilities of the DFG-out and DFG-in conformations of each kinase. Neither contribution has been measured experimentally. We use molecular dynamics simulations to show that contribution i is very small, 0.2 ± 0.6 kcal/mol; imatinib interactions are very similar in the two kinases, including long range electrostatic interactions with the imatinib positive charge. Contribution ii, deduced using the experimental binding free energy difference, is much larger, 4.4 ± 0.9 kcal/mol. Thus, conformational selection, easy in Abl, difficult in Src, underpins imatinib specificity. Contribution ii has a simple interpretation; it closely approximates the stability difference between the DFG-out and DFG-in conformations of apo-Src. Additional calculations show that conformational selection also governs the relative binding of imatinib to the kinases c-Kit and Lck. These results should help clarify the current framework for engineering kinase signaling. PMID:20200154

  7. Conformational Equilibrium of N-Myristoylated cAMP-Dependent Protein Kinase A by Molecular Dynamics Simulations

    PubMed Central

    Cembran, Alessandro; Masterson, Larry R.; McClendon, Christopher L.; Taylor, Susan S.; Gao, Jiali; Veglia, Gianluigi

    2013-01-01

    The catalytic subunit of protein kinase A (PKA-C) is subject to several post- or co-translational modifications that regulate its activity both spatially and temporally. Among those, N-myristoylation increases the kinase affinity for membranes and might also be implicated in substrate recognition and allosteric regulation. Here, we investigated the effects of N-myristoylation on the structure, dynamics, and conformational equilibrium of PKA-C using atomistic molecular dynamics simulations. We found that the myristoyl group inserts into the hydrophobic pocket and leads to a tighter packing of the A-helix against the core of the enzyme. As a result, the A-helix conformational dynamics are reduced and its motions are more coupled with the active site. Our simulations suggest that cation-π interactions between W30, R190, and R93 are responsible for coupling these motions. Two major conformations of the myristoylated N-terminus are the most populated: a long loop (LL conformation), similar to PDB:1CMK, and a helix-turn-helix (HTH conformation), similar to PDB:4DFX, which shows stronger coupling between the conformational dynamics observed at the A-helix and active site. The HTH conformation is stabilized by S10 phosphorylation of the kinase via ionic interactions between the protonated amine of K7 and the phosphate group on S10, further enhancing the dynamic coupling to the active site. These results support a role of N-myristoylation in the allosteric regulation of PKA-C. PMID:23205665

  8. Molecular conformation of the full-length tumor suppressor NF2/Merlin—a small angle neutron scattering study

    PubMed Central

    Khajeh, Jahan Ali; Ju, Jeong Ho; Atchiba, Moussoubaou; Allaire, Marc; Stanley, Christopher; Heller, William T.; Callaway, David J.E.; Bu, Zimei

    2014-01-01

    Summary The tumor suppressor protein Merlin inhibits cell proliferation upon establishing cell-cell contacts. Because Merlin has high sequence similarity to the Ezrin-Radixin-Moesin (ERM) family of proteins, the structural model of ERM protein autoinhibition and cycling between closed/resting and open/active conformational states is often employed to explain Merlin function. However, recent biochemical studies suggest alternative molecular models of Merlin function. Here, we have determined the low resolution molecular structure and binding activity of Merlin and a Merlin(S518D) mutant that mimics the inactivating phosphorylation at S518 using small angle neutron scattering (SANS) and binding experiments. SANS shows that in solution both Merlin and Merlin(S518D) adopt a closed conformation, but binding experiments indicate that a significant fraction of either Merlin or Merlin(S518D) is capable of binding to the target protein NHERF1. Upon binding to the phosphatidylinositol 4,5-bisphosphate lipid, the wild-type Merlin adopts a more open conformation than in solution, but Merlin(S518D) remains in a closed conformation. This study supports a rheostat model of Merlin in NHERF1 binding, and contributes to resolve a controversy about the molecular conformation and binding activity of Merlin. PMID:24882693

  9. Existence and blowup results for asymptotically Euclidean initial data sets generated by the conformal method

    NASA Astrophysics Data System (ADS)

    Dilts, James; Isenberg, James

    2016-11-01

    For each set of (freely chosen) seed data, the conformal method reduces the Einstein constraint equations to a system of elliptic equations, the conformal constraint equations. We prove an admissibility criterion, based on a (conformal) prescribed scalar curvature problem, which provides a necessary condition on the seed data for the conformal constraint equations to (possibly) admit a solution. We then consider sets of asymptotically Euclidean (AE) seed data for which solutions of the conformal constraint equations exist, and examine the blowup properties of these solutions as the seed data sets approach sets for which no solutions exist. We also prove that there are AE seed data sets which include a Yamabe nonpositive metric and lead to solutions of the conformal constraints. These data sets allow the mean curvature function to have 0's.

  10. a Combined Molecular Dynamics and NMR Spectroscopic Protocol for the Conformational Analysis of Oligosaccharides.

    NASA Astrophysics Data System (ADS)

    Varma, Vikram

    A combined experimental and theoretical protocol for the conformational analysis of oligosaccharides is presented. Three disaccharides, methyl alpha - scD-mannopyranosyl-(1 to 3)-alpha- scD-mannopyranoside, methyl beta- scD-galactopyranosyl-(1 to 4)-beta- scD-glucopyranoside, and propyl beta- scD-2-acetamido -2-deoxy glucopyranosyl-(1 to 3)- alpha- scL-rhamnopyranoside, are used to evaluate a protocol for conformational analysis that makes use of molecular dynamics calculations with the CHARMM force field. Dynamics trajectories computed in vacuo and in water are used to calculate time-averaged NMR parameters such as spin-lattice relaxation times (T_1 ), Nuclear Overhauser Enhancements (NOE), and heteronuclear spin-spin coupling constants (^3J _{rm CH}). The calculated NMR parameters are then compared to experimental values and used to evaluate the computational procedure. The energetically accessible conformations are effectively sampled by the simulations. The method has been extended to the conformational analysis of higher-order oligosaccharides corresponding to the cell-wall polysaccharide of the Streptococcus Group A, and the Shigella flexneri Y O-antigen. The Streptococcus Group A cell-wall polysaccharide is comprised of a backbone of rhamnopyranosyl units connected by alternating alpha- scL-(1 to 3) and alpha- scL -(1 to 2) linkages, to which are attached N-acetyl-beta- scD-glucosamine ( beta- scD-GlcpNAc) residues at the 3 positions of the rhamnose backbone.rm A&rm B^'qquad A^'& rm Bqquad Acr[{-alpha}{-}L{-}Rha {it p}{-}(1to2){-alpha }{-}L{-}Rha{it p} {-}(1to3){-alpha}{ -}L{-}Rha{it p}-(1to2) -alpha-L-Rha{it p}{-}(1 to3){-alpha}{-}L{- }Rha{it p}{-}cr&uparrow(1 to3)&uparrow(1to3)crbeta {-}D{-}&rm Glc{it p }NAcqquadbeta{-}D{-}& rm Glc{it p}NAccr&rm C ^'&rm C] A branched trisaccharide (A^' -(C)B), a tetrasaccharide (A^' -(C)B-A), a pentasaccharide (C^' -B^'-A ^'-(C)B), and two hexasaccharides (C^'-B^ '-A^' -(C)B-A) and (A-(C^')B ^'-A^' -(C)B), have been chosen

  11. Effect of urea on peptide conformation in water: molecular dynamics and experimental characterization.

    PubMed

    Caballero-Herrera, Ana; Nordstrand, Kerstin; Berndt, Kurt D; Nilsson, Lennart

    2005-08-01

    Molecular dynamics simulations of a ribonuclease A C-peptide analog and a sequence variant were performed in water at 277 and 300 K and in 8 M urea to clarify the molecular denaturation mechanism induced by urea and the early events in protein unfolding. Spectroscopic characterization of the peptides showed that the C-peptide analog had a high alpha-helical content, which was not the case for the variant. In the simulations, interdependent side-chain interactions were responsible for the high stability of the alpha-helical C-peptide analog in the different solvents. The other peptide displayed alpha-helical unwinding that propagated cooperatively toward the N-terminal. The conformations sampled by the peptides depended on their sequence and on the solvent. The ability of water molecules to form hydrogen bonds to the peptide as well as the hydrogen bond lifetimes increased in the presence of urea, whereas water mobility was reduced near the peptide. Urea accumulated in excess around the peptide, to which it formed long-lived hydrogen bonds. The unfolding mechanisms induced by thermal denaturation and by urea are of a different nature, with urea-aqueous solutions providing a better peptide solvation than pure water. Our results suggest that the effect of urea on the chemical denaturation process involves both the direct and indirect mechanisms.

  12. Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics

    PubMed Central

    Lovera, Silvia; Morando, Maria; Pucheta-Martinez, Encarna; Martinez-Torrecuadrada, Jorge L.; Saladino, Giorgio; Gervasio, Francesco L.

    2015-01-01

    Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated. Here by using long molecular dynamics simulations and large-scale free energy calculations complemented by in vitro mutagenesis and microcalorimetry experiments, we model the effect of several widespread drug-resistant mutations of Abl. By comparing the conformational free energy landscape of the mutants with those of the wild-type tyrosine kinases we clarify their mode of action. It involves significant and complex changes in the inactive-to-active dynamics and entropy/enthalpy balance of two functional elements: the activation-loop and the conserved DFG motif. What is more the T315I gatekeeper mutant has a significant impact on the binding mechanism itself and on the binding kinetics. PMID:26606374

  13. Mechanical response and conformational changes of alpha-actinin domains during unfolding: a molecular dynamics study.

    PubMed

    Soncini, Monica; Vesentini, Simone; Ruffoni, Davide; Orsi, Mario; Deriu, Marco A; Redaelli, Alberto

    2007-11-01

    Alpha-actinin is a cytoskeleton-binding protein involved in the assembly and regulation of the actin filaments. In this work molecular dynamics method was applied to investigate the mechanical behaviour of the human skeletal muscle alpha-actinin. Five configurations were unfolded at an elongation speed of 0.1 nm/ps in order to investigate the conformational changes occurring during the extension process. Moreover, a sensitivity analysis at different velocities was performed for one of the R2-R3 spectrin-like repeat configuration extracted in order to evaluate the effect of the pulling speed on the mechanical behaviour of the molecule. Two different behaviours were recognized with respect to the pulling speed. In particular, at speed higher than 0.025 nm/ps a continuous rearrangement without evident force peaks was obtained, on the contrary at lower speed evident peaks in the range 500-750 pN were detected. R3 repeat resulted more stable than R2 during mechanical unfolding, due to the lower hydrophobic surface available to the solvent. The characterization of the R2-R3 units can be useful for the development of cytoskeleton network models based on stiffness values obtained by analyses performed at the molecular level.

  14. Charge-dependent conformations and dynamics of pamam dendrimers revealed by neutron scattering and molecular dynamics

    NASA Astrophysics Data System (ADS)

    Wu, Bin

    Neutron scattering and fully atomistic molecular dynamics (MD) are employed to investigate the structural and dynamical properties of polyamidoamine (PAMAM) dendrimers with ethylenediamine (EDA) core under various charge conditions. Regarding to the conformational characteristics, we focus on scrutinizing density profile evolution of PAMAM dendrimers as the molecular charge of dendrimer increases from neutral state to highly charged condition. It should be noted that within the context of small angle neutron scattering (SANS), the dendrimers are composed of hydrocarbon component (dry part) and the penetrating water molecules. Though there have been SANS experiments that studied the charge-dependent structural change of PAMAM dendrimers, their results were limited to the collective behavior of the aforementioned two parts. This study is devoted to deepen the understanding towards the structural responsiveness of intra-molecular polymeric and hydration parts separately through advanced contrast variation SANS data analysis scheme available recently and unravel the governing principles through coupling with MD simulations. Two kinds of acids, namely hydrochloric and sulfuric acids, are utilized to tune the pH condition and hence the molecular charge. As far as the dynamical properties, we target at understanding the underlying mechanism that leads to segmental dynamic enhancement observed from quasielstic neutron scattering (QENS) experiment previously. PAMAM dendrimers have a wealth of potential applications, such as drug delivery agency, energy harvesting medium, and light emitting diodes. More importantly, it is regarded as an ideal system to test many theoretical predictions since dendrimers conjugate both colloid-like globular shape and polymer-like flexible chains. This Ph.D. research addresses two main challenges in studying PAMAM dendrimers. Even though neutron scattering is an ideal tool to study this PAMAM dendrimer solution due to its matching temporal and

  15. Modeling of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one derivatives by several conformational searching tools and molecular docking.

    PubMed

    Goodarzi, Mohammad; Bora, Alina; Borota, Ana; Funar-Timofei, Simona; Avram, Sorin; Heyden, Yvan Vander

    2013-01-01

    Neutrophil elastase, a serine proteinase from the chymotrypsin family, has been the object of comprehensive experimental and theoretical studies to develop efficient human neutrophil elastase inhibitors. The serine protease has been linked to the pathology of a variety of inflammatory diseases, making it an attractive target for the development of anti-inflammatory compounds. In this work, we have built a common binding model of the 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one derivatives into the human neutrophil elastase binding site. This was accomplished through a comparative conformational analysis (using OMEGA, HYPERCHEM, and MOPAC software) of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one inhibitors followed by rigid and flexible molecular docking (by the FRED and GLIDE programs) into the target protein. We conclude that OMEGA software generates the most representative conformers to model the protein-ligand interactions.

  16. Coupled binding-bending-folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations.

    PubMed

    van der Vaart, Arjan

    2015-05-01

    Protein-DNA binding often involves dramatic conformational changes such as protein folding and DNA bending. While thermodynamic aspects of this behavior are understood, and its biological function is often known, the mechanism by which the conformational changes occur is generally unclear. By providing detailed structural and energetic data, molecular dynamics simulations have been helpful in elucidating and rationalizing protein-DNA binding. This review will summarize recent atomistic molecular dynamics simulations of the conformational dynamics of DNA and protein-DNA binding. A brief overview of recent developments in DNA force fields is given as well. Simulations have been crucial in rationalizing the intrinsic flexibility of DNA, and have been instrumental in identifying the sequence of binding events, the triggers for the conformational motion, and the mechanism of binding for a number of important DNA-binding proteins. Molecular dynamics simulations are an important tool for understanding the complex binding behavior of DNA-binding proteins. With recent advances in force fields and rapid increases in simulation time scales, simulations will become even more important for future studies. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014. Published by Elsevier B.V.

  17. Conformations of some lower-size large-ring cyclodextrins derived from conformational search with molecular dynamics and principal component analysis

    NASA Astrophysics Data System (ADS)

    Ivanov, Petko

    2012-02-01

    Computational studies were conducted on the conformations of some lower-size large-ring cyclodextrins, CDn (n = 11, 12, 13, 15, 16, 17). Principal component analysis (PCA) was applied for post-processing of trajectories from conformational search based on 100.0 ns molecular dynamics (MD) simulations. The dominant PCA modes for concerted motions of the macroring atoms were monitored in a lower-dimensions subspace. The first six lowest indexed principal components contribute more than 90% of the total atomic motions in all cases, with about 70% (CD12) to 90% (CD17) contribution coming from the three highest-eigenvalue principal components. Representative average geometries of the cyclodextrin macrorings were also obtained for the whole simulation and for the ten 10.0 ns time intervals of the simulation. We concluded that the whole set of structures could be sorted into two clearly distinguished groups, separated by the figure-eight conformation of CD14: (i) open bent boat-like macrorings (CD11 to CD13), and (ii) two winded single helical strands (an anti-parallel double helix with foldbacks at each end), CD15 to CD17, shaped as number eight for the odd-number-residues cases, CD15 and CD17. CD13 and CD14 mark the borderline between lower and higher flexibilities of the lower-size LR-CDs macrorings.

  18. Exploring the structure and conformational landscape of human leptin. A molecular dynamics approach.

    PubMed

    Chimal-Vega, Brenda; Paniagua-Castro, Norma; Carrillo Vazquez, Jonathan; Rosas-Trigueros, Jorge L; Zamorano-Carrillo, Absalom; Benítez-Cardoza, Claudia G

    2015-11-21

    Leptin is a hormone that regulates energy homeostasis, inflammation, hematopoiesis and immune response, among other functions (Houseknecht et al., 1998; Zhang et al., 1995; Paz-Filho et al., 2010). To obtain its crystallographic structure, it was necessary to substitute a tryptophan for a glutamic acid at position 100, thus creating a mutant leptin that has been reported to have biological activity comparable to the activity of the wild type but that crystallizes more readily. Here, we report a comparative study of the conformational space of WT and W100E leptin using molecular dynamics simulations performed at 300, 400, and 500 K. We detected differences between the interactions of the two proteins with local and distal effects, resulting in changes in the conformation, accessible surface area, compactness, electrostatic potential and dynamic behavior. Additionally, the series of unfolding events that occur when leptin is subjected to high temperature differs for the two constructs. We observed that both proteins are mostly unstructured after 20 ns of MD simulation at 500 K. However, WT leptin maintains a significant amount of secondary structure in helix α2, while the most stable region of W100E leptin is helix α3. Furthermore, we found that the region between residues 25 and 42 might adopt interconverting secondary structures ranging from α-helices and random coils to β-strand structures. Thus, this region can be considered an intrinsically disordered region. This atomistic description supports our understanding of leptin signaling and consequently might facilitate the use of leptin in treatments for the pathophysiologies in which it is implicated.

  19. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

    SciTech Connect

    McTigue, Michele; Murray, Brion William; Chen, Jeffrey H.; Deng, Ya-Li; Solowiej, James; Kania, Robert S.

    2012-09-17

    We performed analyses of compounds in clinical development which have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193–1939]. To elucidate how fundamental drug potency–efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug–kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug–kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. Finally, the identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.

  20. Conformational Change in Molecular Assembly of Nickel(II) Tetra(n-propyl)porphycene Triggered by Potential Manipulation.

    PubMed

    Yoshimoto, Soichiro; Kawamoto, Teppei; Okawara, Toru; Hisaeda, Yoshio; Abe, Masaaki

    2016-12-27

    Metal-coordinated porphyrin and related compounds are important for developing molecular architectures that mimic enzymes. Porphycene, a structural isomer of porphyrin, has shown unique properties in semiartificial myoglobin. To explore its potential as a molecular building block, we studied the molecular assembly of nickel(II) tetra(n-propyl)porphycene (NiTPrPc), a metalloporphycene with introduced tetra n-propyl moieties, on the Au(111) electrode surface using in situ scanning tunneling microscopy. Because of the low molecular symmetry of NiTPrPc, the molecular assembly undergoes unique phase transitions due to conformational change of the n-propyl moieties. The phase transitions can be precisely controlled by the electrode potential, demonstrating that the latter can play an important role in the porphycene molecular assembly on Au surface. This new discovery indicates possible uses of this porphycene framework in molecular engineering.

  1. Electroporation-aided DNA immunization generates polyclonal antibodies against the native conformation of human endothelin B receptor.

    PubMed

    Allard, Bertrand; Priam, Fabienne; Deshayes, Frédérique; Ducancel, Frédéric; Boquet, Didier; Wijkhuisen, Anne; Couraud, Jean-Yves

    2011-09-01

    Endothelin B receptor (ET(B)R) is a G protein-coupled receptor (GPCR) specific for endothelin peptides (including endothelin-1, ET1), which mediates a variety of key physiological functions in normal tissues, such as modulation of vasomotor tone, tissue differentiation, or cell proliferation. Moreover, ET(B)R, overexpressed in various cancer cells including melanoma, has been implicated in the growth and progression of tumors, as well as in controlling T cell homing to tumors. To gather information on receptor structure and function, antibodies are generally considered choice molecular probes, but generation of such reagents against the native conformation of GPCRs is a real technical challenge. Here, we show that electroporation-aided genetic immunization, coupled to cardiotoxin pretreatment, is a simple and very efficient method to raise large amounts of polyclonal antibodies highly specific for native human ET(B)R (hET(B)R), as assessed by both flow cytometry analysis of different stably transfected cell lines and a new and rapid cell-based enzyme-linked immunosorbent assay that we also describe. The antibodies recognized two major epitopes on hET(B)R, mapped within the N-terminal extracellular domain. They were used to reveal hET(B)R on membranes of three different human melanoma cell lines, by flow cytometry and confocal microscopy, a method that we show is more relevant than mRNA polymerase chain reaction in assessing receptor expression. In addition, ET-1 partially competed with antibodies for receptor binding. The strategy described here, thus, efficiently generated new immunological tools to further analyze the role of ET(B)R under both normal and pathological conditions, including cancers. Above all, it can now be used to raise monoclonal antibodies against hET(B)R and, more generally, against GPCRs that constitute, by far, the largest reservoir of potential pharmacological targets.

  2. Molecular mechanisms for generating transmembrane proton gradients.

    PubMed

    Gunner, M R; Amin, Muhamed; Zhu, Xuyu; Lu, Jianxun

    2013-01-01

    Membrane proteins use the energy of light or high energy substrates to build a transmembrane proton gradient through a series of reactions leading to proton release into the lower pH compartment (P-side) and proton uptake from the higher pH compartment (N-side). This review considers how the proton affinity of the substrates, cofactors and amino acids are modified in four proteins to drive proton transfers. Bacterial reaction centers (RCs) and photosystem II (PSII) carry out redox chemistry with the species to be oxidized on the P-side while reduction occurs on the N-side of the membrane. Terminal redox cofactors are used which have pKas that are strongly dependent on their redox state, so that protons are lost on oxidation and gained on reduction. Bacteriorhodopsin is a true proton pump. Light activation triggers trans to cis isomerization of a bound retinal. Strong electrostatic interactions within clusters of amino acids are modified by the conformational changes initiated by retinal motion leading to changes in proton affinity, driving transmembrane proton transfer. Cytochrome c oxidase (CcO) catalyzes the reduction of O2 to water. The protons needed for chemistry are bound from the N-side. The reduction chemistry also drives proton pumping from N- to P-side. Overall, in CcO the uptake of 4 electrons to reduce O2 transports 8 charges across the membrane, with each reduction fully coupled to removal of two protons from the N-side, the delivery of one for chemistry and transport of the other to the P-side.

  3. Molecular mechanisms for generating transmembrane proton gradients

    PubMed Central

    Gunner, M.R.; Amin, Muhamed; Zhu, Xuyu; Lu, Jianxun

    2013-01-01

    Membrane proteins use the energy of light or high energy substrates to build a transmembrane proton gradient through a series of reactions leading to proton release into the lower pH compartment (P-side) and proton uptake from the higher pH compartment (N-side). This review considers how the proton affinity of the substrates, cofactors and amino acids are modified in four proteins to drive proton transfers. Bacterial reaction centers (RCs) and photosystem II (PSII) carry out redox chemistry with the species to be oxidized on the P-side while reduction occurs on the N-side of the membrane. Terminal redox cofactors are used which have pKas that are strongly dependent on their redox state, so that protons are lost on oxidation and gained on reduction. Bacteriorhodopsin is a true proton pump. Light activation triggers trans to cis isomerization of a bound retinal. Strong electrostatic interactions within clusters of amino acids are modified by the conformational changes initiated by retinal motion leading to changes in proton affinity, driving transmembrane proton transfer. Cytochrome c oxidase (CcO) catalyzes the reduction of O2 to water. The protons needed for chemistry are bound from the N-side. The reduction chemistry also drives proton pumping from N- to P-side. Overall, in CcO the uptake of 4 electrons to reduce O2 transports 8 charges across the membrane, with each reduction fully coupled to removal of two protons from the N-side, the delivery of one for chemistry and transport of the other to the P-side. PMID:23507617

  4. Exploring conformational states of the bacterial voltage-gated sodium channel NavAb via molecular dynamics simulations.

    PubMed

    Amaral, Cristiano; Carnevale, Vincenzo; Klein, Michael L; Treptow, Werner

    2012-12-26

    The X-ray structure of the bacterial voltage-gated sodium channel NavAb has been reported in a conformation with a closed conduction pore. Comparison between this structure and the activated-open and resting-closed structures of the voltage-gated Kv1.2 potassium channel suggests that the voltage-sensor domains (VSDs) of the reported structure are not fully activated. Using the aforementioned structures of Kv1.2 as templates, molecular dynamics simulations are used to identify analogous functional conformations of NavAb. Specifically, starting from the NavAb crystal structure, conformations of the membrane-bound channel are sampled along likely pathways for activation of the VSD and opening of the pore domain. Gating charge computations suggest that a structural rearrangement comparable to that occurring between activated-open and resting-closed states is required to explain experimental values of the gating charge, thereby confirming that the reported VSD structure is likely an intermediate along the channel activation pathway. Our observation that the X-ray structure exhibits a low pore domain-opening propensity further supports this notion. The present molecular dynamics study also identifies conformations of NavAb that are seemingly related to the resting-closed and activated-open states. Our findings are consistent with recent structural and functional studies of the orthologous channels NavRh, NaChBac, and NavMs and offer possible structures for the functionally relevant conformations of NavAb.

  5. Conformations of an adenine bulge in a DNA octamer and its influence on DNA structure from molecular dynamics simulations.

    PubMed Central

    Feig, M; Zacharias, M; Pettitt, B M

    2001-01-01

    Molecular dynamics simulations have been applied to the DNA octamer d(GCGCA-GAAC). d(GTTCGCGC), which has an adenine bulge at the center to determine the pathway for interconversion between the stacked and extended forms. These forms are known to be important in the molecular recognition of bulges. From a total of ~35 ns of simulation time with the most recent CHARMM27 force field a variety of distinct conformations and subconformations are found. Stacked and fully looped-out forms are in excellent agreement with experimental data from NMR and x-ray crystallography. Furthermore, in a number of conformations the bulge base associates with the minor groove to varying degrees. Transitions between many of the conformations are observed in the simulations and used to propose a complete transition pathway between the stacked and fully extended conformations. The effect on the surrounding DNA sequence is investigated and biological implications of the accessible conformational space and the suggested transition pathway are discussed, in particular for the interaction of the MS2 replicase operator RNA with its coat protein. PMID:11423420

  6. Beta-hairpin conformation of fibrillogenic peptides: structure and alpha-beta transition mechanism revealed by molecular dynamics simulations.

    PubMed

    Daidone, Isabella; Simona, Fabio; Roccatano, Danilo; Broglia, Ricardo A; Tiana, Guido; Colombo, Giorgio; Di Nola, Alfredo

    2004-10-01

    Understanding the conformational transitions that trigger the aggregation and amyloidogenesis of otherwise soluble peptides at atomic resolution is of fundamental relevance for the design of effective therapeutic agents against amyloid-related disorders. In the present study the transition from ideal alpha-helical to beta-hairpin conformations is revealed by long timescale molecular dynamics simulations in explicit water solvent, for two well-known amyloidogenic peptides: the H1 peptide from prion protein and the Abeta(12-28) fragment from the Abeta(1-42) peptide responsible for Alzheimer's disease. The simulations highlight the unfolding of alpha-helices, followed by the formation of bent conformations and a final convergence to ordered in register beta-hairpin conformations. The beta-hairpins observed, despite different sequences, exhibit a common dynamic behavior and the presence of a peculiar pattern of the hydrophobic side-chains, in particular in the region of the turns. These observations hint at a possible common aggregation mechanism for the onset of different amyloid diseases and a common mechanism in the transition to the beta-hairpin structures. Furthermore the simulations presented herein evidence the stabilization of the alpha-helical conformations induced by the presence of an organic fluorinated cosolvent. The results of MD simulation in 2,2,2-trifluoroethanol (TFE)/water mixture provide further evidence that the peptide coating effect of TFE molecules is responsible for the stabilization of the soluble helical conformation.

  7. Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution

    NASA Astrophysics Data System (ADS)

    Cairo, Raúl Ramos; Stevens, Ana María Plutín; de Oliveira, Tamires Donizeth; Batista, Alzir A.; Castellano, Eduardo E.; Duque, Julio; Soria, Delia B.; Fantoni, Adolfo C.; Corrêa, Rodrigo S.; Erben, Mauricio F.

    2017-04-01

    1-Acyl thioureas [R1C(O)NHC(S)NR2R3] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R1 = 2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, 1H and 13C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans-cis geometry of the almost planar thiourea unit is stabilized by intramolecular Nsbnd H ⋯ Odbnd C hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31 + G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular Nsbnd H ⋯ Sdbnd C hydrogen bond forming R22(8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S ⋯ H, O ⋯ H and H ⋯ H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.

  8. Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution.

    PubMed

    Cairo, Raúl Ramos; Stevens, Ana María Plutín; de Oliveira, Tamires Donizeth; Batista, Alzir A; Castellano, Eduardo E; Duque, Julio; Soria, Delia B; Fantoni, Adolfo C; Corrêa, Rodrigo S; Erben, Mauricio F

    2017-04-05

    1-Acyl thioureas [R(1)C(O)NHC(S)NR(2)R(3)] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R(1)=2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, (1)H and (13)C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans-cis geometry of the almost planar thiourea unit is stabilized by intramolecular NH⋯OC hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31+G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular NH⋯SC hydrogen bond forming R2(2)(8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S⋯H, O⋯H and H⋯H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.

  9. MS-DOCK: accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening.

    PubMed

    Sauton, Nicolas; Lagorce, David; Villoutreix, Bruno O; Miteva, Maria A

    2008-04-10

    The number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes. Performing flexible structure-based virtual screening computations on thousands of targets with millions of molecules is intractable to most laboratories nor indeed desirable. Since shape complementarity is of primary importance for most protein-ligand interactions, we have developed a tool/protocol based on rigid-body docking to select compounds that fit well into binding sites. Here we present an efficient multiple conformation rigid-body docking approach, MS-DOCK, which is based on the program DOCK. This approach can be used as the first step of a multi-stage docking/scoring protocol. First, we developed and validated the Multiconf-DOCK tool that generates several conformers per input ligand. Then, each generated conformer (bioactives and 37970 decoys) was docked rigidly using DOCK6 with our optimized protocol into seven different receptor-binding sites. MS-DOCK was able to significantly reduce the size of the initial input library for all seven targets, thereby facilitating subsequent more CPU demanding flexible docking procedures. MS-DOCK can be easily used for the generation of multi-conformer libraries and for shape-based filtering within a multi-step structure-based screening protocol in order to shorten computation times.

  10. Protonation-induced stereoisomerism in nicotine: conformational studies using classical (AMBER) and ab initio (Car-Parrinello) molecular dynamics.

    PubMed

    Hammond, Philip S; Wu, Yudong; Harris, Rebecca; Minehardt, Todd J; Car, Roberto; Schmitt, Jeffrey D

    2005-01-01

    A variety of biologically active small molecules contain prochiral tertiary amines, which become chiral centers upon protonation. S-nicotine, the prototypical nicotinic acetylcholine receptor agonist, produces two diastereomers on protonation. Results, using both classical (AMBER) and ab initio (Car-Parrinello) molecular dynamical studies, illustrate the significant differences in conformational space explored by each diastereomer. As is expected, this phenomenon has an appreciable effect on nicotine's energy hypersurface and leads to differentiation in molecular shape and divergent sampling. Thus, protonation induced isomerism can produce dynamic effects that may influence the behavior of a molecule in its interaction with a target protein. We also examine differences in the conformational dynamics for each diastereomer as quantified by both molecular dynamics methods.

  11. Conformational stability of digestion-resistant peptides of peanut conglutins reveals the molecular basis of their allergenicity

    PubMed Central

    Apostolovic, Danijela; Stanic-Vucinic, Dragana; de Jongh, Harmen H. J.; de Jong, Govardus A. H.; Mihailovic, Jelena; Radosavljevic, Jelena; Radibratovic, Milica; Nordlee, Julie A.; Baumert, Joseph L.; Milcic, Milos; Taylor, Steve L.; Garrido Clua, Nuria; Cirkovic Velickovic, Tanja; Koppelman, Stef J.

    2016-01-01

    Conglutins represent the major peanut allergens and are renowned for their resistance to gastro-intestinal digestion. Our aim was to characterize the digestion-resistant peptides (DRPs) of conglutins by biochemical and biophysical methods followed by a molecular dynamics simulation in order to better understand the molecular basis of food protein allergenicity. We have mapped proteolysis sites at the N- and C-termini and at a limited internal segment, while other potential proteolysis sites remained unaffected. Molecular dynamics simulation showed that proteolysis only occurred in the vibrant regions of the proteins. DRPs appeared to be conformationally stable as intact conglutins. Also, the overall secondary structure and IgE-binding potency of DRPs was comparable to that of intact conglutins. The stability of conglutins toward gastro-intestinal digestion, combined with the conformational stability of the resulting DRPs provide conditions for optimal exposure to the intestinal immune system, providing an explanation for the extraordinary allergenicity of peanut conglutins. PMID:27377129

  12. Two-dimensional NMR and All-atom Molecular Dynamics of Cytochrome P450 CYP119 Reveal Hidden Conformational Substates*

    PubMed Central

    Lampe, Jed N.; Brandman, Relly; Sivaramakrishnan, Santhosh; de Montellano, Paul R. Ortiz

    2010-01-01

    Cytochrome P450 enzymes are versatile catalysts involved in a wide variety of biological processes from hormonal regulation and antibiotic synthesis to drug metabolism. A hallmark of their versatility is their promiscuous nature, allowing them to recognize a wide variety of chemically diverse substrates. However, the molecular details of this promiscuity have remained elusive. Here, we have utilized two-dimensional heteronuclear single quantum coherence NMR spectroscopy to examine a series of mutants site-specific labeled with the unnatural amino acid, [13C]p-methoxyphenylalanine, in conjunction with all-atom molecular dynamics simulations to examine substrate and inhibitor binding to CYP119, a P450 from Sulfolobus acidocaldarius. The results suggest that tight binding hydrophobic ligands tend to lock the enzyme into a single conformational substate, whereas weak binding low affinity ligands bind loosely in the active site, resulting in a distribution of localized conformers. Furthermore, the molecular dynamics simulations suggest that the ligand-free enzyme samples ligand-bound conformations of the enzyme and, therefore, that ligand binding may proceed largely through a process of conformational selection rather than induced fit. PMID:20097757

  13. On the connection between nonmonotonic taste behavior and molecular conformation in solution: The case of rebaudioside-A

    NASA Astrophysics Data System (ADS)

    Chopade, Prashant D.; Sarma, Bipul; Santiso, Erik E.; Simpson, Jeffrey; Fry, John C.; Yurttas, Nese; Biermann, Kari L.; Chen, Jie; Trout, Bernhardt L.; Myerson, Allan S.

    2015-12-01

    The diterpene steviol glycoside, rebaudioside A, is a natural high potency non-caloric sweetener extracted from the leaves of Stevia rebaudiana. This compound shows a parabolic change in sweet taste intensity with temperature which contrasts with the general finding for other synthetic or natural sweeteners whose sweet taste increases with temperature. The nonmonotonic taste behavior was determined by sensory analysis using large taste panels. The conformational landscape of rebaudioside A was established at a range of temperatures by means of nuclear magnetic resonance and molecular dynamics simulation. The relationship between various conformations and the observed sweetness of rebaudioside A is described.

  14. On the connection between nonmonotonic taste behavior and molecular conformation in solution: The case of rebaudioside-A

    SciTech Connect

    Chopade, Prashant D.; Sarma, Bipul; Santiso, Erik E.; Chen, Jie; Trout, Bernhardt L.; Myerson, Allan S.; Simpson, Jeffrey; Fry, John C.; Biermann, Kari L.; Yurttas, Nese

    2015-12-28

    The diterpene steviol glycoside, rebaudioside A, is a natural high potency non-caloric sweetener extracted from the leaves of Stevia rebaudiana. This compound shows a parabolic change in sweet taste intensity with temperature which contrasts with the general finding for other synthetic or natural sweeteners whose sweet taste increases with temperature. The nonmonotonic taste behavior was determined by sensory analysis using large taste panels. The conformational landscape of rebaudioside A was established at a range of temperatures by means of nuclear magnetic resonance and molecular dynamics simulation. The relationship between various conformations and the observed sweetness of rebaudioside A is described.

