Constructing Learning Spaces? Videoconferencing at Local Learning Centres in Sweden

ERIC Educational Resources Information Center

Logdlund, Ulrik

2010-01-01

This article explores videoconferencing in the context of local learning centres in Sweden. The practice is described as a "learning space" in which adult learners construct socio-spatial relations. The study goes beyond a sociological apprehension of actors and opposes the idea of the material as neutral, passive and conformed by…

Toward a detailed understanding of search trajectories in fragment assembly approaches to protein structure prediction

PubMed Central

Handl, Julia; Lovell, Simon C.

2016-01-01

ABSTRACT Energy functions, fragment libraries, and search methods constitute three key components of fragment‐assembly methods for protein structure prediction, which are all crucial for their ability to generate high‐accuracy predictions. All of these components are tightly coupled; efficient searching becomes more important as the quality of fragment libraries decreases. Given these relationships, there is currently a poor understanding of the strengths and weaknesses of the sampling approaches currently used in fragment‐assembly techniques. Here, we determine how the performance of search techniques can be assessed in a meaningful manner, given the above problems. We describe a set of techniques that aim to reduce the impact of the energy function, and assess exploration in view of the search space defined by a given fragment library. We illustrate our approach using Rosetta and EdaFold, and show how certain features of these methods encourage or limit conformational exploration. We demonstrate that individual trajectories of Rosetta are susceptible to local minima in the energy landscape, and that this can be linked to non‐uniform sampling across the protein chain. We show that EdaFold's novel approach can help balance broad exploration with locating good low‐energy conformations. This occurs through two mechanisms which cannot be readily differentiated using standard performance measures: exclusion of false minima, followed by an increasingly focused search in low‐energy regions of conformational space. Measures such as ours can be helpful in characterizing new fragment‐based methods in terms of the quality of conformational exploration realized. Proteins 2016; 84:411–426. © 2016 The Authors Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc. PMID:26799916

Accelerated Adaptive Integration Method

PubMed Central

2015-01-01

Conformational changes that occur upon ligand binding may be too slow to observe on the time scales routinely accessible using molecular dynamics simulations. The adaptive integration method (AIM) leverages the notion that when a ligand is either fully coupled or decoupled, according to λ, barrier heights may change, making some conformational transitions more accessible at certain λ values. AIM adaptively changes the value of λ in a single simulation so that conformations sampled at one value of λ seed the conformational space sampled at another λ value. Adapting the value of λ throughout a simulation, however, does not resolve issues in sampling when barriers remain high regardless of the λ value. In this work, we introduce a new method, called Accelerated AIM (AcclAIM), in which the potential energy function is flattened at intermediate values of λ, promoting the exploration of conformational space as the ligand is decoupled from its receptor. We show, with both a simple model system (Bromocyclohexane) and the more complex biomolecule Thrombin, that AcclAIM is a promising approach to overcome high barriers in the calculation of free energies, without the need for any statistical reweighting or additional processors. PMID:24780083

Metadynamics in the conformational space nonlinearly dimensionally reduced by Isomap

NASA Astrophysics Data System (ADS)

Spiwok, Vojtěch; Králová, Blanka

2011-12-01

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

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.

Exploring the Free Energy Landscape: From Dynamics to Networks and Back

PubMed Central

Prada-Gracia, Diego; Gómez-Gardeñes, Jesús; Echenique, Pablo; Falo, Fernando

2009-01-01

Knowledge of the Free Energy Landscape topology is the essential key to understanding many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Landscape answering questions such as how many meta-stable conformers there are, what the hierarchical relationship among them is, or what the structure and kinetics of the transition paths are. Exploring the landscape by molecular dynamics simulations, the microscopic data of the trajectory are encoded into a Conformational Markov Network. The structure of this graph reveals the regions of the conformational space corresponding to the basins of attraction. In addition, handling the Conformational Markov Network, relevant kinetic magnitudes as dwell times and rate constants, or hierarchical relationships among basins, completes the global picture of the landscape. We show the power of the analysis studying a toy model of a funnel-like potential and computing efficiently the conformers of a short peptide, dialanine, paving the way to a systematic study of the Free Energy Landscape in large peptides. PMID:19557191

Exploring the free energy landscape: from dynamics to networks and back.

PubMed

Prada-Gracia, Diego; Gómez-Gardeñes, Jesús; Echenique, Pablo; Falo, Fernando

2009-06-01

Knowledge of the Free Energy Landscape topology is the essential key to understanding many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Landscape answering questions such as how many meta-stable conformers there are, what the hierarchical relationship among them is, or what the structure and kinetics of the transition paths are. Exploring the landscape by molecular dynamics simulations, the microscopic data of the trajectory are encoded into a Conformational Markov Network. The structure of this graph reveals the regions of the conformational space corresponding to the basins of attraction. In addition, handling the Conformational Markov Network, relevant kinetic magnitudes as dwell times and rate constants, or hierarchical relationships among basins, completes the global picture of the landscape. We show the power of the analysis studying a toy model of a funnel-like potential and computing efficiently the conformers of a short peptide, dialanine, paving the way to a systematic study of the Free Energy Landscape in large peptides.

Purposes, Pedagogies and Practices in Lifewide Adult Education in New Zealand: A Preview

ERIC Educational Resources Information Center

Zepke, Nick

2015-01-01

This paper is interested in projecting the likely purposes, pedagogies and practices influencing lifewide adult education in New Zealand ten years from now. It first identifies learning spaces in which lifewide adult education takes place. It explores formal, non-formal and informal spaces which conform to or oppose dominant ideological policies,…

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

A parallel implementation of the Wuchty algorithm with additional experimental filters to more thoroughly explore RNA conformational space.

PubMed

Stone, Jonathan W; Bleckley, Samuel; Lavelle, Sean; Schroeder, Susan J

2015-01-01

We present new modifications to the Wuchty algorithm in order to better define and explore possible conformations for an RNA sequence. The new features, including parallelization, energy-independent lonely pair constraints, context-dependent chemical probing constraints, helix filters, and optional multibranch loops, provide useful tools for exploring the landscape of RNA folding. Chemical probing alone may not necessarily define a single unique structure. The helix filters and optional multibranch loops are global constraints on RNA structure that are an especially useful tool for generating models of encapsidated viral RNA for which cryoelectron microscopy or crystallography data may be available. The computations generate a combinatorially complete set of structures near a free energy minimum and thus provide data on the density and diversity of structures near the bottom of a folding funnel for an RNA sequence. The conformational landscapes for some RNA sequences may resemble a low, wide basin rather than a steep funnel that converges to a single structure.

Elucidating the ensemble of functionally-relevant transitions in protein systems with a robotics-inspired method.

PubMed

Molloy, Kevin; Shehu, Amarda

2013-01-01

Many proteins tune their biological function by transitioning between different functional states, effectively acting as dynamic molecular machines. Detailed structural characterization of transition trajectories is central to understanding the relationship between protein dynamics and function. Computational approaches that build on the Molecular Dynamics framework are in principle able to model transition trajectories at great detail but also at considerable computational cost. Methods that delay consideration of dynamics and focus instead on elucidating energetically-credible conformational paths connecting two functionally-relevant structures provide a complementary approach. Effective sampling-based path planning methods originating in robotics have been recently proposed to produce conformational paths. These methods largely model short peptides or address large proteins by simplifying conformational space. We propose a robotics-inspired method that connects two given structures of a protein by sampling conformational paths. The method focuses on small- to medium-size proteins, efficiently modeling structural deformations through the use of the molecular fragment replacement technique. In particular, the method grows a tree in conformational space rooted at the start structure, steering the tree to a goal region defined around the goal structure. We investigate various bias schemes over a progress coordinate for balance between coverage of conformational space and progress towards the goal. A geometric projection layer promotes path diversity. A reactive temperature scheme allows sampling of rare paths that cross energy barriers. Experiments are conducted on small- to medium-size proteins of length up to 214 amino acids and with multiple known functionally-relevant states, some of which are more than 13Å apart of each-other. Analysis reveals that the method effectively obtains conformational paths connecting structural states that are significantly different. A detailed analysis on the depth and breadth of the tree suggests that a soft global bias over the progress coordinate enhances sampling and results in higher path diversity. The explicit geometric projection layer that biases the exploration away from over-sampled regions further increases coverage, often improving proximity to the goal by forcing the exploration to find new paths. The reactive temperature scheme is shown effective in increasing path diversity, particularly in difficult structural transitions with known high-energy barriers.

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

PubMed

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

2018-01-01

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

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

PubMed

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

2011-07-25

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

Metadynamics in the conformational space nonlinearly dimensionally reduced by Isomap.

PubMed

Spiwok, Vojtěch; Králová, Blanka

2011-12-14

Atomic motions in molecules are not linear. This infers that nonlinear dimensionality reduction methods can outperform linear ones in analysis of collective atomic motions. In addition, nonlinear collective motions can be used as potentially efficient guides for biased simulation techniques. Here we present a simulation with a bias potential acting in the directions of collective motions determined by a nonlinear dimensionality reduction method. Ad hoc generated conformations of trans,trans-1,2,4-trifluorocyclooctane were analyzed by Isomap method to map these 72-dimensional coordinates to three dimensions, as described by Brown and co-workers [J. Chem. Phys. 129, 064118 (2008)]. Metadynamics employing the three-dimensional embeddings as collective variables was applied to explore all relevant conformations of the studied system and to calculate its conformational free energy surface. The method sampled all relevant conformations (boat, boat-chair, and crown) and corresponding transition structures inaccessible by an unbiased simulation. This scheme allows to use essentially any parameter of the system as a collective variable in biased simulations. Moreover, the scheme we used for mapping out-of-sample conformations from the 72D to 3D space can be used as a general purpose mapping for dimensionality reduction, beyond the context of molecular modeling. © 2011 American Institute of Physics

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.

The Role of High-Dimensional Diffusive Search, Stabilization, and Frustration in Protein Folding

PubMed Central

Rimratchada, Supreecha; McLeish, Tom C.B.; Radford, Sheena E.; Paci, Emanuele

2014-01-01

Proteins are polymeric molecules with many degrees of conformational freedom whose internal energetic interactions are typically screened to small distances. Therefore, in the high-dimensional conformation space of a protein, the energy landscape is locally relatively flat, in contrast to low-dimensional representations, where, because of the induced entropic contribution to the full free energy, it appears funnel-like. Proteins explore the conformation space by searching these flat subspaces to find a narrow energetic alley that we call a hypergutter and then explore the next, lower-dimensional, subspace. Such a framework provides an effective representation of the energy landscape and folding kinetics that does justice to the essential characteristic of high-dimensionality of the search-space. It also illuminates the important role of nonnative interactions in defining folding pathways. This principle is here illustrated using a coarse-grained model of a family of three-helix bundle proteins whose conformations, once secondary structure has formed, can be defined by six rotational degrees of freedom. Two folding mechanisms are possible, one of which involves an intermediate. The stabilization of intermediate subspaces (or states in low-dimensional projection) in protein folding can either speed up or slow down the folding rate depending on the amount of native and nonnative contacts made in those subspaces. The folding rate increases due to reduced-dimension pathways arising from the mere presence of intermediate states, but decreases if the contacts in the intermediate are very stable and introduce sizeable topological or energetic frustration that needs to be overcome. Remarkably, the hypergutter framework, although depending on just a few physically meaningful parameters, can reproduce all the types of experimentally observed curvature in chevron plots for realizations of this fold. PMID:24739172

Computational engineering of cellulase Cel9A-68 functional motions through mutations in its linker region.

PubMed

Costa, M G S; Silva, Y F; Batista, P R

2018-03-14

Microbial cellulosic degradation by cellulases has become a complementary approach for biofuel production. However, its efficiency is hindered by the recalcitrance of cellulose fibres. In this context, computational protein design methods may offer an efficient way to obtain variants with improved enzymatic activity. Cel9A-68 is a cellulase from Thermobifida fusca that is still active at high temperatures. In a previous work, we described a collective bending motion, which governs the overall cellulase dynamics. This movement promotes the approximation of its CBM and CD structural domains (that are connected by a flexible linker). We have identified two residues (G460 and P461) located at the linker that act as a hinge point. Herein, we applied a new level of protein design, focusing on the modulation of this collective motion to obtain cellulase variants with enhanced functional dynamics. We probed whether specific linker mutations would affect Cel9A-68 dynamics through computational simulations. We assumed that P461G and G460+ (with an extra glycine) constructs would present enhanced interdomain motions, while the G460P mutant would be rigid. From our results, the P461G mutation resulted in a broader exploration of the conformational space, as confirmed by clustering and free energy analyses. The WT enzyme was the most rigid system. However, G460P and P460+ explored distinct conformational states described by opposite directions of low-frequency normal modes; they sampled preferentially closed and open conformations, respectively. Overall, we highlight two significant findings: (i) all mutants explored larger conformational spaces than the WT; (ii) the selection of distinct conformational populations was intimately associated with the mutation considered. Thus, the engineering of Cel9A-68 motions through linker mutations may constitute an efficient way to improve cellulase activity, facilitating the disruption of cellulose fibres.