  15. Uniform and Conformal Carbon Nanofilms Produced Based on Molecular Layer Deposition

    PubMed Central

    Yang, Peng; Wang, Guizhen; Gao, Zhe; Chen, He; Wang, Yong; Qin, Yong

    2013-01-01

    Continuous and uniform carbon nanofilms (CNFs) are prepared by pyrolysis of polyimide films which are produced by molecular layer deposition (MLD). The film thickness can be easily controlled at nanometer scale by altering the cycle numbers. During the annealing process at 600 °C, the polyimide film is subject to shrinkage of 70% in thickness. The obtained CNFs do not exhibit a well-graphitized structure due to the low calcination temperature. No clear pore structures are observed in the produced films. CNFs grown on a glass substrate with a thickness of about 1.4 nm shows almost 98% optical transmittance in the visible spectrum range. Au nanoparticles coated with CNFs are produced by this method. Carbon nanotubes with uniform wall thickness are obtained using anodic aluminum oxide as a template by depositing polyimide films into its pores. Our results demonstrate that this method is very effective to coat conformal and uniform CNFs on various substrates, such as nanoparticles and porous templates, to produce functional composite nanomaterials. PMID:28788411

  16. Molecular detection of plant pathogenic bacteria using polymerase chain reaction single-strand conformation polymorphism.

    PubMed

    Srinivasa, Chandrashekar; Sharanaiah, Umesha; Shivamallu, Chandan

    2012-03-01

    The application of polymerase chain reaction (PCR) technology to molecular diagnostics holds great promise for the early identification of agriculturally important plant pathogens. Ralstonia solanacearum, Xanthomoans axonopodis pv. vesicatoria, and Xanthomonas oryzae pv. oryzae are phytopathogenic bacteria, which can infect vegetables, cause severe yield loss. PCR-single-strand conformation polymorphism (PCR-SSCP) is a simple and powerful technique for identifying sequence changes in amplified DNA. The technique of PCR-SSCP is being exploited so far, only to detect and diagnose human bacterial pathogens in addition to plant pathogenic fungi. Selective media and serology are the commonly used methods for the detection of plant pathogens in infected plant materials. In this study, we developed PCR-SSCP technique to identify phytopathogenic bacteria. The PCR product was denatured and separated on a non-denaturing polyacrylamide gel. SSCP banding patterns were detected by silver staining of nucleic acids. We tested over 56 isolates of R. solanacearum, 44 isolates of X. axonopodis pv. vesicatoria, and 20 isolates of X. oryzae pv. oryzae. With the use of universal primer 16S rRNA, we could discriminate such species at the genus and species levels. Species-specific patterns were obtained for bacteria R. solanacearum, X. axonopodis pv. vesicatoria, and X. oryzae pv. oryzae. The potential use of PCR-SSCP technique for the detection and diagnosis of phytobacterial pathogens is discussed in the present paper.

  17. Morphology, functionality and molecular conformation study of CVD diamond surfaces functionalised with organic linkers and DNA

    NASA Astrophysics Data System (ADS)

    Wenmackers, Sylvia

    This PhD thesis fits within a joint-venture of physicists and biomedical researchers, aimed at the development of diamond-based DNA sensors. CVD diamond was chosen as the substrate material, because a strong covalent carbon-carbon bond can be created in this case, creating a highly stable platform for reusable biosensors or even for continuous monitoring. Moreover, diamond has favourable properties for sensing based on optical (transparency for a large spectral range) as well as electrical signals (semiconductor, stable in aqueous solutions with a wide potential window). The first specific goal for this thesis within the project was to establish the initial functionalisation of CVD diamond surfaces that would allow for the covalent linking of biomolecules, in casu DNA. This was obtained by UV attachement of omega-unsaturated fatty acid molecules (10-undecenoic acid) followed by the use of the zero-length crosslinker EDC to attach amino-modified DNA. The second goal was to characterise the diamond surfaces extensively with physical and (bio-)chemical methods to check the effectiveness of various surface treatments, and to elucidate the molecular organisation of the obtained linker layers and DNA brushes. Point mutation-sensitivity was achieved with end-point fluorescence as well as a real-time label-free electrical sensor prototype. The conformation of the end-tethered DNA molecules was investigated with spectroscopic ellipsometry.

  18. Crystal and molecular structure, conformational, vibrational properties and DFT calculations of melaminium bis (hydrogen oxalate)

    NASA Astrophysics Data System (ADS)

    Sangeetha, V.; Govindarajan, M.; Kanagathara, N.; Gunasekaran, S.; Rajakumar, P. R.; Anbalagan, G.

    2014-06-01

    Single crystals of melaminium bis (hydrogen oxalate) (MOX) were grown by slow evaporation method. X-ray powder diffraction analysis indicates that MOX crystallizes in monoclinic system (space group C2/c) and the calculated lattice constants are a = 20.075 ± 0.123 Ǻ, b = 8.477 ± 0.045 Ǻ, c = 6.983 ± 0.015, α = γ 90° and β = 102.6 ± 0.33°. Thermal analysis confirms that MOX is thermally stable up to 250 °C. A detailed interpretation of the FT-IR, FT-Raman and NMR spectra were reported. The equilibrium geometry, bonding features, and harmonic vibrational frequencies have been investigated with the help of PM6, HF and DFT/B3LYP methods. The potential energy curve shows that MOX molecule has two stable structures and the computational results diagnose that Rot I is the most stable conformer. The 1H and 13C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge-Invariant Atomic Orbital (GIAO) method. Stability of the molecule, arising from hyperconjugative interactions and charge delocalization, has been analyzed using Natural Bond Orbital (NBO) analysis. The electronic properties, such as HOMO and LUMO energies, were calculated by Time-Dependent DFT (TD-DFT) approach. To estimate chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map is calculated for the optimized geometry of the molecule.

  19. Conformational analysis of tripeptides: a molecular dynamics study of rigid and non-rigid tripeptides

    NASA Astrophysics Data System (ADS)

    Shibata, John; Mochel, Mark

    2006-03-01

    Molecular dynamics simulations have been performed on different tripeptides classified as structurally rigid and non-rigid (1). The simulations were run using the OPLS-AA force field (2) with and without explicit solvent. Two modeling programs, Tinker (3) and Macromodel (4), were used to simulate the dynamics. The accessible conformations were analyzed using Ramachandran plots of the dihedral angles. The results of this study are compared to the rigidity classification scheme (1), and differences in the results using explicit solvent and a continuum solvent model are noted. (1) Anishetty, S., Pennathur, G., Anishetty, R. BMC Structural Biology 2:9 (2002). Available from http://www.biomedcentral.com/1472-6807/2/9. (2) Jorgensen, W. L., Maxwell, D. S., Tirado-Rives, J. J. Am. Chem. Soc. 118, 11225 (1996). (3) Dudek, M. J., Ramnarayan, K., Ponder, J. W. J. Comput. Chem. 19, 548 (1996). Available from http://dasher.wustl.edu/tinker. (4) Mohamadi, F., Richards, N. G. J., Guida, W. C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrickson, T., Still, W. C. J. Comput. Chem. 11, 440 (1990).

  20. Role of molecular conformations in rubrene polycrystalline films growth from vacuum deposition at various substrate temperatures

    PubMed Central

    Lin, Ku-Yen; Wang, Yan-Jun; Chen, Ko-Lun; Ho, Ching-Yuan; Yang, Chun-Chuen; Shen, Ji-Lin; Chiu, Kuan-Cheng

    2017-01-01

    We report on the optical and structural characterization of rubrene polycrystalline films fabricated from vacuum deposition with various substrate temperatures (Tsub). Depending on Tsub, the role of twisted and planar rubrene conformational isomers on the properties of rubrene films is focused. The temperature (T)-dependent inverse optical transmission (IOT) and photoluminescence (PL) spectra were performed on these rubrene films. The origins of these IOT and PL peaks are explained in terms of the features from twisted and planar rubrene molecules and of the band characteristics from rubrene molecular solid films. Here, two rarely reported weak-peaks at 2.431 and 2.605 eV were observed from IOT spectra, which are associated with planar rubrene. Besides, the T-dependence of optical bandgap deduced from IOT spectra is discussed with respect to Tsub. Together with IOT and PL spectra, for Tsub > 170 °C, the changes in surface morphology and unit cell volume were observed for the first time, and are attributed to the isomeric transformation from twisted to planar rubrenes during the deposition processes. Furthermore, a unified schematic diagram in terms of Frenkel exciton recombination is suggested to explain the origins of the dominant PL peaks performed on these rubrene films at 15 K. PMID:28091620

  1. Role of molecular conformations in rubrene polycrystalline films growth from vacuum deposition at various substrate temperatures

    NASA Astrophysics Data System (ADS)

    Lin, Ku-Yen; Wang, Yan-Jun; Chen, Ko-Lun; Ho, Ching-Yuan; Yang, Chun-Chuen; Shen, Ji-Lin; Chiu, Kuan-Cheng

    2017-01-01

    We report on the optical and structural characterization of rubrene polycrystalline films fabricated from vacuum deposition with various substrate temperatures (Tsub). Depending on Tsub, the role of twisted and planar rubrene conformational isomers on the properties of rubrene films is focused. The temperature (T)-dependent inverse optical transmission (IOT) and photoluminescence (PL) spectra were performed on these rubrene films. The origins of these IOT and PL peaks are explained in terms of the features from twisted and planar rubrene molecules and of the band characteristics from rubrene molecular solid films. Here, two rarely reported weak-peaks at 2.431 and 2.605 eV were observed from IOT spectra, which are associated with planar rubrene. Besides, the T-dependence of optical bandgap deduced from IOT spectra is discussed with respect to Tsub. Together with IOT and PL spectra, for Tsub > 170 °C, the changes in surface morphology and unit cell volume were observed for the first time, and are attributed to the isomeric transformation from twisted to planar rubrenes during the deposition processes. Furthermore, a unified schematic diagram in terms of Frenkel exciton recombination is suggested to explain the origins of the dominant PL peaks performed on these rubrene films at 15 K.

  2. Conformation Analysis of T1 Lipase on Alcohols Solvent using Molecular Dynamics Simulation

    NASA Astrophysics Data System (ADS)

    Putri, A. M.; Sumaryada, T.; Wahyudi, S. T.

    2017-07-01

    Biodiesel usually is produced commercially via a transesterification reaction of vegetable oil with alcohol and alkali catalyst. The alkali catalyst has some drawbacks, such as the soap formation during the reaction. T1 Lipase enzyme had been known as a thermostable biocatalyst which is able to produce biodiesel through a cleaner process. In this paper the performance of T1 lipase enzyme as catalyst for transesterification reaction in pure ethanol, methanol, and water solvents were studied using a Molecular Dynamics (MD) Simulation at temperature of 300 K for 10 nanoseconds. The results have shown that in general the conformation of T1 lipase enzyme in methanol is more dynamics as shown by the value of root mean square deviation (RMSD), root mean squared fluctuation (RMSF), and radius of gyration. The highest solvent accessible surface area (SASA) total was also found in methanol due to the contribution of non-polar amino acid in the interior of the protein. Analysis of MD simulation has also revealed that the enzyme structure tend to be more rigid in ethanol environment. The analysis of electrostatic interactions have shown that Glu359-Arg270 salt-bridge pair might hold the key of thermostability of T1 lipase enzyme as shown by its strong and stable binding in all three solvents.

  3. Role of molecular conformations in rubrene polycrystalline films growth from vacuum deposition at various substrate temperatures.

    PubMed

    Lin, Ku-Yen; Wang, Yan-Jun; Chen, Ko-Lun; Ho, Ching-Yuan; Yang, Chun-Chuen; Shen, Ji-Lin; Chiu, Kuan-Cheng

    2017-01-16

    We report on the optical and structural characterization of rubrene polycrystalline films fabricated from vacuum deposition with various substrate temperatures (Tsub). Depending on Tsub, the role of twisted and planar rubrene conformational isomers on the properties of rubrene films is focused. The temperature (T)-dependent inverse optical transmission (IOT) and photoluminescence (PL) spectra were performed on these rubrene films. The origins of these IOT and PL peaks are explained in terms of the features from twisted and planar rubrene molecules and of the band characteristics from rubrene molecular solid films. Here, two rarely reported weak-peaks at 2.431 and 2.605 eV were observed from IOT spectra, which are associated with planar rubrene. Besides, the T-dependence of optical bandgap deduced from IOT spectra is discussed with respect to Tsub. Together with IOT and PL spectra, for Tsub > 170 °C, the changes in surface morphology and unit cell volume were observed for the first time, and are attributed to the isomeric transformation from twisted to planar rubrenes during the deposition processes. Furthermore, a unified schematic diagram in terms of Frenkel exciton recombination is suggested to explain the origins of the dominant PL peaks performed on these rubrene films at 15 K.

  4. Detection of Ligand-Induced Conformational Changes in Oligonucleotides by Second-Harmonic Generation at a Supported Lipid Bilayer Interface.

    PubMed

    Butko, Margaret T; Moree, Ben; Mortensen, Richard B; Salafsky, Joshua

    2016-11-01

    There is a high demand for characterizing oligonucleotide structural changes associated with binding interactions as well as identifying novel binders that modulate their structure and function. In this study, second-harmonic generation (SHG) was used to study RNA and DNA oligonucleotide conformational changes associated with ligand binding. For this purpose, we developed an avidin-based biotin capture surface based on a supported lipid bilayer membrane. The technique was applied to two well-characterized aptamers, both of which undergo conformational changes upon binding either a protein or a small molecule ligand. In both cases, SHG was able to resolve conformational changes in these oligonucleotides sensitively and specifically, in solution and in real time, using nanogram amounts of material. In addition, we developed a competition assay for the oligonucleotides between the specific ligands and known, nonspecific binders, and we demonstrated that intercalators and minor groove binders affect the conformation of the DNA and RNA oligonucleotides in different ways upon binding and subsequently block specific ligand binding in all cases. Our work demonstrates the broad potential of SHG for studying oligonucleotides and their conformational changes upon interaction with ligands. As SHG offers a powerful, high-throughput screening approach, our results here also open an important new avenue for identifying novel chemical probes or sequence-targeted drugs that disrupt or modulate DNA or RNA structure and function.

  5. Understanding the conformational flexibility and electrostatic properties of curcumin in the active site of rhAChE via molecular docking, molecular dynamics, and charge density analysis.

    PubMed

    Saravanan, Kandasamy; Kalaiarasi, Chinnasamy; Kumaradhas, Poomani

    2017-01-04

    Acetylcholinesterase (AChE) is an important enzyme responsible for Alzheimer's disease, as per report, keto-enol form of curcumin inhibits this enzyme. The present study aims to understand the binding mechanism of keto-enol curcumin with the recombinant human Acetylcholinesterase (rhAChE) from its conformational flexibility, intermolecular interactions, charge density distribution, and the electrostatic properties at the active site of rhAChE. To accomplish this, a molecular docking analysis of curcumin with the rhAChE was performed, which gives the structure and conformation of curcumin in the active site of rhAChE. Further, the charge density distribution and the electrostatic properties of curcumin molecule (lifted from the active site of rhAChE) were determined from the high level density functional theory (DFT) calculations coupled with the charge density analysis. On the other hand, the curcumin molecule was optimized (gas phase) using DFT method and further, the structure and charge density analysis were also carried out. On comparing the conformation, charge density distribution and the electrostatic potential of the active site form of curcumin with the corresponding gas phase form reveals that the above said properties are significantly altered when curcumin is present in the active site of rhAChE. The conformational stability and the interaction of curcumin in the active site are also studied using molecular dynamics simulation, which shows a large variation in the conformational geometry of curcumin as well as the intermolecular interactions.

  6. Optical vortex generation from molecular chromophore arrays.

    PubMed

    Williams, Mathew D; Coles, Matt M; Saadi, Kamel; Bradshaw, David S; Andrews, David L

    2013-10-11

    The generation of light endowed with orbital angular momentum, frequently termed optical vortex light, is commonly achieved by passing a conventional beam through suitably constructed optical elements. This Letter shows that the necessary phase structure for vortex propagation can be directly produced through the creation of twisted light from the vacuum. The mechanism is based on optical emission from a family of chromophore nanoarrays that satisfy specific geometric and symmetry constraints. Each such array can support pairs of electronically delocalized doubly degenerate excitons whose azimuthal phase progression is responsible for the helical wave front of the emitted radiation. The exciton symmetry dictates the maximum magnitude of topological charge; detailed analysis secures the conditions necessary to deliver optical vortices of arbitrary order.

  7. Determination of receptor-bound drug conformations by QSAR using flexible fitting to derive a molecular similarity index

    NASA Astrophysics Data System (ADS)

    Montanari, C. A.; Tute, M. S.; Beezer, A. E.; Mitchell, J. C.

    1996-02-01

    Results are presented for a QSAR analysis of bisamidines, using a similarity index as descriptor. The method allows for differences in conformation of bisamidines at the receptor site to be taken into consideration. In particular, it has been suggested by others that pentamidine binds in the minor groove of DNA in a so-called isohelical conformation, and our QSAR supports this suggestion. The molecular similarity index for comparison of molecules can be used as a parameter for correlating and hence rationalising the activity as well as suggesting the design of bioactive molecules. The studied compounds had been evaluated for potency against Leishmania mexicana amazonensis, and this potency was used as a dependent variable in a series of QSAR analyses. For the calculation of similarity indexes, each analogue was in turn superimposed on a chosen lead compound in a reference conformation, either extended or isohelical, maximising overlap and hence similarity by flexible fitting.

  8. Comparison of Chain Conformation of Poly(vinyl alcohol) in Solutions and Melts from Quantum Chemistry Based Molecular Dynamics Simulations

    NASA Technical Reports Server (NTRS)

    Jaffe, Richard; Han, Jie; Matsuda, Tsunetoshi; Yoon, Do; Langhoff, Stephen R. (Technical Monitor)

    1997-01-01

    Confirmations of 2,4-dihydroxypentane (DHP), a model molecule for poly(vinyl alcohol), have been studied by quantum chemistry (QC) calculations and molecular dynamics (MD) simulations. QC calculations at the 6-311G MP2 level show the meso tt conformer to be lowest in energy followed by the racemic tg, due to intramolecular hydrogen bond between the hydroxy groups. The Dreiding force field has been modified to reproduce the QC conformer energies for DHP. MD simulations using this force field have been carried out for DHP molecules in the gas phase, melt, and CHCl3 and water solutions. Extensive intramolecular hydrogen bonding is observed for the gas phase and CHCl3 solution, but not for the melt or aqueous solution, Such a condensed phase effect due to intermolecular interactions results in a drastic change in chain conformations, in agreement with experiments.

  9. Exploring the conformational and binding properties of unphosphorylated/phosphorylated monomeric and trimeric Bcl-2 through docking and molecular dynamics simulations.

    PubMed

    Zacarías-Lara, Oscar J; Correa-Basurto, José; Bello, Martiniano

    2016-07-01

    B-cell lymphoma (Bcl-2) is commonly associated with the progression and preservation of cancer and certain lymphomas; therefore, it is considered as a biological target against cancer. Nevertheless, evidence of all its structural binding sites has been hidden because of the lack of a complete Bcl-2 model, given the presence of a flexible loop domain (FLD), which is responsible for its complex behavior. FLD region has been implicated in phosphorylation, homotrimerization, and heterodimerization associated with Bcl-2 antiapoptotic function. In this contribution, homology modeling, molecular dynamics (MD) simulations in the microsecond (µs) time-scale and docking calculations were combined to explore the conformational complexity of unphosphorylated/phosphorylated monomeric and trimeric Bcl-2 systems. Conformational ensembles generated through MD simulations allowed for identifying the most populated unphosphorylated/phosphorylated monomeric conformations, which were used as starting models to obtain trimeric complexes through protein-protein docking calculations, also submitted to µs MD simulations. Principal component analysis showed that FLD represents the main contributor to total Bcl-2 mobility, and is affected by phosphorylation and oligomerization. Subsequently, based on the most representative unphosphorylated/phosphorylated monomeric and trimeric Bcl-2 conformations, docking studies were initiated to identify the ligand binding site of several known Bcl-2 inhibitors to explain their influence in homo-complex formation and phosphorylation. Docking studies showed that the different conformational states experienced by FLD, such as phosphorylation and oligomerization, play an essential role in the ability to make homo and hetero-complexes. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 393-413, 2016.

  10. Ab initio studies of molecular structures, conformers and vibrational spectra of heterocyclic organics: I. Nicotinamide and its N-oxide

    NASA Astrophysics Data System (ADS)

    Kumar, M.; Jaiswal, S.; Singh, R.; Srivastav, G.; Singh, P.; Yadav, T. N.; Yadav, R. A.

    2010-01-01

    FTIR spectra of nicotinamide and its N-oxide have been recorded and analyzed in the range 400-4000 cm -1. The stabilities, optimized molecular geometries, APT charges and vibrational characteristics for the two possible conformers of nicotinamide and its N-oxide have been studied theoretically using restricted Hartree-Fock (RHF) and density functional theory (DFT) methods. The E (trans) conformers of nicotinamide and its N-oxide are found to be more stable and less polar than their respective Z (cis) conformers. Due to addition of an O atom at the N 1 site in the NA molecule the magnitudes of atomic charges on all the H atomic sites are found to increase. For all the studied molecules, magnitude of the wagging mode of the NH 2 group is found to be higher than its torsion mode, which is in the reverse order as compared to that for the aniline molecule. Most of the vibrational frequencies have nearly the same magnitude for the two conformers of nicotinamide and its N-oxide, however, significant changes are noticed in their IR intensities, Raman activities and depolarization ratios of the Raman bands. The frequency of the ring breathing mode for the NA molecule is found to decrease by 100 cm -1 in going to the NANO molecule for both the conformers. The IR intensity for the scissoring mode of the CON(H 2) group is found to decrease significantly for the NA-II conformer as compared to that for the NA-I conformer.

  11. Conformational equilibria of terminally blocked single amino acids at the water-hexane interface. A molecular dynamics study.

    PubMed

    Chipot, C; Pohorille, A

    1998-01-01

    The conformational equilibria of the acetyl and methyl amide terminally blocked L-alanine, L-leucine and L-glutamine amino acids are examined in vacuum, in bulk water, and at the water-hexane interface, using multi-nanosecond molecular dynamics simulations. The two-dimensional probability distribution functions of finding the peptides at different dihedral angles of the backbone, phi and psi, are calculated, and free energy differences between different conformational states are determined. All three peptides are interfacially active, i.e. tend to accumulate at the interface even though they are not amphiphilic. Conformational states stable in both gas phase and water are also stable in the interfacial environment. Their populations, however, cannot be simply predicted from the knowledge of conformational equilibria in the bulk phases, indicating that the interface exerts a unique effect on the peptides. Conformational preferences in the interfacial environment arise from the interplay between electrostatic and hydrophobic effects. As in an aqueous solution, electrostatic solute-solvent interactions lead to the stabilization of more polar peptide conformations. The hydrophobic effect is manifested at the interface by a tendency to segregate polar and nonpolar moieties of the solute into the aqueous and the hexane phases, respectively. For the terminally blocked glutamine, this favors conformations for which such a segregation is compatible with the formation of strong, backbone-side chain intramolecular hydrogen bonds on the hexane side of the interface. The influence of the hydrophobic effect can be also noted in the orientational preferences of the peptides at the interface. The terminally blocked leucine is oriented such that its nonpolar side chain is buried in hexane, whereas the polar side chain of glutamine is immersed in water. The free energies of rotating the peptides along the axis parallel to the interface by more than 90 degrees are substantial. This

  12. Molecular dynamics simulation study of conformational changes of transcription factor TFIIS during RNA polymerase II transcriptional arrest and reactivation.

    PubMed

    Eun, Changsun; Ortiz-Sánchez, Juan Manuel; Da, Lintai; Wang, Dong; McCammon, J Andrew

    2014-01-01

    Transcription factor IIS (TFIIS) is a protein known for catalyzing the cleavage reaction of the 3'-end of backtracked RNA transcript, allowing RNA polymerase II (Pol II) to reactivate the transcription process from the arrested state. Recent structural studies have provided a molecular basis of protein-protein interaction between TFIIS and Pol II. However, the detailed dynamic conformational changes of TFIIS upon binding to Pol II and the related thermodynamic information are largely unknown. Here we use computational approaches to investigate the conformational space of TFIIS in the Pol II-bound and Pol II-free (unbound) states. Our results reveal two distinct conformations of TFIIS: the closed and the open forms. The closed form is dominant in the Pol II-free (unbound) state of TFIIS, whereas the open form is favorable in the Pol II-bound state. Furthermore, we discuss the free energy difference involved in the conformational changes between the two forms in the presence or absence of Pol II. Additionally, our analysis indicates that hydrophobic interactions and the protein-protein interactions between TFIIS and Pol II are crucial for inducing the conformational changes of TFIIS. Our results provide novel insights into the functional interplay between Pol II and TFIIS as well as mechanism of reactivation of Pol II transcription by TFIIS.

  13. Characterizing the conformational dynamics of metal-free PsaA using molecular dynamics simulations and electron paramagnetic resonance spectroscopy.

    PubMed

    Deplazes, Evelyne; Begg, Stephanie L; van Wonderen, Jessica H; Campbell, Rebecca; Kobe, Bostjan; Paton, James C; MacMillan, Fraser; McDevitt, Christopher A; O'Mara, Megan L

    2015-12-01

    Prokaryotic metal-ion receptor proteins, or solute-binding proteins, facilitate the acquisition of metal ions from the extracellular environment. Pneumococcal surface antigen A (PsaA) is the primary Mn(2+)-recruiting protein of the human pathogen Streptococcus pneumoniae and is essential for its in vivo colonization and virulence. The recently reported high-resolution structures of metal-free and metal-bound PsaA have provided the first insights into the mechanism of PsaA-facilitated metal binding. However, the conformational dynamics of metal-free PsaA in solution remain unknown. Here, we use continuous wave electron paramagnetic resonance (EPR) spectroscopy and molecular dynamics (MD) simulations to study the relative flexibility of the structural domains in metal-free PsaA and its distribution of conformations in solution. The results show that the crystal structure of metal-free PsaA is a good representation of the dominant conformation in solution, but the protein also samples structurally distinct conformations that are not captured by the crystal structure. Further, these results suggest that the metal binding site is both larger and more solvent exposed than indicated by the metal-free crystal structure. Collectively, this study provides atomic-resolution insight into the conformational dynamics of PsaA prior to metal binding and lays the groundwork for future EPR and MD based studies of PsaA in solution. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Speed of Conformational Change: Comparing Explicit and Implicit Solvent Molecular Dynamics Simulations

    PubMed Central

    Anandakrishnan, Ramu; Drozdetski, Aleksander; Walker, Ross C.; Onufriev, Alexey V.

    2015-01-01

    Adequate sampling of conformation space remains challenging in atomistic simulations, especially if the solvent is treated explicitly. Implicit-solvent simulations can speed up conformational sampling significantly. We compare the speed of conformational sampling between two commonly used methods of each class: the explicit-solvent particle mesh Ewald (PME) with TIP3P water model and a popular generalized Born (GB) implicit-solvent model, as implemented in the AMBER package. We systematically investigate small (dihedral angle flips in a protein), large (nucleosome tail collapse and DNA unwrapping), and mixed (folding of a miniprotein) conformational changes, with nominal simulation times ranging from nanoseconds to microseconds depending on system size. The speedups in conformational sampling for GB relative to PME simulations, are highly system- and problem-dependent. Where the simulation temperatures for PME and GB are the same, the corresponding speedups are approximately onefold (small conformational changes), between ∼1- and ∼100-fold (large changes), and approximately sevenfold (mixed case). The effects of temperature on speedup and free-energy landscapes, which may differ substantially between the solvent models, are discussed in detail for the case of miniprotein folding. In addition to speeding up conformational sampling, due to algorithmic differences, the implicit solvent model can be computationally faster for small systems or slower for large systems, depending on the number of solute and solvent atoms. For the conformational changes considered here, the combined speedups are approximately twofold, ∼1- to 60-fold, and ∼50-fold, respectively, in the low solvent viscosity regime afforded by the implicit solvent. For all the systems studied, 1) conformational sampling speedup increases as Langevin collision frequency (effective viscosity) decreases; and 2) conformational sampling speedup is mainly due to reduction in solvent viscosity rather than

  15. The effective energy transformation scheme as a special continuation approach to global optimization with application to molecular conformation

    SciTech Connect

    Wu, Zhijun

    1996-11-01

    This paper discusses a generalization of the function transformation scheme for global energy minimization applied to the molecular conformation problem. A mathematical theory for the method as a special continuation approach to global optimization is established. We show that the method can transform a nonlinear objective function into a class of gradually deformed, but {open_quote}smoother{close_quote} or {open_quotes}easier{close_quote} functions. An optimization procedure can then be applied to the new functions successively, to trace their solutions back to the original function. Two types of transformation are defined: isotropic and anisotropic. We show that both transformations can be applied to a large class of nonlinear partially separable functions including energy functions for molecular conformation. Methods to compute the transformation for these functions are given.

  16. Peptide binding identifies an ERalpha conformation that generates selective activity in multiple in vitro assays.

    PubMed

    Larson, Christopher J; Osburn, Deborah L; Schmitz, Katherine; Giampa, Leslie; Mong, Shau-Ming; Marschke, Keith; Seidel, H Martin; Rosen, Jonathan; Negro-Vilar, Andrés

    2005-09-01

    Drugs such as tamoxifen, which act at the estrogen receptor (ER), have very different in vitro and in vivo effects from those of the native hormone. Previous research has established that different ligands induce distinct conformational changes in the ER, thus affecting the interactions of the receptor with cell-specific co-activating or co-repressing proteins (cofactors) and estrogen response elements (EREs), thus potentially driving differing biological effects. Affinity-selected peptides have been used to probe the conformational changes that occur within the ER upon binding various ligands. In this study, the authors characterize the ability of several peptides to be recruited to liganded ER under cellular conditions. Approximating ER conformation via recruitment of this peptide to the ER is concluded to be a better predictor of the agonist nature of an ER ligand under these different cellular contexts than is a canonical cotransfection transactivation assay.

  17. Applications of single-strand conformation polymorphism (SSCP) to taxonomy, diagnosis, population genetics and molecular evolution of parasitic nematodes.

    PubMed

    Gasser, R B; Chilton, N B

    2001-11-22

    The analysis of genetic variation in parasitic nematodes has important implications for studying aspects of taxonomy, diagnosis, population genetics, drug resistance and molecular evolution. This article highlights some applications of PCR-based single-strand conformation polymorphism (SSCP) for the analysis of sequence variation in individual parasites (and their populations) to address some of these areas. It also describes the principles and advantages of SSCP, and provides some examples for future applications in parasitology.

  18. Conformational analysis of flavonoids: crystal and molecular structures of morin hydrate and myricetin (1:2) triphenylphosphine oxide complex

    NASA Astrophysics Data System (ADS)

    Cody, Vivian; Luft, Joseph R.

    1994-01-01

    The crystal and molecular structures of morin (2',3,4',5,7-pentahydroxyflavone) hydrate ( I), and myricetin (3',4',5',3,5,7-hexahydroxyflavone) triphenylphosphine oxide (TPPO) (1:2) co-crystal complex ( II) have been studied by X-ray analysis and AM1 molecular orbital methods. The molecular conformation of the two flavones described by the torsion angle θ[C(3)-C(2)-C(1t')-C(2')] between the benzopyrone and phenyl ring is -43.3° and 51.0° for molecules A and B of morin, respectively, and -37.0° for myricetin. Minimum energy conformations from AM1 molecular orbital calculations have θ values of -38.2° for morin and -27.0° for myricetin. The energy profile for rotation about θ for morin has a 28 kcal mol -1 barrier at 0° due to steric interactions between the 2'-hydroxy and the 3-hydroxy group. There are two local minima near 30 and 140°, in good agreement with structural results. The profile for myricetin has two equivalent minima near 30 and 150° with a barrier of less than 2 kcal mol -1. In the crystal both flavones form extensive networks of intra- and intermolecular hydrogen bonds. In ( I), each morin conformer packs in alternating layers linked by water molecules, while in ( II), TPPO stabilizes the crystal by formation of short hydrogen bonds (2.58-2.65 Å) of the phosphoryl oxygen to the flavone. Myricetin also forms a two dimensional sheet-like packing in which myricetin molecules hydrogen bond to each other, as well as to TPPO. These conformational and hydrogen bonding patterns provide insight into specific types of ligand-receptor interactions and support structure activity data which suggest the importance of electronic and hydrogen bonding properties in the bioactivity of flavones.

  19. [Analysis of Conformational Features of Watson-Crick Duplex Fragments by Molecular Mechanics and Quantum Mechanics Methods].

    PubMed

    Poltev, V I; Anisimov, V M; Sanchez, C; Deriabina, A; Gonzalez, E; Garcia, D; Rivas, F; Polteva, N A

    2016-01-01

    It is generally accepted that the important characteristic features of the Watson-Crick duplex originate from the molecular structure of its subunits. However, it still remains to elucidate what properties of each subunit are responsible for the significant characteristic features of the DNA structure. The computations of desoxydinucleoside monophosphates complexes with Na-ions using density functional theory revealed a pivotal role of DNA conformational properties of single-chain minimal fragments in the development of unique features of the Watson-Crick duplex. We found that directionality of the sugar-phosphate backbone and the preferable ranges of its torsion angles, combined with the difference between purines and pyrimidines. in ring bases, define the dependence of three-dimensional structure of the Watson-Crick duplex on nucleotide base sequence. In this work, we extended these density functional theory computations to the minimal' fragments of DNA duplex, complementary desoxydinucleoside monophosphates complexes with Na-ions. Using several computational methods and various functionals, we performed a search for energy minima of BI-conformation for complementary desoxydinucleoside monophosphates complexes with different nucleoside sequences. Two sequences are optimized using ab initio method at the MP2/6-31++G** level of theory. The analysis of torsion angles, sugar ring puckering and mutual base positions of optimized structures demonstrates that the conformational characteristic features of complementary desoxydinucleoside monophosphates complexes with Na-ions remain within BI ranges and become closer to the corresponding characteristic features of the Watson-Crick duplex crystals. Qualitatively, the main characteristic features of each studied complementary desoxydinucleoside monophosphates complex remain invariant when different computational methods are used, although the quantitative values of some conformational parameters could vary lying within the

  20. Steinberg conformal algebras

    NASA Astrophysics Data System (ADS)

    Mikhalev, A. V.; Pinchuk, I. A.

    2005-06-01

    The structure of Steinberg conformal algebras is studied; these are analogues of Steinberg groups (algebras, superalgebras).A Steinberg conformal algebra is defined as an abstract algebra by a system of generators and relations between the generators. It is proved that a Steinberg conformal algebra is the universal central extension of the corresponding conformal Lie algebra; the kernel of this extension is calculated.