Free energy surface of an intrinsically disordered protein: comparison between temperature replica exchange molecular dynamics and bias-exchange metadynamics.

PubMed

Zerze, Gül H; Miller, Cayla M; Granata, Daniele; Mittal, Jeetain

2015-06-09

Intrinsically disordered proteins (IDPs), which are expected to be largely unstructured under physiological conditions, make up a large fraction of eukaryotic proteins. Molecular dynamics simulations have been utilized to probe structural characteristics of these proteins, which are not always easily accessible to experiments. However, exploration of the conformational space by brute force molecular dynamics simulations is often limited by short time scales. Present literature provides a number of enhanced sampling methods to explore protein conformational space in molecular simulations more efficiently. In this work, we present a comparison of two enhanced sampling methods: temperature replica exchange molecular dynamics and bias exchange metadynamics. By investigating both the free energy landscape as a function of pertinent order parameters and the per-residue secondary structures of an IDP, namely, human islet amyloid polypeptide, we found that the two methods yield similar results as expected. We also highlight the practical difference between the two methods by describing the path that we followed to obtain both sets of data.

Chemodiversity and molecular plasticity: recognition processes as explored by property spaces.

PubMed

Vistoli, Giulio; Pedretti, Alessandro; Testa, Bernard

2011-06-01

In the last few years, a need to account for molecular flexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a flexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defines a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure--activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fill this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profiles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences.

Elucidating the ensemble of functionally-relevant transitions in protein systems with a robotics-inspired method

PubMed Central

2013-01-01

Background Many proteins tune their biological function by transitioning between different functional states, effectively acting as dynamic molecular machines. Detailed structural characterization of transition trajectories is central to understanding the relationship between protein dynamics and function. Computational approaches that build on the Molecular Dynamics framework are in principle able to model transition trajectories at great detail but also at considerable computational cost. Methods that delay consideration of dynamics and focus instead on elucidating energetically-credible conformational paths connecting two functionally-relevant structures provide a complementary approach. Effective sampling-based path planning methods originating in robotics have been recently proposed to produce conformational paths. These methods largely model short peptides or address large proteins by simplifying conformational space. Methods We propose a robotics-inspired method that connects two given structures of a protein by sampling conformational paths. The method focuses on small- to medium-size proteins, efficiently modeling structural deformations through the use of the molecular fragment replacement technique. In particular, the method grows a tree in conformational space rooted at the start structure, steering the tree to a goal region defined around the goal structure. We investigate various bias schemes over a progress coordinate for balance between coverage of conformational space and progress towards the goal. A geometric projection layer promotes path diversity. A reactive temperature scheme allows sampling of rare paths that cross energy barriers. Results and conclusions Experiments are conducted on small- to medium-size proteins of length up to 214 amino acids and with multiple known functionally-relevant states, some of which are more than 13Å apart of each-other. Analysis reveals that the method effectively obtains conformational paths connecting structural states that are significantly different. A detailed analysis on the depth and breadth of the tree suggests that a soft global bias over the progress coordinate enhances sampling and results in higher path diversity. The explicit geometric projection layer that biases the exploration away from over-sampled regions further increases coverage, often improving proximity to the goal by forcing the exploration to find new paths. The reactive temperature scheme is shown effective in increasing path diversity, particularly in difficult structural transitions with known high-energy barriers. PMID:24565158

Predictive Sampling of Rare Conformational Events in Aqueous Solution: Designing a Generalized Orthogonal Space Tempering Method.

PubMed

Lu, Chao; Li, Xubin; Wu, Dongsheng; Zheng, Lianqing; Yang, Wei

2016-01-12

In aqueous solution, solute conformational transitions are governed by intimate interplays of the fluctuations of solute-solute, solute-water, and water-water interactions. To promote molecular fluctuations to enhance sampling of essential conformational changes, a common strategy is to construct an expanded Hamiltonian through a series of Hamiltonian perturbations and thereby broaden the distribution of certain interactions of focus. Due to a lack of active sampling of configuration response to Hamiltonian transitions, it is challenging for common expanded Hamiltonian methods to robustly explore solvent mediated rare conformational events. The orthogonal space sampling (OSS) scheme, as exemplified by the orthogonal space random walk and orthogonal space tempering methods, provides a general framework for synchronous acceleration of slow configuration responses. To more effectively sample conformational transitions in aqueous solution, in this work, we devised a generalized orthogonal space tempering (gOST) algorithm. Specifically, in the Hamiltonian perturbation part, a solvent-accessible-surface-area-dependent term is introduced to implicitly perturb near-solute water-water fluctuations; more importantly in the orthogonal space response part, the generalized force order parameter is generalized as a two-dimension order parameter set, in which essential solute-solvent and solute-solute components are separately treated. The gOST algorithm is evaluated through a molecular dynamics simulation study on the explicitly solvated deca-alanine (Ala10) peptide. On the basis of a fully automated sampling protocol, the gOST simulation enabled repetitive folding and unfolding of the solvated peptide within a single continuous trajectory and allowed for detailed constructions of Ala10 folding/unfolding free energy surfaces. The gOST result reveals that solvent cooperative fluctuations play a pivotal role in Ala10 folding/unfolding transitions. In addition, our assessment analysis suggests that because essential conformational events are mainly driven by the compensating fluctuations of essential solute-solvent and solute-solute interactions, commonly employed "predictive" sampling methods are unlikely to be effective on this seemingly "simple" system. The gOST development presented in this paper illustrates how to employ the OSS scheme for physics-based sampling method designs.

Conformational properties of a pyridyl-substituted cinnamic acid studied by NMR measurements and computations

NASA Astrophysics Data System (ADS)

Csankó, K.; Forgo, P.; Boros, K.; Hohmann, J.; Sipos, P.; Pálinkó, I.

2013-07-01

Following a preliminary exploration of the conformational space by the PM3 and HF/6-31 G*ab initio methods the conformational characteristics of the scarcely available Z isomer of an α-pyridyl-substituted cinnamic acid dimer [Z-2(3‧-pyridyl)-3-phenylpropanoic acid] was studied by NMR spectroscopy (NOESY measurements) in DMSO(d6), methanol(d4) and chloroform(d1). Calculations predicted that full conjugation was overruled by steric interactions and the rotation of the pyridyl ring was not restricted. NOESY measurements verified indeed that in all three solvents the pyridyl group was virtually freely rotating, while some restriction applied for that of the phenyl group.

Flexible ligand docking using a genetic algorithm

NASA Astrophysics Data System (ADS)

Oshiro, C. M.; Kuntz, I. D.; Dixon, J. Scott

1995-04-01

Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

Conformational and stereoelectronic investigation of tryptamine. An AIM/NBO study.

PubMed

Lobayan, Rosana M; Pérez Schmit, María C; Jubert, Alicia H; Vitale, Arturo

2012-06-01

Due to the free radical scavenger properties of Tryptamine (TRA), as well as of others indole derivatives, it is in our interest to explore deeply the stereoelectronic aspects that would be relevant in their stabilization and antioxidant activity. In this work the conformational space of TRA was scanned using molecular dynamics complemented with functional density calculations at B3LYP/6-31 + G** level. Twenty one conformers of lowest energy were obtained, their electronic distributions were analyzed at a higher calculation level, thus improving the basis set (B3LYP/6-311++G**). A topological study based on Bader's theory ( atoms in molecules) and natural bond orbital (NBO) framework was performed. The study was enriched by a deep analysis of maps of molecular electrostatic potential (MEP) through a coordinated NBO/AIM analysis. The conformational preferences were explained by hyperconjugative interactions, which were revealed by NBO data. Because radical scavenging by indolic compounds is strongly modulated by their functional residues our study was related to similar analysis done previously on Indole and 1H-indole-3-acetic acid (IAA). Therefore, the conformational space of TRA was studied from a new perspective focusing on a deep analysis of the geometric and electronic properties of TRA conformers. The changes of the electronic distribution introduced by the substituent and the conformational flexibility of the side chain were addressed. The results reported contribute to the understanding of the structure, stability and reactivity of TRA and others indole derivatives.

Peptide models XLV: conformational properties of N-formyl-L-methioninamide and its relevance to methionine in proteins.

PubMed

Láng, András; Csizmadia, Imre G; Perczel, András

2005-02-15

The conformational space of the most biologically significant backbone folds of a suitable methionine peptide model was explored by density functional computational method. Using a medium [6-31G(d)] and a larger basis set [6-311++G(2d,2p)], the systematic exploration of low-energy backbone structures restricted for the "L-region" in the Ramachandran map of N-formyl-L-methioninamide results in conformers corresponding to the building units of an extended backbone structure (betaL), an inverse gamma-turn (gammaL), or a right-handed helical structure (alphaL). However, no poly-proline II type (epsilonL) fold was found, indicating that this conformer has no intrinsic stability, and highlighting the effect of molecular environment in stabilizing this backbone structure. This is in agreement with the abundance of the epsilonL-type backbone conformation of methionine found in proteins. Stability properties (DeltaE) and distinct backbone-side-chain interactions support the idea that specific intramolecular contacts are operative in the selection of the lowest energy conformers. Apart from the number of different folds, all stable conformers are within a 10 kcal x mol(-1) energy range, indicating the highly flexible behavior of methionine. This conformational feature can be important in supporting catalytic processes, facilitating protein folding and dimerization via metal ion binding. In both of the biological examples discussed (HIV-1 reverse transcriptase and PcoC copper-resistant protein), the conformational properties of Met residues were found to be of key importance. Spatial proximity to other types of residues or the same type of residue seems to be crucial for the structural integrity of a protein, whether Met is buried or exposed.

Boundary conformal anomalies on hyperbolic spaces and Euclidean balls

NASA Astrophysics Data System (ADS)

Rodriguez-Gomez, Diego; Russo, Jorge G.

2017-12-01

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

Focused conformational sampling in proteins

NASA Astrophysics Data System (ADS)

Bacci, Marco; Langini, Cassiano; Vymětal, Jiří; Caflisch, Amedeo; Vitalis, Andreas

2017-11-01

A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently. In this feature space, new states are discovered by spontaneous fluctuations alone and in unsupervised fashion. Because there are no energetic biases acting on phase space variables or projections thereof, the trajectories PIGS generates can be analyzed directly in the framework of transition networks. We demonstrate the possibility and usefulness of such focused explorations of biomolecules with two loops that are part of the binding sites of bromodomains, a family of epigenetic "reader" modules. This real-life application uncovers states that are structurally and kinetically far away from the initial crystallographic structures and are also metastable. Representative conformations are intended to be used in future high-throughput virtual screening campaigns.

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

NASA Astrophysics Data System (ADS)

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.

Characterizing RNA ensembles from NMR data with kinematic models

PubMed Central

Fonseca, Rasmus; Pachov, Dimitar V.; Bernauer, Julie; van den Bedem, Henry

2014-01-01

Functional mechanisms of biomolecules often manifest themselves precisely in transient conformational substates. Researchers have long sought to structurally characterize dynamic processes in non-coding RNA, combining experimental data with computer algorithms. However, adequate exploration of conformational space for these highly dynamic molecules, starting from static crystal structures, remains challenging. Here, we report a new conformational sampling procedure, KGSrna, which can efficiently probe the native ensemble of RNA molecules in solution. We found that KGSrna ensembles accurately represent the conformational landscapes of 3D RNA encoded by NMR proton chemical shifts. KGSrna resolves motionally averaged NMR data into structural contributions; when coupled with residual dipolar coupling data, a KGSrna ensemble revealed a previously uncharacterized transient excited state of the HIV-1 trans-activation response element stem–loop. Ensemble-based interpretations of averaged data can aid in formulating and testing dynamic, motion-based hypotheses of functional mechanisms in RNAs with broad implications for RNA engineering and therapeutic intervention. PMID:25114056

Conformational and NBO studies of serotonin as a radical scavenger. Changes induced by the OH group.

PubMed

Lobayan, Rosana M; Schmit, María Celia Pérez

2018-03-01

Serotonin (5-hydroxytryptamine, SER) is a neurotransmitter that affects many different processes within the human body. We studied the conformational space of SER, and explored in depth the significant stereoelectronic features for the structure stabilization and antioxidant activity. Forty-eight equilibrium structures were described at the B3LYP/6-311++G(d,p) level, characterizing four non-previously reported conformers. Electron distributions were analyzed by topological QTAIM (Quantum Theory of atoms in molecules) and natural bond orbital (NBO) studies. The study was supplemented by an exploration of molecular electrostatic potential (MEP). Intramolecular hydrogen interactions were also investigated; N10⋯HC4 or N10⋯HC2 hydrogen bondings were depicted in 5 conformers. The conformer stabilization and the corresponding energy arrangement were explained by hyperconjugation interactions obtained by NBO analysis. The present study is based on the effect of the 5-OH group on geometric and electronic behavior that we have previously reported on the similar structure tryptamine (TRA). Our interest also lies in SER's free radical scavenging capacity as a member of the indole family. The H-atom abstraction and single-electron transfer mechanisms were taken into account. Our results showed that donor-acceptor interactions play a major role in explaining the changes induced by the OH group, and free-radical scavenging capability of the indole compounds. Copyright © 2018 Elsevier Inc. All rights reserved.

A new approach to explore the binding space of polysaccharide-based ligands: selectin antagonists.

PubMed

Calosso, Mickael; Charpentier, Daniel; Vaillancourt, Marc; Bencheqroun, Mohammed; St-Pierre, Gabrielle; Wilkes, Brian C; Guindon, Yvan

2012-12-13

The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can be replaced advantageously by a conformationally locked acyclic molecular entity. A cyclic component of the selectin ligand Sialyl Lewis(x), GlcNAc, is replaced by an acyclic tether, tartaric esters, which link two saccharide units. The conformational bias of this acyclic tether originates from the minimization of intramolecular dipole-dipole interaction and the gauche effect. The evaluation of the binding of these derivatives to P-selectin was measured by surface plasmon resonance spectroscopy. The results obtained in our pilot study suggest that the discovery of tunable tethers could facilitate the exploration of the carbohydrate recognition domain of various receptors.

Space Tethers Programmatic Infusion Opportunities

NASA Technical Reports Server (NTRS)

Bonometti, J. A.; Frame, K. L.

2005-01-01

Programmatic opportunities abound for space Cables, Stringers and Tethers, justified by the tremendous performance advantages that these technologies offer and the rather wide gaps that must be filled by the NASA Exploration program, if the "sustainability goal" is to be met. A definition and characterization of the three categories are presented along with examples. A logical review of exploration requirements shows how each class can be infused throughout the program, from small experimental efforts to large system deployments. The economics of tethers in transportation is considered along with the impact of stringers for structural members. There is an array of synergistic methodologies that interlace their fabrication, implementation and operations. Cables, stringers and tethers can enhance a wide range of other space systems and technologies, including power storage, formation flying, instrumentation, docking mechanisms and long-life space components. The existing tether (i.e., MXER) program's accomplishments are considered consistent with NASA's new vision and can readily conform to requirements-driven technology development.

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

PubMed

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

2012-07-01

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

Secondary structure encodes a cooperative tertiary folding funnel in the Azoarcus ribozyme

PubMed Central

Mustoe, Anthony M.; Al-Hashimi, Hashim M.; Brooks, Charles L.

2016-01-01

A requirement for specific RNA folding is that the free-energy landscape discriminate against non-native folds. While tertiary interactions are critical for stabilizing the native fold, they are relatively non-specific, suggesting additional mechanisms contribute to tertiary folding specificity. In this study, we use coarse-grained molecular dynamics simulations to explore how secondary structure shapes the tertiary free-energy landscape of the Azoarcus ribozyme. We show that steric and connectivity constraints posed by secondary structure strongly limit the accessible conformational space of the ribozyme, and that these so-called topological constraints in turn pose strong free-energy penalties on forming different tertiary contacts. Notably, native A-minor and base-triple interactions form with low conformational free energy, while non-native tetraloop/tetraloop–receptor interactions are penalized by high conformational free energies. Topological constraints also give rise to strong cooperativity between distal tertiary interactions, quantitatively matching prior experimental measurements. The specificity of the folding landscape is further enhanced as tertiary contacts place additional constraints on the conformational space, progressively funneling the molecule to the native state. These results indicate that secondary structure assists the ribozyme in navigating the otherwise rugged tertiary folding landscape, and further emphasize topological constraints as a key force in RNA folding. PMID:26481360

Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM

PubMed Central

Gagnon, Jessica K.; Law, Sean M.; Brooks, Charles L.

2016-01-01

Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an inter-converting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs. PMID:26691274

Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM.

PubMed

Gagnon, Jessica K; Law, Sean M; Brooks, Charles L

2016-03-30

Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an interconverting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs. © 2015 Wiley Periodicals, Inc.

Multi-scale characterization of the energy landscape of proteins with application to the C3D/Efb-C complex.

PubMed

Haspel, Nurit; Geisbrecht, Brian V; Lambris, John; Kavraki, Lydia

2010-03-01

We present a novel multi-level methodology to explore and characterize the low energy landscape and the thermodynamics of proteins. Traditional conformational search methods typically explore only a small portion of the conformational space of proteins and are hard to apply to large proteins due to the large amount of calculations required. In our multi-scale approach, we first provide an initial characterization of the equilibrium state ensemble of a protein using an efficient computational conformational sampling method. We then enrich the obtained ensemble by performing short Molecular Dynamics (MD) simulations on selected conformations from the ensembles as starting points. To facilitate the analysis of the results, we project the resulting conformations on a low-dimensional landscape to efficiently focus on important interactions and examine low energy regions. This methodology provides a more extensive sampling of the low energy landscape than an MD simulation starting from a single crystal structure as it explores multiple trajectories of the protein. This enables us to obtain a broader view of the dynamics of proteins and it can help in understanding complex binding, improving docking results and more. In this work, we apply the methodology to provide an extensive characterization of the bound complexes of the C3d fragment of human Complement component C3 and one of its powerful bacterial inhibitors, the inhibitory domain of Staphylococcus aureus extra-cellular fibrinogen-binding domain (Efb-C) and two of its mutants. We characterize several important interactions along the binding interface and define low free energy regions in the three complexes. Proteins 2010. (c) 2009 Wiley-Liss, Inc.

Conformal symmetries of Einstein's field equations and initial data

NASA Astrophysics Data System (ADS)

Sharma, Ramesh

2005-04-01

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

Conformal Ablative Thermal Protection System for Planetary and Human Exploration Missions:An Overview of the Technology Maturation Effort

NASA Technical Reports Server (NTRS)

Beck, Robin A S.; Arnold, James O.; Gasch, Matthew J.; Stackpoole, Margaret M.; Prabhu, Dinesh K.; Szalai, Christine E.; Wercinski, Paul F.; Venkatapathy, Ethiraj

2013-01-01

The Office of Chief Technologist, NASA identified the need for research and technology development in part from NASAs Strategic Goal 3.3 of the NASA Strategic Plan to develop and demonstrate the critical technologies that will make NASAs exploration, science, and discovery missions more affordable and more capable. Furthermore, the Game Changing Development Program is a primary avenue to achieve the Agencys 2011 strategic goal to Create the innovative new space technologies for our exploration, science, and economic future. The National Research Council (NRC) Space Technology Roadmaps and Priorities report highlights six challenges and they are: Mass to Surface, Surface Access, Precision Landing, Surface Hazard Detection and Avoidance, Safety and Mission Assurance, and Affordability. In order for NASA to meet these challenges, the report recommends immediate focus on Rigid and Flexible Thermal Protection Systems. Rigid TPS systems such as Avcoat or SLA are honeycomb based and PICA is in the form of tiles. The honeycomb systems are manufactured using techniques that require filling of each (38 cell) by hand, and in a limited amount of time all of the cells must be filled and the heatshield must be cured. The tile systems such as PICA pose a different challenge as the low strain-to-failure and manufacturing size limitations require large number of small tiles with gap-fillers between the tiles. Recent investments in flexible ablative systems have given rise to the potential for conformal ablative TPS. A conformal TPS over a rigid aeroshell has the potential to solve a number of challenges faced by traditional rigid TPS materials. The high strain-to-failure nature of the conformal ablative materials will allow integration of the TPS with the underlying aeroshell structure much easier and enable monolithic-like configuration and larger segments (or parts) to be used. By reducing the overall part count, the cost of installation (based on cost comparisons between blanket and tile materials on shuttle) should be significantly reduced. The conformal ablator design will include a simplified design of seams between gore panels, which should eliminate the need for gap filler design, and should accommodate a wider range of allowable carrier structure imperfections when compared to a rigid material such as PICA.The Conformal TPS development project leverages the past investments made by earlier projects with a goal to develop and deliver a TRL 5 conformal TPS capable of 250 Wcm2 for missions such as MSL or COTS missions. The capabilities goal for the conformal TPS is similar to an MSL design reference mission (250 Wcm2) with matching pressures and shear environments. Both conformal and flexible carbon-felt based materials were successfully tested in stagnation aerothermal environments above 500 Wcm2 under earlier programs. Results on a myriad of materials developed during FY11 were used to determine which materials to start with in FY12. In FY12, the conformal TPS element focused on establishing materials requirements based on MSL-type and COTS Low Earth orbit (LEO) conditions (q 250 Wcm2) to develop and deliver a Conformal Ablative TPS. In FY13, development and refining metrics for mission utilization of conformal ablator technology along with assessment for potential mission stakeholders will be carried out.

A generative, probabilistic model of local protein structure.

PubMed

Boomsma, Wouter; Mardia, Kanti V; Taylor, Charles C; Ferkinghoff-Borg, Jesper; Krogh, Anders; Hamelryck, Thomas

2008-07-01

Despite significant progress in recent years, protein structure prediction maintains its status as one of the prime unsolved problems in computational biology. One of the key remaining challenges is an efficient probabilistic exploration of the structural space that correctly reflects the relative conformational stabilities. Here, we present a fully probabilistic, continuous model of local protein structure in atomic detail. The generative model makes efficient conformational sampling possible and provides a framework for the rigorous analysis of local sequence-structure correlations in the native state. Our method represents a significant theoretical and practical improvement over the widely used fragment assembly technique by avoiding the drawbacks associated with a discrete and nonprobabilistic approach.

Conformations of peptoids in nanosheets result from the interplay of backbone energetics and intermolecular interactions.

PubMed

Edison, John R; Spencer, Ryan K; Butterfoss, Glenn L; Hudson, Benjamin C; Hochbaum, Allon I; Paravastu, Anant K; Zuckermann, Ronald N; Whitelam, Stephen

2018-05-29

The conformations adopted by the molecular constituents of a supramolecular assembly influence its large-scale order. At the same time, the interactions made in assemblies by molecules can influence their conformations. Here we study this interplay in extended flat nanosheets made from nonnatural sequence-specific peptoid polymers. Nanosheets exist because individual polymers can be linear and untwisted, by virtue of polymer backbone elements adopting alternating rotational states whose twists oppose and cancel. Using molecular dynamics and quantum mechanical simulations, together with experimental data, we explore the design space of flat nanostructures built from peptoids. We show that several sets of peptoid backbone conformations are consistent with their being linear, but the specific combination observed in experiment is determined by a combination of backbone energetics and the interactions made within the nanosheet. Our results provide a molecular model of the peptoid nanosheet consistent with all available experimental data and show that its structure results from a combination of intra- and intermolecular interactions.

Mapping the Protein Fold Universe Using the CamTube Force Field in Molecular Dynamics Simulations.

PubMed

Kukic, Predrag; Kannan, Arvind; Dijkstra, Maurits J J; Abeln, Sanne; Camilloni, Carlo; Vendruscolo, Michele

2015-10-01

It has been recently shown that the coarse-graining of the structures of polypeptide chains as self-avoiding tubes can provide an effective representation of the conformational space of proteins. In order to fully exploit the opportunities offered by such a 'tube model' approach, we present here a strategy to combine it with molecular dynamics simulations. This strategy is based on the incorporation of the 'CamTube' force field into the Gromacs molecular dynamics package. By considering the case of a 60-residue polyvaline chain, we show that CamTube molecular dynamics simulations can comprehensively explore the conformational space of proteins. We obtain this result by a 20 μs metadynamics simulation of the polyvaline chain that recapitulates the currently known protein fold universe. We further show that, if residue-specific interaction potentials are added to the CamTube force field, it is possible to fold a protein into a topology close to that of its native state. These results illustrate how the CamTube force field can be used to explore efficiently the universe of protein folds with good accuracy and very limited computational cost.