  1. Applying Molecular Dynamics Simulations to Identify Rarely Sampled Ligand-bound Conformational States of Undecaprenyl Pyrophosphate Synthase, an Antibacterial Target

    SciTech Connect

    Sinko, William; de Oliveira, César; Williams, Sarah; Van Wynsberghe, Adam; Durrant, Jacob D.; Cao, Rong; Oldfield, Eric; McCammon, J. Andrew

    2012-04-30

    Undecaprenyl pyrophosphate synthase is a cis-prenyltransferase enzyme, which is required for cell wall biosynthesis in bacteria. Undecaprenyl pyrophosphate synthase is an attractive target for antimicrobial therapy. We performed long molecular dynamics simulations and docking studies on undecaprenyl pyrophosphate synthase to investigate its dynamic behavior and the influence of protein flexibility on the design of undecaprenyl pyrophosphate synthase inhibitors. We also describe the first X-ray crystallographic structure of Escherichia coli apo-undecaprenyl pyrophosphate synthase. The molecular dynamics simulations indicate that undecaprenyl pyrophosphate synthase is a highly flexible protein, with mobile binding pockets in the active site. By carrying out docking studies with experimentally validated undecaprenyl pyrophosphate synthase inhibitors using high- and low-populated conformational states extracted from the molecular dynamics simulations, we show that structurally dissimilar compounds can bind preferentially to different and rarely sampled conformational states. By performing structural analyses on the newly obtained apo-undecaprenyl pyrophosphate synthase and other crystal structures previously published, we show that the changes observed during the molecular dynamics simulation are very similar to those seen in the crystal structures obtained in the presence or absence of ligands. We believe that this is the first time that a rare 'expanded pocket' state, key to drug design and verified by crystallography, has been extracted from a molecular dynamics simulation.

  2. The molecular structure and conformational characteristics of some specific benzodiazepine receptor ligands: A molecular orbital study of C3-substituted betacarboline derivatives

    SciTech Connect

    Konschin, H.; Tylli, H. ); Gynther, J. ); Rouvinen, J. )

    1989-01-01

    The molecular structures of the benzodiazepine receptor ligands {beta}-carboline-3-carboxylic acid (BCCA), its methyl, ethyl, and propyl esters (BCCM, BCCE, and BCCP, respectively), and 3-CN-{beta}-carboline (BC-3-CN) have been investigated on a minimal basis STO-3G level of accuracy. For BCCM, BCCE, and BCCP semiempirical AM 1 calculations have also been performed. Fully optimized molecular geometries are reported. Comparisons with available experimental structures indicate that minimal basis results may have a useful predictive value. For the mobile ester side chains, a study of chosen points on the conformational surface was made. Both the STO-3G and the AM 1 results give the planar conformers is the most stable structures with small barriers to internal rotation, provided the ester side chain remains extended. The calculated STO-3G rotational barriers are higher than are the corresponding AM 1 barriers. Partial optimization, i.e., of side-chain structure parameters only, seems sufficient to map the conformational characteristics of these compounds. The orientation of the dipole moment vector and its magnitude may have consequences for possible interaction with a receptor. On the basis of the sidechain internal dynamics, the intramolecular flexibility tends to be confined to certain regions of conformational space.

  3. Molecular dynamics simulation reveals conformational switching of water-mediated uracil-cytosine base-pairs in an RNA duplex.

    PubMed

    Schneider, C; Brandl, M; Sühnel, J

    2001-01-26

    A 4 ns molecular dynamics simulation of an RNA duplex (r-GGACUUCGGUCC)(2 )in solution with Na+ and Cl- as counterions was performed. The X-ray structure of this duplex includes two water-mediated uracil-cytosine pairs. In contrast to the other base-pairs in the duplex the water-mediated pairs switch between different conformations. One conformation corresponds to the geometry of the water-mediated UC pairs in the duplex X-ray structure with water acting both as hydrogen-bond donor and acceptor. Another conformation is close to that of a water-mediated UC base-pair found in the X-ray structure of the 23 S rRNA sarcin/ricin domain. In this case the oxygen of the water molecule is linked to two-base donor sites. For a very short time also a direct UC base-pair and a further conformation that is similar to the one found in the RNA duplex structure but exhibits an increased H3(U)...N3(C) distance is observed. Water molecules with unusually long residence times are involved in the water-mediated conformations. These results indicate that the dynamic behaviour of the water-mediated UC base-pairs differs from that of the duplex Watson-Crick and non-canonical guanine-uracil pairs with two or three direct hydrogen bonds. The conformational variability and increased flexibility has to be taken into account when considering these base-pairs as RNA building blocks and as recognition motifs. Copyright 2001 Academic Press.

  4. Optical second harmonic generation from Langmuir-type molecular monolayers

    SciTech Connect

    Berkovic, G.; Rasing, Th.; Shen, Y.R.

    1987-01-01

    A single molecular layer is generally sufficient to produce observable optical second harmonic generation (SHG). Furthermore, the selection rules governing this process make the SHG from a single monolayer often stronger than that from the medium supporting the monolayer. We have studied SHG from various Langmuir-type monolayers (i.e., monolayers spread on a water surface) in the following contexts: Study of chemical reactions (e.g., polymerization) and two-dimensional phase transitions in molecular monolayers on water. Development of a new technique to evaluate optical nonlinear coefficients of organic molecules, and their relationship to the molecular structure.

  5. A molecular dynamics description of the conformational flexibility of the L-iduronate ring in glycosaminoglycans.

    PubMed

    Angulo, Jesús; Nieto, Pedro M; Martín-Lomas, Manuel

    2003-07-07

    For a synthetic hexasaccharide model it is shown that the conformational flexibility of the L-iduronate ring in glycosaminoglycans can be adequately described by using the PME methodology together with simulation protocols suitable for highly charged systems.

  6. 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.

  7. Electronic transport in biphenyl single-molecule junctions with carbon nanotubes electrodes: The role of molecular conformation and chirality

    SciTech Connect

    Brito Silva, C. A. Jr.; Granhen, E. R.; Silva, S. J. S. da; Leal, J. F. P.; Del Nero, J.; Pinheiro, F. A.

    2010-08-15

    We investigate, by means of ab initio calculations, electronic transport in molecular junctions composed of a biphenyl molecule attached to metallic carbon nanotubes. We find that the conductance is proportional to cos{sup 2} {theta}, with {theta} the angle between phenyl rings, when the Fermi level of the contacts lies within the frontier molecular orbitals energy gap. This result, which agrees with experiments in biphenyl junctions with nonorganic contacts, suggests that the cos{sup 2} {theta} law has a more general applicability, irrespective of the nature of the electrodes. We calculate the geometrical degree of chirality of the junction, which only depends on the atomic positions, and demonstrate that it is not only proportional to cos{sup 2} {theta} but also is strongly correlated with the current through the system. These results indicate that molecular conformation plays the preponderant role in determining transport properties of biphenyl-carbon nanotubes molecular junctions.

  8. Molecular Dynamics Investigations of the Local Structural Characteristics of DNA Oligonucleotides: Studies of Helical Axis Deformations, Conformational Sequence Dependence and Modified Nucleoside Perturbations.

    NASA Astrophysics Data System (ADS)

    Louise-May, Shirley

    The present DNA studies investigate the local structure of DNA oligonucleotides in order to characterize helical axis deformations, sequence dependent fine structure and modified nucleoside perturbations of selected oligonucleotide sequences. The molecular dynamics method is used to generate an ensemble of energetically feasible DNA conformations which can then be analyzed for dynamical conformational properties, some of which can be compared to experimentally derived values. A theory and graphical presentation for the analysis of helical deformations of DNA based on the configurational statistics of polymers, called "Persistence Analysis", was designed. The results of the analysis on prototype forms, static crystal structures and two solvated MD simulations of the sequence d(CGCGAATTCGCG) indicate that all of the expected features of bending can be sensitively and systematically identified by this approach. Comparison of the relative performance of three molecular dynamics potential functions commonly used for dynamical modeling of biological macromolecules; CHARMm, AMBER and GROMOS was investigated via in vacuo MD simulations on the dodecamer sequence d(CGCGAATTCGCG)_2 with respect to the conformational properties of each dynamical model and their ability to support A and B families of DNA. Vacuum molecular dynamics simulations using the CHARMm force field carried out on simple homo- and heteropolymers of DNA led to the conclusion that sequence dependent fine structure appears to be well defined for adenine-thymine rich sequences both at the base pair and base step level whereas much of the the fine structure found in cytosine -guanine rich sequences appears to be context dependent. The local conformational properties of the homopolymer poly (dA) -poly (dT) revealed one dynamical model which was found in general agreement with fiber models currently available. Investigation of the relative structural static and dynamical effect of the misincorporation of

  9. Characterization of Molecular Determinants of the Conformational Stability of Macrophage Migration Inhibitory Factor: Leucine 46 Hydrophobic Pocket

    PubMed Central

    El-Turk, Farah; Fauvet, Bruno; Ashrafi, Amer; Ouertatani-Sakouhi, Hajer; Cho, Min-Kyu; Neri, Marilisa; Cascella, Michele; Rothlisberger, Ursula; Pojer, Florence; Zweckstetter, Markus; Lashuel, Hilal

    2012-01-01

    Macrophage Migration Inhibitory Factor (MIF) is a key mediator of inflammatory responses and innate immunity and has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. The oligomerization of MIF, more specifically trimer formation, is essential for its keto-enol tautomerase activity and probably mediates several of its interactions and biological activities, including its binding to its receptor CD74 and activation of certain signaling pathways. Therefore, understanding the molecular factors governing the oligomerization of MIF and the role of quaternary structure in modulating its structural stability and multifunctional properties is crucial for understanding the function of MIF in health and disease. Herein, we describe highly conserved intersubunit interactions involving the hydrophobic packing of the side chain of Leu46 onto the β-strand β3 of one monomer within a hydrophobic pocket from the adjacent monomer constituted by residues Arg11, Val14, Phe18, Leu19, Val39, His40, Val41, Val42, and Pro43. To elucidate the structural significance of these intersubunit interactions and their relative contribution to MIF’s trimerization, structural stability and catalytic activity, we generated three point mutations where Leu46 was replaced by glycine (L46G), alanine (L46A) and phenylalanine (L46F), and their structural properties, stability, oligomerization state, and catalytic activity were characterized using a battery of biophysical methods and X-ray crystallography. Our findings provide new insights into the role of the Leu46 hydrophobic pocket in stabilizing the conformational state of MIF in solution. Disrupting the Leu46 hydrophobic interaction perturbs the secondary and tertiary structure of the protein but has no effect on its oligomerization state. PMID:23028743

  10. Characterization of molecular determinants of the conformational stability of macrophage migration inhibitory factor: leucine 46 hydrophobic pocket.

    PubMed

    El-Turk, Farah; Fauvet, Bruno; Ashrafi, Amer; Ouertatani-Sakouhi, Hajer; Cho, Min-Kyu; Neri, Marilisa; Cascella, Michele; Rothlisberger, Ursula; Pojer, Florence; Zweckstetter, Markus; Lashuel, Hilal

    2012-01-01

    Macrophage Migration Inhibitory Factor (MIF) is a key mediator of inflammatory responses and innate immunity and has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. The oligomerization of MIF, more specifically trimer formation, is essential for its keto-enol tautomerase activity and probably mediates several of its interactions and biological activities, including its binding to its receptor CD74 and activation of certain signaling pathways. Therefore, understanding the molecular factors governing the oligomerization of MIF and the role of quaternary structure in modulating its structural stability and multifunctional properties is crucial for understanding the function of MIF in health and disease. Herein, we describe highly conserved intersubunit interactions involving the hydrophobic packing of the side chain of Leu46 onto the β-strand β3 of one monomer within a hydrophobic pocket from the adjacent monomer constituted by residues Arg11, Val14, Phe18, Leu19, Val39, His40, Val41, Val42, and Pro43. To elucidate the structural significance of these intersubunit interactions and their relative contribution to MIF's trimerization, structural stability and catalytic activity, we generated three point mutations where Leu46 was replaced by glycine (L46G), alanine (L46A) and phenylalanine (L46F), and their structural properties, stability, oligomerization state, and catalytic activity were characterized using a battery of biophysical methods and X-ray crystallography. Our findings provide new insights into the role of the Leu46 hydrophobic pocket in stabilizing the conformational state of MIF in solution. Disrupting the Leu46 hydrophobic interaction perturbs the secondary and tertiary structure of the protein but has no effect on its oligomerization state.

  11. Mapping molecular conformation and orientation of polyimide surfaces for homeotropicliquid crystal alignment by nonlinear optical spectroscopy

    NASA Astrophysics Data System (ADS)

    Oh-E, Masahito; Yokoyama, Hiroshi; Kim, Doseok

    2004-05-01

    Surface-specific sum-frequency vibrational spectroscopy and second-harmonic generation were used to study the structures of polyimide (PI) surfaces for homeotropic liquid crystal (LC) alignment and the molecular orientation of LC adsobates on these surfaces. The imide ring was perpendicular to the surface with one of CO bonds protruding out of the surface and the other pointing into the bulk rather than flat on the surface. The ester CO bond in the side chain was sticking out of the surface with a tilt angle of about 45° 55° from the surface normal, indicating that the rigid side chain core was, more or less, along the surface normal. The part of alkyl chain on the top of the side chain followed the orientation of the side chain core and protruded out of the surface with some gauche defects. The cyano biphenyl LC molecules were adsorbed on the PI preferentially with the terminal cyano group facing the PI surface.

  12. Direct Identification and Determination of Conformational Response in Adsorbed Individual Nonplanar Molecular Species Using Noncontact Atomic Force Microscopy.

    PubMed

    Albrecht, Florian; Bischoff, Felix; Auwärter, Willi; Barth, Johannes V; Repp, Jascha

    2016-12-14

    In recent years atomic force microscopy (AFM) at highest resolution was widely applied to mostly planar molecules, while its application toward exploring species with structural flexibility and a distinct 3D character remains a challenge. Herein, the scope of noncontact AFM is widened by investigating subtle conformational differences occurring in the well-studied reference systems 2H-TPP and Cu-TPP on Cu(111). Different saddle-shape conformations of both species can be recognized in conventional constant-height AFM images. To unambiguously identify the behavior of specific molecular moieties, we extend data acquisition to distances that are inaccessible with constant-height measurements by introducing vertical imaging, that is, AFM mapping in a plane perpendicular to the sample surface. Making use of this novel technique the vertical displacement of the central Cu atom upon tip-induced conformational switching of Cu-TPP is quantified. Further, for 2H-TPP two drastically different geometries are observed, which are systematically characterized. Our results underscore the importance of structural flexibility in adsorbed molecules with large conformational variability and, consequently, the objective to characterize their geometry at the single-molecule level in real space.

  13. Targeted molecular dynamics simulation studies of calcium binding and conformational change in the C-terminal half of gelsolin

    SciTech Connect

    Lee, Hui Sun; Robinson, Robert Charles; Joo, Chul Hyun; Lee, Heuiran; Kim, Yoo Kyum . E-mail: ykkim@amc.seoul.kr; Choe, Han . E-mail: hchoe@amc.seoul.kr

    2006-04-14

    Gelsolin consists of six related domains (G1-G6) and the C-terminal half (G4-G6) acts as a calcium sensor during the activation of the whole molecule, a process that involves large domain movements. In this study, we used targeted molecular dynamics simulations to elucidate the conformational transitions of G4-G6 at an atomic level. Domains G4 and G6 are initially ruptured, followed by a rotation of G6 by {approx}90{sup o}, which is the dominant conformational change. During this period, local conformational changes occur at the G4 and G5 calcium-binding sites, facilitating large changes in interdomain distances. Alterations in the binding affinities of the calcium ions in these three domains appear to be related to local conformational changes at their binding sites. Analysis of the relative stabilities of the G4-G6-bound calcium ions suggests that they bind first to G6, then to G4, and finally to G5.

  14. (13)CHD2-CEST NMR spectroscopy provides an avenue for studies of conformational exchange in high molecular weight proteins.

    PubMed

    Rennella, Enrico; Huang, Rui; Velyvis, Algirdas; Kay, Lewis E

    2015-10-01

    An NMR experiment for quantifying slow (millisecond) time-scale exchange processes involving the interconversion between visible ground state and invisible, conformationally excited state conformers is presented. The approach exploits chemical exchange saturation transfer (CEST) and makes use of (13)CHD2 methyl group probes that can be readily incorporated into otherwise highly deuterated proteins. The methodology is validated with an application to a G48A Fyn SH3 domain that exchanges between a folded conformation and a sparsely populated and transiently formed unfolded ensemble. Experiments on a number of different protein systems, including a 360 kDa half-proteasome, establish that the sensitivity of this (13)CHD2 (13)C-CEST technique can be upwards of a factor of 5 times higher than for a previously published (13)CH3 (13)C-CEST approach (Bouvignies and Kay in J Biomol NMR 53:303-310, 2012), suggesting that the methodology will be powerful for studies of conformational exchange in high molecular weight proteins.

  15. Quantitative sampling of conformational heterogeneity of a DNA hairpin using molecular dynamics simulations and ultrafast fluorescence spectroscopy

    PubMed Central

    Voltz, Karine; Léonard, Jérémie; Touceda, Patricia Tourón; Conyard, Jamie; Chaker, Ziyad; Dejaegere, Annick; Godet, Julien; Mély, Yves; Haacke, Stefan; Stote, Roland H.

    2016-01-01

    Molecular dynamics (MD) simulations and time resolved fluorescence (TRF) spectroscopy were combined to quantitatively describe the conformational landscape of the DNA primary binding sequence (PBS) of the HIV-1 genome, a short hairpin targeted by retroviral nucleocapsid proteins implicated in the viral reverse transcription. Three 2-aminopurine (2AP) labeled PBS constructs were studied. For each variant, the complete distribution of fluorescence lifetimes covering 5 orders of magnitude in timescale was measured and the populations of conformers experimentally observed to undergo static quenching were quantified. A binary quantification permitted the comparison of populations from experimental lifetime amplitudes to populations of aromatically stacked 2AP conformers obtained from simulation. Both populations agreed well, supporting the general assumption that quenching of 2AP fluorescence results from pi-stacking interactions with neighboring nucleobases and demonstrating the success of the proposed methodology for the combined analysis of TRF and MD data. Cluster analysis of the latter further identified predominant conformations that were consistent with the fluorescence decay times and amplitudes, providing a structure-based rationalization for the wide range of fluorescence lifetimes. Finally, the simulations provided evidence of local structural perturbations induced by 2AP. The approach presented is a general tool to investigate fine structural heterogeneity in nucleic acid and nucleoprotein assemblies. PMID:26896800

  16. Quantitative sampling of conformational heterogeneity of a DNA hairpin using molecular dynamics simulations and ultrafast fluorescence spectroscopy.

    PubMed

    Voltz, Karine; Léonard, Jérémie; Touceda, Patricia Tourón; Conyard, Jamie; Chaker, Ziyad; Dejaegere, Annick; Godet, Julien; Mély, Yves; Haacke, Stefan; Stote, Roland H

    2016-04-20

    Molecular dynamics (MD) simulations and time resolved fluorescence (TRF) spectroscopy were combined to quantitatively describe the conformational landscape of the DNA primary binding sequence (PBS) of the HIV-1 genome, a short hairpin targeted by retroviral nucleocapsid proteins implicated in the viral reverse transcription. Three 2-aminopurine (2AP) labeled PBS constructs were studied. For each variant, the complete distribution of fluorescence lifetimes covering 5 orders of magnitude in timescale was measured and the populations of conformers experimentally observed to undergo static quenching were quantified. A binary quantification permitted the comparison of populations from experimental lifetime amplitudes to populations of aromatically stacked 2AP conformers obtained from simulation. Both populations agreed well, supporting the general assumption that quenching of 2AP fluorescence results from pi-stacking interactions with neighboring nucleobases and demonstrating the success of the proposed methodology for the combined analysis of TRF and MD data. Cluster analysis of the latter further identified predominant conformations that were consistent with the fluorescence decay times and amplitudes, providing a structure-based rationalization for the wide range of fluorescence lifetimes. Finally, the simulations provided evidence of local structural perturbations induced by 2AP. The approach presented is a general tool to investigate fine structural heterogeneity in nucleic acid and nucleoprotein assemblies.

  17. Use of restrained molecular dynamics to predict the conformations of phosphorylated receiver domains in two‐component signaling systems

    PubMed Central

    Foster, Clay A.

    2016-01-01

    ABSTRACT Two‐component signaling (TCS) is the primary means by which bacteria, as well as certain plants and fungi, respond to external stimuli. Signal transduction involves stimulus‐dependent autophosphorylation of a sensor histidine kinase and phosphoryl transfer to the receiver domain of a downstream response regulator. Phosphorylation acts as an allosteric switch, inducing structural and functional changes in the pathway's components. Due to their transient nature, phosphorylated receiver domains are challenging to characterize structurally. In this work, we provide a methodology for simulating receiver domain phosphorylation to predict conformations that are nearly identical to experimental structures. Using restrained molecular dynamics, phosphorylated conformations of receiver domains can be reliably sampled on nanosecond timescales. These simulations also provide data on conformational dynamics that can be used to identify regions of functional significance related to phosphorylation. We first validated this approach on several well‐characterized receiver domains and then used it to compare the upstream and downstream components of the fungal Sln1 phosphorelay. Our results demonstrate that this technique provides structural insight, obtained in the absence of crystallographic or NMR information, regarding phosphorylation‐induced conformational changes in receiver domains that regulate the output of their associated signaling pathway. To our knowledge, this is the first time such a protocol has been described that can be broadly applied to TCS proteins for predictive purposes. Proteins 2016; 85:155–176. © 2016 Wiley Periodicals, Inc. PMID:27802580

  18. Conformations, dynamics and interactions of di-, tri- and pentamannoside with mannose binding lectin: a molecular dynamics study.

    PubMed

    Mazumder, Parichita; Mukhopadhyay, Chaitali

    2012-02-15

    The binding of serum mannose-binding protein A (MBP-A) to high mannose N-linked glycoproteins, present on the surface of microorganism, activates the complement system. It is very important to explore the overall conformations of these ligands in the binding site of the MBP-A, which is very much dependent on the conformation of the manno-di-, tri- and the penta-saccharides that represent the component structures of these high-mannose type oligosaccharides. Herein, we report the possible conformations of α-(1→6)-linked dimannoside, benzyl-substituted trimannoside and core pentamannoside of the N-linked glycan in the binding site of MBP-A, with the help of molecular dynamics simulations. The results indicate that for all three ligands in addition to the non-reducing terminal mannose moiety the reducing moieties also interact with protein. Binding free energy calculations also indicate that the benzyl-substituted trisaccharide has higher affinity in comparison to the methyl substituted one. We have also found some conformers of the pentasaccharide, which have higher binding affinity than the monosaccharide.

  19. Analysis of conformational equilibria in aplidine using selective excitation 2D NMR spectroscopy and molecular mechanics/dynamics calculations.

    PubMed

    Cárdenas, Francisco; Caba, Josep Maria; Feliz, Miguel; Lloyd-Williams, Paul; Giralt, Ernest

    2003-12-12

    Aplidine (dehydrodidemnin B), a natural product with potent antitumor activity currently in multicenter phase II clinical trials, exists in DMSO as a mixture of four slowly interconverting conformations in a ratio of 47:33:13:7. NMR spectroscopy shows that these arise as a consequence of cis/trans isomerization about the NMe-Leu(7)-Pro(8) and Pro(8)-Pyr amide bonds of the molecule's side chain. Two major conformations account for 47% and 33% of the total population, a ratio of 60:40 between the two. They correspond to the cis- and trans-isomers, respectively, about the Pro(8)-Pyr amide bond. Two minor conformers arise as a consequence of similar isomerism about the Pro(8)-Pyr amide bond, but in structures in which the NMe-Leu(7)-Pro(8) amide bond is cis rather than trans. These account for approximately 13% and 7% of the total population, corresponding to a ratio of 65:35 cis/trans, respectively. Molecular dynamics simulations show that the three-dimensional structures of all four conformational isomers are similar in the macrocycle and that all are essentially unchanged with respect to the macrocycle of didemnin B. Significant differences in the conformation of the molecule's side chain are, however, observed between major and minor pairs. Analysis of hydrogen-bonding patterns shows that each major conformer exhibits a beta-turn like structure and is stabilized by hydrogen bonding between a different carbonyl group of the pyruvyl unit of the molecule's side chain and the NH of the Thr(6) residue. The minor isomers have a cis-amide bond between the NMe-Leu(7) and Pro(8) residues that obliges the side chain to adopt an extended disposition where hydrogen bonding to the macrocycle is absent. These results suggest that the ability of the molecule's side chain to adopt a beta-turn-like conformation may not be a prerequisite for biological activity in the didemnins and that conformations having an extended side-chain may play a role in the biological activity of

  20. New generation of breast cancer clinical trials implementing molecular profiling

    PubMed Central

    Zardavas, Dimitrios; Piccart-Gebhart, Martine

    2016-01-01

    The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients' enrolment in oncology trials shifts towards the implementation of molecular profiling as pre-screening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i) longitudinal cohort studies that implement (or not) "nested" downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) "master" protocol trials, iv) "basket" trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials. PMID:27458530

  1. New generation of breast cancer clinical trials implementing molecular profiling.

    PubMed

    Zardavas, Dimitrios; Piccart-Gebhart, Martine

    2016-06-01

    The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients' enrolment in oncology trials shifts towards the implementation of molecular profiling as pre-screening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i) longitudinal cohort studies that implement (or not) "nested" downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) "master" protocol trials, iv) "basket" trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials.

  2. Molecular conformation of clusters by genetic algorithm using spatial operators and unlabeled distance data

    NASA Astrophysics Data System (ADS)

    Cherba, David M.

    A set of Genetic Algorithm (GA) operators based on spatial location concepts will provide improved performance for a class of NP hard search problems in N dimensional spaces. A set of spatial operators for use with genetic algorithms is proposed for a class of problems with real-valued genes that consist of N-dimensional homogeneous vectors. Evolutionary computation is capable of providing solutions to problems that would be intractable using more conventional methods. A subset of these problems is represented in real-valued three dimensional spaces or other more complex vector spaces. This thesis addresses a number of issues related to the natural influences that adjacent locations in these spaces have on the fitness functions used in genetic algorithms. A subset of building blocks (schema) will be utilized based on these natural influences. It will be shown that these operators can be described by a building block style of theory that supports the experiment results. Further, the spatial base operators naturally preserve the interactions between genes for this class of problems. Genes have a natural influence on each other based on proximity. To be an effective genetic algorithm, operators need to take these proximity effects into consideration in order to preserve good contributions to fitness. Failure to utilize these spatial relationships will lead to very poor performance of the genetic algorithm or require statistical methods to try to capture the relationships. As a demonstration of these spatial operators, this dissertation will focus on the conformation of molecular clusters, where each atom's location represents a gene with real-valued coordinates. Further, the algorithm presented will work from unlabeled distance information available from experiments with limited preparation. A set of theories will be presented that form the basis for prediction of operator effectiveness, population size and convergence for this class of problems. The theory will be

  3. Conformity in a generative linguistic task: the role of category and strategic nonword use.

    PubMed

    Hussey, Karen A; Katz, Albert N

    2006-03-01

    Marsh, Ward, and Landau (1999) demonstrated that participants asked to create novel words use elements of sample nonwords they are given, even when instructed to avoid use of the examples. In four studies, we replicated the effect of conformity to sample nonwords and found the effect was not influenced by the semantic category of the words unless those words shared orthographic characteristics. We found that although we could increase conformity to examples when word exemplars were grouped by category, it was likely that much of this increase was strategically driven. We propose that the presence of the sample non-words, presented in groups with the same word rules, created an orthographic category used by participants in the word creation task.

  4. Manipulations that disrupt generative processes decrease conformity to examples: evidence from two paradigms.

    PubMed

    Landau, Joshua D; Leynes, P Andrew

    2004-01-01

    Participants in six experiments viewed experimenter-provided examples of space creatures (Experiments 1-3) or nonwords (Experiments 4-5b) and then created their own novel space creatures or nonwords. Consistent with previous research, people borrowed many of the features found in the examples despite instructions to avoid using any aspects of the experimenter's examples. However, requiring people to include a designated shape in their space creatures or a designated letter in their nonwords attenuated this effect. Additionally, the type of shape or letter (conventional versus unconventional) also affected conformity. These results suggest that the strategies that people use to create novel products can affect the level of conformity and also highlight the importance of adopting unconventional, or at the very least, new strategies when creating new products.

  5. Solid-state 19F MAS NMR study on the conformation and molecular mobility of poly(chlorotrifluoroethylene).

    PubMed

    Tatsuno, Hiroto; Aimi, Keitaro; Ando, Shinji

    2007-05-01

    The temperature dependence of molecular mobility and conformational changes of poly(chlorotrifluoro- ethylene) (PCTFE) have been investigated by solid-state (19)F magic angle spinning (MAS) NMR spectroscopy. The pulse techniques of dipolar-filter and T(1rho)-filter allow selective observation of the amorphous and crystalline domains, respectively. The temperature dependence of T(1rho) (F) revealed that the segmental motion in the amorphous domain becomes vigorous above ca 80 degrees C, which is well above the glass transition (T(g)) temperature (52 degrees C) and more close to the beta-relaxation temperature (95 degrees C). On the other hand, vigorous molecular motions in the crystalline domain occur above 120 degrees C, which is much below the melting temperature (212 degrees C). This indicates that the polymer chains in the PCTFE crystallites are more mobile than those of typical semicrystalline fluoropolymers like poly(vinylidene fluoride) (PVDF), which can be associated with structural imperfections in the crystallites. In addition, the density functional theory (DFT) calculations of (19)F magnetic shielding suggest that the high-frequency shifts observed for the crystalline signals above 80 degrees C can be ascribed to the conformational change around meso diads toward more twisted and/or helical conformations in the main chain.

  6. Self-assembled monolayers from biphenyldithiol derivatives: optimization of the deprotection procedure and effect of the molecular conformation.

    PubMed

    Shaporenko, Andrey; Elbing, Mark; Błaszczyk, Alfred; von Hänisch, Carsten; Mayor, Marcel; Zharnikov, Michael

    2006-03-09

    A series of biphenyl-derived dithiol (BDDT) compounds with terminal acetyl-protected sulfur groups and different structural arrangements of both phenyl rings have been synthesized and fully characterized. The different arrangements were achieved by introducing hydrocarbon substituents in the 2 and 2' positions of the biphenyl backbone. The presented model compounds enable the investigation of the correlation between the intramolecular conformation and other physical properties of interest, like, e.g., molecular assembly or electronic transport properties. Here, the ability of these model compounds to form self-assembled monolayers (SAMs) on Au(111) and Ag(111) is investigated in details. The deprotection of the target molecules was performed in situ using either NH4OH or triethylamine (TEA) deprotection agent. The fabricated films were characterized by synchrotron-based high-resolution photoelectron spectroscopy and near-edge absorption fine structure spectroscopy. Whereas the deprotection by NH4OH was found to result in the formation of multilayer films, the deprotection by TEA allowed the preparation of densely packed BDDT SAMs with a noticeably higher orientational order and smaller molecular inclination on Ag than on Au. Introduction of the alkyl bridge between the individual rings of the biphenyl backbone did not lead to a noticeable change in the structure and packing density of the BDDT SAMs as long as the molecule had a planar conformation in the respective SAM. The deviation from this conformation resulted in the deterioration of the film quality and a decrease of the orientational order.

  7. A 99 percent purity molecular sieve oxygen generator

    NASA Technical Reports Server (NTRS)

    Miller, G. W.

    1991-01-01

    Molecular sieve oxygen generating systems (MSOGS) have become the accepted method for the production of breathable oxygen on military aircraft. These systems separate oxygen for aircraft engine bleed air by application of pressure swing adsorption (PSA) technology. Oxygen is concentrated by preferential adsorption in nitrogen in a zeolite molecular sieve. However, the inability of current zeolite molecular sieves to discriminate between oxygen and argon results in an oxygen purity limitations of 93-95 percent (both oxygen and argon concentrate). The goal was to develop a new PSA process capable of exceeding the present oxygen purity limitations. A novel molecular sieve oxygen concentrator was developed which is capable of generating oxygen concentrations of up to 99.7 percent directly from air. The process is comprised of four absorbent beds, two containing a zeolite molecular sieve and two containing a carbon molecular sieve. This new process may find use in aircraft and medical breathing systems, and industrial air separation systems. The commercial potential of the process is currently being evaluated.

  8. Generation of monoclonal antibodies specific of the postfusion conformation of the Pneumovirinae fusion (F) protein.

    PubMed

    Rodríguez, Laura; Olmedillas, Eduardo; Mas, Vicente; Vázquez, Mónica; Cano, Olga; Terrón, María C; Luque, Daniel; Palomo, Concepción; Melero, José A

    2015-11-01

    Paramyxovirus entry into cells requires fusion of the viral and cell membranes mediated by one of the major virus glycoproteins, the fusion (F) glycoprotein which transits from a metastable pre-fusion conformation to a highly stable post-fusion structure during the membrane fusion process. F protein refolding involves large conformational changes of the protein trimer. One of these changes results in assembly of two heptad repeat sequences (HRA and HRB) from each protomer into a six-helix bundle (6HB) motif. To assist in distinguishing pre- and post-fusion conformations of the Pneumovirinae F proteins, and as extension of previous work (Palomo et al., 2014), a general strategy was designed to obtain polyclonal and particularly monoclonal antibodies specific of the 6HB motif of the Pneumovirinae fusion protein. The antibodies reported here should assist in the characterization of the structural changes that the F protein of human metapneumovirus or respiratory syncytial virus experiences during the process of membrane fusion. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Molecular modeling, mutational analysis and conformational switching in IL27: An in silico structural insight towards AIDS research.

    PubMed

    Banerjee, Arundhati; Ray, Sujay

    2016-01-15

    The advancement in proteomics and bioinformatics provokes to discern the molecular-level probe for HIV inhibitor; human interleukin-27 (IL27). Documentation documents that tyrosine residues in IL27 play a pivotal role for interacting with HIV, causing apoptosis of the HIV+ cells. Primarily, 3D structure of human wild-type (WT) IL27 was built through manifold molecular modeling techniques after the satisfaction of stereo-chemical properties. Its essential tyrosine residues were identified. Two mutant models for IL27 were prepared following the similar protocol by first substituting the tyrosine residues with glycine (MT_G) and then with alanine (MT_A) in the WT protein. Molecular dynamics (MD) simulation was performed to obtain a stable conformation. Conformational alterations in WT, MT_G and MT_A (before and after MD simulation) disclosed that MT_A was the steadiest one with the best secondary structure conformation supported by statistical significances. Though huge RMSD variations were observed on superimposing the MT structures on WT individually, the MTs were examined to share similar SCOP/CATH fold with TM-score=0.8, indicating that they retained their functionality even after mutation. Electrostatic surface potential again unveiled MT_A to be the most stable one. MT_A was thereby revealed to be the potent peptide inhibitor for HIV. This probe presents a pathway to investigate and compare the bio-molecular interaction of WT IL27 and MT_A IL27 (strongest model) with HIV in the future. This is the first report regarding the structural biology of IL27 accompanied by alteration at its genetic level and delving into the unknown residue-level and functional biochemistry for bringing about an annihilation towards AIDS.

  10. Efficient Handling of Molecular Flexibility in Ab Initio Generation of Crystal Structures.

    PubMed

    Habgood, Matthew; Sugden, Isaac J; Kazantsev, Andrei V; Adjiman, Claire S; Pantelides, Constantinos C

    2015-04-14

    A key step in many approaches to crystal structure prediction (CSP) is the initial generation of large numbers of candidate crystal structures via the exploration of the lattice energy surface. By using a relatively simple lattice energy approximation, this global search step aims to identify, in a computationally tractable manner, a limited number of likely candidate structures for further refinement using more detailed models. This paper presents an effective and efficient approach to modeling the effects of molecular flexibility during this initial global search. Local approximate models (LAMs), constructed via quantum mechanical (QM) calculations, are used to model the conformational energy, molecular geometry, and atomic charge distributions as functions of a subset of the conformational degrees of freedom (e.g., flexible torsion angles). The effectiveness of the new algorithm is demonstrated via its application to the recently studied 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) molecule and to two molecules, β-D-glucose and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione, a Bristol Myers Squibb molecule referenced as BMS-488043. All three molecules present significant challenges due to their high degree of flexibility.