Mapping the Protein Fold Universe Using the CamTube Force Field in Molecular Dynamics Simulations

PubMed Central

Dijkstra, Maurits J. J.; Abeln, Sanne; Camilloni, Carlo; Vendruscolo, Michele

2015-01-01

It has been recently shown that the coarse-graining of the structures of polypeptide chains as self-avoiding tubes can provide an effective representation of the conformational space of proteins. In order to fully exploit the opportunities offered by such a ‘tube model’ approach, we present here a strategy to combine it with molecular dynamics simulations. This strategy is based on the incorporation of the ‘CamTube’ force field into the Gromacs molecular dynamics package. By considering the case of a 60-residue polyvaline chain, we show that CamTube molecular dynamics simulations can comprehensively explore the conformational space of proteins. We obtain this result by a 20 μs metadynamics simulation of the polyvaline chain that recapitulates the currently known protein fold universe. We further show that, if residue-specific interaction potentials are added to the CamTube force field, it is possible to fold a protein into a topology close to that of its native state. These results illustrate how the CamTube force field can be used to explore efficiently the universe of protein folds with good accuracy and very limited computational cost. PMID:26505754

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

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.

Essential elements of a framework for future space exploration and use: the role of science

NASA Astrophysics Data System (ADS)

Rummel, John; Ehrenfreund, Pascale

The objective of the COSPAR Panel on Exploration (PEX) is to provide independent scientific advice to support the development of exploration programs and to safeguard the potential scientific assets of solar system objects. The Outer Space Treaty (OST) of 1967 provides (Article I) for “exploration and use of outer space” as well as an obligation for States to authorize and supervise space activities (Article VI) so “that national activities are carried out in conformity with the provisions set forth in the. . Treaty,” while the provisions of Article IX of the Treaty include pursuing “studies of outer space, including the Moon and other celestial bodies, and conduct[ing] exploration of them so as to avoid their harmful contamination." In short, the Treaty provides for many activities to take place in outer space, but it also leaves to the future the definitions of “harmful contamination,” “adverse changes,” and even “use.” In order to provide for both protection and use in outer space, and therefore to provide for both scientific and economic exploration, an extension of the OST (or its replacement) will be required. Whatever policy choices are made in constructing such a framework, it is clear that scientific understanding of the solar system, and each of its individual planetary bodies, will be required to determine the balance—and it may be a dynamic balance—between protection and use of outer space environments. This paper will consider the role of scientific advice and continuing research and education within such a framework, and as an essential complement to the necessary regulation distinguishing between protection and use of different locations in outer space.

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

PubMed

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

2018-02-06

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

Minimum Free Energy Path of Ligand-Induced Transition in Adenylate Kinase

PubMed Central

Matsunaga, Yasuhiro; Fujisaki, Hiroshi; Terada, Tohru; Furuta, Tadaomi; Moritsugu, Kei; Kidera, Akinori

2012-01-01

Large-scale conformational changes in proteins involve barrier-crossing transitions on the complex free energy surfaces of high-dimensional space. Such rare events cannot be efficiently captured by conventional molecular dynamics simulations. Here we show that, by combining the on-the-fly string method and the multi-state Bennett acceptance ratio (MBAR) method, the free energy profile of a conformational transition pathway in Escherichia coli adenylate kinase can be characterized in a high-dimensional space. The minimum free energy paths of the conformational transitions in adenylate kinase were explored by the on-the-fly string method in 20-dimensional space spanned by the 20 largest-amplitude principal modes, and the free energy and various kinds of average physical quantities along the pathways were successfully evaluated by the MBAR method. The influence of ligand binding on the pathways was characterized in terms of rigid-body motions of the lid-shaped ATP-binding domain (LID) and the AMP-binding (AMPbd) domains. It was found that the LID domain was able to partially close without the ligand, while the closure of the AMPbd domain required the ligand binding. The transition state ensemble of the ligand bound form was identified as those structures characterized by highly specific binding of the ligand to the AMPbd domain, and was validated by unrestrained MD simulations. It was also found that complete closure of the LID domain required the dehydration of solvents around the P-loop. These findings suggest that the interplay of the two different types of domain motion is an essential feature in the conformational transition of the enzyme. PMID:22685395

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

PubMed

Tresadern, Gary; Agrafiotis, Dimitris K

2009-12-01

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

Sparsity-weighted outlier FLOODing (OFLOOD) method: Efficient rare event sampling method using sparsity of distribution.

PubMed

Harada, Ryuhei; Nakamura, Tomotake; Shigeta, Yasuteru

2016-03-30

As an extension of the Outlier FLOODing (OFLOOD) method [Harada et al., J. Comput. Chem. 2015, 36, 763], the sparsity of the outliers defined by a hierarchical clustering algorithm, FlexDice, was considered to achieve an efficient conformational search as sparsity-weighted "OFLOOD." In OFLOOD, FlexDice detects areas of sparse distribution as outliers. The outliers are regarded as candidates that have high potential to promote conformational transitions and are employed as initial structures for conformational resampling by restarting molecular dynamics simulations. When detecting outliers, FlexDice defines a rank in the hierarchy for each outlier, which relates to sparsity in the distribution. In this study, we define a lower rank (first ranked), a medium rank (second ranked), and the highest rank (third ranked) outliers, respectively. For instance, the first-ranked outliers are located in a given conformational space away from the clusters (highly sparse distribution), whereas those with the third-ranked outliers are nearby the clusters (a moderately sparse distribution). To achieve the conformational search efficiently, resampling from the outliers with a given rank is performed. As demonstrations, this method was applied to several model systems: Alanine dipeptide, Met-enkephalin, Trp-cage, T4 lysozyme, and glutamine binding protein. In each demonstration, the present method successfully reproduced transitions among metastable states. In particular, the first-ranked OFLOOD highly accelerated the exploration of conformational space by expanding the edges. In contrast, the third-ranked OFLOOD reproduced local transitions among neighboring metastable states intensively. For quantitatively evaluations of sampled snapshots, free energy calculations were performed with a combination of umbrella samplings, providing rigorous landscapes of the biomolecules. © 2015 Wiley Periodicals, Inc.

Conformal Nets II: Conformal Blocks

NASA Astrophysics Data System (ADS)

Bartels, Arthur; Douglas, Christopher L.; Henriques, André

2017-08-01

Conformal nets provide a mathematical formalism for conformal field theory. Associated to a conformal net with finite index, we give a construction of the `bundle of conformal blocks', a representation of the mapping class groupoid of closed topological surfaces into the category of finite-dimensional projective Hilbert spaces. We also construct infinite-dimensional spaces of conformal blocks for topological surfaces with smooth boundary. We prove that the conformal blocks satisfy a factorization formula for gluing surfaces along circles, and an analogous formula for gluing surfaces along intervals. We use this interval factorization property to give a new proof of the modularity of the category of representations of a conformal net.

Making Space for Diverse Masculinities: Difference, Intersectionality, and Engagement in an Urban High School. Adolescent Cultures, School and Society, Volume 50

ERIC Educational Resources Information Center

McCready, Lance T.

2010-01-01

What's it like for Black male students who are openly gay or "gender non-conforming" to navigate the social geography of urban schools? In the tradition of critical ethnographies of schooling, Lance T. McCready mobilizes feminist theories of intersectionality to explore the voices of Black gay male students and their teachers in a…

Advanced Air Transportation Technologies (AATT) Project: Distributed Air-Ground Traffic Management

NASA Technical Reports Server (NTRS)

Mogford, Richard; Green, Steve; Ballin, Mark

2002-01-01

This viewgraph presentation provides an overview of active Distributed Air Ground Traffic Management (DAG-TM) work and reported on its overall progress to date. It does not include details on the concept elements (CEs).The DAG-TM research project is defined as a concept development and definition project and no tools will be delivered. Of the 14 CEs, three are being explored actively: CE-5, CE-6, and CE-11. Overviews of CE-5 (Free Maneuvering for User-Preferred Separation Assurance and Local TFM Conformance), CE-6 (En Route and Transition Trajectory Negotiation for User-Preferred Separation and Local TFM Conformance) and CE-11 (Self-Spacing for Merging and In-Trail Separation) are presented.

Euclidean sections of protein conformation space and their implications in dimensionality reduction

PubMed Central

Duan, Mojie; Li, Minghai; Han, Li; Huo, Shuanghong

2014-01-01

Dimensionality reduction is widely used in searching for the intrinsic reaction coordinates for protein conformational changes. We find the dimensionality–reduction methods using the pairwise root–mean–square deviation as the local distance metric face a challenge. We use Isomap as an example to illustrate the problem. We believe that there is an implied assumption for the dimensionality–reduction approaches that aim to preserve the geometric relations between the objects: both the original space and the reduced space have the same kind of geometry, such as Euclidean geometry vs. Euclidean geometry or spherical geometry vs. spherical geometry. When the protein free energy landscape is mapped onto a 2D plane or 3D space, the reduced space is Euclidean, thus the original space should also be Euclidean. For a protein with N atoms, its conformation space is a subset of the 3N-dimensional Euclidean space R3N. We formally define the protein conformation space as the quotient space of R3N by the equivalence relation of rigid motions. Whether the quotient space is Euclidean or not depends on how it is parameterized. When the pairwise root–mean–square deviation is employed as the local distance metric, implicit representations are used for the protein conformation space, leading to no direct correspondence to a Euclidean set. We have demonstrated that an explicit Euclidean-based representation of protein conformation space and the local distance metric associated to it improve the quality of dimensionality reduction in the tetra-peptide and β–hairpin systems. PMID:24913095

Transition Pathway and Its Free-Energy Profile: A Protocol for Protein Folding Simulations

PubMed Central

Lee, In-Ho; Kim, Seung-Yeon; Lee, Jooyoung

2013-01-01

We propose a protocol that provides a systematic definition of reaction coordinate and related free-energy profile as the function of temperature for the protein-folding simulation. First, using action-derived molecular dynamics (ADMD), we investigate the dynamic folding pathway model of a protein between a fixed extended conformation and a compact conformation. We choose the pathway model to be the reaction coordinate, and the folding and unfolding processes are characterized by the ADMD step index, in contrast to the common a priori reaction coordinate as used in conventional studies. Second, we calculate free-energy profile as the function of temperature, by employing the replica-exchange molecular dynamics (REMD) method. The current method provides efficient exploration of conformational space and proper characterization of protein folding/unfolding dynamics from/to an arbitrary extended conformation. We demonstrate that combination of the two simulation methods, ADMD and REMD, provides understanding on molecular conformational changes in proteins. The protocol is tested on a small protein, penta-peptide of met-enkephalin. For the neuropeptide met-enkephalin system, folded, extended, and intermediate sates are well-defined through the free-energy profile over the reaction coordinate. Results are consistent with those in the literature. PMID:23917881

Effects of force fields on the conformational and dynamic properties of amyloid β(1-40) dimer explored by replica exchange molecular dynamics simulations.

PubMed

Watts, Charles R; Gregory, Andrew; Frisbie, Cole; Lovas, Sándor

2018-03-01

The conformational space and structural ensembles of amyloid beta (Aβ) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8 ± 6.4%) and CHARMM36 (2.7 ± 4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3 ± 5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3 ± 12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of β-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected β-sheet-turn-β-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different. © 2017 Wiley Periodicals, Inc.

Evaluating and learning from RNA pseudotorsional space: quantitative validation of a reduced representation for RNA structure.

PubMed

Wadley, Leven M; Keating, Kevin S; Duarte, Carlos M; Pyle, Anna Marie

2007-09-28

Quantitatively describing RNA structure and conformational elements remains a formidable problem. Seven standard torsion angles and the sugar pucker are necessary to characterize the conformation of an RNA nucleotide completely. Progress has been made toward understanding the discrete nature of RNA structure, but classifying simple and ubiquitous structural elements such as helices and motifs remains a difficult task. One approach for describing RNA structure in a simple, mathematically consistent, and computationally accessible manner involves the invocation of two pseudotorsions, eta (C4'(n-1), P(n), C4'(n), P(n+1)) and theta (P(n), C4'(n), P(n+1), C4'(n+1)), which can be used to describe RNA conformation in much the same way that varphi and psi are used to describe backbone configuration of proteins. Here, we conduct an exploration and statistical evaluation of pseudotorsional space and of the Ramachandran-like eta-theta plot. We show that, through the rigorous quantitative analysis of the eta-theta plot, the pseudotorsional descriptors eta and theta, together with sugar pucker, are sufficient to describe RNA backbone conformation fully in most cases. These descriptors are also shown to contain considerable information about nucleotide base conformation, revealing a previously uncharacterized interplay between backbone and base orientation. A window function analysis is used to discern statistically relevant regions of density in the eta-theta scatter plot and then nucleotides in colocalized clusters in the eta-theta plane are shown to have similar 3-D structures through RMSD analysis of the RNA structural constituents. We find that major clusters in the eta-theta plot are few, underscoring the discrete nature of RNA backbone conformation. Like the Ramachandran plot, the eta-theta plot is a valuable system for conceptualizing biomolecular conformation, it is a useful tool for analyzing RNA tertiary structures, and it is a vital component of new approaches for solving the 3-D structures of large RNA molecules and RNA assemblies.

The Paragon Algorithm, a next generation search engine that uses sequence temperature values and feature probabilities to identify peptides from tandem mass spectra.

PubMed

Shilov, Ignat V; Seymour, Sean L; Patel, Alpesh A; Loboda, Alex; Tang, Wilfred H; Keating, Sean P; Hunter, Christie L; Nuwaysir, Lydia M; Schaeffer, Daniel A

2007-09-01

The Paragon Algorithm, a novel database search engine for the identification of peptides from tandem mass spectrometry data, is presented. Sequence Temperature Values are computed using a sequence tag algorithm, allowing the degree of implication by an MS/MS spectrum of each region of a database to be determined on a continuum. Counter to conventional approaches, features such as modifications, substitutions, and cleavage events are modeled with probabilities rather than by discrete user-controlled settings to consider or not consider a feature. The use of feature probabilities in conjunction with Sequence Temperature Values allows for a very large increase in the effective search space with only a very small increase in the actual number of hypotheses that must be scored. The algorithm has a new kind of user interface that removes the user expertise requirement, presenting control settings in the language of the laboratory that are translated to optimal algorithmic settings. To validate this new algorithm, a comparison with Mascot is presented for a series of analogous searches to explore the relative impact of increasing search space probed with Mascot by relaxing the tryptic digestion conformance requirements from trypsin to semitrypsin to no enzyme and with the Paragon Algorithm using its Rapid mode and Thorough mode with and without tryptic specificity. Although they performed similarly for small search space, dramatic differences were observed in large search space. With the Paragon Algorithm, hundreds of biological and artifact modifications, all possible substitutions, and all levels of conformance to the expected digestion pattern can be searched in a single search step, yet the typical cost in search time is only 2-5 times that of conventional small search space. Despite this large increase in effective search space, there is no drastic loss of discrimination that typically accompanies the exploration of large search space.

Thermodynamic and kinetic characterization of a beta-hairpin peptide in solution: an extended phase space sampling by molecular dynamics simulations in explicit water.

PubMed

Daidone, Isabella; Amadei, Andrea; Di Nola, Alfredo

2005-05-15

The folding of the amyloidogenic H1 peptide MKHMAGAAAAGAVV taken from the syrian hamster prion protein is explored in explicit aqueous solution at 300 K using long time scale all-atom molecular dynamics simulations for a total simulation time of 1.1 mus. The system, initially modeled as an alpha-helix, preferentially adopts a beta-hairpin structure and several unfolding/refolding events are observed, yielding a very short average beta-hairpin folding time of approximately 200 ns. The long time scale accessed by our simulations and the reversibility of the folding allow to properly explore the configurational space of the peptide in solution. The free energy profile, as a function of the principal components (essential eigenvectors) of motion, describing the main conformational transitions, shows the characteristic features of a funneled landscape, with a downhill surface toward the beta-hairpin folded basin. However, the analysis of the peptide thermodynamic stability, reveals that the beta-hairpin in solution is rather unstable. These results are in good agreement with several experimental evidences, according to which the isolated H1 peptide adopts very rapidly in water beta-sheet structure, leading to amyloid fibril precipitates [Nguyen et al., Biochemistry 1995;34:4186-4192; Inouye et al., J Struct Biol 1998;122:247-255]. Moreover, in this article we also characterize the diffusion behavior in conformational space, investigating its relations with folding/unfolding conditions. Copyright 2005 Wiley-Liss, Inc.

Galactic conformity measured in semi-analytic models

NASA Astrophysics Data System (ADS)

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

2018-03-01

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

Blind Pose Prediction, Scoring, and Affinity Ranking of the CSAR 2014 Dataset.

PubMed

Martiny, Virginie Y; Martz, François; Selwa, Edithe; Iorga, Bogdan I

2016-06-27

The 2014 CSAR Benchmark Exercise was focused on three protein targets: coagulation factor Xa, spleen tyrosine kinase, and bacterial tRNA methyltransferase. Our protocol involved a preliminary analysis of the structural information available in the Protein Data Bank for the protein targets, which allowed the identification of the most appropriate docking software and scoring functions to be used for the rescoring of several docking conformations datasets, as well as for pose prediction and affinity ranking. The two key points of this study were (i) the prior evaluation of molecular modeling tools that are most adapted for each target and (ii) the increased search efficiency during the docking process to better explore the conformational space of big and flexible ligands.

How to Run FAST Simulations.

PubMed

Zimmerman, M I; Bowman, G R

2016-01-01

Molecular dynamics (MD) simulations are a powerful tool for understanding enzymes' structures and functions with full atomistic detail. These physics-based simulations model the dynamics of a protein in solution and store snapshots of its atomic coordinates at discrete time intervals. Analysis of the snapshots from these trajectories provides thermodynamic and kinetic properties such as conformational free energies, binding free energies, and transition times. Unfortunately, simulating biologically relevant timescales with brute force MD simulations requires enormous computing resources. In this chapter we detail a goal-oriented sampling algorithm, called fluctuation amplification of specific traits, that quickly generates pertinent thermodynamic and kinetic information by using an iterative series of short MD simulations to explore the vast depths of conformational space. © 2016 Elsevier Inc. All rights reserved.

High Energy Scattering in the AdS/CFT Correspondence

NASA Astrophysics Data System (ADS)

Penedones, Joao

2007-12-01

This work explores the celebrated AdS/CFT correspondence in the regime of high energy scattering in Anti--de Sitter (AdS) spacetime. In particular, we develop the eikonal approximation to high energy scattering in AdS and explore its consequences for the dual Conformal Field Theory (CFT). Using position space Feynman rules, we rederive the eikonal approximation for high energy scattering in flat space. Following this intuitive position space perspective, we then generalize the eikonal approximation for high energy scattering in AdS and other spacetimes. Remarkably, we are able to resum, in terms of a generalized phase shift, ladder and cross ladder Witten diagrams associated to the exchange of an AdS spin j field, to all orders in the coupling constant. By the AdS/CFT correspondence, the eikonal amplitude in AdS is related to the four point function of CFT primary operators in the regime of large 't Hooft coupling, including all terms of the 1/N expansion. We then show that the eikonal amplitude determines the behavior of the CFT four point function for small values of the cross ratios in a Lorentzian regime and that this controls its high spin and dimension conformal partial wave decomposition. These results allow us to determine the anomalous dimension of high spin and dimension double trace primary operators, by relating it to the AdS eikonal phase shift. Finally we find that, at large energies and large impact parameters in AdS, the gravitational interaction dominates all other interactions, as in flat space. Therefore, the anomalous dimension of double trace operators, associated to graviton exchange in AdS, yields a universal prediction for CFT's with AdS gravitational duals.

Enabling High Performance Instruments for Astronomy and Space Exploration and ALD

NASA Technical Reports Server (NTRS)

Greer, Frank; Lee, M. C.; Hoenk, M. E.; Jones, T. J.; Jacquot, B. C.; Dickie, M.; Monacos, S.; Nikzad, S.; Day, P.; Leduc, R.;

Nearest Neighbor Interactions Affect the Conformational Distribution in the Unfolded State of Peptides

NASA Astrophysics Data System (ADS)

Toal, Siobhan; Schweitzer-Stenner, Reinhard; Rybka, Karin; Schwalbe, Hardol

2013-03-01

In order to enable structural predictions of intrinsically disordered proteins (IDPs) the intrinsic conformational propensities of amino acids must be complimented by information on nearest-neighbor interactions. To explore the influence of nearest-neighbors on conformational distributions, we preformed a joint vibrational (Infrared, Vibrational Circular Dichroism (VCD), polarized Raman) and 2D-NMR study of selected GxyG host-guest peptides: GDyG, GSyG, GxLG, GxVG, where x/y ={A,K,LV}. D and S (L and V) were chosen at the x (y) position due to their observance to drastically change the distribution of alanine in xAy tripeptide sequences in truncated coil libraries. The conformationally sensitive amide' profiles of the respective spectra were analyzed in terms of a statistical ensemble described as a superposition of 2D-Gaussian functions in Ramachandran space representing sub-ensembles of pPII-, β-strand-, helical-, and turn-like conformations. Our analysis and simulation of the amide I' band profiles exploits excitonic coupling between the local amide I' vibrational modes in the tetra-peptides. The resulting distributions reveal that D and S, which themselves have high propensities for turn-structures, strongly affect the conformational distribution of their downstream neighbor. Taken together, our results indicate that Dx and Sx motifs might act as conformational randomizers in proteins, attenuating intrinsic propensities of neighboring residues. Overall, our results show that nearest neighbor interactions contribute significantly to the Gibbs energy landscape of disordered peptides and proteins.

Conformal Yano-Killing Tensors for Space-times with Cosmological Constant

NASA Astrophysics Data System (ADS)

Czajka, P.; Jezierski, J.

We present a new method for constructing conformal Yano-Killing tensors in five-di\\-men\\-sio\\-nal Anti-de Sitter space-time. The found tensors are represented in two different coordinate systems. We also discuss, in terms of CYK tensors, global charges which are well defined for asymptotically (five-dimensional) Anti-de Sitter space-time. Additionally in Appendix we present our own derivation of conformal Killing one-forms in four-dimensional Anti-de Sitter space-time as an application of the Theorem presented in the paper.

Towards conformal loop quantum gravity

NASA Astrophysics Data System (ADS)

H-T Wang, Charles

2006-03-01

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

PinaColada: peptide-inhibitor ant colony ad-hoc design algorithm.

PubMed

Zaidman, Daniel; Wolfson, Haim J

2016-08-01

Design of protein-protein interaction (PPI) inhibitors is a major challenge in Structural Bioinformatics. Peptides, especially short ones (5-15 amino acid long), are natural candidates for inhibition of protein-protein complexes due to several attractive features such as high structural compatibility with the protein binding site (mimicking the surface of one of the proteins), small size and the ability to form strong hotspot binding connections with the protein surface. Efficient rational peptide design is still a major challenge in computer aided drug design, due to the huge space of possible sequences, which is exponential in the length of the peptide, and the high flexibility of peptide conformations. In this article we present PinaColada, a novel computational method for the design of peptide inhibitors for protein-protein interactions. We employ a version of the ant colony optimization heuristic, which is used to explore the exponential space ([Formula: see text]) of length n peptide sequences, in combination with our fast robotics motivated PepCrawler algorithm, which explores the conformational space for each candidate sequence. PinaColada is being run in parallel, on a DELL PowerEdge 2.8 GHZ computer with 20 cores and 256 GB memory, and takes up to 24 h to design a peptide of 5-15 amino acids length. An online server available at: http://bioinfo3d.cs.tau.ac.il/PinaColada/. danielza@post.tau.ac.il; wolfson@tau.ac.il. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Efficient conformational space exploration in ab initio protein folding simulation.

PubMed

Ullah, Ahammed; Ahmed, Nasif; Pappu, Subrata Dey; Shatabda, Swakkhar; Ullah, A Z M Dayem; Rahman, M Sohel

2015-08-01

Ab initio protein folding simulation largely depends on knowledge-based energy functions that are derived from known protein structures using statistical methods. These knowledge-based energy functions provide us with a good approximation of real protein energetics. However, these energy functions are not very informative for search algorithms and fail to distinguish the types of amino acid interactions that contribute largely to the energy function from those that do not. As a result, search algorithms frequently get trapped into the local minima. On the other hand, the hydrophobic-polar (HP) model considers hydrophobic interactions only. The simplified nature of HP energy function makes it limited only to a low-resolution model. In this paper, we present a strategy to derive a non-uniform scaled version of the real 20×20 pairwise energy function. The non-uniform scaling helps tackle the difficulty faced by a real energy function, whereas the integration of 20×20 pairwise information overcomes the limitations faced by the HP energy function. Here, we have applied a derived energy function with a genetic algorithm on discrete lattices. On a standard set of benchmark protein sequences, our approach significantly outperforms the state-of-the-art methods for similar models. Our approach has been able to explore regions of the conformational space which all the previous methods have failed to explore. Effectiveness of the derived energy function is presented by showing qualitative differences and similarities of the sampled structures to the native structures. Number of objective function evaluation in a single run of the algorithm is used as a comparison metric to demonstrate efficiency.

On the measure of conformal difference between Euclidean and Lobachevsky spaces

NASA Astrophysics Data System (ADS)

Zorich, Vladimir A.

2011-12-01

Euclidean space R^n and Lobachevsky space H^n are known to be not equivalent either conformally or quasiconformally. In this work we give exact asymptotics of the critical order of growth at infinity for the quasiconformality coefficient of a diffeomorphism f\\colon R^n\\to H^n for which such a mapping f is possible. We also consider the general case of immersions f\\colon M^n\\to N^n of conformally parabolic Riemannian manifolds. Bibliography: 17 titles.