  11. Single-molecule FRET reveals nucleotide-driven conformational changes in molecular machines and their link to RNA unwinding and DNA supercoiling.

    PubMed

    Klostermeier, Dagmar

    2011-04-01

    Many complex cellular processes in the cell are catalysed at the expense of ATP hydrolysis. The enzymes involved bind and hydrolyse ATP and couple ATP hydrolysis to the catalysed process via cycles of nucleotide-driven conformational changes. In this review, I illustrate how smFRET (single-molecule fluorescence resonance energy transfer) can define the underlying conformational changes that drive ATP-dependent molecular machines. The first example is a DEAD-box helicase that alternates between two different conformations in its catalytic cycle during RNA unwinding, and the second is DNA gyrase, a topoisomerase that undergoes a set of concerted conformational changes during negative supercoiling of DNA.

  12. Conformational analysis of vitamin D 3 derivatives by molecular mechanics . Part II. 1α,25-dihydroxyvitamin D 3 and analogues

    NASA Astrophysics Data System (ADS)

    Mosquera, Ricardo A.; Rios, Miguel A.; Tovar, Clara A.; Maestro, Miguel

    1989-10-01

    The conformational analysis of vitamin D 3 derivatives, including the biologically active form 1α,25-dihydroxyvitamin D 3 (III) and several synthetic analogues: b-deoxy-1α,25-dihydroxyvitamin D 3 (IV), 3-deoxy-3α-methyl-1α,25-dihydroxyvitamin D 3 (V), 3-deoxy-3β-methyl-1α,25-dihydroxyvitamin D 3 (VI), and 3-deoxy-3,3-dimethyl-1α,25-dihydroxyvitamin D 3 (VII), has been carried out employing Allinger's molecular mechanics method. The results obtained for conformational equilibrium populations are found to be in good agreement with those provided by NMR studies. Comparison of the active form of vitamin D 3 (1α,25-dihydroxyvitamin D 3) with the other species reveals no important geometrical differences.

  13. Effect of DNA on the conformational dynamics of the endonucleases I-DmoI as provided by molecular dynamics simulations.

    PubMed

    Grottesi, Alessandro; Cecconi, Simone; Molina, Rafael; D'abramo, Marco

    2016-12-01

    The conformational behavior of the wild-type endonucleases I-DmoI and two of its mutants has been studied in the presence and in the absence of DNA target sequences by means of extended molecular dynamics simulations. Our results show that in the absence of DNA, the three protein forms explore a similar essential conformational space, whereas when bound to the same DNA target sequence of 25 base pairs, they diversify and restrain the subspace explored. In addition, the differences in the essential subspaces explored by the residues near the catalytic site for both the bound and unbound forms are discussed in background of the experimental protein activity. © 2016 Wiley Periodicals, Inc.

  14. Molecular dynamics simulations on the conformational transitions from the GA 98 (GA 88) to GB 98 (GB 88) proteins.

    PubMed

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

    2016-12-01

    We performed conventional and targeted molecular dynamics simulations to address the dynamic transition mechanisms of the conformational transitions from the GA 98 protein with only 1 mutation of Leu45Tyr to GB 98 and from the GA 88 protein with 7 mutations of Gly24Ala, Ile25Thr, Ile30Phe, Ile33Tyr, Leu45Tyr, Ile49Thr, and Leu50Lys to GB 88. The results show that the conformational transition mechanism from the mutated 3α GA 98 (GA 88) state to the α+4β GB 98 (GB 88) state via several intermediate conformations involves the bending of loops at the N and C termini firstly, the unfolding of αA and αC, then the traversing of αB, and the formation of the 4β layer with the conversion of the hydrophobic core. The bending of loops at the N and C termini and the formation of the crucial transition conformation with the full unfolded structure are key factors in their transition processes. The communication of the interaction network, the bending directions of loops, and the traversing site of αB in the transition of GA 98 to GB 98 are markedly different from those in GA 88 to GB 88 because of the different mutated residues. The analysis of the correlations and the calculated mass center distances between some segments further supported their conformational transition mechanisms. These results could help people to better understand the Paracelsus challenge. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Influence of a cis,syn-cyclobutane pyrimidine dimer damage on DNA conformation studied by molecular dynamics simulations.

    PubMed

    Knips, Alexander; Zacharias, Martin

    2015-04-01

    The photo-induced formation of cis-syn-cyclobutane pyrimidine dimers (CPD) is a highly mutagenic and cancerogenic DNA lesion. In bacteria photolyases can efficiently reverse the dimer formation employing a light-driven reaction after looping out the CPD damaged bases into the enzyme active site. The exact mechanism how the repair enzyme identifies a damaged site within a large surplus of undamaged DNA is not fully understood. The CPD damage may alter the DNA structure and dynamics already in the absence of the repair enzyme which can facilitate the initial binding of a photolyase repair enzyme. To characterize the effect of a CPD damage, extensive comparative molecular dynamics (MD) simulations on duplex DNA with central regular or CPD damaged nucleotides were performed supplemented with simulations of the DNA-photolyase complex. Although no spontaneous flipping out transitions of the damaged bases were observed, the simulations showed significant differences in the conformational states of regular and CPD damage DNA. The isolated damaged DNA adopted transient conformations which resembled the global shape of the repair enzyme bound conformation more closely compared to regular B-DNA. In particular, these conformational changes were observed in most of helical and structural parameters where the protein bound DNA differs drastically from regular B-DNA. It is likely that the transient overlap of isolated DNA with the enzyme bound DNA conformation plays a decisive role for the specific and rapid initial recognition by the repair enzyme prior to the looping out process of the damaged DNA. © 2014 Wiley Periodicals, Inc.

  16. Effect of low molecular weight additives on immobilization strength, activity, and conformation of protein immobilized on PVC and UHMWPE.

    PubMed

    Kondyurin, Alexey; Nosworthy, Neil J; Bilek, Marcela M M

    2011-05-17

    Horseradish peroxidase (HRP) was immobilized onto both plasticized and unplasticized polyvinylchloride (PVC) and ultrahigh molecular weight polyethylene (UHMWPE). Plasma immersion ion implantation (PIII) in a nitrogen plasma with 20 kV bias was used to facilitate covalent immobilization and to improve the wettability of the surfaces. The surfaces and immobilized protein were studied using attenuated total reflection infrared (ATR-IR) spectroscopy and water contact angle measurements. Protein elution on exposure to repeated sodium dodecyl sulfate (SDS) washing was used to assess the strength of HRP immobilization. The presence of low molecular weight components (plasticizer, additives in solvent, unreacted monomers, adsorbed molecules on surface) was found to have a major influence on the strength of immobilization and the conformation of the protein on the samples not exposed to the PIII treatment. A phenomenological model considering interactions between the low molecular weight components, the protein molecule, and the surface is developed to explain these observations.

  17. Activity and conformation of lysozyme in molecular solvents, protic ionic liquids (PILs) and salt-water systems.

    PubMed

    Wijaya, Emmy C; Separovic, Frances; Drummond, Calum J; Greaves, Tamar L

    2016-09-21

    Improving protein stabilisation is important for the further development of many applications in the pharmaceutical, specialty chemical, consumer product and agricultural sectors. However, protein stabilization is highly dependent on the solvent environment and, hence, it is very complex to tailor protein-solvent combinations for stable protein maintenance. Understanding solvent features that govern protein stabilization will enable selection or design of suitable media with favourable solution environments to retain protein native conformation. In this work the structural conformation and activity of lysozyme in 29 solvent systems were investigated to determine the role of various solvent features on the stability of the enzyme. The solvent systems consisted of 19 low molecular weight polar solvents and 4 protic ionic liquids (PILs), both at different water content levels, and 6 aqueous salt solutions. Small angle X-ray scattering, Fourier transform infrared spectroscopy and UV-vis spectroscopy were used to investigate the tertiary and secondary structure of lysozyme along with the corresponding activity in various solvation systems. At low non-aqueous solvent concentrations (high water content), the presence of solvents and salts generally maintained lysozyme in its native structure and enhanced its activity. Due to the presence of a net surface charge on lysozyme, electrostatic interactions in PIL-water systems and salt solutions enhanced lysozyme activity more than the specific hydrogen-bond interactions present in non-ionic molecular solvents. At higher solvent concentrations (lower water content), solvents with a propensity to exhibit the solvophobic effect, analogous to the hydrophobic effect in water, retained lysozyme native conformation and activity. This solvophobic effect was observed particularly for solvents which contained hydroxyl moieties. Preferential solvophobic effects along with bulky chemical structures were postulated to result in less

  18. Molecular Mechanism and Energy Basis of Conformational Diversity of Antibody SPE7 Revealed by Molecular Dynamics Simulation and Principal Component Analysis

    PubMed Central

    Chen, Jianzhong; Wang, Jinan; Zhu, Weiliang

    2016-01-01

    More and more researchers are interested in and focused on how a limited repertoire of antibodies can bind and correspondingly protect against an almost limitless diversity of invading antigens. In this work, a series of 200-ns molecular dynamics (MD) simulations followed by principal component (PC) analysis and free energy calculations were performed to probe potential mechanism of conformational diversity of antibody SPE7. The results show that the motion direction of loops H3 and L3 is different relative to each other, implying that a big structural difference exists between these two loops. The calculated energy landscapes suggest that the changes in the backbone angles ψ and φ of H-Y101 and H-Y105 provide significant contributions to the conformational diversity of SPE7. The dihedral angle analyses based on MD trajectories show that the side-chain conformational changes of several key residues H-W33, H-Y105, L-Y34 and L-W93 around binding site of SPE7 play a key role in the conformational diversity of SPE7, which gives a reasonable explanation for potential mechanism of cross-reactivity of single antibody toward multiple antigens. PMID:27830740

  19. Molecular Mechanism and Energy Basis of Conformational Diversity of Antibody SPE7 Revealed by Molecular Dynamics Simulation and Principal Component Analysis

    NASA Astrophysics Data System (ADS)

    Chen, Jianzhong; Wang, Jinan; Zhu, Weiliang

    2016-11-01

    More and more researchers are interested in and focused on how a limited repertoire of antibodies can bind and correspondingly protect against an almost limitless diversity of invading antigens. In this work, a series of 200-ns molecular dynamics (MD) simulations followed by principal component (PC) analysis and free energy calculations were performed to probe potential mechanism of conformational diversity of antibody SPE7. The results show that the motion direction of loops H3 and L3 is different relative to each other, implying that a big structural difference exists between these two loops. The calculated energy landscapes suggest that the changes in the backbone angles ψ and φ of H-Y101 and H-Y105 provide significant contributions to the conformational diversity of SPE7. The dihedral angle analyses based on MD trajectories show that the side-chain conformational changes of several key residues H-W33, H-Y105, L-Y34 and L-W93 around binding site of SPE7 play a key role in the conformational diversity of SPE7, which gives a reasonable explanation for potential mechanism of cross-reactivity of single antibody toward multiple antigens.

  20. GRID3C: Computer program for generation of C type multilevel, three dimensional and boundary conforming periodic grids

    NASA Technical Reports Server (NTRS)

    Dulikravich, D. S.

    1982-01-01

    A fast computer program, GRID3C, was developed for accurately generating periodic, boundary conforming, three dimensional, consecutively refined computational grids applicable to realistic axial turbomachinery geometries. The method is based on using two functions to generate two dimensional grids on a number of coaxial axisymmetric surfaces positioned between the centerbody and the outer radial boundary. These boundary fitted grids are of the C type and are characterized by quasi-orthogonality and geometric periodicity. The built in nonorthogonal coordinate stretchings and shearings cause the grid clustering in the regions of interest. The stretching parameters are part of the input to GRID3C. In its present version GRID3C can generate and store a maximum of four consecutively refined three dimensional grids. The output grid coordinates can be calculated either in the Cartesian or in the cylindrical coordinate system.

  1. Third-Generation Light-Driven Symmetric Molecular Motors.

    PubMed

    Kistemaker, Jos C M; Štacko, Peter; Roke, Diederik; Wolters, Alexander T; Heideman, G Henrieke; Chang, Mu-Chieh; van der Meulen, Pieter; Visser, Johan; Otten, Edwin; Feringa, Ben L

    2017-07-19

    Symmetric molecular motors based on two overcrowded alkenes with a notable absence of a stereogenic center show potential to function as novel mechanical systems in the development of more advanced nanomachines offering controlled motion over surfaces. Elucidation of the key parameters and limitations of these third-generation motors is essential for the design of optimized molecular machines based on light-driven rotary motion. Herein we demonstrate the thermal and photochemical rotational behavior of a series of third-generation light-driven molecular motors. The steric hindrance of the core unit exerted upon the rotors proved pivotal in controlling the speed of rotation, where a smaller size results in lower barriers. The presence of a pseudo-asymmetric carbon center provides the motor with unidirectionality. Tuning of the steric effects of the substituents at the bridgehead allows for the precise control of the direction of disrotary motion, illustrated by the design of two motors which show opposite rotation with respect to a methyl substituent. A third-generation molecular motor with the potential to be the fastest based on overcrowded alkenes to date was used to visualize the equal rate of rotation of both its rotor units. The autonomous rotational behavior perfectly followed the predicted model, setting the stage for more advanced motors for functional dynamic systems.

  2. Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase.

    PubMed

    Ambrus, Attila; Adam-Vizi, Vera

    2013-10-15

    Human dihydrolipoamide dehydrogenase (LADH, E3) is a component in the pyruvate-, alpha-ketoglutarate- and branched-chain ketoacid dehydrogenase complexes and in the glycine cleavage system. The pathogenic mutations of LADH cause severe metabolic disturbances, called E3 deficiency that often involve cardiological and neurological symptoms and premature death. Our laboratory has recently shown that some of the known pathogenic mutations augment the reactive oxygen species (ROS) generation capacity of LADH, which may contribute to the clinical presentations. A recent report concluded that elevated oxidative stress generated by the above mutants turns the lipoic acid cofactor on the E2 subunits dysfunctional. In the present contribution we generated by molecular dynamics (MD) simulation the conformation of LADH that is proposed to be compatible with ROS generation. We propose here for the first time the structural changes, which are likely to turn the physiological LADH conformation to its ROS-generating conformation. We also created nine of the pathogenic mutants of the ROS-generating conformation and again used MD simulation to detect structural changes that the mutations induced in this LADH conformation. We propose the structural changes that may lead to the modulation in ROS generation of LADH by the pathogenic mutations. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Determination of the conformation of d(GGAAATTTCC) sub 2 in solution by use of sup 1 H NMR and restrained molecular dynamics

    SciTech Connect

    Katahira, Masato; Sugeta, Hiromu; Kyogoku, Yoshimasa; Fujii, S. )

    1990-08-07

    The conformation of the putative bent DNA d(GGAAATTTCC){sub 2} in solution was studied by use of {sup 1}H NMR and restrained molecular dynamics. Most of the resonances were assigned sequentially. A total of 182 interproton distance restraints were determined from two-dimensional nuclear Overhauser effect spectra with short mixing times. Torsion angle restraints for each sugar moiety were determined by qualitative analysis of a two-dimensional correlated spectrum. Restrained molecular dynamics was carried out with the interproton distances and torsion angles incorporated into the total energy function of the system in the form of effective potential terms. On the other hand, the conformations obtained by use of molecular dynamics without experimental restraints or restrained energy minimization depended heavily on the initial conformations, and convergence to a similar conformation was not attained. The conformation obtained by use of restrained molecular dynamics exhibits a few remarkable features. The second G residue takes on the BII conformation rather than the standard BI conformation. There is discontinuity of the sugar puckering between the eight T and ninth C. The minor groove of the oligo(dA) tract is rather compressed. As a result, d(GGAAATTTCC){sub 2} is bent.

  4. Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape

    PubMed Central

    Manibog, Kristine; Sankar, Kannan; Kim, Sun-Ae; Zhang, Yunxiang; Jernigan, Robert L.; Sivasankar, Sanjeevi

    2016-01-01

    Classical cadherin cell–cell adhesion proteins are essential for the formation and maintenance of tissue structures; their primary function is to physically couple neighboring cells and withstand mechanical force. Cadherins from opposing cells bind in two distinct trans conformations: strand-swap dimers and X-dimers. As cadherins convert between these conformations, they form ideal bonds (i.e., adhesive interactions that are insensitive to force). However, the biophysical mechanism for ideal bond formation is unknown. Here, we integrate single-molecule force measurements with coarse-grained and atomistic simulations to resolve the mechanistic basis for cadherin ideal bond formation. Using simulations, we predict the energy landscape for cadherin adhesion, the transition pathways for interconversion between X-dimers and strand-swap dimers, and the cadherin structures that form ideal bonds. Based on these predictions, we engineer cadherin mutants that promote or inhibit ideal bond formation and measure their force-dependent kinetics using single-molecule force-clamp measurements with an atomic force microscope. Our data establish that cadherins adopt an intermediate conformation as they shuttle between X-dimers and strand-swap dimers; pulling on this conformation induces a torsional motion perpendicular to the pulling direction that unbinds the proteins and forms force-independent ideal bonds. Torsional motion is blocked when cadherins associate laterally in a cis orientation, suggesting that ideal bonds may play a role in mechanically regulating cadherin clustering on cell surfaces. PMID:27621473

  5. Probing dynamic conformations of the high-molecular-weight αB-crystallin heat shock protein ensemble by NMR spectroscopy.

    PubMed

    Baldwin, Andrew J; Walsh, Patrick; Hansen, D Flemming; Hilton, Gillian R; Benesch, Justin L P; Sharpe, Simon; Kay, Lewis E

    2012-09-19

    Solution- and solid-state nuclear magnetic resonance (NMR) spectroscopy are highly complementary techniques for studying supra-molecular structure. Here they are employed for investigating the molecular chaperone αB-crystallin, a polydisperse ensemble of between 10 and 40 identical subunits with an average molecular mass of approximately 600 kDa. An IxI motif in the C-terminal region of each of the subunits is thought to play a critical role in regulating the size distribution of oligomers and in controlling the kinetics of subunit exchange between them. Previously published solid-state NMR and X-ray results are consistent with a bound IxI conformation, while solution NMR studies provide strong support for a highly dynamic state. Here we demonstrate through FROSTY (freezing rotational diffusion of protein solutions at low temperature and high viscosity) MAS (magic angle spinning) NMR that both populations are present at low temperatures (<0 °C), while at higher temperatures only the mobile state is observed. Solution NMR relaxation dispersion experiments performed under physiologically relevant conditions establish that the motif interchanges between flexible (highly populated) and bound (sparsely populated) states. This work emphasizes the importance of using multiple methods in studies of supra-molecules, especially for highly dynamic ensembles where sample conditions can potentially affect the conformational properties observed.

  6. Pseudo generators for under-resolved molecular dynamics

    NASA Astrophysics Data System (ADS)

    Bittracher, A.; Hartmann, C.; Junge, O.; Koltai, P.

    2015-09-01

    Many features of a molecule which are of physical interest (e.g. molecular conformations, reaction rates) are described in terms of its dynamics in configuration space. This article deals with the projection of molecular dynamics in phase space onto configuration space. Specifically, we study the situation that the phase space dynamics is governed by a stochastic Langevin equation and study its relation with the configurational Smoluchowski equation in the three different scaling regimes: Firstly, the Smoluchowski equations in non-Cartesian geometries are derived from the overdamped limit of the Langevin equation. Secondly, transfer operator methods are used to describe the metastable behaviour of the system at hand, and an explicit small-time asymptotics is derived on which the Smoluchowski equation turns out to govern the dynamics of the position coordinate (without any assumptions on the damping). By using an adequate reduction technique, these considerations are then extended to one-dimensional reaction coordinates. Thirdly, we sketch three different approaches to approximate the metastable dynamics based on time-local information only.

  7. Molecular cobalt pentapyridine catalysts for generating hydrogen from water.

    PubMed

    Sun, Yujie; Bigi, Julian P; Piro, Nicholas A; Tang, Ming Lee; Long, Jeffrey R; Chang, Christopher J

    2011-06-22

    A set of robust molecular cobalt catalysts for the generation of hydrogen from water is reported. The cobalt complex supported by the parent pentadentate polypyridyl ligand PY5Me(2) features high stability and activity and 100% Faradaic efficiency for the electrocatalytic production of hydrogen from neutral water, with a turnover number reaching 5.5 × 10(4) mol of H(2) per mole of catalyst with no loss in activity over 60 h. Control experiments establish that simple Co(II) salts, the free PY5Me(2) ligand, and an isostructural PY5Me(2) complex containing redox-inactive Zn(II) are all ineffective for this reaction. Further experiments demonstrate that the overpotential for H(2) evolution can be tuned by systematic substitutions on the ancillary PY5Me(2) scaffold, presaging opportunities to further optimize this first-generation platform by molecular design.

  8. Molecular simulations of conformation change and aggregation of HIV-1 Vpr13-33 on graphene oxide

    NASA Astrophysics Data System (ADS)

    Zeng, Songwei; Zhou, Guoquan; Guo, Jianzhong; Zhou, Feng; Chen, Junlang

    2016-04-01

    Recent experiments have reported that the fragment of viral protein R (Vpr), Vpr13-33, can assemble and change its conformation after adsorbed on graphene oxide (GO) and then reduce its cytotoxicity. This discovery is of great importance, since the mutation of Vpr13-33 can decrease the viral replication, viral load and delay the disease progression. However, the interactions between Vpr13-33 and GO at atomic level are still unclear. In this study, we performed molecular dynamics simulation to investigate the dynamic process of the adsorption of Vpr13-33 onto GO and the conformation change after aggregating on GO surface. We found that Vpr13-33 was adsorbed on GO surface very quickly and lost its secondary structure. The conformation of peptides-GO complex was highly stable because of π-π stacking and electrostatic interactions. When two peptides aggregated on GO, they did not dimerize, since the interactions between the two peptides were much weaker than those between each peptide and GO.

  9. Crystal structure analysis, covalent docking and molecular dynamics calculations reveal a conformational switch in PhaZ7 PHB depolymerase.

    PubMed

    Kellici, Tahsin F; Mavromoustakos, Thomas; Jendrossek, Dieter; Papageorgiou, Anastassios C

    2017-04-03

    An open and a closed conformation of a surface loop in PhaZ7 extracellular poly(3-hydroxybutyrate) depolymerase were identified in two high resolution crystal structures of a PhaZ7 Y105E mutant. Molecular dynamics (MD) simulations revealed high root mean square fluctuations (RMSF) of the 281-295 loop, in particular at residue Asp289 (RMSF 7.62 Å). Covalent docking between a 3-hydroxybutyric acid trimer and the catalytic residue Ser136 showed that the binding energy of the substrate is significantly more favourable in the open loop conformation compared to that in the closed loop conformation. MD simulations with the substrate covalently bound depicted 1 Å RMSF higher values for the residues 281-295 in comparison to the apo (substrate-free) form. In addition, the presence of the substrate in the active site enhanced the ability of the loop to adopt a closed form. Taken together, the analysis suggests that the flexible loop 281-295 of PhaZ7 depolymerase can act as a lid domain to control substrate access to the active site of the enzyme. This article is protected by copyright. All rights reserved.

  10. PERSPECTIVE: Intra-molecular chaperone: the role of the N-terminal in conformational selection and kinetic control

    NASA Astrophysics Data System (ADS)

    Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth

    2009-03-01

    The vast majority of the proteins in nature are under thermodynamic control, consistent with the universally accepted notion that proteins exist in their thermodynamically most stable state. Yet, recently a number of examples of proteins whose fold is under kinetic control have come to light. Their functions and environments vary. The first among these are some proteases, discovered in the early 1990s. There, an N-terminal proregion is self-cleaved after the protein folded, leaving the remainder of the chain in a kinetically trapped state. A related scenario was observed for microcin J25, an antibacterial peptide. This peptide presents a trapped covalently knotted conformation. The third and the most recently discovered case is the multidrug-resistant transporter protein, P-glycoprotein. There, a synonymous 'silent' mutation leads to ribosome stalling with a consequent altered kinetically trapped state. Here we argue that in all three examples, the N-terminal plays the role of an intra-molecular chaperone, that is, the N-terminal conformation selects among all competing local conformations of a downstream segment. By providing a pattern, the N-terminal chaperone segment assists the protein folding process. If the N-terminal is subsequently cleaved, the protein can be under kinetic control, since it is trapped in a thermodynamically less-stable state.

  11. Impact of molecular conformation on barriers to internal methyl rotation: the rotational spectrum of m-methylbenzaldehyde.

    PubMed

    Shirar, Amanda J; Wilcox, David S; Hotopp, Kelly M; Storck, Giana L; Kleiner, Isabelle; Dian, Brian C

    2010-11-25

    The ground state spectrum of m-methylbenzaldehyde (m-MBA) was measured with a chirped-pulse Fourier transform microwave (CP-FTMW) spectrometer. The methyl rotor on m-MBA introduces an internal rotation barrier, which leads to splitting of the torsional energy level degeneracy into A and E states. Ab initio calculations predict a low torsional barrier for both the O-cis and O-trans conformers, resulting in a large doublet splitting up to several gigahertz in the frequency spectrum. The rotational constants, distortion terms, and V(3) values for both species have been determined from the ground state rotational spectrum using the BELGI-C(s) fitting program. There are significant differences in the torsional potential for the O-cis and O-trans m-MBA conformers. Molecular orbitals and resonance structures for each conformer are analyzed to understand the difference in torsional barrier height as well as the irregular shape of the O-trans torsional potential.

  12. Rules for generating conformers and their relative energies in n-alkanes with a heteroelement O or S: ethers and alcohols, or sulfides and thiols.

    PubMed

    Vansteenkiste, P; Pauwels, E; Van Speybroeck, V; Waroquier, M

    2005-10-27

    With the aid of density functional theory calculations, all conformers of several single-chain alcohols, thiols, ethers, and sulfides are investigated. Starting from earlier computational works on n-alkanes, we construct an extended set of general rules for predicting the number and occurrence of conformers in these oxygen- or sulfur-containing compounds. In alcohols and thiols, it is found that only the conformers generated by internal rotations in the HXCH(2)CH(2)CH(2) (X = O or S) top are distinctive from those in n-alkanes. In ethers and sulfides, the primary influence of the heteroelement also extends up to three internal rotations, but many more conformers are possible. However, a number of double gauche sequences are forbidden, and therefore, several conformers can be eliminated. These exclusions in particular make up a set of rules for eventually deducing all possible conformers. Furthermore, on the basis of only an exact calculation of these gg conformations in addition to single gauche conformers, it is possible to make an accurate estimate of the relative energy. This two-dimensional approximation scheme constitutes an effective tool for adequately describing the relative energies of all possible conformers at a minimal computational cost.

  13. Vibrational spectra and molecular conformation of taurine and its related compounds

    NASA Astrophysics Data System (ADS)

    Ohno, Keiichi; Mandai, Yoshitaka; Matsuura, Hiroatsu

    1992-04-01

    IR and Raman spectra have been measured for taurine (2-aminoethanesulfonic acid) and its sodium salt in the solid state and Raman spectra for aqueous solutions of taurine with different pH values. Normal coordinate treatment has been carried out. The analysis of the spectra has indicated that, in the solid state, the molecule of taurine takes the gauche form while that of the sodium salt takes the trans form, and that the trans and gauche forms coexist in both acidic and basic aqueous solutions. The CS stretching bands for the gauche and trans forms were observed at 742 cm -1 and 803 cm -1 respectively. These bands were applied to a conformational analysis of other compounds containing a taurine skeleton; sodium taurocholate takes the gauche conformation about the bond axis NCCS.

  14. An enhanced molecular dynamics study of HPPK-ATP conformation space exploration and ATP binding to HPPK.

    PubMed

    Su, Li; Cukier, Robert I

    2009-03-12

    HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase) catalyzes the transfer of pyrophosphate from ATP to HP (6-hydroxymethyl-7,8-dihydropterin). This first reaction in the folate biosynthetic pathway is an important target for potential antimicrobial agents. In this work, the mechanism by which HPPK traps and binds ATP is studied by molecular dynamics (MD)-based methods. Based on the ternary crystal structure of HPPK with an ATP mimic and HP, a complex of ATPMg(2) and HPPK is simulated and found to undergo small conformational changes with conventional MD, as does also conventional MD when started from the apo crystal structure. The introduction of restraints in the MD that serve to move HPPK-ATP from its ternary complex (closed) to apo-like (open) forms shows that throughout the restraint path ATP remains bound to HPPK. That ATP remains bound suggests that there is an ensemble of conformations with ATP bound to HPPK that span the apo to more ligand-bound-like conformations, consistent with the pre-existing equilibrium hypothesis of ligand binding, whereby a ligand can select from and bind to a broad range of protein conformations. In the apo-like conformations, ATPMg(2) remains bound to HPPK through a number of mainly salt-bridge-like interactions between several negatively charged residues and the two magnesium cations. The introduction of a reweight method that enhances the sampling of MD by targeting explicit terms in the force field helps define the interactions that bind ATP to HPPK. Using the reweight method, conformational and center of mass motions of ATP, driven by the breaking and making of hydrogen bonds and salt bridges, are identified that lead to ATP separating from HPPK. An elastic normal mode (ENM) approach to opening the ternary complex and closing the apo crystal structures was carried out. The ENM analysis of the apo structure analysis shows one mode that does have a closing motion of HPPK loops, but the direction does not correlate

  15. Molecular Docking Study of Conformational Polymorph: Building Block of Crystal Chemistry

    PubMed Central

    Dubey, Rashmi; Tewari, Ashish Kumar; Singh, Ved Prakash; Singh, Praveen; Dangi, Jawahar Singh; Puerta, Carmen; Valerga, Pedro; Kant, Rajni

    2013-01-01

    Two conformational polymorphs of novel 2-[2-(3-cyano-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-ethoxy]-4,6-dimethyl nicotinonitrile have been developed. The crystal structure of both polymorphs (1a and 1b) seems to be stabilized by weak interactions. A difference was observed in the packing of both polymorphs. Polymorph 1b has a better binding affinity with the cyclooxygenase (COX-2) receptor than the standard (Nimesulide). PMID:24250264

  16. Molecular docking sites designed for the generation of highly crystalline covalent organic frameworks

    NASA Astrophysics Data System (ADS)

    Ascherl, Laura; Sick, Torben; Margraf, Johannes T.; Lapidus, Saul H.; Calik, Mona; Hettstedt, Christina; Karaghiosoff, Konstantin; Döblinger, Markus; Clark, Timothy; Chapman, Karena W.; Auras, Florian; Bein, Thomas

    2016-04-01

    Covalent organic frameworks (COFs) formed by connecting multidentate organic building blocks through covalent bonds provide a platform for designing multifunctional porous materials with atomic precision. As they are promising materials for applications in optoelectronics, they would benefit from a maximum degree of long-range order within the framework, which has remained a major challenge. We have developed a synthetic concept to allow consecutive COF sheets to lock in position during crystal growth, and thus minimize the occurrence of stacking faults and dislocations. Hereby, the three-dimensional conformation of propeller-shaped molecular building units was used to generate well-defined periodic docking sites, which guided the attachment of successive building blocks that, in turn, promoted long-range order during COF formation. This approach enables us to achieve a very high crystallinity for a series of COFs that comprise tri- and tetradentate central building blocks. We expect this strategy to be transferable to a broad range of customized COFs.

  17. Molecular interactions of proteins and peptides at interfaces studied by sum frequency generation vibrational spectroscopy.

    PubMed

    Liu, Yuwei; Jasensky, Joshua; Chen, Zhan

    2012-01-31

    Interfacial peptides and proteins are critical in many biological processes and thus are of interest to various research fields. To study these processes, surface sensitive techniques are required to completely describe different interfacial interactions intrinsic to many complicated processes. Sum frequency generation (SFG) spectroscopy has been developed into a powerful tool to investigate these interactions and mechanisms of a variety of interfacial peptides and proteins. It has been shown that SFG has intrinsic surface sensitivity and the ability to acquire conformation, orientation, and ordering information about these systems. This paper reviews recent studies on peptide/protein-substrate interactions, peptide/protein-membrane interactions, and protein complexes at interfaces and demonstrates the ability of SFG on unveiling the molecular pictures of complicated interfacial biological processes. © 2011 American Chemical Society

  18. Electrospinning of gelatin for tissue engineering--molecular conformation as one of the overlooked problems.

    PubMed

    Sajkiewicz, P; Kołbuk, D

    2014-01-01

    Gelatin is one of the most promising materials in tissue engineering as a scaffold component. This biopolymer indicates biocompatibility and bioactivity caused by the existence of specific amino acid sequences, being preferred sites for interactions with cells, with high similarity to natural extracellular matrix. The present paper does not aspire to be a full review of electrospinning of gelatin and gelatin containing nanofibers as scaffolds in tissue engineering. It is focused on the still open question of the role of the higher order structures of gelatin in scaffold's bioactivity/functionality. Gelatin molecules can adopt various conformations depending on temperature, solvent, pH, etc. Our review indicates the potential ways for formation of α-helix conformation during electrospinning and the methods of further structure stabilization. It is intuitively expected that the native α-helix conformation appearing as a result of partial renaturation of gelatin can be beneficial from the viewpoint of bioactivity of scaffolds, providing thus a much cheaper alternative approach as opposed to expensive electrospinning of native collagen.

  19. Conformational Dynamics in FKBP Domains: Relevance to Molecular Signaling and Drug Design.

    PubMed

    LeMaster, David M; Hernandez, Griselda

    2015-01-01

    Among the 22 FKBP domains in the human genome, FKBP12.6 and the first FKBP domains (FK1) of FKBP51 and FKBP52 are evolutionarily and structurally most similar to the archetypical FKBP12. As such, the development of inhibitors with selectivity among these four FKBP domains poses a significant challenge for structure-based design. The pleiotropic effects of these FKBP domains in a range of signaling processes such as the regulation of ryanodine receptor calcium channels by FKBP12 and FKBP12.6 and steroid receptor regulation by the FK1 domains of FKBP51 and FKBP52 amply justify the efforts to develop selective therapies. In contrast to their close structural similarities, these four FKBP domains exhibit a substantial diversity in their conformational flexibility. A number of distinct conformational transitions have been characterized for FKBP12 spanning timeframes from 20 s to 10 ns and in each case these dynamics have been shown to markedly differ from the conformational behavior for one or more of the other three FKBP domains. Protein flexibilitybased inhibitor design could draw upon the transitions that are significantly populated in only one of the targeted proteins. Both the similarities and differences among these four proteins valuably inform the understanding of how dynamical effects propagate across the FKBP domains as well as potentially how such intramolecular transitions might couple to the larger scale transitions that are central to the signaling complexes in which these FKBP domains function.

  20. Conformational variation of the central CG site in d(ATGACGTCAT)2 and d(GAAAACGTTTTC)2. An NMR, molecular modelling and 3D-homology investigation.