Purposes, pedagogies and practices in lifewide adult education in New Zealand: A preview

NASA Astrophysics Data System (ADS)

Zepke, Nick

2015-02-01

This paper is interested in projecting the likely purposes, pedagogies and practices influencing lifewide adult education in New Zealand ten years from now. It first identifies learning spaces in which lifewide adult education takes place. It explores formal, non-formal and informal spaces which conform to or oppose dominant ideological policies, trends and discourses. Second, it discusses current purposes, pedagogies and practices in lifewide adult education. The official purposes are seen as adult education contributing to New Zealand's success in a global marketplace. While lifewide adult education provides spaces to achieve such official purposes, it also creates spaces of neutrality and opposition. In the third section, the paper uses causal layered analysis (CLA) to project the likely future of lifewide adult education. The paper concludes that that while neoliberal purposes, pedagogies and practices will remain dominant, what will be flourishing in diverse spaces is counter-learning.

Designing heteropolymers to fold into unique structures via water-mediated interactions.

PubMed

Jamadagni, Sumanth N; Bosoy, Christian; Garde, Shekhar

2010-10-28

Hydrophobic homopolymers collapse into globular structures in water driven by hydrophobic interactions. Here we employ extensive molecular dynamics simulations to study the collapse of heteropolymers containing one or two pairs of oppositely charged monomers. We show that charging a pair of monomers can dramatically alter the most stable conformations from compact globular to more open hairpin-like. We systematically explore a subset of the sequence space of one- and two-charge-pair polymers, focusing on the locations of the charge pairs. Conformational stability is governed by a balance of hydrophobic interactions, hydration and interactions of charge groups, water-mediated charged-hydrophobic monomer repulsions, and other factors. As a result, placing charge pairs in the middle, away from the hairpin ends, leads to stable hairpin-like structures. Turning off the monomer-water attractions enhances hydrophobic interactions significantly leading to a collapse into compact globular structures even for two-charge-pair heteropolymers. In contrast, the addition of salt leads to open and extended structures, suggesting that solvation of charged monomer sites by salt ions dominates the salt-induced enhancement of hydrophobic interactions. We also test the ability of a predictive scheme based on the additivity of free energy of contact formation. The success of the scheme for symmetric two-charge-pair sequences and the failure for their flipped versions highlight the complexity of the heteropolymer conformation space and of the design problem. Collectively, our results underscore the ability of tuning water-mediated interactions to design stable nonglobular structures in water and present model heteropolymers for further studies in the extended thermodynamic space and in inhomogeneous environments.

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

PubMed Central

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

2008-01-01

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

Pilot Non-Conformance to Alerting System Commands During Closely Spaced Parallel Approaches

NASA Technical Reports Server (NTRS)

Pritchett, Amy R.; Hansman, R. John

1997-01-01

Pilot non-conformance to alerting system commands has been noted in general and to a TCAS-like collision avoidance system in a previous experiment. This paper details two experiments studying collision avoidance during closely-spaced parallel approaches in instrument meteorological conditions (IMC), and specifically examining possible causal factors of, and design solutions to, pilot non-conformance.

Conformational space comparison of GnRH and lGnRH-III using molecular dynamics, cluster analysis and Monte Carlo thermodynamic integration.

PubMed

Watts, C R; Mezei, M; Murphy, R F; Lovas, S

2001-04-01

The conformational space available to GnRH and lGnRH-III was compared using 5.2 ns constant temperature and pressure molecular dynamics simulations with explicit TIP3P solvation and the AMBER v. 5.0 force field. Cluster analysis of both trajectories resulted in two groups of conformations. Results of free energy calculations, in agreement with previous experimental data, indicate that a conformation with a turn from residues 5 through 8 is preferred for GnRH in an aqueous environment. By contrast, a conformation with a helix from residues 2 through 7 with a bend from residues 6 through 10 is preferred for lGnRH-III in an aqueous environment. The side chains of His2 and Trp3 in lGnRH-III occupy different regions of phase space and participate in weakly polar interactions different from those in GnRH. The unique conformational properties of lGnRH-III may account for its specific anti cancer activity.

Invariant classification of second-order conformally flat superintegrable systems

NASA Astrophysics Data System (ADS)

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

2014-12-01

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

Conformal superalgebras via tractor calculus

NASA Astrophysics Data System (ADS)

Lischewski, Andree

2015-01-01

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

Principles of protein folding--a perspective from simple exact models.

PubMed Central

Dill, K. A.; Bromberg, S.; Yue, K.; Fiebig, K. M.; Yee, D. P.; Thomas, P. D.; Chan, H. S.

1995-01-01

General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics--fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse. PMID:7613459

Exploring the free-energy landscape of a short peptide using an average force

NASA Astrophysics Data System (ADS)

Chipot, Christophe; Hénin, Jérôme

2005-12-01

The reversible folding of deca-alanine is chosen as a test case for characterizing a method that uses an adaptive biasing force (ABF) to escape from the minima and overcome the barriers of the free-energy landscape. This approach relies on the continuous estimation of a biasing force that yields a Hamiltonian in which no average force is exerted along the ordering parameter ξ. Optimizing the parameters that control how the ABF is applied, the method is shown to be extremely effective when a nonequivocal ordering parameter can be defined to explore the folding pathway of the peptide. Starting from a β-turn motif and restraining ξ to a region of the conformational space that extends from the α-helical state to an ensemble of extended structures, the ABF scheme is successful in folding the peptide chain into a compact α helix. Sampling of this conformation is, however, marginal when the range of ξ values embraces arrangements of greater compactness, hence demonstrating the inherent limitations of free-energy methods when ambiguous ordering parameters are utilized.

Projective mappings and dimensions of vector spaces of three types of Killing-Yano tensors on pseudo Riemannian manifolds of constant curvature

NASA Astrophysics Data System (ADS)

Mikeš, Josef; Stepanov, Sergey; Hinterleitner, Irena

2012-07-01

In our paper we have determined the dimension of the space of conformal Killing-Yano tensors and the dimensions of its two subspaces of closed conformal Killing-Yano and Killing-Yano tensors on pseudo Riemannian manifolds of constant curvature. This result is a generalization of well known results on sharp upper bounds of the dimensions of the vector spaces of conformal Killing-Yano, Killing-Yano and concircular vector fields on pseudo Riemannian manifolds of constant curvature.

A Projective-to-Conformal Fefferman-Type Construction

NASA Astrophysics Data System (ADS)

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

2017-10-01

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

Enabling High Performance Instruments for UV Astronomy and Space Exploration with ALD

NASA Technical Reports Server (NTRS)

Greer, F.; Hoenk, M. E.; Jones, T. J.; Jacquot, B. C.; Monacos, S.; Nikzad, S.; Hamden, E.; Schiminovich, D.

2011-01-01

Benefits of Atomic Layer Deposition (ALD) for UV instruments and application are: (1) Ultrathin, highly conformal, and uniform films over arbitrarily large surface area (2) High quality films (density, roughness, conductivity, etc.) (3) Angstrom level control of stoichiometry, interfaces, and surface properties (3a) Multilayer nanolaminates/nanocomposites (3b) Low temperature surface engineering UV flight applications enabled by ALD. (1) Anti -reflective coatings/Mirrors/Filters/Optics for UV/Vis/NIR Detectors (2) Surface Passivation for III -N detectors

4D Flexible Atom-Pairs: An efficient probabilistic conformational space comparison for ligand-based virtual screening

PubMed Central

2011-01-01

Background The performance of 3D-based virtual screening similarity functions is affected by the applied conformations of compounds. Therefore, the results of 3D approaches are often less robust than 2D approaches. The application of 3D methods on multiple conformer data sets normally reduces this weakness, but entails a significant computational overhead. Therefore, we developed a special conformational space encoding by means of Gaussian mixture models and a similarity function that operates on these models. The application of a model-based encoding allows an efficient comparison of the conformational space of compounds. Results Comparisons of our 4D flexible atom-pair approach with over 15 state-of-the-art 2D- and 3D-based virtual screening similarity functions on the 40 data sets of the Directory of Useful Decoys show a robust performance of our approach. Even 3D-based approaches that operate on multiple conformers yield inferior results. The 4D flexible atom-pair method achieves an averaged AUC value of 0.78 on the filtered Directory of Useful Decoys data sets. The best 2D- and 3D-based approaches of this study yield an AUC value of 0.74 and 0.72, respectively. As a result, the 4D flexible atom-pair approach achieves an average rank of 1.25 with respect to 15 other state-of-the-art similarity functions and four different evaluation metrics. Conclusions Our 4D method yields a robust performance on 40 pharmaceutically relevant targets. The conformational space encoding enables an efficient comparison of the conformational space. Therefore, the weakness of the 3D-based approaches on single conformations is circumvented. With over 100,000 similarity calculations on a single desktop CPU, the utilization of the 4D flexible atom-pair in real-world applications is feasible. PMID:21733172

A comparative study of structural and conformational properties of casein kinase-1 isoforms: insights from molecular dynamics and principal component analysis.

PubMed

Singh, Surya Pratap; Gupta, Dwijendra K

2015-04-21

Wnt signaling pathway regulates several developmental processes in human; however recently this pathway has been associated with development of different types of cancers. Casein kinase-1 (CK1) constitutes a family of serine-threonine protein kinase; various members of this family participate in Wnt signal transduction pathway and serve as molecular switch to this pathway. Among the known six isoforms of CK1, in human, at least three isoforms (viz. alpha, delta and epsilon) have been reported as oncogenic. The development of common therapeutics against these kinases is an arduous task; unless we have the detailed information of their tertiary structures and conformational properties. In the present work, the dynamical and conformational properties for each of three isoforms of CK1 are explored through molecular dynamics (MD) simulations. The conformational space distribution of backbone atoms is evaluated using principal component analysis of MD data, which are further validated on the basis of potential energy surface. Based on these analytics, it is suggested that conformational subspace shifts upon binding to ligands and guides the kinase action of CK1 isoforms. Further, this paper as a first effort to concurrently study all the three isoforms of CK1 provides structural basis for development of common anticancer therapeutics against three isoforms of CK1. Copyright © 2015 Elsevier Ltd. All rights reserved.

Vertical Field of View Reference Point Study for Flight Path Control and Hazard Avoidance

NASA Technical Reports Server (NTRS)

Comstock, J. Raymond, Jr.; Rudisill, Marianne; Kramer, Lynda J.; Busquets, Anthony M.

2002-01-01

Researchers within the eXternal Visibility System (XVS) element of the High-Speed Research (HSR) program developed and evaluated display concepts that will provide the flight crew of the proposed High-Speed Civil Transport (HSCT) with integrated imagery and symbology to permit path control and hazard avoidance functions while maintaining required situation awareness. The challenge of the XVS program is to develop concepts that would permit a no-nose-droop configuration of an HSCT and expanded low visibility HSCT operational capabilities. This study was one of a series of experiments exploring the 'design space' restrictions for physical placement of an XVS display. The primary experimental issues here was 'conformality' of the forward display vertical position with respect to the side window in simulated flight. 'Conformality' refers to the case such that the horizon and objects appear in the same relative positions when viewed through the forward windows or display and the side windows. This study quantified the effects of visual conformality on pilot flight path control and hazard avoidance performance. Here, conformality related to the positioning and relationship of the artificial horizon line and associated symbology presented on the forward display and the horizon and associated ground, horizon, and sky textures as they would appear in the real view through a window presented in the side window display. No significant performance consequences were found for the non-conformal conditions.

Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations.

PubMed

Islam, Barira; Stadlbauer, Petr; Gil-Ley, Alejandro; Pérez-Hernández, Guillermo; Haider, Shozeb; Neidle, Stephen; Bussi, Giovanni; Banas, Pavel; Otyepka, Michal; Sponer, Jiri

2017-06-13

We have carried out a series of extended unbiased molecular dynamics (MD) simulations (up to 10 μs long, ∼162 μs in total) complemented by replica-exchange with the collective variable tempering (RECT) approach for several human telomeric DNA G-quadruplex (GQ) topologies with TTA propeller loops. We used different AMBER DNA force-field variants and also processed simulations by Markov State Model (MSM) analysis. The slow conformational transitions in the propeller loops took place on a scale of a few μs, emphasizing the need for long simulations in studies of GQ dynamics. The propeller loops sampled similar ensembles for all GQ topologies and for all force-field dihedral-potential variants. The outcomes of standard and RECT simulations were consistent and captured similar spectrum of loop conformations. However, the most common crystallographic loop conformation was very unstable with all force-field versions. Although the loss of canonical γ-trans state of the first propeller loop nucleotide could be related to the indispensable bsc0 α/γ dihedral potential, even supporting this particular dihedral by a bias was insufficient to populate the experimentally dominant loop conformation. In conclusion, while our simulations were capable of providing a reasonable albeit not converged sampling of the TTA propeller loop conformational space, the force-field description still remained far from satisfactory.

Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations

PubMed Central

2017-01-01

We have carried out a series of extended unbiased molecular dynamics (MD) simulations (up to 10 μs long, ∼162 μs in total) complemented by replica-exchange with the collective variable tempering (RECT) approach for several human telomeric DNA G-quadruplex (GQ) topologies with TTA propeller loops. We used different AMBER DNA force-field variants and also processed simulations by Markov State Model (MSM) analysis. The slow conformational transitions in the propeller loops took place on a scale of a few μs, emphasizing the need for long simulations in studies of GQ dynamics. The propeller loops sampled similar ensembles for all GQ topologies and for all force-field dihedral-potential variants. The outcomes of standard and RECT simulations were consistent and captured similar spectrum of loop conformations. However, the most common crystallographic loop conformation was very unstable with all force-field versions. Although the loss of canonical γ-trans state of the first propeller loop nucleotide could be related to the indispensable bsc0 α/γ dihedral potential, even supporting this particular dihedral by a bias was insufficient to populate the experimentally dominant loop conformation. In conclusion, while our simulations were capable of providing a reasonable albeit not converged sampling of the TTA propeller loop conformational space, the force-field description still remained far from satisfactory. PMID:28475322

Predicting protein structures with a multiplayer online game.

PubMed

Cooper, Seth; Khatib, Firas; Treuille, Adrien; Barbero, Janos; Lee, Jeehyung; Beenen, Michael; Leaver-Fay, Andrew; Baker, David; Popović, Zoran; Players, Foldit

2010-08-05

People exert large amounts of problem-solving effort playing computer games. Simple image- and text-recognition tasks have been successfully 'crowd-sourced' through games, but it is not clear if more complex scientific problems can be solved with human-directed computing. Protein structure prediction is one such problem: locating the biologically relevant native conformation of a protein is a formidable computational challenge given the very large size of the search space. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology, while they compete and collaborate to optimize the computed energy. We show that top-ranked Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop a rich assortment of new strategies and algorithms; unlike computational approaches, they explore not only the conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development capabilities with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems.

Using the conformity to masculine norms inventory to work with men in a clinical setting.

PubMed

Mahalik, James R; Talmadge, W Tracy; Locke, Benjamin D; Scott, Ryan P J

2005-06-01

Given that gender roles are increasingly viewed as salient in clinical work with men, this article describes a process of exploring masculine gender roles with male clients in therapy by using the Conformity to Masculine Norms Inventory (CMNI). Specifically, this article (a) discusses how men's degree of conformity to masculine norms may be connected to a variety of benefits and costs, (b) describes the CMNI as a tool that can be used to explore men's degree of conformity to masculine norms, (c) describes a process by which to use the CMNI to explore the relevance of men's masculine selves to their presenting concerns, and (d) illustrates the process with a case example. As such, the paper is intended to provide a systematic procedure for clinicians working with men who want to explore the benefits and costs that both conformity, and nonconformity, to specific masculinity norms brings for male clients. Copyright 2005 Wiley Periodicals, Inc.

Optimal Mass Transport for Shape Matching and Comparison

PubMed Central

Su, Zhengyu; Wang, Yalin; Shi, Rui; Zeng, Wei; Sun, Jian; Luo, Feng; Gu, Xianfeng

2015-01-01

Surface based 3D shape analysis plays a fundamental role in computer vision and medical imaging. This work proposes to use optimal mass transport map for shape matching and comparison, focusing on two important applications including surface registration and shape space. The computation of the optimal mass transport map is based on Monge-Brenier theory, in comparison to the conventional method based on Monge-Kantorovich theory, this method significantly improves the efficiency by reducing computational complexity from O(n2) to O(n). For surface registration problem, one commonly used approach is to use conformal map to convert the shapes into some canonical space. Although conformal mappings have small angle distortions, they may introduce large area distortions which are likely to cause numerical instability thus resulting failures of shape analysis. This work proposes to compose the conformal map with the optimal mass transport map to get the unique area-preserving map, which is intrinsic to the Riemannian metric, unique, and diffeomorphic. For shape space study, this work introduces a novel Riemannian framework, Conformal Wasserstein Shape Space, by combing conformal geometry and optimal mass transport theory. In our work, all metric surfaces with the disk topology are mapped to the unit planar disk by a conformal mapping, which pushes the area element on the surface to a probability measure on the disk. The optimal mass transport provides a map from the shape space of all topological disks with metrics to the Wasserstein space of the disk and the pullback Wasserstein metric equips the shape space with a Riemannian metric. We validate our work by numerous experiments and comparisons with prior approaches and the experimental results demonstrate the efficiency and efficacy of our proposed approach. PMID:26440265

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

PubMed

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

2017-04-27

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

ClustENM: ENM-Based Sampling of Essential Conformational Space at Full Atomic Resolution

PubMed Central

Kurkcuoglu, Zeynep; Bahar, Ivet; Doruker, Pemra

2016-01-01

Accurate sampling of conformational space and, in particular, the transitions between functional substates has been a challenge in molecular dynamic (MD) simulations of large biomolecular systems. We developed an Elastic Network Model (ENM)-based computational method, ClustENM, for sampling large conformational changes of biomolecules with various sizes and oligomerization states. ClustENM is an iterative method that combines ENM with energy minimization and clustering steps. It is an unbiased technique, which requires only an initial structure as input, and no information about the target conformation. To test the performance of ClustENM, we applied it to six biomolecular systems: adenylate kinase (AK), calmodulin, p38 MAP kinase, HIV-1 reverse transcriptase (RT), triosephosphate isomerase (TIM), and the 70S ribosomal complex. The generated ensembles of conformers determined at atomic resolution show good agreement with experimental data (979 structures resolved by X-ray and/or NMR) and encompass the subspaces covered in independent MD simulations for TIM, p38, and RT. ClustENM emerges as a computationally efficient tool for characterizing the conformational space of large systems at atomic detail, in addition to generating a representative ensemble of conformers that can be advantageously used in simulating substrate/ligand-binding events. PMID:27494296

Repair of Electronics for Long Duration Spaceflight

NASA Technical Reports Server (NTRS)

Pettegrew, Richard D.; Easton, John; Struk, Peter

2007-01-01

To reduce mission risk, long duration spaceflight and exploration activities will require greater degrees of self-sufficiency with regards to repair capability than have ever been employed before in space exploration. The current repair paradigm of replacing Orbital Replacement Units (ORUs) of malfunctioning avionics and electronic hardware will be impractical, since carrying all of the spares that could possibly be needed for a long duration mission would require upmass and volume at unprecedented and unacceptable levels. A strategy of component-level repair for electronics, however, could significantly reduce the mass and volume necessary for spares and enhance mission safety via a generic contingency capability. This approach is already used to varying degrees by the U.S. Navy, where vessels at sea experience some similar constraints such as the need for self sufficiency for moderately long time periods, and restrictions on volume of repair spares and infrastructure. The concept of conducting component-level repairs of electronics in spacecraft requires the development of design guidelines for future avionics (to enable repair), development of diagnostic techniques to allow an astronaut to pinpoint the faulty component aboard a vastly complex vehicle, and development of tools and methodologies for dealing with the physical processes of replacing the component. This physical process includes tasks such as conformal coating removal and replacement, component removal, replacement, and alignment--all in the difficulty of a reduced gravity environment. Further, the gravitational effects on the soldering process must be characterized and accounted for to ensure reliability of the newly repaired components. The Component-Level Electronics-Assembly Repair (CLEAR) project under the NASA Supportability program was established to develop and demonstrate the practicality of this repair approach. CLEAR involves collaborative efforts between NASA s Glenn Research Center, Langley Research Center, Johnson Space Center, the National Center for Space Exploration Research, and the U.S. Navy. The project goals are 1) develop and demonstrate a manually-operated electronics repair capability to be conducted in a spacecraft environment; and 2) develop guidelines for designs of electronics that facilitates component-level repair for future space exploration efforts. This multi-faceted program utilizes a cross-disciplinary approach to examine pre- and post-repair diagnostics, conformal coating removal and replacement, component soldering, and electronics design for supportability. These areas are investigated by a combination of trade studies, ground based testing, reduced gravity aircraft testing, and actual spaceflight testing on the International Space Station (ISS) in multiple experiments. This paper details the efforts of this program, with emphasis on early trade study results, ground-based efforts, and two upcoming ISS experiments.

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

NASA Astrophysics Data System (ADS)

Batista, Carlos

2015-01-01

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

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

PubMed

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

2012-03-26

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

Operator product expansion for conformal defects

NASA Astrophysics Data System (ADS)

Fukuda, Masayuki; Kobayashi, Nozomu; Nishioka, Tatsuma

2018-01-01

We study the operator product expansion (OPE) for scalar conformal defects of any codimension in CFT. The OPE for defects is decomposed into "defect OPE blocks", the irreducible representations of the conformal group, each of which packages the contribution from a primary operator and its descendants. We use the shadow formalism to deduce an integral representation of the defect OPE blocks. They are shown to obey a set of constraint equations that can be regarded as equations of motion for a scalar field propagating on the moduli space of the defects. By employing the Radon transform between the AdS space and the moduli space, we obtain a formula of constructing an AdS scalar field from the defect OPE block for a conformal defect of any codimension in a scalar representation of the conformal group, which turns out to be the Euclidean version of the HKLL formula. We also introduce a duality between conformal defects of different codimensions and prove the equivalence between the defect OPE block for codimension-two defects and the OPE block for a pair of local operators.

Simulations of a Membrane-Anchored Peptide: Structure, Dynamics, and Influence on Bilayer Properties

PubMed Central

Jensen, Morten Ø.; Mouritsen, Ole G.; Peters, Günther H.

2004-01-01

A three-dimensional structure of a model decapeptide is obtained by performing molecular dynamics simulations of the peptide in explicit water. Interactions between an N-myristoylated form of the folded peptide anchored to dipalmitoylphosphatidylcholine fluid phase lipid membranes are studied at different applied surface tensions by molecular dynamics simulations. The lipid membrane environment influences the conformational space explored by the peptide. The overall secondary structure of the anchored peptide is found to deviate at times from its structure in aqueous solution through reversible conformational transitions. The peptide is, despite the anchor, highly mobile at the membrane surface with the peptide motion along the bilayer normal being integrated into the collective modes of the membrane. Peptide anchoring moderately alters the lateral compressibility of the bilayer by changing the equilibrium area of the membrane. Although membrane anchoring moderately affects the elastic properties of the bilayer, the model peptide studied here exhibits conformational flexibility and our results therefore suggest that peptide acylation is a feasible way to reinforce peptide-membrane interactions whereby, e.g., the lifetime of receptor-ligand interactions can be prolonged. PMID:15189854

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

Comparison of molecular dynamics and superfamily spaces of protein domain deformation.

PubMed

Velázquez-Muriel, Javier A; Rueda, Manuel; Cuesta, Isabel; Pascual-Montano, Alberto; Orozco, Modesto; Carazo, José-María

2009-02-17

It is well known the strong relationship between protein structure and flexibility, on one hand, and biological protein function, on the other hand. Technically, protein flexibility exploration is an essential task in many applications, such as protein structure prediction and modeling. In this contribution we have compared two different approaches to explore the flexibility space of protein domains: i) molecular dynamics (MD-space), and ii) the study of the structural changes within superfamily (SF-space). Our analysis indicates that the MD-space and the SF-space display a significant overlap, but are still different enough to be considered as complementary. The SF-space space is wider but less complex than the MD-space, irrespective of the number of members in the superfamily. Also, the SF-space does not sample all possibilities offered by the MD-space, but often introduces very large changes along just a few deformation modes, whose number tend to a plateau as the number of related folds in the superfamily increases. Theoretically, we obtained two conclusions. First, that function restricts the access to some flexibility patterns to evolution, as we observe that when a superfamily member changes to become another, the path does not completely overlap with the physical deformability. Second, that conformational changes from variation in a superfamily are larger and much simpler than those allowed by physical deformability. Methodologically, the conclusion is that both spaces studied are complementary, and have different size and complexity. We expect this fact to have application in fields as 3D-EM/X-ray hybrid models or ab initio protein folding.