    PubMed

    Cordier, C; Marcourt, L; Petitjean, M; Dodin, G

    1999-05-01

    The determination of the solution structure of two self-complementary oligomers d(ATGACGTCAT)2 (CG10) and d(GAAAACGTTTTC)2 (CG12), both containing the 5'-pur-ACGT-pyr-3' sequence, is reported. The impact of the base context on the conformation of the central CpG site has been examined by a combined approach of: (a) 2D 1H-NMR and 31P-NMR; (b) molecular mechanics under experimental constraints; (c) back-calculations of NOESY spectra and iterative refinements of distances; and (d) 3D-homology search of the central tetrad ACGT within the complete oligonucleotides. A full NMR study of each fragment is achieved by means of standard 2D experiments: NOESY, 2D homonuclear Hartmann-Hahn spectroscopy, double-quantum-filtered COSY and heteronuclear 1H-31P correlation. Sugar phase angle, epsilon-zeta difference angle and NOE-derived distances are input as experimental constraints to generate molecular models by energy minimization with the help of jumna. The morass program is used to iteratively refine the structures obtained. The similarity of the two ACGTs within the whole oligonucleotides is investigated. Both the decamer and the dodecamer adopt a B-like DNA conformation. However, the helical parameters within this conformational type are significantly different in CG12 and CG10. The central CpG step conformation is not locked by its nearest environment (5'A and 3'T) as seen from the structural analysis of ACGT in the two molecules. In CG12, despite the presence of runs of A-T pairs, CpG presents a high twist of 43 degrees and a sugar phase at the guanine of about 180 degrees, previously observed in other ACGT-containing-oligomers. Conversely, ACGT in CG10 exhibits strong inclinations, positive rolls, a flat profile of sugar phase, twist and glycosidic angles, as a result of the nucleotide sequence extending beyond the tetrad. The structural specificity of CG10 and its flexibility (as reflected by its energy) are tentatively related to the process of recognition of the

  1. Effect of hydrophobic groups on the adsorption conformation of modified polycarboxylate superplasticizer investigated by molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Zhao, Hongxia; Wang, Yanwei; Yang, Yong; Shu, Xin; Yan, Han; Ran, Qianping

    2017-06-01

    All-atom molecular dynamics (MD) simulations were used to study the adsorption conformations of hydrophobically-modified comb-shaped polycarboxylate ether-based (PCE) superplasticizer molecules on a model surface of dicalcium silicate (C2S) in vacuum and in an explicit solution, respectively. Three different hydrophobic modifying groups, namely, the ethyl group, the n-butyl group and the phenyl group, decorated to the backbone, were examined. Comparing the hydrophobically-modified PCEs to the unmodified one, differences were found in the binding energy, the adsorption conformation and the water density at the interface. The interaction between PCE molecules and C2S was weakened in a solution with explicit solvents than that obtained from vacuum-based simulations. The presence of hydrophobic groups lowered the polymer-surface binding energy, decreased the radius of gyration (Rg) of the adsorbed polymer, increased the peak position in the heavy-atom density profiles in the direction perpendicular to the surface, and also caused the adsorbed conformations to be more globular in shape. The parallel and perpendicular components (relative to the surface plane) of the geometric sizes of the adsorbed polymers were calculated, and the results showed that the presence of hydrophobically modifying groups decreased the in-plane radius while increased the adsorption layer thickness compared to the unmodified control. The presence of PCEs perturbed the dense water layer above the C2S surface and lowered the water density. Perturbations to the interfacial water density were found to correlate nicely with the adsorbed conformations of PCEs.

  2. Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) for Conformational Space Search of Peptide and Miniprotein.

    PubMed

    Hao, Ge-Fei; Xu, Wei-Fang; Yang, Sheng-Gang; Yang, Guang-Fu

    2015-10-23

    Protein and peptide structure predictions are of paramount importance for understanding their functions, as well as the interactions with other molecules. However, the use of molecular simulation techniques to directly predict the peptide structure from the primary amino acid sequence is always hindered by the rough topology of the conformational space and the limited simulation time scale. We developed here a new strategy, named Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) to identify the native states of a peptide and miniprotein. A cluster of near native structures could be obtained by using the MSA-MD method, which turned out to be significantly more efficient in reaching the native structure compared to continuous MD and conventional SA-MD simulation.

  3. Conformation, structure and molecular solvation: a spectroscopic and computational study of 2-phenoxy ethanol and its singly and multiply hydrated clusters

    NASA Astrophysics Data System (ADS)

    Macleod, Neil A.; Simons, John P.

    2002-10-01

    The conformational landscapes of 2-phenoxy ethanol (POX) and its hydrated clusters have been studied in the gas-phase, providing a model for pharmaceutical β-blockers. A combination of experimental techniques, including resonant two-photon ionisation (R2PI), laser-induced-fluorescence (LIF) and resonant ion-dip infra-red spectroscopy (RIDIRS), coupled with high-level ab initio calculations has allowed the assignment of the individually resolved spectral features to discrete conformational and supra-molecular structures. Assignments were made by comparison of experimental vibrational spectra and partially resolved ultra-violet rotational band contours with those predicted from quantum chemical calculations. The isolated molecule displays a solitary structure with an extended geometry of the side-chain which is stabilised by an intramolecular hydrogen-bond between the alcohol (proton donor) and the ether (proton acceptor) groups of the side-chain. In singly hydrated clusters the water molecule is accommodated by insertion into the intramolecular hydrogen-bond. In the doubly hydrated and higher clusters cyclic structures are generated which incorporate both the water molecules and the terminal OH group of the side-chain; additional (weak) hydrogen bonded interactions with the phenoxy group provide a degree of selectivity but essentially, the water 'droplet' forms on the end of the alcohol side-chain.

  4. Markov models of molecular kinetics: generation and validation.

    PubMed

    Prinz, Jan-Hendrik; Wu, Hao; Sarich, Marco; Keller, Bettina; Senne, Martin; Held, Martin; Chodera, John D; Schütte, Christof; Noé, Frank

    2011-05-07

    Markov state models of molecular kinetics (MSMs), in which the long-time statistical dynamics of a molecule is approximated by a Markov chain on a discrete partition of configuration space, have seen widespread use in recent years. This approach has many appealing characteristics compared to straightforward molecular dynamics simulation and analysis, including the potential to mitigate the sampling problem by extracting long-time kinetic information from short trajectories and the ability to straightforwardly calculate expectation values and statistical uncertainties of various stationary and dynamical molecular observables. In this paper, we summarize the current state of the art in generation and validation of MSMs and give some important new results. We describe an upper bound for the approximation error made by modeling molecular dynamics with a MSM and we show that this error can be made arbitrarily small with surprisingly little effort. In contrast to previous practice, it becomes clear that the best MSM is not obtained by the most metastable discretization, but the MSM can be much improved if non-metastable states are introduced near the transition states. Moreover, we show that it is not necessary to resolve all slow processes by the state space partitioning, but individual dynamical processes of interest can be resolved separately. We also present an efficient estimator for reversible transition matrices and a robust test to validate that a MSM reproduces the kinetics of the molecular dynamics data.

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

    SciTech Connect

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

    2008-01-01

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

  6. Modular hyperthermostable bacterial endo-β-1,4-mannanase: molecular shape, flexibility and temperature-dependent conformational changes.

    PubMed

    da Silva, Viviam M; Colussi, Francieli; de Oliveira Neto, Mario; Braz, Antonio S K; Squina, Fabio M; Oliveira, Cristiano L P; Garcia, Wanius

    2014-01-01

    Endo-β-1,4-mannanase from Thermotoga petrophila (TpMan) is a hyperthermostable enzyme that catalyzes the hydrolysis of β-1,4-mannoside linkages in various mannan-containing polysaccharides. A recent study reported that TpMan is composed of a GH5 catalytic domain joined by a linker to a carbohydrate-binding domain. However, at this moment, there is no three-dimensional structure determined for TpMan. Little is known about the conformation of the TpMan as well as the role of the length and flexibility of the linker on the spatial arrangement of the constitutive domains. In this study, we report the first structural characterization of the entire TpMan by small-angle X-ray scattering combined with the three-dimensional structures of the individual domains in order to shed light on the low-resolution model, overall dimensions, and flexibility of this modular enzyme at different temperatures. The results are consistent with a linker with a compact structure and that occupies a small volume with respect to its large number of amino acids. Furthermore, at 20°C the results are consistent with a model where TpMan is a molecule composed of three distinct domains and that presents some level of molecular flexibility in solution. Even though the full enzyme has some degree of molecular flexibility, there might be a preferable conformation, which could be described by the rigid-body modeling procedure. Finally, the results indicate that TpMan undergoes a temperature-driven transition between conformational states without a significant disruption of its secondary structure. Our results suggest that the linker can optimize the geometry between the other two domains with respect to the substrate at high temperatures. These studies should provide a useful basis for future biophysical studies of entire TpMan.

  7. Modular Hyperthermostable Bacterial Endo-β-1,4-Mannanase: Molecular Shape, Flexibility and Temperature-Dependent Conformational Changes

    PubMed Central

    de Oliveira Neto, Mario; Braz, Antonio S. K.; Squina, Fabio M.; Oliveira, Cristiano L. P.; Garcia, Wanius

    2014-01-01

    Endo-β-1,4-mannanase from Thermotoga petrophila (TpMan) is a hyperthermostable enzyme that catalyzes the hydrolysis of β-1,4-mannoside linkages in various mannan-containing polysaccharides. A recent study reported that TpMan is composed of a GH5 catalytic domain joined by a linker to a carbohydrate-binding domain. However, at this moment, there is no three-dimensional structure determined for TpMan. Little is known about the conformation of the TpMan as well as the role of the length and flexibility of the linker on the spatial arrangement of the constitutive domains. In this study, we report the first structural characterization of the entire TpMan by small-angle X-ray scattering combined with the three-dimensional structures of the individual domains in order to shed light on the low-resolution model, overall dimensions, and flexibility of this modular enzyme at different temperatures. The results are consistent with a linker with a compact structure and that occupies a small volume with respect to its large number of amino acids. Furthermore, at 20°C the results are consistent with a model where TpMan is a molecule composed of three distinct domains and that presents some level of molecular flexibility in solution. Even though the full enzyme has some degree of molecular flexibility, there might be a preferable conformation, which could be described by the rigid-body modeling procedure. Finally, the results indicate that TpMan undergoes a temperature-driven transition between conformational states without a significant disruption of its secondary structure. Our results suggest that the linker can optimize the geometry between the other two domains with respect to the substrate at high temperatures. These studies should provide a useful basis for future biophysical studies of entire TpMan. PMID:24671161

  8. Study on relationship between expression level and molecular conformations of gene drugs targeting to hepatoma cells in vitro

    PubMed Central

    Yang, Dong-Ye; Lu, Fang-Gen; Tang, Xi-Xiang; Zhao, Shui-Ping; Ouyang, Chun-Hui; Wu, Xiao-Ping; Liu, Xiao-Wei; Wu, Xiao-Ying

    2003-01-01

    AIM: To increase exogenous gene expression level by modulating molecular conformations of targeting gene drugs. METHODS: The full length cDNAs of both P40 and P35 subunits of human interleukin 12 were amplified through polymerase chain reaction (PCR) and cloned into eukaryotic expressing vectors pcDNA3.1 (±) to construct plasmids of P (+)/IL-12, P (+)/P40 and P (-)/P35. These plasmids were combined with ASOR-PLL to form two targeting gene drugs [ASOR-PLL-P (+)/IL-12 and ASOR-PLL-P (+)/P40 + ASOR-PLL-P (-)/P35] in optimal ratios. The conformations of these two drugs at various concentrations adjuvant were examined under electron microscope (EM) and the drugs were transfected into HepG2 (ASGr+) cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed with total RNA extracted from the transfected cells to determine the hIL12 mRNA transcript level. The hIL12 protein in the cultured supernatant was measured with enzyme-linked immunosorbent assay (ELISA) 48 hours after transfection. RESULTS: Targeting gene drugs, whose structures were granular and circle-like and diameters ranged from 25 nm to 150 nm, had the highest hIL-12 expression level. The hIL-12 expression level in the group co-transfected with ASOR-PLL-P (+)/P40 and ASOR-PLL-P (-)/P35 was higher than that of ASOR-PLL-P (+)/IL-12 transfected group. CONCLUSION: The molecular conformations of targeting gene drugs play an important role in exogenous gene expression level, the best structures are granular and circle-like and their diameters range from 25 nm to 150 nm. The sizes and linking styles of exogenous genes also have some effects on their expression level. PMID:12970883

  9. The effect of poly(trimethylene carbonate) molecular weight on macrophage behavior and enzyme adsorption and conformation.

    PubMed

    Vyner, Moira C; Li, Anne; Amsden, Brian G

    2014-11-01

    Poly(trimethylene carbonate) (PTMC) with molecular weights greater than 100 kg/mol is known to degrade readily in vivo while PTMC of less than 70 kg/mol is resistant to degradation. The reason for the molecular weight dependent degradation rate of PTMC is unclear, and may be due to differences in macrophage behavior or enzyme adsorption or activity. Macrophage number and production of reactive oxygen species (ROS) and esterase were measured when cultured on 60 and 100 kg/mol PTMC. Cholesterol esterase and lipase were adsorbed to 60 and 100 kg/mol PTMC and mass and viscoelastic properties of the adsorbed enzyme layers were measured. No significant differences were observed in macrophage number or production of degradative species. Significant differences were measured in mass, shear modulus and viscosity of the adsorbed cholesterol esterase layer, suggesting that the cholesterol esterase is adsorbing in a different conformation on the 60 and 100 kg/mol PTMC. Despite similar bulk moduli, the surface modulus of 60 kg/mol PTMC was significantly lower than 100 kg/mol. It is proposed that the difference in surface stiffness and polymer chain flexibility affect the arrangement of water bound to and freed from the polymer chains during adsorption, thus affecting enzymatic adsorption, conformation, and activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    PubMed

    Wei, Hsien-Hung; Li, Yen-Ching

    2016-07-01

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

  11. Effect of molecular conformation on spectroscopic properties of symmetrical Schiff bases derived from 1,4-phenylenediamine

    NASA Astrophysics Data System (ADS)

    Fang, Zhengjun; Cao, Chenzhong

    2013-03-01

    The relationship between the molecular conformation and spectroscopic properties of symmetrical bis-Schiff bases was explored experimentally. Seven samples of compounds p-X-C6H4CHdbnd NC6H4Ndbnd CHC6H4-p-X (X = OMe, Me, Et, Cl, F, CF3, or CN) were prepared for this study, and their crystal structures were measured by X-ray diffraction. Their λmax values in ethanol, acetonitrile, chloroform and cyclohexane solvents were measured, and their δC(Cdbnd N) values in chloroform-d were determined. The results show that the νmax is dependent on the substituents at the benzylidene ring and the dihedral angle τ of the titled molecules, and the term sin(τ) is suitable to modify the substituent effects on the νmax. However, experimental investigations indicate that the dihedral angle τ has a limited effect on the values of δC(Cdbnd N). This study provides a new understanding for the molecular conformation on spectroscopic properties of symmetrical Schiff bases.

  12. A molecular dynamics study of Fe2S2 putidaredoxin: multiple conformations of the C-terminal region.

    PubMed Central

    Roitberg, A E

    1997-01-01

    Putidaredoxin (Pdx) plays an essential role as an electron donor and effector in the biochemical cycle involving cytochrome P450cam. Only recently has an NMR-derived structure for this protein been published, but because of the presence of a paramagnetic Fe2S2 center, the NMR assignment could not be completed for residues within a region of 8 A around the active site. That region was modeled by homology with a related protein. The structural refinement for those experiments was done in vacuum, without the use of electrostatic terms in the force field. The present manuscript will describe and discuss a series of long-time, unrestrained, solution molecular dynamic runs for this system. Results will be presented that construct a molecular-level picture that rationalizes experimental results concerning the conformation and mobility of the C-terminal residue Trp106. At least two different conformers are found for this residue during the simulations. The time scale for interconversion between them is found to be in the subnanosecond regime. The results presented here open the possibility for studying binding and electron transfer between Pdx and P450cam, in a framework that allows for dynamical information to be used during the computational process, instead of the single structures deposited on the protein data base. PMID:9336209

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

    NASA Astrophysics Data System (ADS)

    Wei, Hsien-Hung; Li, Yen-Ching

    2016-07-01

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

  14. Glycation induces conformational changes in the amyloid-β peptide and enhances its aggregation propensity: molecular insights.

    PubMed

    Jana, Asis K; Batkulwar, Kedar B; Kulkarni, Mahesh J; Sengupta, Neelanjana

    2016-11-23

    The cytotoxicity of the amyloid beta (Aβ) peptide, implicated in the pathogenesis of Alzheimer's disease (AD), can be enhanced by its post-translational glycation, a series of non-enzymatic reactions with reducing sugars and reactive dicarbonyls. However, little is known about the underlying mechanisms that potentially enhance the cytotoxicity of the advanced glycation modified Aβ. In this work, fully atomistic molecular dynamics (MD) simulations are exploited to obtain direct molecular insights into the process of early Aβ self-assembly in the presence and absence of glycated lysine residues. Analyses of data exceeding cumulative timescales of 1 microsecond for each system reveal that glycation results in a stronger enthalpy of association between Aβ monomers and lower conformational entropy, in addition to a sharp overall increase in the beta-sheet content. Further analyses reveal that the enhanced interactions originate, in large part, due to markedly stronger, as well as new, inter-monomer salt bridging propensities in the glycated variety. Interestingly, these conformational and energetic effects are broadly reflected in preformed protofibrillar forms of Aβ small oligomers modified with glycation. Our combined results imply that glycation consolidates Aβ self-assembly regardless of its point of occurrence in the pathway. They provide a basis for further mechanistic studies and therapeutic endeavors that could potentially result in novel ways of combating AGE related AD progression.

  15. Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric α-Synuclein and Reduce Its Aggregation in Cells*

    PubMed Central

    Moree, Ben; Yin, Guowei; Lázaro, Diana F.; Munari, Francesca; Strohäker, Timo; Giller, Karin; Becker, Stefan; Outeiro, Tiago F.; Zweckstetter, Markus; Salafsky, Joshua

    2015-01-01

    Proteins are structurally dynamic molecules that perform specialized functions through unique conformational changes accessible in physiological environments. An ability to specifically and selectively control protein function via conformational modulation is an important goal for development of novel therapeutics and studies of protein mechanism in biological networks and disease. Here we applied a second-harmonic generation-based technique for studying protein conformation in solution and in real time to the intrinsically disordered, Parkinson disease related protein α-synuclein. From a fragment library, we identified small molecule modulators that bind to monomeric α-synuclein in vitro and significantly reduce α-synuclein aggregation in a neuronal cell culture model. Our results indicate that the conformation of α-synuclein is linked to the aggregation of protein in cells. They also provide support for a therapeutic strategy of targeting specific conformations of the protein to suppress or control its aggregation. PMID:26396193

  16. Solution NMR conformation of glycosaminoglycans.

    PubMed

    Pomin, Vitor H

    2014-04-01

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

  17. MoFlow: visualizing conformational changes in molecules as molecular flow improves understanding

    PubMed Central

    2015-01-01

    Background Current visualizations of molecular motion use a Timeline-analogous representation that conveys "first the molecule was shaped like this, then like this...". This scheme is orthogonal to the Pathline-like human understanding of motion "this part of the molecule moved from here to here along this path". We present MoFlow, a system for visualizing molecular motion using a Pathline-analogous representation. Results The MoFlow system produces high-quality renderings of molecular motion as atom pathlines, as well as interactive WebGL visualizations, and 3D printable models. In a preliminary user study, MoFlow representations are shown to be superior to canonical representations for conveying molecular motion. Conclusions Pathline-based representations of molecular motion are more easily understood than timeline representations. Pathline representations provide other advantages because they represent motion directly, rather than representing structure with inferred motion. PMID:26361501

  18. Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

    PubMed Central

    Liu, Lei; Li, Qiang; Zhang, Shuai; Wang, Xiaofeng; Hoffmann, Søren Vrønning; Li, Jingyuan; Liu, Zheng

    2016-01-01

    The differentiation of protein properties and biological functions arises from the variation in the primary and secondary structure. Specifically, in abnormal assemblies of protein, such as amyloid peptide, the secondary structure is closely correlated with the stable ensemble and the cytotoxicity. In this work, the early Aβ33‐42 aggregates forming the molecular monolayer at hydrophobic interface are investigated. The molecular monolayer of amyloid peptide Aβ33‐42 consisting of novel parallel β‐strand‐like structure is further revealed by means of a quantitative nanomechanical spectroscopy technique with force controlled in pico‐Newton range, combining with molecular dynamic simulation. The identified parallel β‐strand‐like structure of molecular monolayer is distinct from the antiparallel β‐strand structure of Aβ33‐42 amyloid fibril. This finding enriches the molecular structures of amyloid peptide aggregation, which could be closely related to the pathogenesis of amyloid disease. PMID:27818898

  19. Direct observation of bis(dicarbollyl)nickel conformers in solution by fluorescence spectroscopy: an approach to redox-controlled metallacarborane molecular motors.

    PubMed

    Safronov, Alexander V; Shlyakhtina, Natalia I; Everett, Thomas A; VanGordon, Monika R; Sevryugina, Yulia V; Jalisatgi, Satish S; Hawthorne, M Frederick

    2014-10-06

    As a continuation of work on metallacarborane-based molecular motors, the structures of substituted bis(dicarbollyl)nickel complexes in Ni(III) and Ni(IV) oxidation states were investigated in solution by fluorescence spectroscopy. Symmetrically positioned cage-linked pyrene molecules served as fluorescent probes to enable the observation of mixed meso-trans/dl-gauche (pyrene monomer fluorescence) and dl-cis/dl-gauche (intramolecular pyrene excimer fluorescence with residual monomer fluorescence) cage conformations of the nickelacarboranes in the Ni(III) and Ni(IV) oxidation states, respectively. The absence of energetically disfavored conformers in solution--dl-cis in the case of nickel(III) complexes and meso-trans in the case of nickel(IV)--was demonstrated based on spectroscopic data and conformer energy calculations in solution. The conformational persistence observed in solution indicates that bis(dicarbollyl)nickel complexes may provide attractive templates for building electrically driven and/or photodriven molecular motors.

  20. Structural and spectroscopic properties of the second generation phosphorus-viologen “molecular asterisk”

    NASA Astrophysics Data System (ADS)

    Furer, V. L.; Vandukov, A. E.; Katir, N.; Majoral, J. P.; El Kadib, A.; Caminade, A. M.; Bousmina, M.; Kovalenko, V. I.

    2013-11-01

    The FTIR and FT Raman spectra of the second generation phosphorus-viologen "molecular asterisk" G2 built from cyclotriphosphazene core with 12 viologen units and 6 terminal phosphonate groups have been recorded and analyzed. The experimental X-ray data of 1,1-bis(4-formylbenzyl)-4,4‧-bipyridinium bis(hexaflurophosphate) was used in molecular modeling studies. The optimization of isolated 1,1-bis(4-formylbenzyl)-4,4‧-bipyridinium (BFBP) molecule without counter ions PF6- does not lead to significant changes of dihedral angles, thus the molecular conformation does not depend on interactions with the counter ions. The structural optimization and normal mode analysis were performed for G2 on the basis of the density functional theory (DFT). The calculated geometrical parameters and harmonic vibrational frequencies are predicted in a good agreement with the experimental data. It was found that G2 has a kind of "egg timer" structure with planar Osbnd C6H4sbnd CHdbnd Nsbnd N(CH3)sbnd fragments and slightly non-planar cyclotriphosphazene core. The experimental IR and Raman spectra of G2 were interpreted by means of potential energy distribution.

  1. Structural and spectroscopic properties of the second generation phosphorus-viologen "molecular asterisk".

    PubMed

    Furer, V L; Vandukov, A E; Katir, N; Majoral, J P; El Kadib, A; Caminade, A M; Bousmina, M; Kovalenko, V I

    2013-11-01

    The FTIR and FT Raman spectra of the second generation phosphorus-viologen "molecular asterisk" G2 built from cyclotriphosphazene core with 12 viologen units and 6 terminal phosphonate groups have been recorded and analyzed. The experimental X-ray data of 1,1-bis(4-formylbenzyl)-4,4'-bipyridinium bis(hexaflurophosphate) was used in molecular modeling studies. The optimization of isolated 1,1-bis(4-formylbenzyl)-4,4'-bipyridinium (BFBP) molecule without counter ions PF6(-) does not lead to significant changes of dihedral angles, thus the molecular conformation does not depend on interactions with the counter ions. The structural optimization and normal mode analysis were performed for G2 on the basis of the density functional theory (DFT). The calculated geometrical parameters and harmonic vibrational frequencies are predicted in a good agreement with the experimental data. It was found that G2 has a kind of "egg timer" structure with planar OC6H4CHNN(CH3) fragments and slightly non-planar cyclotriphosphazene core. The experimental IR and Raman spectra of G2 were interpreted by means of potential energy distribution.

  2. Extended blood group molecular typing and next-generation sequencing.

    PubMed

    Liu, Zhugong; Liu, Meihong; Mercado, Teresita; Illoh, Orieji; Davey, Richard

    2014-10-01

    Several high-throughput multiplex blood group molecular typing platforms have been developed to predict blood group antigen phenotypes. These molecular systems support extended donor/patient matching by detecting commonly encountered blood group polymorphisms as well as rare alleles that determine the expression of blood group antigens. Extended molecular typing of a large number of blood donors by high-throughput platforms can increase the likelihood of identifying donor red blood cells that match those of recipients. This is especially important in the management of multiply-transfused patients who may have developed several alloantibodies. Nevertheless, current molecular techniques have limitations. For example, they detect only predefined genetic variants. In contrast, target enrichment next-generation sequencing (NGS) is an emerging technology that provides comprehensive sequence information, focusing on specified genomic regions. Target enrichment NGS is able to assess genetic variations that cannot be achieved by traditional Sanger sequencing or other genotyping platforms. Target enrichment NGS has been used to detect both known and de novo genetic polymorphisms, including single-nucleotide polymorphisms, indels (insertions/deletions), and structural variations. This review discusses the methodology, advantages, and limitations of the current blood group genotyping techniques and describes various target enrichment NGS approaches that can be used to develop an extended blood group genotyping assay system.

  3. 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.

  4. Mean-field calculations of chain packing and conformational statistics in lipid bilayers: comparison with experiments and molecular dynamics studies.

    PubMed Central

    Fattal, D R; Ben-Shaul, A

    1994-01-01

    A molecular, mean-field theory of chain packing statistics in aggregates of amphiphilic molecules is applied to calculate the conformational properties of the lipid chains comprising the hydrophobic cores of dipalmitoyl-phosphatidylcholine (DPPC), dioleoyl-phosphatidylcholine (DOPC), and palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayers in their fluid state. The central quantity in this theory, the probability distribution of chain conformations, is evaluated by minimizing the free energy of the bilayer assuming only that the segment density within the hydrophobic region is uniform (liquidlike). Using this distribution we calculate chain conformational properties such as bond orientational order parameters and spatial distributions of the various chain segments. The lipid chains, both the saturated palmitoyl (-(CH2)14-CH3) and the unsaturated oleoyl (-(CH2)7-CH = CH-(CH2)7-CH3) chains are modeled using rotational isomeric state schemes. All possible chain conformations are enumerated and their statistical weights are determined by the self-consistency equations expressing the condition of uniform density. The hydrophobic core of the DPPC bilayer is treated as composed of single (palmitoyl) chain amphiphiles, i.e., the interactions between chains originating from the same lipid headgroup are assumed to be the same as those between chains belonging to different molecules. Similarly, the DOPC system is treated as a bilayer of oleoyl chains. The POPC bilayer is modeled as an equimolar mixture of palmitoyl and oleoyl chains. Bond orientational order parameter profiles, and segment spatial distributions are calculated for the three systems above, for several values of the bilayer thickness (or, equivalently, average area/headgroup) chosen, where possible, so as to allow for comparisons with available experimental data and/or molecular dynamics simulations. In most cases the agreement between the mean-field calculations, which are relatively easy to perform, and the

  5. APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation.

    PubMed

    Tesco, Giuseppina; Ginestroni, Andrea; Hiltunen, Mikko; Kim, Minji; Dolios, Georgia; Hyman, Bradley T; Wang, Rong; Berezovska, Oksana; Tanzi, Rudolph E

    2005-10-01

    The 37-43 amino acid Abeta peptide is the principal component of beta-amyloid deposits in Alzheimer's disease (AD) brain, and is derived by serial proteolysis of the amyloid precursor protein (APP) by beta- and gamma-secretase. gamma-Secretase also cleaves APP at Val50 in the Abeta numbering (epsilon cleavage), resulting in the release of a fragment called APP intracellular domain (AICD). The aim of this study was to determine whether amino acid substitutions in the APP transmembrane domain differentially affect Abeta and AICD generation. We found that the APPV715F substitution, which has been previously shown to dramatically decrease Abeta40 and Abeta42 while increasing Abeta38 levels, does not affect in vitro generation of AICD. Furthermore, we found that the APPL720P substitution, which has been previously shown to prevent in vitro generation of AICD, completely prevents Abeta generation. Using a fluorescence resonance energy transfer (FRET) method, we next found that both the APPV715F and APPL720P substitutions significantly increase the distance between the N- and C-terminus of presenilin 1 (PS1), which has been proposed to contain the catalytic site of gamma-secretase. In conclusion, both APPV715F and APPL720P change PS1 conformation with differential effects on Abeta and AICD production.

  6. On the use of Schwarz-Christoffel conformal mappings to the grid generation for global ocean models

    NASA Astrophysics Data System (ADS)

    Xu, S.; Wang, B.; Liu, J.

    2015-10-01

    In this article we propose two grid generation methods for global ocean general circulation models. Contrary to conventional dipolar or tripolar grids, the proposed methods are based on Schwarz-Christoffel conformal mappings that map areas with user-prescribed, irregular boundaries to those with regular boundaries (i.e., disks, slits, etc.). The first method aims at improving existing dipolar grids. Compared with existing grids, the sample grid achieves a better trade-off between the enlargement of the latitudinal-longitudinal portion and the overall smooth grid cell size transition. The second method addresses more modern and advanced grid design requirements arising from high-resolution and multi-scale ocean modeling. The generated grids could potentially achieve the alignment of grid lines to the large-scale coastlines, enhanced spatial resolution in coastal regions, and easier computational load balance. Since the grids are orthogonal curvilinear, they can be easily utilized by the majority of ocean general circulation models that are based on finite difference and require grid orthogonality. The proposed grid generation algorithms can also be applied to the grid generation for regional ocean modeling where complex land-sea distribution is present.

  7. The isoforms generated by alternative translation initiation adopt similar conformation in the selectivity filter in TREK-2.

    PubMed

    Zhuo, Ren-Gong; Peng, Peng; Liu, Xiao-Yan; Zhang, Shu-Zhuo; Xu, Jiang-Ping; Zheng, Jian-Quan; Wei, Xiao-Li; Ma, Xiao-Yun

    2015-12-01

    TREK-2 (TWIK-related K(+) channel-2), a member of two-pore domain potassium (K2P) channel family, tunes cellular excitability via conducting leak or background currents. In TREK-2, the isoforms generated by alternative translation initiation (ATI) mechanism exhibit large divergence in unitary conductance, but similar in selectivity to K(+). Up to now, the structural basis for this similarity in ion selectivity is unknown. Here, we report that externally applied Ba(2+) inhibits the currents of TREK-2 in a concentration- and time-dependent manner. The blocking effect is blunted by elevated extracellular K(+) or mutation of S4 K(+) binding site, which suggests that the inhibitory mechanism of Ba(2+) is due to its competitive docking properties within the selectivity filter (SF). Next, we demonstrate that all the ATI isoforms exhibit analogous behaviors upon the application of Ba(2+) and alteration of extracellular pH (pHo), which acts on the outer position of the SF. These results strongly support the notion that all the ATI isoforms of TREK-2 possess resembled SF conformation in S4 site and the position defined by pHo, which implicates that neither the role of N-terminus (Nt) nor the unitary conductance is associated with SF conformation. Our findings might help to understand the detail gating mechanism of TREK-2 and K2P channels.

  8. Thermally induced irreversible conformational changes in collagen probed by optical second harmonic generation and laser-induced fluorescence.

    PubMed

    Theodossiou, T; Rapti, G S; Hovhannisyan, V; Georgiou, E; Politopoulos, K; Yova, D

    2002-01-01

    Irreversible thermal conformational changes induced to collagen have been studied by optical methods. More specifically, second harmonic generation (SHG) from incident nanosecond Ng:YAG 1064 nm radiation and laser-induced fluorescence by 337 nm, pulsed nanosecond nitrogen laser excitation, at 405, 410 and 415 nm emission wavelengths were registered at eight temperatures (40 degrees, 50 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees and 80 degrees C) and normalised with respect to the corresponding values at the ambient temperature of 30 degrees C. The heating protocol used in this work, was selected to monitor only permanent changes reflecting in the optical properties of the samples under investigation. In this context, the SHG, directly related to the collagen fibril population in triple helix conformation, indicated on irreversible phase transition around 64 degrees C. On the other hand fluorescence related to the destruction of cross-linked chromophores in collagen, some of which are related to the triple helix tertiary structure, also indicated a permanent phase transition around 63 degrees C. These results are in agreement with previous results from studies with differential scanning calorimetry. However SHG and fluorescence, being non-invasive optical methods are expected to have a significant impact in the fields of laser ablative surgery and laser tissue welding.

  9. The Effect of Molecular Conformation on the Accuracy of Theoretical (1)H and (13)C Chemical Shifts Calculated by Ab Initio Methods for Metabolic Mixture Analysis.

    PubMed

    Chikayama, Eisuke; Shimbo, Yudai; Komatsu, Keiko; Kikuchi, Jun

    2016-04-14

    NMR spectroscopy is a powerful method for analyzing metabolic mixtures. The information obtained from an NMR spectrum is in the form of physical parameters, such as chemical shifts, and construction of databases for many metabolites will be useful for data interpretation. To increase the accuracy of theoretical chemical shifts for development of a database for a variety of metabolites, the effects of sets of conformations (structural ensembles) and the levels of theory on computations of theoretical chemical shifts were systematically investigated for a set of 29 small molecules in the present study. For each of the 29 compounds, 101 structures were generated by classical molecular dynamics at 298.15 K, and then theoretical chemical shifts for 164 (1)H and 123 (13)C atoms were calculated by ab initio quantum chemical methods. Six levels of theory were used by pairing Hartree-Fock, B3LYP (density functional theory), or second order Møller-Plesset perturbation with 6-31G or aug-cc-pVDZ basis set. The six average fluctuations in the (1)H chemical shift were ±0.63, ± 0.59, ± 0.70, ± 0.62, ± 0.75, and ±0.66 ppm for the structural ensembles, and the six average errors were ±0.34, ± 0.27, ± 0.32, ± 0.25, ± 0.32, and ±0.25 ppm. The results showed that chemical shift fluctuations with changes in the conformation because of molecular motion were larger than the differences between computed and experimental chemical shifts for all six levels of theory. In conclusion, selection of an appropriate structural ensemble should be performed before theoretical chemical shift calculations for development of an accurate database for a variety of metabolites.

  10. 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

  11. Molecular structure of 1,2-bis(trifluoromethyl)-1,1,2,2-tetramethyldisilane in the gas, liquid, and solid phases: unusual conformational changes between phases.

    PubMed

    Masters, Sarah L; Robertson, Heather E; Wann, Derek A; Hölbling, Margit; Hassler, Karl; Bjornsson, Ragnar; Wallevik, Sunna Ó; Arnason, Ingvar

    2015-03-05

    The molecular structure of 1,2-bis(trifluoromethyl)-1,1,2,2-tetramethyldisilane has been determined in three different phases (solid, liquid, and gas) using various spectroscopic and diffraction techniques. Both the solid-state and gas-phase investigations revealed only one conformer to be present in the sample analyzed, whereas the liquid phase revealed the presence of three conformers. The data have been reproduced using computational methods and a rationale is presented for the observation of three conformers in the liquid state.

  12. Effects of Counterface Roughness and Conformity on the Tribological Performance of Crosslinked and Non-crosslinked Medical-Grade Ultra-High Molecular Weight Polyethylene

    DTIC Science & Technology

    2002-04-01

    Tribological Performance of Crosslinked and Non-crosslinked Medical-Grade Ultra-High Molecular Weight Polyethylene DISTRIBUTION: Approved for public...Conformity on the Tribological Performance of Crosslinked and Non-crosslinked Medical-Grade Ultra-High Molecular Weight Polyethylene A. D. Chawan,’ A...Berkeley, CA 94720 ABSTRACT The tribological behavior of crosslinked ultra-high molecular weight polyethylene (UHMWPE) was compared to that of non

  13. Materials for next-generation molecularly selective synthetic membranes

    NASA Astrophysics Data System (ADS)

    Koros, William J.; Zhang, Chen

    2017-03-01

    Materials research is key to enable synthetic membranes for large-scale, energy-efficient molecular separations. Materials with rigid, engineered pore structures add an additional degree of freedom to create advanced membranes by providing entropically moderated selectivities. Scalability -- the capability to efficiently and economically pack membranes into practical modules -- is a critical yet often neglected factor to take into account for membrane materials screening. In this Progress Article, we highlight continuing developments and identify future opportunities in scalable membrane materials based on these rigid features, for both gas and liquid phase applications. These advanced materials open the door to a new generation of membrane processes beyond existing materials and approaches.

  14. Materials for next-generation molecularly selective synthetic membranes.

    PubMed

    Koros, William J; Zhang, Chen

    2017-03-01

    Materials research is key to enable synthetic membranes for large-scale, energy-efficient molecular separations. Materials with rigid, engineered pore structures add an additional degree of freedom to create advanced membranes by providing entropically moderated selectivities. Scalability - the capability to efficiently and economically pack membranes into practical modules - is a critical yet often neglected factor to take into account for membrane materials screening. In this Progress Article, we highlight continuing developments and identify future opportunities in scalable membrane materials based on these rigid features, for both gas and liquid phase applications. These advanced materials open the door to a new generation of membrane processes beyond existing materials and approaches.

  15. Molecular Dynamics Simulations of Membrane-Bound STIM1 to Investigate Conformational Changes during STIM1 Activation upon Calcium Release.

    PubMed

    Mukherjee, Sreya; Karolak, Aleksandra; Debant, Marjolaine; Buscaglia, Paul; Renaudineau, Yves; Mignen, Olivier; Guida, Wayne C; Brooks, Wesley H

    2017-02-27

    Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically, calcium levels are kept at less than 100 nM in the nucleus and cytosol, but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intracellular calcium-dependent functions. Stromal interacting molecule 1 (STIM1) plays a critical role in early sensing of changes in the ER's calcium level, especially when there is a sudden release of stored calcium from the ER. Inactive STIM1, which has a bound calcium ion, is activated upon ion release. Following activation of STIM1, there is STIM1-assisted initiation of extracellular calcium entry through channels in the cell membrane. This extracellular calcium entering the cell then amplifies intracellular calcium-dependent actions. At the end of the process, ER levels of stored calcium are reestablished. The main focus of this work was to study the conformational changes accompanying homo- or heterodimerization of STIM1. For this purpose, the ER luminal portion of STIM1 (residues 58-236), which includes the sterile alpha motif (SAM) domain plus the calcium-binding EF-hand domains 1 and 2 attached to the STIM1 transmembrane region (TM), was modeled and embedded in a virtual membrane. Next, molecular dynamics simulations were performed to study the conformational changes that take place during STIM1 activation and subsequent protein-protein interactions. Indeed, the simulations revealed exposure of residues in the EF-hand domains, which may be important for dimerization steps. Altogether, understanding conformational changes in STIM1 can help in drug discovery when targeting this key protein in intracellular calcium functions.

  16. Combination of molecular dynamics method and 3D-RISM theory for conformational sampling of large flexible molecules in solution.

    PubMed

    Miyata, Tatsuhiko; Hirata, Fumio

    2008-04-30

    We have developed an algorithm for sampling the conformational space of large flexible molecules in solution, which combines the molecular dynamics (MD) method and the three-dimensional reference interaction site model (3D-RISM) theory. The solvent-induced force acting on solute atoms was evaluated as the gradient of the solvation free energy with respect to the solute-atom coordinates. To enhance the computation speed, we have applied a multiple timestep algorithm based on the RESPA (Reversible System Propagator Algorithm) to the combined MD/3D-RISM method. By virtue of the algorithm, one can choose a longer timestep for renewing the solvent-induced force compared with that of the conformational update. To illustrate the present MD/3D-RISM simulation, we applied the method to a model of acetylacetone in aqueous solution. The multiple timestep algorithm succeeded in enhancing the computation speed by 3.4 times for this model case. Acetylacetone possesses an intramolecular hydrogen-bonding capability between the hydroxyl group and the carbonyl oxygen atom, and the molecule is significantly stabilized due to this hydrogen bond, especially in gas phase. The intramolecular hydrogen bond was kept intact during almost entire course of the MD simulation in gas phase, while in the aqueous solutions the bond is disrupted in a significant number of conformations. This result qualitatively agrees with the behavior on a free energy barrier lying upon the process for rotating a torsional degree of freedom of the hydroxyl group, where it is significantly reduced in aqueous solution by a cancellation between the electrostatic interaction and the solvation free energy.

  17. Temperature-dependent conformational changes of PNIPAM grafted chains in water : effects of molecular weight and grafting density.

    SciTech Connect

    Satija, Sushil K.; Mendez, Sergio; Kent, Michael Stuart; Yim, Hyun; Lopez, Gabriel P.

    2005-03-01

    Poly(N-isopropyl acrylamide) (PNIPAM) is perhaps the most well known member of the class of responsive polymers. Free PNIPAM chains have a lower critical solution temperature in water at {approx}31 C. This very sharp transition ({approx}5 C) is attributed to alterations in the hydrogen bonding interactions of the amide group. Grafted chains of PNIPAM have shown promise for creating responsive surfaces. Examples include controlling the adsorption of proteins or bacteria, regulating the flow of liquids in narrow filaments or mesoporous materials, control of enzymatic activity, and releasing the contents of liposomes. Conformational changes of the polymer are likely to play a role in some of these applications, in addition to changes in local interactions. In this work we investigated the T-dependent conformational changes of grafted PNIPAM chains in D2O using neutron reflection and AFM. The molecular weight (M) and surface density of the PNIPAM brushes were controlled using atom-transfer radical polymerization. We discovered a strong effect of surface density. At lower surface densities, in the range typically achieved with grafting-to methods, we observed very little conformational change. At higher surface densities, significant changes with T were observed. The results will be compared with numerical SCF calculations employing an effective (conc.-dependent) Flory-Huggins chi parameter extracted from the solution phase diagram. For the case of high M and high surface density, a non-monotonic change in profile shape with T was observed. This will be discussed in the context of vertical phase separation predicted for brushes of water-soluble polymers within two-state models.

  18. Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches.

    PubMed

    Tran, Linh; Ha-Duong, Tâp

    2015-07-01

    Alzheimer's disease is one of the most common dementia among elderly worldwide. There is no therapeutic drugs until now to treat effectively this disease. One main reason is due to the poorly understood mechanism of Aβ peptide aggregation, which plays a crucial role in the development of Alzheimer's disease. It remains challenging to experimentally or theoretically characterize the secondary and tertiary structures of the Aβ monomer because of its high flexibility and aggregation propensity, and its conformations that lead to the aggregation are not fully identified. In this review, we highlight various structural ensembles of Aβ peptide revealed and characterized by computational approaches in order to find converging structures of Aβ monomer. Understanding how Aβ peptide forms transiently stable structures prior to aggregation will contribute to the design of new therapeutic molecules against the Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. From molecular to supramolecular: an exploration into the modes of self- assembly in conformationally locked polycyclitols.

    PubMed

    Mehta, Goverdhan; Sen, Saikat

    2012-01-01

    This brief account highlights the notable findings of our investigation into the supramolecular chemistry of conformationally locked polycyclitols in the solid state. The study was aimed at analyzing the crystal packing and unraveling the modalities of non-covalent interactions (particularly, intramolecular vis-à-vis intermolecular O-H˙˙˙O hydrogen bonds) in polyols. The know-how obtained thereof, was successfully utilized to engineer self-assemblies of designer polycyclitols, having hydrogen bond donors and acceptors fettered onto a trans-decalin scaffold. The results seek to draw particular attention to the intrinsic attribute of this rigid carbocyclic framework to lock functional groups into spatially invariant positions and bring potential intramolecular hydrogen bonding partners into favorable interaction geometry to engender predictability in the self-assembly patterns.

  20. Inter-helical conformational preferences of HIV-1 TAR-RNA from maximum occurrence analysis of NMR data and molecular dynamics simulations.

    PubMed

    Andrałojć, Witold; Ravera, Enrico; Salmon, Loïc; Parigi, Giacomo; Al-Hashimi, Hashim M; Luchinat, Claudio

    2016-02-17

    Detecting conformational heterogeneity in biological macromolecules is a key for the understanding of their biological function. We here provide a comparison between two independent approaches to assess conformational heterogeneity: molecular dynamics simulations, performed without inclusion of any experimental data, and maximum occurrence (MaxOcc) distribution over the topologically available conformational space. The latter only reflects the extent of the averaging and identifies regions which are most compliant with the experimentally measured NMR Residual Dipolar Couplings (RDCs). The analysis was performed for the HIV-1 TAR RNA, consisting of two helical domains connected by a flexible bulge junction, for which four sets of RDCs were available as well as an 8.2 μs all-atom molecular dynamics simulation. A sample and select approach was previously applied to extract from the molecular dynamics trajectory conformational ensembles in agreement with the four sets of RDCs. The MaxOcc analysis performed here identifies the most likely sampled region in the conformational space of the system which, strikingly, overlaps well with the structures independently sampled in the molecular dynamics calculations and even better with the RDC selected ensemble.

  1. Molecular dynamics study displays near in-line attack conformations in the hammerhead ribozyme self-cleavage reaction

    PubMed Central

    Torres, Rhonda A.; Bruice, Thomas C.

    1998-01-01

    We have performed molecular dynamics (MD) calculations by using one of the recently solved crystal structures of a hammerhead ribozyme. By rotating the α, β, γ, δ, ɛ, and ζ torsion angles of the phosphate linkage of residue 17, the nucleobase at the cleavage site was slightly rotated out of the active site toward the solution. Unconstrained MD simulations exceeding 1 ns were performed on this starting structure solvated in water with explicit counter ions and two Mg2+ ions at the active site. Our results reveal that near attack conformations consistently were formed in the simulation. These near attack conformations are characterized by assumption of the 2′-hydroxyl to a near in-line position for attack on the -O-(PO2−)-O- phosphorous. Also during the time course of the MD study, one Mg2+ moved immediately to associate with a pro-R phosphate oxygen in the conserved core region, and the second Mg2+ remained associated with the pro-R oxygen on the phosphate linkage undergoing hydrolysis. These results are in accord with a one-metal ion mechanism of catalysis and give insight into the possible roles of many of the conserved residues in the ribozyme. PMID:9736692

  2. Mapping the molecular determinant of pathogenicity in a hammerhead viroid: A tetraloop within the in vivo branched RNA conformation

    PubMed Central

    De la Peña, Marcos; Navarro, Beatriz; Flores, Ricardo

    1999-01-01

    Chrysanthemum chlorotic mottle viroid (CChMVd) is an RNA of 398–399 nt that can adopt hammerhead structures in both polarity strands. We have identified by Northern-blot hybridization a nonsymptomatic strain (CChMVd-NS) that protects against challenge inoculation with the symptomatic strain (CChMVd-S). Analysis of CChMVd-NS cDNA clones has revealed a size and sequence very similar to those of the CChMVd-S strain. Some of the mutations observed in CChMVd-NS molecular variants were previously identified in CChMVd-S RNA, but others were never found in this RNA. When bioassayed in chrysanthemum, cDNA clones containing the CChMVd-NS specific mutations were infectious but nonsymptomatic. Site-directed mutagenesis showed that one of the CChMVd-NS-specific mutations, a UUUC → GAAA substitution, was sufficient to change the symptomatic phenotype into the nonsymptomatic one without altering the final accumulation level of the viroid RNA. The pathogenicity determinant–to our knowledge, a determinant of this class has not been described previously in hammerhead viroids–is located in a tetraloop of the computer-predicted branched conformation for CChMVd RNA. Analysis of the sequence heterogeneity found in CChMVd-S and -NS variants strongly supports the existence of such a conformation in vivo, showing that the rod-like or quasi-rod-like secondary structure is not a universal paradigm for viroids. PMID:10449802

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

    PubMed

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

    2015-09-01

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

  4. Mapping the molecular determinant of pathogenicity in a hammerhead viroid: a tetraloop within the in vivo branched RNA conformation.

    PubMed

    de la Peña, M; Navarro, B; Flores, R

    1999-08-17

    Chrysanthemum chlorotic mottle viroid (CChMVd) is an RNA of 398-399 nt that can adopt hammerhead structures in both polarity strands. We have identified by Northern-blot hybridization a nonsymptomatic strain (CChMVd-NS) that protects against challenge inoculation with the symptomatic strain (CChMVd-S). Analysis of CChMVd-NS cDNA clones has revealed a size and sequence very similar to those of the CChMVd-S strain. Some of the mutations observed in CChMVd-NS molecular variants were previously identified in CChMVd-S RNA, but others were never found in this RNA. When bioassayed in chrysanthemum, cDNA clones containing the CChMVd-NS specific mutations were infectious but nonsymptomatic. Site-directed mutagenesis showed that one of the CChMVd-NS-specific mutations, a UUUC --> GAAA substitution, was sufficient to change the symptomatic phenotype into the nonsymptomatic one without altering the final accumulation level of the viroid RNA. The pathogenicity determinant-to our knowledge, a determinant of this class has not been described previously in hammerhead viroids-is located in a tetraloop of the computer-predicted branched conformation for CChMVd RNA. Analysis of the sequence heterogeneity found in CChMVd-S and -NS variants strongly supports the existence of such a conformation in vivo, showing that the rod-like or quasi-rod-like secondary structure is not a universal paradigm for viroids.

  5. Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

    PubMed Central

    Kurkcuoglu, Zeynep; Doruker, Pemra

    2016-01-01

    Incorporating receptor flexibility in small ligand-protein docking still poses a challenge for proteins undergoing large conformational changes. In the absence of bound structures, sampling conformers that are accessible by apo state may facilitate docking and drug design studies. For this aim, we developed an unbiased conformational search algorithm, by integrating global modes from elastic network model, clustering and energy minimization with implicit solvation. Our dataset consists of five diverse proteins with apo to complex RMSDs 4.7–15 Å. Applying this iterative algorithm on apo structures, conformers close to the bound-state (RMSD 1.4–3.8 Å), as well as the intermediate states were generated. Dockings to a sequence of conformers consisting of a closed structure and its “parents” up to the apo were performed to compare binding poses on different states of the receptor. For two periplasmic binding proteins and biotin carboxylase that exhibit hinge-type closure of two dynamics domains, the best pose was obtained for the conformer closest to the bound structure (ligand RMSDs 1.5–2 Å). In contrast, the best pose for adenylate kinase corresponded to an intermediate state with partially closed LID domain and open NMP domain, in line with recent studies (ligand RMSD 2.9 Å). The docking of a helical peptide to calmodulin was the most challenging case due to the complexity of its 15 Å transition, for which a two-stage procedure was necessary. The technique was first applied on the extended calmodulin to generate intermediate conformers; then peptide docking and a second generation stage on the complex were performed, which in turn yielded a final peptide RMSD of 2.9 Å. Our algorithm is effective in producing conformational states based on the apo state. This study underlines the importance of such intermediate states for ligand docking to proteins undergoing large transitions. PMID:27348230

  6. Molecular dynamics simulations reveal the conformational dynamics of Arabidopsis thaliana BRI1 and BAK1 receptor-like kinases.

    PubMed

    Moffett, Alexander S; Bender, Kyle W; Huber, Steven C; Shukla, Diwakar

    2017-07-28

    The structural motifs responsible for activation and regulation of eukaryotic protein kinases in animals have been studied extensively in recent years, and a coherent picture of their activation mechanisms has begun to emerge. In contrast, non-animal eukaryotic protein kinases are not as well understood from a structural perspective, representing a large knowledge gap. To this end, we investigated the conformational dynamics of two key Arabidopsis thaliana receptor-like kinases, brassinosteroid-insensitive 1 (BRI1) and BRI1-associated kinase 1 (BAK1), through extensive molecular dynamics simulations of their fully phosphorylated kinase domains. Molecular dynamics simulations calculate the motion of each atom in a protein based on classical approximations of interatomic forces, giving researchers insight into protein function at unparalleled spatial and temporal resolutions. We found that in an otherwise "active" BAK1 the αC helix is highly disordered, a hallmark of deactivation, whereas the BRI1 αC helix is moderately disordered and displays swinging behavior similar to numerous animal kinases. An analysis of all known sequences in the A. thaliana kinome found that αC helix disorder may be a common feature of plant kinases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Low molecular weight oligomers of amyloid peptides display β-barrel conformations: A replica exchange molecular dynamics study in explicit solvent

    NASA Astrophysics Data System (ADS)

    De Simone, Alfonso; Derreumaux, Philippe

    2010-04-01

    The self-assembly of proteins and peptides into amyloid fibrils is connected to over 40 pathological conditions including neurodegenerative diseases and systemic amyloidosis. Diffusible, low molecular weight protein and peptide oligomers that form in the early steps of aggregation appear to be the harmful cytotoxic species in the molecular etiology of these diseases. So far, the structural characterization of these oligomers has remained elusive owing to their transient and dynamic features. We here address, by means of full atomistic replica exchange molecular dynamics simulations, the energy landscape of heptamers of the amyloidogenic peptide NHVTLSQ from the beta-2 microglobulin protein. The simulations totaling 5 μs show that low molecular weight oligomers in explicit solvent consist of β-barrels in equilibrium with amorphous states and fibril-like assemblies. The results, also accounting for the influence of the pH on the conformational properties, provide a strong evidence of the formation of transient β-barrel assemblies in the early aggregation steps of amyloid-forming systems. Our findings are discussed in terms of oligomers cytotoxicity.

  8. Low molecular weight oligomers of amyloid peptides display beta-barrel conformations: a replica exchange molecular dynamics study in explicit solvent.

    PubMed

    De Simone, Alfonso; Derreumaux, Philippe

    2010-04-28

    The self-assembly of proteins and peptides into amyloid fibrils is connected to over 40 pathological conditions including neurodegenerative diseases and systemic amyloidosis. Diffusible, low molecular weight protein and peptide oligomers that form in the early steps of aggregation appear to be the harmful cytotoxic species in the molecular etiology of these diseases. So far, the structural characterization of these oligomers has remained elusive owing to their transient and dynamic features. We here address, by means of full atomistic replica exchange molecular dynamics simulations, the energy landscape of heptamers of the amyloidogenic peptide NHVTLSQ from the beta-2 microglobulin protein. The simulations totaling 5 micros show that low molecular weight oligomers in explicit solvent consist of beta-barrels in equilibrium with amorphous states and fibril-like assemblies. The results, also accounting for the influence of the pH on the conformational properties, provide a strong evidence of the formation of transient beta-barrel assemblies in the early aggregation steps of amyloid-forming systems. Our findings are discussed in terms of oligomers cytotoxicity.

  9. Molecular conformational analysis, vibrational spectra, NBO, NLO analysis and molecular docking study of bis[(E)-anthranyl-9-acrylic]anhydride based on density functional theory calculations.

    PubMed

    Mary, Y Sheena; Panicker, C Yohannan; Thiemann, Thies; Al-Azani, Mariam; Al-Saadi, Abdulaziz A; Van Alsenoy, C; Raju, K; War, Javeed Ahmad; Srivastava, S K

    2015-01-01

    FT-IR and FT-Raman spectra of bis[(E)-anthranyl-9-acrylic]anhydride were recorded and analyzed. The conformational behavior is also investigated. The vibrational wave numbers were calculated using density functional theory (DFT) quantum chemical calculations. The data obtained from wave number calculations are used to assign vibrational bands obtained in Infrared and Raman spectra. Potential energy distribution was done using GAR2PED program. The geometrical parameters are compared with related structures. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using Natural Bonding Orbital (NBO) analysis. The Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) analysis are used to determine the charge transfer within the molecule. Molecular Electrostatic Potential (MEP) was performed by the DFT method. The calculated first hyperpolarizability of the title compound is comparable with the reported values of similar derivatives and is 4.23 times that of the standard nonlinear optical (NLO) material urea and the title compound and its derivatives are an attractive object for future studies of nonlinear optical properties. To evaluate the in silico antitumor activity of the title compound molecular docking studies were carried out against protein Bcl-xL. The (1)H-NMR spectrum is also reported. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach

    PubMed Central

    Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P.

    2016-01-01

    Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions. PMID:26908260

  11. Ab initio molecular orbital and infrared spectroscopic study of the conformation of secondary amides: derivatives of formanilide, acetanilide and benzylamides

    NASA Astrophysics Data System (ADS)

    Ilieva, S.; Hadjieva, B.; Galabov, B.

    1999-09-01

    Ab initio molecular orbital calculations at HF/4-31G level and infrared spectroscopic data for the frequencies are applied to analyse the grouping in a series model aromatic secondary amides: formanilide; acetanilide; o-methylacetanilide; 2,6-dimethylformanilide, 2,6-dimethylacetanilide; N-benzylacetamide and N-benzylformamide. The theoretical and experimental data obtained show that the conformational state of the molecules studied is determined by the fine balance of several intramolecular factors: resonance effect between the amide group and the aromatic ring, steric interaction between various substituents around the -NH-CO- grouping in the aromatic ring, conjugation between the carbonyl bond and the nitrogen lone pair as well as direct field influences inside the amide group.

  12. A theoretical approach to the influence of the macrocycle conformation on the molecular electronic structure in Mg-porphyrins.

    PubMed

    Poveda, L A; Ferro, V R; García de la Vega, J M; González-Jonte, R H

    2001-02-01

    Nonplanar saddled (sad) ruffled (ruf) and domed (dom) conformations of the Mg-porphyrin (MgP) macrocycle in several degrees of deformation have been computed. These symmetrical distortion modes were induced in unsubstituted macrocycle using molecular definitions for calculations which permits us to achieve a systematical variation of the nonplanarity varying only a convenient geometrical parameter of the molecule. Series of nonplanar macrocycles like those synthesized in previous works employing peripheral substitutions are obtained. The procedure here used to induce deformations gives the possibility of investigating the modulator role of the out-of-plane distortions on the geometry and electronic properties of the porphyrin avoiding additional influences due to the substituents or the surrounding protein scaffolding.

  13. Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

    PubMed Central

    Kaushik, Swati; Sowdhamini, Ramanathan

    2011-01-01

    Prolyl oligopeptidase (POP) is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD) simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases. PMID:22132071

  14. Interfacial molecular interactions based on the conformation recognition between the insoluble antitumor drug AD-1 and DSPC.

    PubMed

    Yin, Tian; Cao, Xiuxiu; Liu, Xiaolin; Wang, Jian; Shi, Caihong; Su, Jia; Zhang, Yu; Gou, Jingxin; He, Haibing; Guo, Haiyan; Tang, Xing; Zhao, Yuqing

    2016-10-01

    In this study, molecular interactions between the anti-cancer agent 20(R)-25-methoxyl-dammarane-3β, 12β, 20-triol (AD-1) and phospholipid 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) were investigated using the Langmuir film balance technique. The characteristics of binary Langmuir monolayers consisting of DSPC and AD-1 were conducted on the basis of the surface pressure-area per molecule (π-A) isotherms. It was found that the drug was able to become efficiently inserted into preformed DSPC monolayers, indicating a preferential interaction between AD-1 and DSPC. For the examined lateral pressure at 20mN/m, the largest negative values of ΔGex were found for the AD-1/DSPC monolayer, which should be the most stable. Based on the calculated values of ΔGex, we found that the AD-1/DSPC systems exhibited the best mixed characteristics when the molar fraction of the AD-1 was 0.8; at that relative concentration, the AD-1 molecules can mix better and interact with the phospholipid molecules. In addition, the drug-DSPC binary supramolecular structure was also deposited on the mica plates as shown by atomic force microscopy (AFM). Finally, molecular docking calculations explained satisfactorily that, based on the conformations interactions (conformation recognition), even at an AD-1/DSPC molar ratio as high as 8:2, the interfacial stabilization of the AD-1/DSPC system was fairly strong due to hydrophobic interactions. A higher loading capacity of DSPC might be possible, as it is associated with a more flexible geometrical environment, which allows these supramolecular structures to accept larger increases in drug loading upon steric binding.

  15. Comparison of a quantum random number generator with pseudorandom number generators for their use in molecular Monte Carlo simulations.

    PubMed

    Ghersi, Dario; Parakh, Abhishek; Mezei, Mihaly

    2017-09-18

    Four pseudorandom number generators were compared with a physical, quantum-based random number generator using the NIST suite of statistical tests, which only the quantum-based random number generator could successfully pass. We then measured the effect of the five random number generators on various calculated properties in different Markov-chain Monte Carlo simulations. Two types of systems were tested: conformational sampling of a small molecule in aqueous solution and liquid methanol under constant temperature and pressure. The results show that poor quality pseudorandom number generators produce results that deviate significantly from those obtained with the quantum-based random number generator, particularly in the case of the small molecule in aqueous solution setup. In contrast, the widely used Mersenne Twister pseudorandom generator and a 64-bit Linear Congruential Generator with a scrambler produce results that are statistically indistinguishable from those obtained with the quantum-based random number generator. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  16. Molecular interactions and residues involved in force generation in the T4 viral DNA packaging motor.

    PubMed

    Migliori, Amy D; Smith, Douglas E; Arya, Gaurav

    2014-12-12

    Many viruses utilize molecular motors to package their genomes into preformed capsids. A striking feature of these motors is their ability to generate large forces to drive DNA translocation against entropic, electrostatic, and bending forces resisting DNA confinement. A model based on recently resolved structures of the bacteriophage T4 motor protein gp17 suggests that this motor generates large forces by undergoing a conformational change from an extended to a compact state. This transition is proposed to be driven by electrostatic interactions between complementarily charged residues across the interface between the N- and C-terminal domains of gp17. Here we use atomistic molecular dynamics simulations to investigate in detail the molecular interactions and residues involved in such a compaction transition of gp17. We find that although electrostatic interactions between charged residues contribute significantly to the overall free energy change of compaction, interactions mediated by the uncharged residues are equally if not more important. We identify five charged residues and six uncharged residues at the interface that play a dominant role in the compaction transition and also reveal salt bridging, van der Waals, and solvent hydrogen-bonding interactions mediated by these residues in stabilizing the compact form of gp17. The formation of a salt bridge between Glu309 and Arg494 is found to be particularly crucial, consistent with experiments showing complete abrogation in packaging upon Glu309Lys mutation. The computed contributions of several other residues are also found to correlate well with single-molecule measurements of impairments in DNA translocation activity caused by site-directed mutations.

  17. A Replica Exchange Molecular Dynamics Simulation of a Single Polyethylene Chain: Temperature Dependence of Structural Properties and Chain Conformational Study at the Equilibrium Melting Temperature.

    PubMed

    Li, Ting; Yang, Xiaozhen; Nies, Erik

    2011-01-11

    The conformational properties of a finite length polyethylene chain were explored over a wide range of temperatures using a replica exchange molecular dynamics simulation providing high quality simulation data representative for the equilibrium behavior of the chain molecule. The radial distribution function (RDF) and the structure factor S(q) of the chain as a function of temperature are analyzed in detail. The different characteristic peaks in the RDF and S(q) were assigned to specific distances in the chain and structural changes occurring with the temperature. In S(q), a peak characteristic for the order in the solid state was found and used to determine the equilibrium melting temperature. A detailed scaling analysis of the structure factor covering the full q range was performed according to the work of Hammouda. In the Θ region, a quantitative analysis of the full structure factor was done using the equivalent Kuhn chain, which enabled us to assign the Θ region of our chain and to demonstrate, in our particular case, the failure of the Gaussian chain approach. The chain conformational properties at the equilibrium melting temperature are discussed using conformational distribution functions, using the largest principal component of the radius of gyration and shape parameters as order parameters. We demonstrate that for the system studied here, the Landau free energy expression based on this conformational distribution information leads to erroneous conclusions concerning the thermodynamic transition behavior. Finally, we focus on the instantaneous conformational properties at the equilibrium melting temperature and give a detailed analysis of the conformational shapes using different shape parameters and a simulation snapshot. We show that the chain does not only take the lamellar rod-like and globular conformational shapes, typical of the solid and liquid states, but can also explore many other conformational states, including the toroidal conformational

  18. Investigation on the low energy conformational surface of tabun to probe the role of its different conformers on biological activity

    NASA Astrophysics Data System (ADS)

    Paukku, Yuliya; Michalkova, Andrea; Majumdar, D.; Leszczynski, Jerzy

    2006-05-01

    Conformational studies have been carried out on the two different enantiomers of tabun at the density functional and second order Møller-Plesset perturbation levels of theory to generate low energy potential energy surfaces in the gas phase as well as in aqueous environment. The structures of the low energy conformers together with their molecular electrostatic potential surfaces have been compared with those of the non-aged acetylcholinesterase-tabun complex to locate the active conformer of this molecule.

  19. Determination of individual side-chain conformations, tertiary conformations, and molecular topography of tyrocidine A from scalar coupling constants and chemical shifts.

    PubMed

    Kuo, M C; Gibbons, W A

    1979-12-25

    We report for the decapeptide tyrocidine A: (a) H alpha and H beta chemical shifts and scalar coupling constants for most residues of tyrocidine A in methanol-d4 and dimethyl-d6 sulfoxide (Me2so-d6) and the H alpha and H beta chemical shifts for other residues; (b) scalar coupling constants 3J alpha beta for nine side chains in methanol-d4 but only seven side chains in Me2SO-d6, due to chemical shift degeneracy; the Gln9 and Tyr10 side chains in methanol-d4 were only approximately analyzed; (c) a total spin-spin analysis of Pro5 in Me2SO-d6 and, partly by comparison, also in methanol-d4; (d) conversion of 3J alpha beta values to side-chain conformations for all residues in methanol-d4; comparisons, where possible, led to the conclusion that side-chain conformations are similar in methanol-d4 and Me2SO-d6; (e) an absolute conformational analysis of Pro5 from 3J values and a method of assigning all pro-R,S protons; Pro5 has a Ramachandran B, C2-Cexo-Cendo conformation; (f) chi 1, chi 2 conformations of several aromatic residues based upon proton-chromophore distance measurement from anomalous chemical shifts and Johnson-Bovey diagrams; (g) pro-R and pro-S assignments of H beta's from anomalous chemical shifts, high-temperature dependence of anomalous chemical shifts, and backbone side-chain nuclear Overhauser effects; (h) most tertiary conformations of the whole tyrocidine A molecule possessing residues 4--8 and 10 in highly preferred (ca. 90%) chi 1 conformations, but residues 1--3 and 9 having at least two chi 1 rotamers; (2) description of three topographical regions of the molecule--a hydrophobic region, a flat hydrophilic surface on the other side of the molecule, and a hydrophilic region consisting of two peptide backbone units and the side chains of Asn8, Gln9, and Tyr10; (j) proposed side chain, beta-turn, and beta-pleated sheet conformations that readily account for all "normal" and anomalous chemical shifts.

  20. Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions

    PubMed Central

    Eibl, Clarissa; Hessenberger, Manuel; Wenger, Julia; Brandstetter, Hans

    2014-01-01

    The cytosolic tripartite NLR receptors serve as important signalling platforms in innate immunity. While the C-terminal domains act as sensor and activation modules, the N-terminal death-like domain, e.g. the CARD or pyrin domain, is thought to recruit downstream effector molecules by homotypic interactions. Such homotypic complexes have been determined for all members of the death-domain superfamily except for pyrin domains. Here, crystal structures of human NLRP14 pyrin-domain variants are reported. The wild-type protein as well as the clinical D86V mutant reveal an unexpected rearrangement of the C-terminal helix α6, resulting in an extended α5/6 stem-helix. This reordering mediates a novel symmetric pyrin-domain dimerization mode. The conformational switching is controlled by a charge-relay system with a drastic impact on protein stability. How the identified charge relay allows classification of NLRP receptors with respect to distinct recruitment mechanisms is discussed. PMID:25004977

  1. Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions

    SciTech Connect

    Eibl, Clarissa; Hessenberger, Manuel; Wenger, Julia; Brandstetter, Hans

    2014-07-01

    Pyrin domains (PYDs) recruit downstream effector molecules in NLR signalling. A specific charge-relay system suggests a the formation of a signalling complex involving a PYD dimer. The cytosolic tripartite NLR receptors serve as important signalling platforms in innate immunity. While the C-terminal domains act as sensor and activation modules, the N-terminal death-like domain, e.g. the CARD or pyrin domain, is thought to recruit downstream effector molecules by homotypic interactions. Such homotypic complexes have been determined for all members of the death-domain superfamily except for pyrin domains. Here, crystal structures of human NLRP14 pyrin-domain variants are reported. The wild-type protein as well as the clinical D86V mutant reveal an unexpected rearrangement of the C-terminal helix α6, resulting in an extended α5/6 stem-helix. This reordering mediates a novel symmetric pyrin-domain dimerization mode. The conformational switching is controlled by a charge-relay system with a drastic impact on protein stability. How the identified charge relay allows classification of NLRP receptors with respect to distinct recruitment mechanisms is discussed.

  2. Phase behavior in quaternary ammonium ionic liquid-propanol solutions: Hydrophobicity, molecular conformations, and isomer effects

    NASA Astrophysics Data System (ADS)

    Abe, Hiroshi; Kohki, Erica; Nakada, Ayumu; Kishimura, Hiroaki

    2017-07-01

    In ionic liquids (ILs), the effects of a quaternary ammonium cation containing a hydroxyl group were investigated and compared with the effect of a standard quaternary ammonium cation. The cation possessing a hydroxyl group is choline, Chol+, and the anion is bis(trifluoromethylsulfonyl)imide, TFSI-. Crystal polymorphism of pure [Chol][TFSI] was observed upon both cooling and heating by simultaneous X-ray diffraction and differential scanning calorimetry measurements. In contrast, [N3111][TFSI] (N3111+: N-trimethyl-N-propylammonium), a standard IL, demonstrated simple crystallization upon cooling. By adding 1-propanol or 2-propanol, the phase behaviors of the [Chol][TFSI]-based and [N3111][TFSI]-based mixtures were clearly distinguished. By Raman spectroscopy, the TFSI- anion conformers in the liquid state were shown to vary according to the propanol concentration, propanol isomer, and type of cation. The anomalous behaviors of pure [Chol][TFSI] and its mixtures are derived from hydrogen bonding of the hydroxyl group of Chol+ cation coupled with the hydrophobicity and packing efficiency of propanol.

  3. Reconstitution of biological molecular generators of electric current. Inorganic pyrophosphatase.

    PubMed

    Kondrashin, A A; Remennikov, V G; Samuilov, V D; Skulachev, V P

    1980-12-01

    Proteoliposomes have been reconstituted from soy-bean phospholipids (asolectin) and inorganic pyrophosphatase isolated from Rhodospirillum rubrum chromatophores. In the presence of Mg2+ ions, pyrophosphatase proteoliposomes were incorporated into a phospholipid-impregnated Teflon filter separating two solutions of an identical electrolyte content. Addition of inorganic pyrophosphate to the same compartment as proteoliposomes was found to induce generation of an electric potential difference between the two filter-separated compartments, the proteoliposomes-containing compartment being negatively charged. An electric potential difference of 15 mV and a current of 20 pA were observed. The electrogenic effect required Mg2+ and proved to be sensitive to fluoride, an inorganic pyrophosphatase inhibitor. Treatment with 10 microM N,N'-dicyclohexylcarbodiimide for several minutes was without influence upon pyrophosphate-induced membrane potential generation. Similar results were obtained in experiments with a proteoliposome suspension and a penetrating anion, tetraphenyl borate, which is a probe for membrane potential. The obtained data are discussed in connection with the results of studies on other enzymes as molecular generators of electric current.

  4. Optimization of capillary array electrophoresis single-strand conformation polymorphism analysis for routine molecular diagnostics.

    PubMed

    Jespersgaard, Cathrine; Larsen, Lars Allan; Baba, Shingo; Kukita, Yoji; Tahira, Tomoko; Christiansen, Michael; Vuust, Jens; Hayashi, Kenshi; Andersen, Paal Skytt

    2006-10-01

    Mutation screening is widely used for molecular diagnostics of inherited disorders. Furthermore, it is anticipated that the present and future identification of genetic risk factors for complex disorders will increase the need for high-throughput mutation screening technologies. Capillary array electrophoresis (CAE) SSCP analysis is a low-cost, automated method with a high throughput and high reproducibility. Thus, the method fulfills many of the demands to be met for application in routine molecular diagnostics. However, the need for performing the electrophoresis at three temperatures between 18 degrees C and 35 degrees C for achievement of high sensitivity is a disadvantage of the method. Using a panel of 185 mutant samples, we have analyzed the effect of sample purification, sample medium and separation matrix on the sensitivity of CAE-SSCP analysis to optimize the method for molecular diagnostic use. We observed different effects from sample purification and sample medium at different electrophoresis temperatures, probably reflecting the complex interplay between sequence composition, electrophoresis conditions and sensitivity in SSCP analysis. The effect on assay sensitivity from three different polymers was tested using a single electrophoresis temperature of 27 degrees C. The data suggest that a sensitivity of 98-99% can be obtained using a 10% long chain poly-N,N-dimethylacrylamide polymer.

  5. All-atom molecular dynamics study of EAK16 peptide: the effect of pH on single-chain conformation, dimerization and self-assembly behavior.

    PubMed

    Emamyari, Soheila; Fazli, Hossein

    2014-05-01

    Single-chain equilibrium conformation and dimerization of the three types of ionic EAK16 peptide are studied under three pH conditions using all-atom molecular dynamics simulations. It is found that both the single-chain conformation and the dimerization process of EAK16-IV are considerably different from those of the two other types, EAK16-I and EAK16-II. The value of pH is found to have a stronger effect on the single-chain conformation and dimerization of EAK16-IV. It is shown that in addition to the charge pattern on the peptide chains, the size of the side chains of the charged amino acids plays role in the conformation of the peptide chains and their dimerization. The results shed light on the pH-dependent self-assembly behavior of EAK16 peptide in the bulk solution, which has been reported in the literature.

  6. Co-conformational Exchange Triggered by Molecular Recognition in a Di(acylamino)pyridine-Based Molecular Shuttle Containing Two Pyridine Rings at the Macrocycle.

    PubMed

    Martinez-Cuezva, Alberto; Carro-Guillen, Fernando; Pastor, Aurelia; Marin-Luna, Marta; Orenes, Raul-Angel; Alajarin, Mateo; Berna, Jose

    2016-06-17

    We describe the incorporation of endo-pyridine units into the tetralactam ring of di(acylamino)pyridine-based rotaxanes. This macrocycle strongly associates with the linear interlocked component as confirmed by X-ray diffraction studies of rotaxane 2 b. Dynamic NMR studies of 2 b in solution revealed a rotational energy barrier that was higher than that of the related rotaxane 2 a, which lacks of pyridine rings in the macrocycle. The macrocycle distribution of the molecular shuttle 4 b, containing two endo-pyridine rings, shows that the major co-conformer is that with the cyclic component sitting over the di(acylamino)pyridine station. DFT calculations also support the marked preference of the ring for occupying the heterocyclic binding site. The association of N-hexylthymine with the di(acylamino)pyridine binding site of 4 b led to the formation of a rare 'S'-shaped co-conformer in which the tetralactam ring interacts simultaneously with both stations of the thread.

  7. Theoretical study on fulvic acid structure, conformation and aggregation. A molecular modelling approach.

    PubMed

    Alvarez-Puebla, R A; Valenzuela-Calahorro, C; Garrido, J J

    2006-04-01

    The ubiquitous presence of humic substances (HS), combined with their ability to provide multiple sites for chemical reaction, makes them relevant to numerous biogeochemical processes such as mineral weathering, nutrient bioavailability, and contaminant transport. The reactivity of HS depends on their functional group chemistry and microstructure, which are in turn influenced by the composition of the surrounding media. In order to help towards an understanding of structure conformations and aggregation process of HS in soils and waters and to get a better knowledge of these kinds of materials, a fulvic acid (FA) has been modelled as a function of its ionic state under different conditions. Our proposed theoretical model based on the Temple-Northeastern-Birmingham (TNB) monomer fits well with experimental observations on the solubility (dipolar moment) and electronic and vibrational spectra of FAs. The presence of water molecules has a great stabilization effect on the electrostatic energy; this effect is greater as ionized rate increases. In vacuum, the non-ionized aggregated species are more stable than monomers because of the increase in their interaction due to H-bonding and non-bonding forces. When the molecules are ionized, no aggregation process takes place. In solution, the FA concentration is a critical factor for the aggregation. The system containing two FA molecules probably did not form aggregates because its equivalent concentration was too low. When the concentration was increased, the system gave rise to the formation of aggregates. The ionic state is another critical factor in the aggregation process. The ionized FA has a higher electric negative charge, which increases the energetic barriers and inhibits the approximation of FA caused by the Brownian movement.

  8. SLITHER: a web server for generating contiguous conformations of substrate molecules entering into deep active sites of proteins or migrating through channels in membrane transporters.

    PubMed

    Lee, Po-Hsien; Kuo, Kuei-Ling; Chu, Pei-Ying; Liu, Eric M; Lin, Jung-Hsin

    2009-07-01

    Many proteins use a long channel to guide the substrate or ligand molecules into the well-defined active sites for catalytic reactions or for switching molecular states. In addition, substrates of membrane transporters can migrate to another side of cellular compartment by means of certain selective mechanisms. SLITHER (http://bioinfo.mc.ntu.edu.tw/slither/or http://slither.rcas.sinica.edu.tw/) is a web server that can generate contiguous conformations of a molecule along a curved tunnel inside a protein, and the binding free energy profile along the predicted channel pathway. SLITHER adopts an iterative docking scheme, which combines with a puddle-skimming procedure, i.e. repeatedly elevating the potential energies of the identified global minima, thereby determines the contiguous binding modes of substrates inside the protein. In contrast to some programs that are widely used to determine the geometric dimensions in the ion channels, SLITHER can be applied to predict whether a substrate molecule can crawl through an inner channel or a half-channel of proteins across surmountable energy barriers. Besides, SLITHER also provides the list of the pore-facing residues, which can be directly compared with many genetic diseases. Finally, the adjacent binding poses determined by SLITHER can also be used for fragment-based drug design.

  9. Non-equilibrium conformational dynamics in the function of molecular chaperones.

    PubMed

    Barducci, Alessandro; De Los Rios, Paolo

    2015-02-01

    Why do chaperones need ATP hydrolysis to help proteins reach their native, functional states? In this review, we highlight the most recent experimental and theoretical evidences suggesting that ATP hydrolysis allows molecular chaperones to escape the bounds imposed by equilibrium thermodynamics. We argue here that energy consumption must be fully taken into account to understand the mechanism of these intrinsically non-equilibrium machines and we propose a novel perspective in the way the relation between function and ATP hydrolysis is viewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Conformationally Constrained Penta(hetero)cyclic Molecular Architectures via Photoassisted Diversity-Oriented Synthesis

    PubMed Central

    Umstead, Weston J.; Mukhina, Olga A.

    2015-01-01

    Intramolecular cycloadditions of photogenerated azaxylylenes provide access to unprecedented polyheterocyclic scaffolds, suitable for subsequent postphotochemical modifications to further grow molecular complexity. Here we explore approaches to rapid “assembly” of novel photoprecursors with nitrogen/oxygen-rich tethers capable of producing potential pharmacophores and also compatible with subsequent 1,3-dipolar cycloadditions to furnish pentacyclic heterocycles with new structural cores, minimal number of rotatable bonds, and a high content of sp3 hybridized carbons. The modular “assembly” of the photoprecursors and potential variety of postphotochemical modifications of primary photoproducts provide framework for combinatorial implementation of this synthetic strategy. PMID:26257575

  11. Molecular Dynamics Investigations of the alpha-helix to Beta-barrel Conformational Transformation in RfaH

    NASA Astrophysics Data System (ADS)

    Gc, Jeevan; Bhandari, Yuba; Gerstman, Bernard; Chapagain, Prem

    2015-03-01

    We used combination of replica exchange molecular dynamics simulations with implicit solvent and detailed all-atom simulations with explicit solvent to investigate the α-helix to β-structure transformation of RfaH-CTD. While interacting with the N-terminal domain (NTD), the C-terminal domain (CTD) of RfaH folds to a α-helix bundle but it undergoes an all- α to all- β conformational transformation when it does not interact with the NTD. The RfaH-CTD in the all- α topology is involved in regulating transcription whereas in the all- β topology it is involved in stimulating translation by recruiting a ribosome to an mRNA. Calculations of free-energy landscape and transfer entropy elucidate the details of the RfaH-CTD transformation process. The importance of interfacial interactions between the two domains of RfaH is highlighted by the compromised structural integrity of the helical form of the CTD in the absence NTD. We also studied interdomain and intradomain interactions in RfaH using Steered Molecular Dynamics Simulations. We investigated the role of the interdomain salt-bridge interaction in the domain stability Potential mean force was calculated to obtain free energy profile using Jarzynski Equality.

  12. High-order-harmonic generation in atomic and molecular systems

    NASA Astrophysics Data System (ADS)

    Suárez, Noslen; Chacón, Alexis; Pérez-Hernández, Jose A.; Biegert, Jens; Lewenstein, Maciej; Ciappina, Marcelo F.

    2017-03-01

    High-order-harmonic generation (HHG) results from the interaction of ultrashort laser pulses with matter. It configures an invaluable tool to produce attosecond pulses, moreover, to extract electron structural and dynamical information of the target, i.e., atoms, molecules, and solids. In this contribution, we introduce an analytical description of atomic and molecular HHG, that extends the well-established theoretical strong-field approximation (SFA). Our approach involves two innovative aspects: (i) First, the bound-continuum and rescattering matrix elements can be analytically computed for both atomic and multicenter molecular systems, using a nonlocal short range model, but separable, potential. When compared with the standard models, these analytical derivations make possible to directly examine how the HHG spectra depend on the driven media and laser-pulse features. Furthermore, we can turn on and off contributions having distinct physical origins or corresponding to different mechanisms. This allows us to quantify their importance in the various regions of the HHG spectra. (ii) Second, as reported recently [N. Suárez et al., Phys. Rev. A 94, 043423 (2016), 10.1103/PhysRevA.94.043423], the multicenter matrix elements in our theory are free from nonphysical gauge- and coordinate-system-dependent terms; this is accomplished by adapting the coordinate system to the center from which the corresponding time-dependent wave function originates. Our SFA results are contrasted, when possible, with the direct numerical integration of the time-dependent Schrödinger equation in reduced and full dimensionality. Very good agreement is found for single and multielectronic atomic systems, modeled under the single active electron approximation, and for simple diatomic molecular systems. Interference features, ubiquitously present in every strong-field phenomenon involving a multicenter target, are also captured by our model.

  13. The generation of meaningful information in molecular systems.

    PubMed

    Wills, Peter R

    2016-03-13

    The physico-chemical processes occurring inside cells are under the computational control of genetic (DNA) and epigenetic (internal structural) programming. The origin and evolution of genetic information (nucleic acid sequences) is reasonably well understood, but scant attention has been paid to the origin and evolution of the molecular biological interpreters that give phenotypic meaning to the sequence information that is quite faithfully replicated during cellular reproduction. The near universality and age of the mapping from nucleotide triplets to amino acids embedded in the functionality of the protein synthetic machinery speaks to the early development of a system of coding which is still extant in every living organism. We take the origin of genetic coding as a paradigm of the emergence of computation in natural systems, focusing on the requirement that the molecular components of an interpreter be synthesized autocatalytically. Within this context, it is seen that interpreters of increasing complexity are generated by series of transitions through stepped dynamic instabilities (non-equilibrium phase transitions). The early phylogeny of the amino acyl-tRNA synthetase enzymes is discussed in such terms, leading to the conclusion that the observed optimality of the genetic code is a natural outcome of the processes of self-organization that produced it.

  14. Resistively Heated SiC Nozzle for Generating Molecular Beams

    NASA Technical Reports Server (NTRS)

    Cagiano, Steven; Abell, Robert; Patrick, Edward; Bendt, Miri; Gundersen, Cynthia

    2007-01-01

    An improved nozzle has been developed to replace nozzles used previously in an apparatus that generates a substantially unidirectional beam of molecules passing through a vacuum at speeds of several kilometers per second. The basic principle of operation of the apparatus is the same for both the previous and the present nozzle designs. The main working part of the nozzle is essentially a cylinder that is closed except that there is an inlet for a pressurized gas and, at one end, the cylinder is closed by a disk that contains a narrow central hole that serves as an outlet. The cylinder is heated to increase the thermal speeds of the gas molecules into the desired high-speed range. Heated, pressurized gas escapes through the outlet into a portion of the vacuum chamber that is separated, by a wall, from the rest of the vacuum chamber. In this portion of the vacuum chamber, the gas undergoes a free jet expansion. Most of the expanded gas is evacuated and thus does not become part of the molecular beam. A small fraction of the expanded beam passes through a narrow central orifice in the wall and thereby becomes a needle- thin molecular beam in the portion of the vacuum on the downstream side of the wall.

  15. Conformational evolution of ubiquitin ions in electrospray mass spectrometry: molecular dynamics simulations at gradually increasing temperatures.

    PubMed

    Segev, Elad; Wyttenbach, Thomas; Bowers, Michael T; Gerber, R Benny

    2008-06-07

    Evidence from cross section data indicates that ubiquitin +13 ions lose their secondary and tertiary structure in mass spectrometric experiments. These transitions from the folded state into the near linear final structure occur at the experimental temperatures on time scales that are far too long for conventional molecular dynamics simulations. In this study, an approach to mass spectrometric unfolding processes is developed and a detailed application to an ubiquitin +13 ion system is presented. The approach involves a sequence of molecular dynamics simulations at gradually increasing temperatures leading to identification of major intermediate states, and the unfolding pathway. The unfolding rate at any temperature can then be calculated by a Rice-Ramsperger-Kassel (RRK) approach. For ubiquitin +13, three interesting intermediate states were found and the final near linear geometry was computed. The several relevant energy barriers calculated for the process are in the range of 7 to 15 kcal mol(-1). The unfolding time scale at 300 K was computed to be 2 ms. Cross section calculations using a hard sphere scattering model were carried out for the final structure and found to be in good accord with the results of electrospray experiments supporting the theoretical model used. The approach employed here should be applicable to any other solvent-free protein system.

  16. Conformational contribution to thermodynamics of binding in protein-peptide complexes through microscopic simulation.

    PubMed

    Das, Amit; Chakrabarti, J; Ghosh, Mahua

    2013-03-19

    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.

  17. Detection of conformational changes in immunoglobulin G using isothermal titration calorimetry with low-molecular-weight probes.

    PubMed

    Rispens, Theo; Lakemond, Catriona M M; Derksen, Ninotska I L; Aalberse, Rob C

    2008-09-15

    Proteins for therapeutic use may contain small amounts of partially misfolded monomeric precursors to postproduction aggregation. To detect these misfolded proteins in the presence of an excess of properly folded protein, fluorescent probes such as 8-anilino-1-naphthalene sulfonate (ANS) are commonly used. We investigated the possibility of using isothermal titration calorimetry (ITC) to improve the detection of this type of conformational change using hydrophobic probes. As a case study, conformational changes in human polyclonal immunoglobulin G (IgG) were monitored by measuring the enthalpies of binding of ANS using ITC. Results were compared with those using fluorescence spectroscopy. IgG heated at 63 degrees C was used as a model system for "damaged" IgG. Heat-treated IgG can be detected already at levels below 5% with both ITC and fluorescence. However, ITC allows a much wider molar probe-to-protein ratio to be sampled. In particular, using reverse titration experiments (allowing high probe-to-protein ratios not available to fluorescence spectroscopy), an increase in the number of binding sites with a K(d)>10 mM was observed for heat-treated IgG, reflecting subtle changes in structure. Both ITC and fluorescence spectroscopy showed low background signals for native IgG. The nature of the background signals was not clear from the fluorescence measurements. However, further analysis of the ITC background signals shows that a fraction (8%) binds ANS with a dissociation constant of approximately 0.2 mM. Measurements were also carried out at pH 4.5. Precipitation of IgG was induced by ANS at concentrations above 0.5 mM, interfering with the ITC measurements. Instead, with the nonfluorescent probes 4-amino-1-naphthalene sulfonate and 1-naphthalene sulfonate, no precipitation is observed. These probes yield differences in the enthalpies of binding to heated and nonheated IgG similar to ANS. The data illustrate that ITC with low-molecular-weight probes is a versatile

  18. [Which molecular biology techniques must conform to the armamentarium for basic research in uro-oncology?].

    PubMed

    Oriola, Josep

    2013-06-01

    Molecular biology has been one of the scientific disciplines in which there has been more advances in the last years. The first impulse in the study of genetic alterations came from the discovery of DNA structure, followed by elucidation of the genetic code, the discovery of restriction enzymes and subsequently the invention of PCR, not forgetting the exponential development of computer science. All of them have allowed us to know much more about our genome and its regulation than we could imagine. The impulse in proteomics has been especially in tune up of soft methods of ionization coupled with mass spectrometry. Nevertheless, this seems to be only the beginning since today there are continuous methodological advances that will increase more, without doubt, the knowledge and applications in this discipline.

  19. Effects of osmolytes on the helical conformation of model peptide: Molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Mehrnejad, Faramarz; Ghahremanpour, Mohammad Mehdi; Khadem-Maaref, Mahmoud; Doustdar, Farahnoosh

    2011-01-01

    Co-solvents such as glycerol and sorbitol are small organic molecules solvated in the cellular solutions that can have profound effects on the protein structures. Here, the molecular dynamics simulations and comparative structural analysis of magainin, as a peptide model, in pure water, 2,2,2-trifluoroethanol/water, glycerol/water, and sorbitol/water are reported. Our results show that the peptide NMR structure is largely maintained its native structure in osmolytes-water mixtures. The simulation data indicates that the stabilizing effect of glycerol and sorbitol is induced by preferential accumulation of glycerol and sorbitol molecules around the nonpolar and aromatic residues. Thus, the presence of glycerol and sorbitol molecules decreases the interactions of water molecules with the hydrophobic residues of the peptide, and the alpha helical structure is stabilized.

  20. Conformational and Molecular Structures of α,β-Unsaturated Acrylonitrile Derivatives: Photophysical Properties and Their Frontier Orbitals.

    PubMed

    Percino, María Judith; Cerón, Margarita; Rodríguez, Oscar; Soriano-Moro, Guillermo; Castro, María Eugenia; Chapela, Víctor M; Siegler, Maxime A; Pérez-Gutiérrez, Enrique

    2016-03-28

    We report single crystal X-ray diffraction (hereafter, SCXRD) analyses of derivatives featuring the electron-donor N-ethylcarbazole or the (4-diphenylamino)phenyl moieties associated with a -CN group attached to a double bond. The compounds are (2Z)-3-(4-(diphenylamino)-phenyl)-2-(pyridin-3-yl)prop-2-enenitrile (I), (2Z)-3-(4-(diphenylamino)phenyl)-2-(pyridin-4-yl)-prop-2-enenitrile (II) and (2Z)-3-(9-ethyl-9H-carbazol-3-yl)-2-(pyridin-2-yl)enenitrile (III). SCXRD analyses reveal that I and III crystallize in the monoclinic space groups P2/c with Z' = 2 and C2/c with Z' = 1, respectively. Compound II crystallized in the orthorhombic space group Pbcn with Z' = 1. The molecular packing analysis was conducted to examine the pyridine core effect, depending on the ortho, meta- and para-positions of the nitrogen atom, with respect to the optical properties and number of independent molecules (Z'). It is found that the double bond bearing a diphenylamino moiety introduced properties to exhibit a strong π-π-interaction in the solid state. The compounds were examined to evaluate the effects of solvent polarity, the role of the molecular structure, and the molecular interactions on their self-assembly behaviors. Compound I crystallized with a cell with two conformers, anti and syn, due to interaction with solvent. DFT calculations indicated the anti and syn structures of I are energetically stable (less than 1 eV). Also electrochemical and photophysical properties of the compounds were investigated, as well as the determination of optimization calculations in gas and different solvent (chloroform, cyclohexane, methanol, ethanol, tetrahydrofuran, dichloromethane and dimethyl sulfoxide) in the Gaussian09 program. The effect of solvent by PCM method was also investigated. The frontier HOMO and LUMO energies and gap energies are reported.

  1. Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope

    PubMed Central

    Theunis, Clara; Adolfsson, Oskar; Crespo-Biel, Natalia; Piorkowska, Kasia; Pihlgren, Maria; Hickman, David T.; Gafner, Valérie; Borghgraef, Peter; Devijver, Herman; Pfeifer, Andrea; Van Leuven, Fred; Muhs, Andreas

    2016-01-01

    The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer’s disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer’s disease. PMID:28035925

  2. Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation

    NASA Astrophysics Data System (ADS)

    Mo, Yuxiang; Lei, Jiangtao; Sun, Yunxiang; Zhang, Qingwen; Wei, Guanghong

    2016-09-01

    Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer – dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel β-sheet and contain the previously reported β-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide β-sheet formation and intra-peptide interaction crucial for β-hairpin formation, thus abolishes the three-stranded β-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation.

  3. Computational diagnosis of protein conformational diseases: short molecular dynamics simulations reveal a fast unfolding of r-LDL mutants that cause familial hypercholesterolemia.

    PubMed

    Cuesta-López, S; Falo, F; Sancho, J

    2007-01-01

    The molecular basis of conformational diseases frequently resides in mutant proteins constituting a subset of the vast mutational space. While the subtleties of protein structure point to molecular dynamics (MD) techniques as promising tools for an efficient exploration of such a space, the average size of proteins and the time scale of unfolding events make this goal difficult with present computational capabilities. We show here, nevertheless, that an efficient approach is already feasible for modular proteins. Familial hypercholesterolemia (FH) is a conformational disease linked to mutations in the gene encoding the low density lipoprotein receptor. A high percentage of these mutations has been found in the seven small modular binding repeats of the receptor. Taking advantage of its small size, we have performed an in depth MD study of the fifth binding repeat. Fast unfolding dynamics have been observed in the absence of a structural bound calcium ion, which agrees with its reported essential role in the stability of the module. In addition, several mutations detected in FH patients have been analyzed, starting from the native conformation. Our results indicate that in contrast with the wild type protein and an innocuous control mutant, disease-related mutants experience, in short simulation times (2-8 ns), gross departures from the native state that lead to unfolded conformations and, in some cases, to binding site desorganization deriving in calcium release. Computational diagnosis of mutations leading to conformational diseases seems thus feasible, at least for small or modular pathogenic proteins.

  4. Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation

    PubMed Central

    Mo, Yuxiang; Lei, Jiangtao; Sun, Yunxiang; Zhang, Qingwen; Wei, Guanghong

    2016-01-01

    Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer – dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel β-sheet and contain the previously reported β-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide β-sheet formation and intra-peptide interaction crucial for β-hairpin formation, thus abolishes the three-stranded β-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation. PMID:27620620

  5. Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence

    SciTech Connect

    Kamberaj, Hiqmet

    2015-09-28

    In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4,  5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias.

  6. Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence

    NASA Astrophysics Data System (ADS)

    Kamberaj, Hiqmet

    2015-09-01

    In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4, 5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias.

  7. Conformational study of insect adipokinetic hormones using NMR constrained molecular dynamics

    NASA Astrophysics Data System (ADS)

    Nair, Margie M.; Jackson, Graham E.; Gäde, Gerd

    2001-03-01

    Mem-CC (pGlu-Leu-Asn-Tyr-Ser-Pro-Asp-Trp-NH2), Tem-HrTH (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-NH2) and Del-CC (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-Gly-Asn-NH2) are adipokinetic hormones, isolated from the corpora cardiaca of different insect species. These hormones regulate energy metabolism during flight and so are intimately involved in an insect's mobility. Secondary structural elements of these peptides and the N7 analogue, [N7]-Mem-CC (pGlu-Leu-Asn-Tyr-Ser-Pro-Asn-Trp-NH2), have been determined in dimethylsulfoxide solution using NMR restrained molecular mechanic simulations. The neuropeptides were all found to have an extended structure for the first 4 residues and a β-turn between residues 4-8. For Tem-HrTH and Del-CC, asparagine (N7) which is postulated to be involved in receptor binding and/or activation, projects outward form the β-turn. Mem-CC does not have an asparagine at position 7 while, for [N7]-Mem-CC, the N7 sidechain folds inside the β-turn preventing its interaction with the receptor.

  8. Molecular dynamics study of the conformational stability of esterase 2 from Alicyclobacillus acidocaldarius.

    PubMed

    Pagano, Bruno; Del Vecchio, Pompea; Mattia, Carlo A; Graziano, Giuseppe

    2011-12-01

    Circular dichroism and differential scanning calorimetry measurements showed that esterase 2 from the thermophilic microorganism Alicyclobacillus acidocaldarius, EST2, and its variant in which the first 35 residues have been deleted, EST2-36 del, unfold reversibly on increasing temperature, and possess two cooperative and coupled domains [12]. Structural features of the α/β hydrolase fold of EST2, with nine α-helices packed against the central twisted β-sheet, do not allow a straightforward identification of these two cooperative and coupled domains. Molecular dynamics simulations, each one 20 ns long, have been performed at 300, 400 and 500 K, on both proteins in explicit water. Suitable analysis of MD trajectories has allowed a reliable identification of the two cooperative domains (i.e., the less stable one corresponds to external α-helices, whereas the more stable one corresponds to the central twisted β-sheet) and the attribution of the key coupling role to the last and long α-helix of EST2. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Dynamic neutron scattering from conformational dynamics. II. Application using molecular dynamics simulation and Markov modeling

    SciTech Connect

    Yi, Zheng; Lindner, Benjamin; Prinz, Jan -Hendrik; Noe, Frank; Smith, Jeremy C.

    2013-11-01

    Here, neutron scattering experiments directly probe the dynamics of complex molecules on the sub pico- to microsecond time scales. However, the assignment of the relaxations seen experimentally to specific structural rearrangements is difficult, since many of the underlying dynamical processes may exist on similar timescales. In an accompanying article, we present a theoretical approach to the analysis of molecular dynamics simulations with a Markov State Model (MSM) that permits the direct identification of structural transitions leading to each contributing relaxation process. Here, we demonstrate the use of the method by applying it to the configurational dynamics of the well-characterized alanine dipeptide. A practical procedure for deriving the MSM from an MD is introduced. The result is a 9-state MSM in the space of the backbone dihedral angles and the side-chain methyl group. The agreement between the quasielastic spectrum calculated directly from the atomic trajectories and that derived from the Markov state model is excellent. The dependence on the wavevector of the individual Markov processes is described. The procedure means that it is now practicable to interpret quasielastic scattering spectra in terms of well-defined intramolecular transitions with minimal a priori assumptions as to the nature of the dynamics taking place.

  10. Conformation change of an isotactic poly (N-isopropylacrylamide) membrane: Molecular dynamics.

    PubMed

    Adroher-Benítez, Irene; Moncho-Jordá, Arturo; Odriozola, Gerardo

    2017-05-21

    In this work, isotactic Poly (N-Isopropylacrylamide)-PNIPAM-in neat water and in electrolyte solutions is studied by means of molecular dynamics simulations. This is done for an infinitely diluted oligomer and for an assembly of several PNIPAM chains arranged into a planar membrane configuration with a core-shell morphology. We employed two different force fields, AMBER (assisted model building with energy refinement) and OPLS-AA (all atom - optimized potentials for liquid simulations) in combination with extended simple point charge water. Despite the more water insoluble character of isotactic oligomers, our results support the existence of a coil to globule transition for the isolated 30-mer. This may imply the existence of an oligomer rich phase of coil-like structures in equilibrium with a water rich phase for temperatures close but below the coil to globule transition temperature, TΘ. However, the obtained coil structure is much more compact than that corresponding to the syndiotactic chain. Our estimations of TΘ are (308±5) K and (303±5) K for AMBER and OPLS-AA, respectively. The membrane configuration allows one to include chain-chain interactions, to follow density profiles of water, polymer, and solutes, and accessing the membrane-water interface tension. Results show gradual shrinking and swelling of the membrane by switching temperature above and below TΘ, as well as the increase and decrease of the membrane-water interface tension. Finally, concentration profiles for 1M NaCl and 1M NaI electrolytes are shown, depicting a strong salting-out effect for NaCl and a much lighter effect for NaI, in good qualitative agreement with experiments.

  11. Conformation change of an isotactic poly (N-isopropylacrylamide) membrane: Molecular dynamics

    NASA Astrophysics Data System (ADS)

    Adroher-Benítez, Irene; Moncho-Jordá, Arturo; Odriozola, Gerardo

    2017-05-01

    In this work, isotactic Poly (N-Isopropylacrylamide)—PNIPAM—in neat water and in electrolyte solutions is studied by means of molecular dynamics simulations. This is done for an infinitely diluted oligomer and for an assembly of several PNIPAM chains arranged into a planar membrane configuration with a core-shell morphology. We employed two different force fields, AMBER (assisted model building with energy refinement) and OPLS-AA (all atom - optimized potentials for liquid simulations) in combination with extended simple point charge water. Despite the more water insoluble character of isotactic oligomers, our results support the existence of a coil to globule transition for the isolated 30-mer. This may imply the existence of an oligomer rich phase of coil-like structures in equilibrium with a water rich phase for temperatures close but below the coil to globule transition temperature, TΘ. However, the obtained coil structure is much more compact than that corresponding to the syndiotactic chain. Our estimations of TΘ are (308 ±5 ) K and (303 ±5 ) K for AMBER and OPLS-AA, respectively. The membrane configuration allows one to include chain-chain interactions, to follow density profiles of water, polymer, and solutes, and accessing the membrane-water interface tension. Results show gradual shrinking and swelling of the membrane by switching temperature above and below TΘ, as well as the increase and decrease of the membrane-water interface tension. Finally, concentration profiles for 1M NaCl and 1M NaI electrolytes are shown, depicting a strong salting-out effect for NaCl and a much lighter effect for NaI, in good qualitative agreement with experiments.

  12. Conformational analysis of the antiulcer drug pirenzepine. X-ray investigations, molecular mechanics and quantum mechanical calculations and comparisons with structurally or pharmacologically related compounds.

    PubMed

    Trummlitz, G; Schmidt, G; Wagner, H U; Luger, P

    1984-01-01

    The crystal structures of the antiulcer drug 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one dihydrochloride (pirenzepine dihydrochloride, L-S 519 CL 2, Gastrozepin) and its monoprotonated form (pirenzepine monohydrochloride, L-S 519 CL) were determined by X-ray analysis. Molecular mechanics (MMPI) and semiempirical quantum chemical (MNDO) calculations showed that the calculated minimum energy conformations of the tricycle and of the exocyclic amide group are in agreement with the crystal structures. The conformational energies of pirenzepine as a function of four important torsional angles were calculated using different semiempirical quantum chemical methods with the CNDO/2 (complete neglect of differential overlap)-, MNDO (modified neglect of diatomic overlap)- and PCILO (perturbative configuration interaction using localized orbitals)-approximations. The conformation of one local energy minimum corresponds closely to the crystal structure of pirenzepine monohydrochloride. This conformation has a spatial arrangement which is analogous to a single consistent conformation known from the literature of 24 anticholinergic agents determined from their crystal structures by a computer graphics analysis. On the other hand there are no structural relationships of any low energy conformation of pirenzepine to conformations of other classes of tricyclic compounds which could rationalize their antidepressant, neuroleptic or antihistaminic activity. This finding explains the absence of any central effect of pirenzepine following intracerebral application. The computational elucidation of the conformational requirements for the interaction with the muscarinic receptors may be helpful for the interpretation of the selectivity of pirenzepine within the muscarinic system.

  13. Denaturing gradient electrophoresis (DGE) and single-strand conformation polymorphism (SSCP) molecular fingerprintings revisited by simulation and used as a tool to measure microbial diversity.

    PubMed

    Loisel, Patrice; Harmand, Jérôme; Zemb, Olivier; Latrille, Eric; Lobry, Claude; Delgenès, Jean-Philippe; Godon, Jean-Jacques

    2006-04-01

    The exact extent of microbial diversity remains unknowable. Nevertheless, fingerprinting patterns [denaturing gradient electrophoresis (DGE), single-strand conformation polymorphism (SSCP)] provide an image of a microbial ecosystem and contain diversity data. We generated numerical simulation fingerprinting patterns based on three types of distribution (uniform, geometric and lognormal) with a range of units from 10 to 500,000. First, simulated patterns containing a diversity of around 1000 units or more gave patterns similar to those obtained in experiments. Second, the number of bands or peaks saturated quickly to about 35 and were unrelated to the degree of diversity. Finally, assuming lognormal distribution, we used an estimator of diversity on in silico and experimental fingerprinting patterns. Results on in silico patterns corresponded to the simulation inputs. Diversity results in experimental patterns were in the same range as those obtained from the same DNA sample in molecular inventories. Thus, fingerprinting patterns contain extractable data about diversity although not on the basis of a number of bands or peaks, as is generally assumed to be the case.

  14. Theoretical study on conformation dynamics of three-station molecular shuttle in different environments and its influence on NMR chemical shifts and binding interactions.

    PubMed

    Liu, Pingying; Li, Wei; Liu, Li; Wang, Leyong; Ma, Jing

    2014-10-02

    Microscopic information on conformational flexibility and macrocycle-thread binding interactions is helpful in rational design of novel multistation molecular shuttles with interesting topology and functions. Molecular dynamics (MD) was applied to simulate conformational changes of thread and macrocycle of a three-station molecular shuttle in different chemical environments (vacuum, CD3CN-CDCl3 solution, and crystal). In contrast with the highly distorted thread conformation in the gas phase and nonpolar CDCl3 solution, the solvated thread in CD3CN-CDCl3 (1:1) mix solvents exhibited a relatively rigid structure. Experimental observations of preferential binding at the protonated dibenzylammonium group (station I) were rationalized by quantum chemical calculations of macrocycle-thread binding energies at three different stations. The orthogonality of site-specific binding interactions at three different stations was also revealed by the nearly constant binding energy obtained at each specific recognition center with the replacement of different neighboring groups and terminal stoppers on the thread. Conformational flexibility has little effect on NMR signals of binding sites, but for some protons that are close to the solvent molecules in the first solvent shell, their chemical shifts are sensitive to the local electrostatic environment caused by nearby solvents. In crystal, π stacking induced evident upfield shifts of NMR signals in comparison with the isolated monomer.

  15. Molecular structure of unsubstituted oxadiazolic analog of ortho-POPOP and peculiarities of conformational structure of this class of sterically hindered organic compounds

    NASA Astrophysics Data System (ADS)

    Doroshenko, A. O.; Baumer, V. N.; Verezubova, A. A.; Ptyagina, L. M.

    2002-05-01

    X-ray molecular structure of unsubstituted oxadiazolic ortho-analog of 1,4-bis-(5-phenyl-oxazolyl-2)-benzene (POPOP), synthesized via the 2,5-diphenyl-1,3,4-oxadiazole ortho-carbonic acid was revealed. Its conformation was found to be the same as for the compound obtained earlier from the 2,5-diphenyl-oxazole ortho-carbonic acid. Quantum-chemical modeling was conducted to understand the peculiarities of conformational structure of the investigated class of sterically hindered compounds.

  16. Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

    NASA Astrophysics Data System (ADS)

    Ciemny, Maciej Pawel; Debinski, Aleksander; Paczkowska, Marta; Kolinski, Andrzej; Kurcinski, Mateusz; Kmiecik, Sebastian

    2016-12-01

    Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.

  17. Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering

    DOE PAGES

    Wall, Michael E.; Van Benschoten, Andrew H.; Sauter, Nicholas K.; ...

    2014-12-01

    X-ray diffraction from protein crystals includes both sharply peaked Bragg reflections and diffuse intensity between the peaks. The information in Bragg scattering is limited to what is available in the mean electron density. The diffuse scattering arises from correlations in the electron density variations and therefore contains information about collective motions in proteins. Previous studies using molecular-dynamics (MD) simulations to model diffuse scattering have been hindered by insufficient sampling of the conformational ensemble. To overcome this issue, we have performed a 1.1-μs MD simulation of crystalline staphylococcal nuclease, providing 100-fold more sampling than previous studies. This simulation enables reproducible calculationsmore » of the diffuse intensity and predicts functionally important motions, including transitions among at least eight metastable states with different active-site geometries. The total diffuse intensity calculated using the MD model is highly correlated with the experimental data. In particular, there is excellent agreement for the isotropic component of the diffuse intensity, and substantial but weaker agreement for the anisotropic component. The decomposition of the MD model into protein and solvent components indicates that protein–solvent interactions contribute substantially to the overall diffuse intensity. In conclusion, diffuse scattering can be used to validate predictions from MD simulations and can provide information to improve MD models of protein motions.« less

  18. Structural insights for designed alanine-rich helices: Comparing NMR helicity measures and conformational ensembles from molecular dynamics simulation

    PubMed Central

    Song, Kun; Stewart, James M.; Fesinmeyer, R. Matthew

    2013-01-01

    The temperature dependence of helical propensities for the peptides Ac-ZGG-(KAAAA)3X-NH2 (Z = Y or G, X = A, K, and d-Arg) were studied both experimentally and by molecular dynamics simulations. Good agreement is observed in both the absolute helical propensities as well as relative helical content along the sequence; the global minimum on the calculated free energy landscape corresponds to a single α-helical conformation running from K4 – A18 with some terminal fraying, particularly at the C-terminus. Energy component analysis shows that the single helix state has favorable intramolecular electrostatic energy due to hydrogen bonds, and that less-favorable two-helix globular states have favorable solvation energy. The central lysine residues do not appear to increase helicity; however, both experimental and simulation studies show increasing helicity in the series X = Ala → Lys → d-Arg. This C-capping preference was also experimentally confirmed in Ac-(KAAAA)3X-GY-NH2 and (KAAAA)3X-GY-NH2 sequences. The roles of the C-capping groups, and of lysines throughout the sequence, in the MD-derived ensembles are analyzed in detail. PMID:18428207

  19. The molecular structure and conformation of trans-1,2,3-trichloropropene as determined by gas-phase electron diffraction

    NASA Astrophysics Data System (ADS)

    Shen, Quang

    1989-09-01

    The gas-phase molecular structure of trans-1,2,3-trichloropropene has been studied by electron diffraction at a nozzle-tip temperature of 110°C. The data are consistent with the presence of only a conformation with a torsional angle of 110° (8), where 0° corresponds to the eclipsing of the CCl and CC bonds. The principal geometrical parameter values ( rg and ∠ α) obtained from least squares refinement are: r(CH) = 1.06(3) Å, r(CC) = 1.365(12) Å, r(CC) = 1.467(15) Å, r(C 1Cl) = 1.733(25) Å, r(C 2Cl) = 1.727(25) Å, r(C 3Cl) = 1.800(9) Å, ∠ CCC = 124(2)°, ∠ ClC 1C 2 = 124(2)°, ∠ ClC 2C 1 = 115.2(14)°, ∠ClC 3C 2 = 110.9(13)°, and τ (ClC 3C 2C 1) = 110(8)°.

  20. Targeted molecular dynamics reveals overall common conformational changes upon hybrid domain swing-out in beta3 integrins.

    PubMed

    Provasi, Davide; Murcia, Marta; Coller, Barry S; Filizola, Marta

    2009-11-01

    The beta3 integrin family members alphaIIbeta3 and alphaVbeta3 signal bidirectionally through long-range allosteric changes, including a transition from a bent unliganded-closed low-affinity state to an extended liganded-open high-affinity state. To obtain an atomic-level description of this transition in an explicit solvent, we carried out targeted molecular dynamics simulations of the headpieces of alphaIIbeta3 and alphaVbeta3 integrins. Although minor differences were observed between these receptors, our results suggest a common transition pathway in which the hybrid domain swing-out is accompanied by conformational changes within the beta3 betaA (I-like) domain that propagate through the alpha7 helix C-terminus, and are followed by the alpha7 helix downward motion and the opening of the beta6-alpha7 loop. Breaking of contact interactions between the beta6-alpha7 loop and the alpha1 helix N-terminus results in helix straightening, internal rearrangements of the specificity determining loop (SDL), movement of the beta1-alpha1 loop toward the metal ion dependent adhesion site (MIDAS), and final changes at the interfaces between the beta3 betaA (I-like) domain and either the hybrid or the alpha beta-propeller domains. Taken together, our results suggest novel testable hypotheses of intradomain and interdomain interactions responsible for beta3 integrin activation.

  1. Correlation of moth sex pheromone activities with molecular characteristics involved in conformers of bombykol and its derivatives.

    PubMed

    Kikuchi, T

    1975-09-01

    Molecular characteristics of bombykol and its 11 derivatives, which reveal significant correlations with biological activities for single sex pheromone receptor cells of four moth species, Bombyx mori, Aglia tau, Endromis versicolora, and Deilephila euphorbiae, were examined on the assumption of the "bifunctional unit model." Probabilities of bifunctional unit formations of those 12 compounds were assessed with frequency distribution patterns of distances between the proton acceptor, the proton donor, and the methyl group involved in a total of 1,200 conformers. A highly significant correlation exists between biological activity for each species and the probability of a particular bifunctional unit formation: a proton acceptor (A)--a methyl group (Me) unit (A--Me distances: about 6 A) for Deilephila (r = 0.94); a proton acceptor (A)--a proton donor (D)(A--D: about 11 A) for Aglia (r = 0.83); two antagonistic proton donor--methyl units (D--Me: about 14 and 5 A for favorable and adverse unit, respectively) for Bombyx (r = 0.94) and Endromis (r = 0.92).

  2. Coherent transients generated at molecular levels dressed by electromagnetic field

    NASA Astrophysics Data System (ADS)

    Rubtsova, Natalia N.; Konstantinova, T. P.

    2002-05-01

    Free polarization decay and photon echo were studied experimentally in polar gas 13CH3F at the transition R(4,3) of vibrational mode 0 yields 1 (nu) 3 by Stark switching of molecular levels under irradiation by CW CO2 laser at 9P(32) line. Application of 4.5 mcs pulse to the Stark electrodes inside the gas cell allows to detect the free polarization decay signal, combined with the optical nutation. The sign of the signal corresponds to the increase of absorption in the limit of low intensity (not over 0.01 W/cm2) saturating radiation. Exciting intensity growth till the level of 6.0 W/cm2 implies decrease of signal absolute value, till the change of its sign, while the oscillation of the free polarization decay signal reveals remarkable frequency shift. Such behavior is attributed to the combined action of the dynamic Stark effect of CW radiation field and the levels splitting by the Stark voltage. Two shorter (of about 0.1 and 0.2 mcs) Stark pulses, applied to the gas, generate the photon echo signals detected by the same heterodyne technique. The study of the variations of photon echo parameters versus exciting radiation intensity is in progress.

  3. R-dependent molecular harmonic generation from H2+

    NASA Astrophysics Data System (ADS)

    Feng, Liqiang; Liu, Hang

    2017-03-01

    R-dependent high-order harmonic spectra (R is the nuclear distance) from H2+ have been investigated through solving the Non-Bohn-Oppenheimer time-dependent Schrödinger equation. We found that (i) for the case of the few-cycle pulse, the harmonic emission mainly occurs from R = 3.7 to R = 6, caused by the charge-resonance-enhanced-ionization (CREI) process. (ii) For the case of the multi-cycle pulse, the harmonic emission can be separated into two parts, that is the charge-resonance-enhanced-ionization region from R = 3.7 to R = 8; and the dissociative ionization region when R > 10. (iii) Isotopic investigation showed that the R-dependent harmonic emission process can be moved towards the smaller-R region as the masses of the nuclei are increased (D2+ and T2+). (iv) Multi-minima on the harmonic spectra can be obtained, which is attributed to the two-center interference and the electron-nuclear coupling during the generation of the harmonics. The R-dependent ionization probabilities, the time-dependent nuclear motions and the time-frequency analyses of the harmonic spectra have been shown to explain the R-dependent molecular harmonic emission process.

  4. Molecular farming on rescue of pharma industry for next generations.

    PubMed

    Moustafa, Khaled; Makhzoum, Abdullah; Trémouillaux-Guiller, Jocelyne

    2016-10-01

    Recombinant proteins expressed in plants have been emerged as a novel branch of the biopharmaceutical industry, offering practical and safety advantages over traditional approaches. Cultivable in various platforms (i.e. open field, greenhouses or bioreactors), plants hold great potential to produce different types of therapeutic proteins with reduced risks of contamination with human and animal pathogens. To maximize the yield and quality of plant-made pharmaceuticals, crucial factors should be taken into account, including host plants, expression cassettes, subcellular localization, post-translational modifications, and protein extraction and purification methods. DNA technology and genetic transformation methods have also contributed to great parts with substantial improvements. To play their proper function and stability, proteins require multiple post-translational modifications such as glycosylation. Intensive glycoengineering research has been performed to reduce the immunogenicity of recombinant proteins produced in plants. Important strategies have also been developed to minimize the proteolysis effects and enhance protein accumulation. With growing human population and new epidemic threats, the need for new medications will be paramount so that the traditional pharmaceutical industry will not be alone to answer medication demands for upcoming generations. Here, we review several aspects of plant molecular pharming and outline some important challenges that hamper these ambitious biotechnological developments.

  5. Cas9-catalyzed DNA Cleavage Generates Staggered Ends: Evidence from Molecular Dynamics Simulations

    PubMed Central

    Zuo, Zhicheng; Liu, Jin

    2016-01-01

    The CRISPR-associated endonuclease Cas9 from Streptococcus pyogenes (spCas9) along with a single guide RNA (sgRNA) has emerged as a versatile toolbox for genome editing. Despite recent advances in the mechanism studies on spCas9-sgRNA-mediated double-stranded DNA (dsDNA) recognition and cleavage, it is still unclear how the catalytic Mg2+ ions induce the conformation changes toward the catalytic active state. It also remains controversial whether Cas9 generates blunt-ended or staggered-ended breaks with overhangs in the DNA. To investigate these issues, here we performed the first all-atom molecular dynamics simulations of the spCas9-sgRNA-dsDNA system with and without Mg2+ bound. The simulation results showed that binding of two Mg2+ ions at the RuvC domain active site could lead to structurally and energetically favorable coordination ready for the non-target DNA strand cleavage. Importantly, we demonstrated with our simulations that Cas9-catalyzed DNA cleavage produces 1-bp staggered ends rather than generally assumed blunt ends. PMID:27874072

  6. Cas9-catalyzed DNA Cleavage Generates Staggered Ends: Evidence from Molecular Dynamics Simulations

    NASA Astrophysics Data System (ADS)

    Zuo, Zhicheng; Liu, Jin

    2016-11-01

    The CRISPR-associated endonuclease Cas9 from Streptococcus pyogenes (spCas9) along with a single guide RNA (sgRNA) has emerged as a versatile toolbox for genome editing. Despite recent advances in the mechanism studies on spCas9-sgRNA-mediated double-stranded DNA (dsDNA) recognition and cleavage, it is still unclear how the catalytic Mg2+ ions induce the conformation changes toward the catalytic active state. It also remains controversial whether Cas9 generates blunt-ended or staggered-ended breaks with overhangs in the DNA. To investigate these issues, here we performed the first all-atom molecular dynamics simulations of the spCas9-sgRNA-dsDNA system with and without Mg2+ bound. The simulation results showed that binding of two Mg2+ ions at the RuvC domain active site could lead to structurally and energetically favorable coordination ready for the non-target DNA strand cleavage. Importantly, we demonstrated with our simulations that Cas9-catalyzed DNA cleavage produces 1-bp staggered ends rather than generally assumed blunt ends.

  7. Molecular-level Simulations of Shock Generation and Propagation in Polyurea

    DTIC Science & Technology

    2011-01-26

    Polyurea Shock-wave generation and propagation Molecular-level calculations a b s t r a c t A non -equilibrium molecular dynamics method is employed in order...homepage: www.e lsev ier .com/ locate /msea Molecular-level simulations of shock generation and propagation in polyurea M. Grujicica,∗, B. Pandurangana...to study various phenomena accompanying the generation and propagation of shock waves in polyurea (a micro-phase segregated elastomer). Several

  8. Generation of a novel high-affinity monoclonal antibody with conformational recognition epitope on human IgM.

    PubMed

    Sarikhani, Sina; Mirshahi, Manouchehr; Gharaati, Mohammad Reza; Mirshahi, Tooran

    2010-11-01

    As IgM is the first isotype of antibody which appears in blood after initial exposure to a foreign antigen in the pattern of primary response, detection, and quantification of this molecule in blood seems invaluable. To approach these goals, generation, and characterization of a highly specific mAb (monoclonal antibody) against human IgM were investigated. Human IgM immunoglobulins were used to immunize Balb/c mice. Spleen cells taken from the immunized animals were fused with SP2/O myeloma cells using PEG (polyethylene glycol, MW 1450) as fusogen. The hybridomas were cultured in HAT containing medium and supernatants from the growing hybrids were screened by enzyme-linked immunosorbent assay (ELISA) using plates coated with pure human IgM and the positive wells were then cloned at limiting dilutions. The best clone designated as MAN-1, was injected intraperitoneally to some Pristane-injected mice. Anti-IgM mAb was purified from the animals' ascitic fluid by protein-G sepharose followed by DEAE-cellulose ion exchange chromatography. MAN-1 interacted with human IgM with a very high specificity and affinity. The purity of the sample was tested by SDS-PAGE and the affinity constant was measured (K(a) = 3.5 x 10(9)M(-1). Immunoblotting and competitive ELISA were done and the results showed that the harvested antibody recognizes a conformational epitope on the mu chain of human IgM and there was no cross-reactivity with other subclasses of immunoglobulins. Furthermore, isotyping test was done and the results showed the subclass of the obtained mAb which was IgG(1)kappa.

  9. Differential tapasin dependence of MHC class I molecules correlates with conformational changes upon peptide dissociation: A molecular dynamics simulation study

    SciTech Connect

    Sieker, Florian; Straatsma, TP; Springer, Sebastian; Zacharias, Martin W

    2008-08-01

    Efficiency of peptide loading to MHC class I molecules in the endoplasmatic reticulum depends on the class I allele and can involve interaction with tapasin and other proteins of the loading complex. Allele HLA-B*4402 (Asp at position 116) depends on tapasin for efficient peptide loading whereas HLA-B*4405 (identical to B*4402 except for Tyr116) can efficiently load peptides in the absence of tapasin. Both alleles adopt very similar structures in the presence of the same peptide. Molecular dynamics (MD) simulations on induced peptide termini dissociation from the α1/α2 peptide binding domains have been performed to characterize free energy changes and associated structural changes in the two alleles. A smooth free energy change along the distance dissociation coordinate was obtained for N terminus dissociation. A different shape and magnitude of the calculated free energy change and was obtained for induced peptide C terminus dissociation in case of the tapasin independent allele B*4405 compared to B*4402. Structural changes during C terminus dissociation occurred mainly in the first segment of the α2-1 helix that flanks the peptide C-terminus binding region (F-pocket) and contacts residue 116. This segment is also close to the proposed tapasin contact region. For B*4402, a stable shift towards an altered open F-pocket structure deviating significantly from the bound form was observed. In contrast, B*4405 showed only a transient opening of the F-pocket followed by relaxation towards a structure close to the bound form upon C terminus dissociation. The greater tendency for peptide-receptive conformation in the absence of peptide combined with a more long-range character of the interactions with the peptide C terminus facilitates peptide binding to B*4405 and could be responsible for the tapasin independence of this allele. A possible role of tapasin in case of HLA-B*4402 and other tapasin-dependent alleles could be the stabilization of a peptide receptive class I

  10. Multi-drug resistance profile of PR20 HIV-1 protease is attributed to distorted conformational and drug binding landscape: molecular dynamics insights.

    PubMed

    Chetty, Sarentha; Bhakat, Soumendranath; Martin, Alberto J M; Soliman, Mahmoud E S

    2016-01-01

    The PR20 HIV-1 protease, a variant with 20 mutations, exhibits high levels of multi-drug resistance; however, to date, there has been no report detailing the impact of these 20 mutations on the conformational and drug binding landscape at a molecular level. In this report, we demonstrate the first account of a comprehensive study designed to elaborate on the impact of these mutations on the dynamic features as well as drug binding and resistance profile, using extensive molecular dynamics analyses. Comparative MD simulations for the wild-type and PR20 HIV proteases, starting from bound and unbound conformations in each case, were performed. Results showed that the apo conformation of the PR20 variant of the HIV protease displayed a tendency to remain in the open conformation for a longer period of time when compared to the wild type. This led to a phenomena in which the inhibitor seated at the active site of PR20 tends to diffuse away from the binding site leading to a significant change in inhibitor-protein association. Calculating the per-residue fluctuation (RMSF) and radius of gyration, further validated these findings. MM/GBSA showed that the occurrence of 20 mutations led to a drop in the calculated binding free energies (ΔGbind) by ~25.17 kcal/mol and ~5 kcal/mol for p2-NC, a natural peptide substrate, and darunavir, respectively, when compared to wild type. Furthermore, the residue interaction network showed a diminished inter-residue hydrogen bond network and changes in inter-residue connections as a result of these mutations. The increased conformational flexibility in PR20 as a result of loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces led to a loss of protease grip on ligand. It is interesting to note that the difference in conformational flexibility between PR20 and WT conformations was much higher in the case of substrate-bound conformation as compared to DRV. Thus, developing analogues of DRV by

  11. Full relative stereochemistry assignment and conformational analysis of 13,19-didesmethyl spirolide C via NMR- and molecular modeling-based techniques. A step towards understanding spirolide's mechanism of action.

    PubMed

    Ciminiello, Patrizia; Catalanotti, Bruno; Dell'aversano, Carmela; Fattorusso, Caterina; Fattorusso, Ernesto; Forino, Martino; Grauso, Laura; Leo, Angela; Tartaglione, Luciana

    2009-09-21

    The relative stereochemistry of 13,19-didesmethyl spirolide C was determined through careful analysis of NMR parameters strongly dependent upon molecular conformations supported and extended by computational studies. This work has also shed light on the conformational behavior of spirolides in solution. An equilibrium between two possible conformers of the identified diastereoisomer was inferred, while the uncommon cyclic imine moiety of spirolides-the putative pharmacophore of this class of toxins-was interestingly found to adopt only a single dominant conformation. The insightful details provided on spirolide conformations may represent a key means to pharmacologists involved in clarifying the mechanism of action of spirolide, which is yet to be totally defined.

  12. Structural function of C-terminal amidation of endomorphin. Conformational comparison of mu-selective endomorphin-2 with its C-terminal free acid, studied by 1H-NMR spectroscopy, molecular calculation, and X-ray crystallography.

    PubMed

    In, Yasuko; Minoura, Katsuhiko; Tomoo, Koji; Sasaki, Yusuke; Lazarus, Lawrence H; Okada, Yoshio; Ishida, Toshimasa

    2005-10-01

    To investigate the structural function of the C-terminal amide group of endomorphin-2 (EM2, H-Tyr-Pro-Phe-Phe-NH(2)), an endogenous micro-opioid receptor ligand, the solution conformations of EM2 and its C-terminal free acid (EM2OH, H-Tyr-Pro-Phe-Phe-OH) in TFE (trifluoroethanol), water (pH 2.7 and 5.2), and aqueous DPC (dodecylphosphocholine) micelles (pH 3.5 and 5.2) were investigated by the combination of 2D (1)H-NMR measurement and molecular modelling calculation. Both peptides were in equilibrium between the cis and trans rotamers around the Tyr--Pro w bond with population ratios of 1 : 1 to 1 : 2 in dimethyl sulfoxide, TFE and water, whereas they predominantly took the trans rotamer in DPC micelle, except in EM2OH at pH 5.2, which had a trans/cis rotamer ratio of 2 : 1. Fifty possible 3D conformers were generated for each peptide, taking different electronic states depending on the type of solvent and pH (neutral and monocationic forms for EM2, and zwitterionic and monocation forms for EM2OH) by the dynamical simulated annealing method, under the proton-proton distance constraints derived from the ROE cross-peak intensities. These conformers were then roughly classified into four groups of two open [reverse S (rS)- and numerical 7 (n7)-type] and two folded (F1- and F2-type) conformers according to the conformational pattern of the backbone structure. Most EM2 conformers in neutral (in TFE) and monocationic (in water and DPC micelles) forms adopted the open structure (mixture of major rS-type and minor n7-type conformers) despite the trans/cis rotamer form. On the other hand, the zwitterionic EM2OH in TFE, water and DPC micelles showed an increased population of F1- and F2-type folded conformers, the population of which varied depending on their electronic state and pH. Most of these folded conformers took an F1-type structure similar to that stabilized by an intramolecular hydrogen bond of (Tyr1)NH(3) (+)...COO(-)(Phe4), observed in its crystal structure

  13. Hyperthermophile Protein Behavior: Partially-Structured Conformations of Pyrococcus furiosus Rubredoxin Monomers Generated through Forced Cold-Denaturation and Refolding

    PubMed Central

    Ahmed, Shubbir; Guptasarma, Purnananda

    2014-01-01

    Some years ago, we showed that thermo-chemically denatured, partially-unfolded forms of Pyrococcus furiosus triosephosphateisomerase (PfuTIM) display cold-denaturation upon cooling, and heat-renaturation upon reheating, in proportion with the extent of initial partial unfolding achieved. This was the first time that cold-denaturation was demonstrated for a hyperthermophile protein, following unlocking of surface salt bridges. Here, we describe the behavior of another hyperthermophile protein, the small, monomeric, 53 residues-long rubredoxin from Pyrococcus furiosus (PfRd), which is one of the most thermostable proteins known to man. Like PfuTIM, PfRd too displays cold-denaturation after initial thermo-chemical perturbation, however, with two differences: (i) PfRd requires considerably higher temperatures as well as higher concentrations of guanidium hydrochloride (Gdm.HCl) than PfuTIM; (ii) PfRd's cold-denaturation behavior during cooling after thermo-chemical perturbation is incompletely reversible, unlike PfuTIM's, which was clearly reversible (from each different conformation generated). Differential cold-denaturation treatments allow PfRd to access multiple partially-unfolded states, each of which is clearly highly kinetically-stable. We refer to these as ‘Trishanku’ unfolding intermediates (or TUIs). Fascinatingly, refolding of TUIs through removal of Gdm.HCl generates multiple partially-refolded, monomeric, kinetically-trapped, non-native ‘Trishanku’ refolding intermediates (or TRIs), which differ from each other and from native PfRd and TUIs, in structural content and susceptibility to proteolysis. We find that the occurrence of cold denaturation and observations of TUI and TRI states is contingent on the oxidation status of iron, with redox agents managing to modulate the molecule's behavior upon gaining access to PfRd's iron atom. Mass spectrometric examination provides no evidence of the formation of disulfide bonds, but other experiments suggest

  14. Conformation and molecular structure of 1,5-hexadiene-3-yne(divinylacetylene) and perchloro-1,5-hexadiene-3-yne as determined by gas-phase electron diffraction and molecular-mechanics calculations

    NASA Astrophysics Data System (ADS)

    Almenningen, A.; Gogstad, E.; Hagen, K.; Schei, H.; Stølevik, R.; Thingstad, Ø.; Traetteberg, M.

    1984-04-01

    Gaseous divinylacetylene (DVA) and perchlorodivinylacetylene (XDVA) have been studied by electron diffraction. The ED data for DVA are consistent with free rotation. For XDVA the ED data are best explained in terms of a conformational mixture of 70% gauche, with a torsion angle φ = 38°, and 30% anti (φ = 180°). The same conclusions were obtained by molecular-mechanics calculations.

  15. Conformational analysis, X-ray crystallographic, FT-IR, FT-Raman, DFT, MEP and molecular docking studies on 1-(1-(3-methoxyphenyl) ethylidene) thiosemicarbazide.

    PubMed

    Saravanan, R R; Seshadri, S; Gunasekaran, S; Mendoza-Meroño, R; Garcia-Granda, S

    2015-03-15

    Conformational analysis, X-ray crystallographic, FT-IR, FT-Raman, DFT, MEP and molecular docking studies on 1-(1-(3-methoxyphenyl) ethylidene) thiosemicarbazide (MPET) are investigated. From conformational analysis the examination of the positions of a molecule taken and the energy changes is observed. The docking studies of the ligand MPET with target protein showed that this is a good molecule which docks well with target related to HMG-CoA. Hence MPET can be considered for developing into a potent anti-cholesterol drug. MEP assists in optimization of electrostatic interactions between the protein and the ligand. The MEP surface displays the molecular shape, size and electrostatic potential values. The optimized geometry of the compound was calculated from the DFT-B3LYP gradient calculations employing 6-31G (d, p) basis set and calculated vibrational frequencies are evaluated via comparison with experimental values. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Regulation of sporulation initiation by NprR and its signaling peptide NprRB: molecular recognition and conformational changes.

    PubMed

    Cabrera, Rosina; Rocha, Jorge; Flores, Víctor; Vázquez-Moreno, Luz; Guarneros, Gabriel; Olmedo, Gabriela; Rodríguez-Romero, Adela; de la Torre, Mayra

    2014-11-01

    NprR belongs to the RNPP family of quorum-sensing receptors, a group of intracellular regulators activated directly by signaling oligopeptides in Gram-positive bacteria. In Bacillus thuringiensis (Bt), nprR is located in a transcriptional cassette with nprRB that codes for the precursor of the signaling peptide NprRB. NprR is a transcriptional regulator activated by binding of reimported NprRB; however, several reports suggest that NprR also participates in sporulation but the mechanism is unknown. Our in silico results, based on the structural similarity between NprR from Bt and Spo0F-binding Rap proteins from Bacillus subtilis, suggested that NprR could bind Spo0F to modulate the sporulation phosphorelay in Bt. Deletion of nprR-nprRB cassette from Bt caused a delay in sporulation and defective trigger of the Spo0A∼P-activated genes spoIIA and spoIIIG. The DNA-binding domain of NprR was not necessary for this second function, since truncated NprRΔHTH together with nprRB gene was able to restore the sporulation wild type phenotype in the ΔnprR-nprRB mutant. Fluorescence assays showed direct binding between NprR and Spo0F, supporting that NprR is a bifunctional protein. To understand how the NprR activation by NprRB could result in two different functions, we studied the molecular recognition mechanism between the signaling peptide and the receptor. Using synthetic variants of NprRB, we found that SSKPDIVG displayed the highest affinity (Kd = 7.19 nM) toward the recombinant NprR and demonstrated that recognition involves conformational selection. We propose that the peptide concentration in the cell controls the oligomerization state of the NprR-NprRB complex for switching between its two functions.

  17. Generation and release of molecular markers for Poa Arachnifera Torr

    USDA-ARS?s Scientific Manuscript database

    DNA based molecular markers can be utilized in a wide array of plant genetic studies, marker-trait associations, seed purity evaluations and cultivar protection. However, for the genus Poa, the use of molecular markers is limited by the current lack of informative DNA based markers. This report r...

  18. 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

  19. A method to generate conformal finite-element meshes from 3D measurements of microstructurally small fatigue-crack propagation: 3D Meshes of Microstructurally Small Crack Growth

    DOE PAGES

    Spear, A. D.; Hochhalter, J. D.; Cerrone, A. R.; ...

    2016-04-27

    In an effort to reproduce computationally the observed evolution of microstructurally small fatigue cracks (MSFCs), a method is presented for generating conformal, finite-element (FE), volume meshes from 3D measurements of MSFC propagation. The resulting volume meshes contain traction-free surfaces that conform to incrementally measured 3D crack shapes. Grain morphologies measured using near-field high-energy X-ray diffraction microscopy are also represented within the FE volume meshes. Proof-of-concept simulations are performed to demonstrate the utility of the mesh-generation method. The proof-of-concept simulations employ a crystal-plasticity constitutive model and are performed using the conformal FE meshes corresponding to successive crack-growth increments. Although the simulationsmore » for each crack increment are currently independent of one another, they need not be, and transfer of material-state information among successive crack-increment meshes is discussed. The mesh-generation method was developed using post-mortem measurements, yet it is general enough that it can be applied to in-situ measurements of 3D MSFC propagation.« less

  20. Phase Transition, Conformational Exchange, and Nonlinear Optical Third Harmonic Generation of A CsP 2 Se 8 ( A = K, Rb, Cs)

    SciTech Connect

    Haynes, Alyssa S.; Banerjee, Abhishek; Saouma, Felix O.; Otieno, Calford O.; Jang, Joon I.; Kanatzidis, Mercouri G.

    2016-04-12

    The soluble molecular selenophosphate salts ACsP(2)Se(8) (A = K, Rb, Cs) crystallize in the orthorhombic space group Ccce with a = 14.982(3) A, b = 24.579(5) A, and c = 13.065(3) A for the Cs salt and a = 14.782(3) A, b = 23.954(5) A, and c = 13.044(3) A for the K analogue. ACsP2Se8 is composed of the molecular 6-membered ring, [P2Se8](2-), in the twist conformation charge balanced by alkali metals. The band gaps of these compounds are 2.44 +/- 0.2 eV for Cs2P2Se8, 2.41 +/- 0.2 eV for RbCsP2Se8, and 2.36 +/- 0.2 eV for KCsP2Se8. The amorphous versions of these materials can be made by water quenching the melt and have band gaps for all ACsP(2)Se(8) of 2.12 +/- 0.2 eV. Raman spectroscopic studies exhibit active modes of PSe4 and Se Se in the compound. Solution P-31 NMR studies shed light into the interesting conformational fluxionality of the [P2Se8](2-) anion, including a conformation that has not been previously observed. Thermal analysis reveals ACsP(2)Se(8) exhibits a phase transition, which we investigate by in situ synchrotron powder X-ray diffraction. Third harmonic generation (THG) nonlinear optical measurements determined the THG coefficient, chi(3), for amorphous and crystalline Cs2P2Se8 of 1.8 +/- 0.2 X 105 pm(2)/V-2 and 2.4 +/- 0.1 X 105 pm2/V2, respectively.

  1. Next generation extended Lagrangian first principles molecular dynamics

    NASA Astrophysics Data System (ADS)

    Niklasson, Anders M. N.

    2017-08-01

    Extended Lagrangian Born-Oppenheimer molecular dynamics [A. M. N. Niklasson, Phys. Rev. Lett. 100, 123004 (2008)] is formulated for general Hohenberg-Kohn density-functional theory and compared with the extended Lagrangian framework of first principles molecular dynamics by Car and Parrinello [Phys. Rev. Lett. 55, 2471 (1985)]. It is shown how extended Lagrangian Born-Oppenheimer molecular dynamics overcomes several shortcomings of regular, direct Born-Oppenheimer molecular dynamics, while improving or maintaining important features of Car-Parrinello simulations. The accuracy of the electronic degrees of freedom in extended Lagrangian Born-Oppenheimer molecular dynamics, with respect to the exact Born-Oppenheimer solution, is of second-order in the size of the integration time step and of fourth order in the potential energy surface. Improved stability over recent formulations of extended Lagrangian Born-Oppenheimer molecular dynamics is achieved by generalizing the theory to finite temperature ensembles, using fractional occupation numbers in the calculation of the inner-product kernel of the extended harmonic oscillator that appears as a preconditioner in the electronic equations of motion. Material systems that normally exhibit slow self-consistent field convergence can be simulated using integration time steps of the same order as in direct Born-Oppenheimer molecular dynamics, but without the requirement of an iterative, non-linear electronic ground-state optimization prior to the force evaluations and without a systematic drift in the total energy. In combination with proposed low-rank and on the fly updates of the kernel, this formulation provides an efficient and general framework for quantum-based Born-Oppenheimer molecular dynamics simulations.

  2. Next generation extended Lagrangian first principles molecular dynamics.

    PubMed

    Niklasson, Anders M N

    2017-08-07

    Extended Lagrangian Born-Oppenheimer molecular dynamics [A. M. N. Niklasson, Phys. Rev. Lett. 100, 123004 (2008)] is formulated for general Hohenberg-Kohn density-functional theory and compared with the extended Lagrangian framework of first principles molecular dynamics by Car and Parrinello [Phys. Rev. Lett. 55, 2471 (1985)]. It is shown how extended Lagrangian Born-Oppenheimer molecular dynamics overcomes several shortcomings of regular, direct Born-Oppenheimer molecular dynamics, while improving or maintaining important features of Car-Parrinello simulations. The accuracy of the electronic degrees of freedom in extended Lagrangian Born-Oppenheimer molecular dynamics, with respect to the exact Born-Oppenheimer solution, is of second-order in the size of the integration time step and of fourth order in the potential energy surface. Improved stability over recent formulations of extended Lagrangian Born-Oppenheimer molecular dynamics is achieved by generalizing the theory to finite temperature ensembles, using fractional occupation numbers in the calculation of the inner-product kernel of the extended harmonic oscillator that appears as a preconditioner in the electronic equations of motion. Material systems that normally exhibit slow self-consistent field convergence can be simulated using integration time steps of the same order as in direct Born-Oppenheimer molecular dynamics, but without the requirement of an iterative, non-linear electronic ground-state optimization prior to the force evaluations and without a systematic drift in the total energy. In combination with proposed low-rank and on the fly updates of the kernel, this formulation provides an efficient and general framework for quantum-based Born-Oppenheimer molecular dynamics simulations.

  3. Non-destructive analysis of the conformational differences among feedstock sources and their corresponding co-products from bioethanol production with molecular spectroscopy

    NASA Astrophysics Data System (ADS)

    Gamage, I. H.; Jonker, A.; Zhang, X.; Yu, P.

    2014-01-01

    The objective of this study was to determine the possibility of using molecular spectroscopy with multivariate technique as a fast method to detect the source effects among original feedstock sources of wheat and their corresponding co-products, wheat DDGS, from bioethanol production. Different sources of the bioethanol feedstock and their corresponding bioethanol co-products, three samples per source, were collecte