Comparison of molecular dynamics and superfamily spaces of protein domain deformation

PubMed Central

Velázquez-Muriel, Javier A; Rueda, Manuel; Cuesta, Isabel; Pascual-Montano, Alberto; Orozco, Modesto; Carazo, José-María

2009-01-01

Background It is well known the strong relationship between protein structure and flexibility, on one hand, and biological protein function, on the other hand. Technically, protein flexibility exploration is an essential task in many applications, such as protein structure prediction and modeling. In this contribution we have compared two different approaches to explore the flexibility space of protein domains: i) molecular dynamics (MD-space), and ii) the study of the structural changes within superfamily (SF-space). Results Our analysis indicates that the MD-space and the SF-space display a significant overlap, but are still different enough to be considered as complementary. The SF-space space is wider but less complex than the MD-space, irrespective of the number of members in the superfamily. Also, the SF-space does not sample all possibilities offered by the MD-space, but often introduces very large changes along just a few deformation modes, whose number tend to a plateau as the number of related folds in the superfamily increases. Conclusion Theoretically, we obtained two conclusions. First, that function restricts the access to some flexibility patterns to evolution, as we observe that when a superfamily member changes to become another, the path does not completely overlap with the physical deformability. Second, that conformational changes from variation in a superfamily are larger and much simpler than those allowed by physical deformability. Methodologically, the conclusion is that both spaces studied are complementary, and have different size and complexity. We expect this fact to have application in fields as 3D-EM/X-ray hybrid models or ab initio protein folding. PMID:19220918

Conformal field theories and compact curves in moduli spaces

NASA Astrophysics Data System (ADS)

Donagi, Ron; Morrison, David R.

2018-05-01

We show that there are many compact subsets of the moduli space M g of Riemann surfaces of genus g that do not intersect any symmetry locus. This has interesting implications for N=2 supersymmetric conformal field theories in four dimensions.

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

PubMed

Sullivan, David C; Lim, Carmay

2006-08-24

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

Real-space visualization of conformation-independent oligothiophene electronic structure

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

Taber, Benjamen N.; Kislitsyn, Dmitry A.; Gervasi, Christian F.

2016-05-21

We present scanning tunneling microscopy and spectroscopy (STM/STS) investigations of the electronic structures of different alkyl-substituted oligothiophenes on the Au(111) surface. STM imaging showed that on Au(111), oligothiophenes adopted distinct straight and bent conformations. By combining STS maps with STM images, we visualize, in real space, particle-in-a-box-like oligothiophene molecular orbitals. We demonstrate that different planar conformers with significant geometrical distortions of oligothiophene backbones surprisingly exhibit very similar electronic structures, indicating a low degree of conformation-induced electronic disorder. The agreement of these results with gas-phase density functional theory calculations implies that the oligothiophene interaction with the Au(111) surface is generally insensitivemore » to molecular conformation.« less

Improving the iterative Linear Interaction Energy approach using automated recognition of configurational transitions.

PubMed

Vosmeer, C Ruben; Kooi, Derk P; Capoferri, Luigi; Terpstra, Margreet M; Vermeulen, Nico P E; Geerke, Daan P

2016-01-01

Recently an iterative method was proposed to enhance the accuracy and efficiency of ligand-protein binding affinity prediction through linear interaction energy (LIE) theory. For ligand binding to flexible Cytochrome P450s (CYPs), this method was shown to decrease the root-mean-square error and standard deviation of error prediction by combining interaction energies of simulations starting from different conformations. Thereby, different parts of protein-ligand conformational space are sampled in parallel simulations. The iterative LIE framework relies on the assumption that separate simulations explore different local parts of phase space, and do not show transitions to other parts of configurational space that are already covered in parallel simulations. In this work, a method is proposed to (automatically) detect such transitions during the simulations that are performed to construct LIE models and to predict binding affinities. Using noise-canceling techniques and splines to fit time series of the raw data for the interaction energies, transitions during simulation between different parts of phase space are identified. Boolean selection criteria are then applied to determine which parts of the interaction energy trajectories are to be used as input for the LIE calculations. Here we show that this filtering approach benefits the predictive quality of our previous CYP 2D6-aryloxypropanolamine LIE model. In addition, an analysis is performed of the gain in computational efficiency that can be obtained from monitoring simulations using the proposed filtering method and by prematurely terminating simulations accordingly.

Conformation-driven quantum interference effects mediated by through-space conjugation in self-assembled monolayers

NASA Astrophysics Data System (ADS)

Carlotti, Marco; Kovalchuk, Andrii; Wächter, Tobias; Qiu, Xinkai; Zharnikov, Michael; Chiechi, Ryan C.

2016-12-01

Tunnelling currents through tunnelling junctions comprising molecules with cross-conjugation are markedly lower than for their linearly conjugated analogues. This effect has been shown experimentally and theoretically to arise from destructive quantum interference, which is understood to be an intrinsic, electronic property of molecules. Here we show experimental evidence of conformation-driven interference effects by examining through-space conjugation in which π-conjugated fragments are arranged face-on or edge-on in sufficiently close proximity to interact through space. Observing these effects in the latter requires trapping molecules in a non-equilibrium conformation closely resembling the X-ray crystal structure, which we accomplish using self-assembled monolayers to construct bottom-up, large-area tunnelling junctions. In contrast, interference effects are completely absent in zero-bias simulations on the equilibrium, gas-phase conformation, establishing through-space conjugation as both of fundamental interest and as a potential tool for tuning tunnelling charge-transport in large-area, solid-state molecular-electronic devices.

Diffusion maps, clustering and fuzzy Markov modeling in peptide folding transitions

NASA Astrophysics Data System (ADS)

Nedialkova, Lilia V.; Amat, Miguel A.; Kevrekidis, Ioannis G.; Hummer, Gerhard

2014-09-01

Using the helix-coil transitions of alanine pentapeptide as an illustrative example, we demonstrate the use of diffusion maps in the analysis of molecular dynamics simulation trajectories. Diffusion maps and other nonlinear data-mining techniques provide powerful tools to visualize the distribution of structures in conformation space. The resulting low-dimensional representations help in partitioning conformation space, and in constructing Markov state models that capture the conformational dynamics. In an initial step, we use diffusion maps to reduce the dimensionality of the conformational dynamics of Ala5. The resulting pretreated data are then used in a clustering step. The identified clusters show excellent overlap with clusters obtained previously by using the backbone dihedral angles as input, with small—but nontrivial—differences reflecting torsional degrees of freedom ignored in the earlier approach. We then construct a Markov state model describing the conformational dynamics in terms of a discrete-time random walk between the clusters. We show that by combining fuzzy C-means clustering with a transition-based assignment of states, we can construct robust Markov state models. This state-assignment procedure suppresses short-time memory effects that result from the non-Markovianity of the dynamics projected onto the space of clusters. In a comparison with previous work, we demonstrate how manifold learning techniques may complement and enhance informed intuition commonly used to construct reduced descriptions of the dynamics in molecular conformation space.

Diffusion maps, clustering and fuzzy Markov modeling in peptide folding transitions

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

Nedialkova, Lilia V.; Amat, Miguel A.; Kevrekidis, Ioannis G., E-mail: yannis@princeton.edu, E-mail: gerhard.hummer@biophys.mpg.de

Using the helix-coil transitions of alanine pentapeptide as an illustrative example, we demonstrate the use of diffusion maps in the analysis of molecular dynamics simulation trajectories. Diffusion maps and other nonlinear data-mining techniques provide powerful tools to visualize the distribution of structures in conformation space. The resulting low-dimensional representations help in partitioning conformation space, and in constructing Markov state models that capture the conformational dynamics. In an initial step, we use diffusion maps to reduce the dimensionality of the conformational dynamics of Ala5. The resulting pretreated data are then used in a clustering step. The identified clusters show excellent overlapmore » with clusters obtained previously by using the backbone dihedral angles as input, with small—but nontrivial—differences reflecting torsional degrees of freedom ignored in the earlier approach. We then construct a Markov state model describing the conformational dynamics in terms of a discrete-time random walk between the clusters. We show that by combining fuzzy C-means clustering with a transition-based assignment of states, we can construct robust Markov state models. This state-assignment procedure suppresses short-time memory effects that result from the non-Markovianity of the dynamics projected onto the space of clusters. In a comparison with previous work, we demonstrate how manifold learning techniques may complement and enhance informed intuition commonly used to construct reduced descriptions of the dynamics in molecular conformation space.« less

Diffusion maps, clustering and fuzzy Markov modeling in peptide folding transitions

PubMed Central

Nedialkova, Lilia V.; Amat, Miguel A.; Kevrekidis, Ioannis G.; Hummer, Gerhard

2014-01-01

Using the helix-coil transitions of alanine pentapeptide as an illustrative example, we demonstrate the use of diffusion maps in the analysis of molecular dynamics simulation trajectories. Diffusion maps and other nonlinear data-mining techniques provide powerful tools to visualize the distribution of structures in conformation space. The resulting low-dimensional representations help in partitioning conformation space, and in constructing Markov state models that capture the conformational dynamics. In an initial step, we use diffusion maps to reduce the dimensionality of the conformational dynamics of Ala5. The resulting pretreated data are then used in a clustering step. The identified clusters show excellent overlap with clusters obtained previously by using the backbone dihedral angles as input, with small—but nontrivial—differences reflecting torsional degrees of freedom ignored in the earlier approach. We then construct a Markov state model describing the conformational dynamics in terms of a discrete-time random walk between the clusters. We show that by combining fuzzy C-means clustering with a transition-based assignment of states, we can construct robust Markov state models. This state-assignment procedure suppresses short-time memory effects that result from the non-Markovianity of the dynamics projected onto the space of clusters. In a comparison with previous work, we demonstrate how manifold learning techniques may complement and enhance informed intuition commonly used to construct reduced descriptions of the dynamics in molecular conformation space. PMID:25240340

Transmembrane Segments Form Tertiary Hairpins in the Folding Vestibule of the Ribosome.

PubMed Central

Tu, LiWei; Khanna, Pooja; Deutsch, Carol

2013-01-01

Folding of membrane proteins begins in the ribosome as the peptide is elongated. During this process, the nascent peptide navigates along 100 Å of tunnel from the peptidyltransferase center to the exit port. Proximal to the exit port is a ‘folding vestibule’ that permits the nascent peptide to compact and explore conformational space for potential tertiary folding partners. The latter occurs for cytosolic subdomains, but has not yet been shown for transmembrane segments. We now demonstrate, using an accessibility assay and an improved, intramolecular crosslinking assay, that the helical transmembrane S3b-S4 hairpin (‘paddle’) of a voltage-gated potassium (Kv) channel, a critical region of the Kv voltage sensor, forms in the vestibule. S3-S4 hairpin interactions are detected at an early stage of Kv biogenesis. Moreover, this vestibule hairpin is consistent with a closed-state conformation of the Kv channel in the plasma membrane. PMID:24055377

Bioactive Conformations of Two Seminal Delta Opioid Receptor Penta-peptides Inferred from Free-Energy Profiles

PubMed Central

Scarabelli, Guido; Provasi, Davide; Negri, Ana; Filizola, Marta

2013-01-01

Delta-opioid (DOP) receptors are members of the G protein-coupled receptor (GPCR) sub-family of opioid receptors, and are evolutionarily related, with homology exceeding 70%, to cognate mu-opioid (MOP), kappa-opioid (KOP), and nociceptin opioid (NOP) receptors. DOP receptors are considered attractive drug targets for pain management because agonists at these receptors are reported to exhibit strong antinociceptive activity with relatively few side effects. Among the most potent analgesics targeting the DOP receptor are the linear and cyclic enkephalin analogs known as DADLE (Tyr-D-Ala-GlyPhe-D-Leu) and DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen), respectively. Several computational and experimental studies have been carried out over the years to characterize the conformational profile of these penta-peptides with the ultimate goal of designing potent peptidomimetic agonists for the DOP receptor. The computational studies published to date, however, have investigated only a limited range of timescales and used over-simplified representations of the solvent environment. We provide here a thorough exploration of the conformational space of DADLE and DPDPE in an explicit solvent, using microsecond-scale molecular dynamics and bias-exchange metadynamics simulations. Free-energy profiles derived from these simulations point to a small number of DADLE and DPDPE conformational minima in solution, which are separated by relatively small energy barriers. Candidate bioactive forms of these peptides are selected from identified common spatial arrangements of key pharmacophoric points within all sampled conformations. PMID:23564013

Natural-product-derived fragments for fragment-based ligand discovery

NASA Astrophysics Data System (ADS)

Over, Björn; Wetzel, Stefan; Grütter, Christian; Nakai, Yasushi; Renner, Steffen; Rauh, Daniel; Waldmann, Herbert

2013-01-01

Fragment-based ligand and drug discovery predominantly employs sp2-rich compounds covering well-explored regions of chemical space. Despite the ease with which such fragments can be coupled, this focus on flat compounds is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biologically validated natural products are rich in stereogenic centres and populate areas of chemical space not occupied by average synthetic molecules. Here, we have analysed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centres. The structures of the cluster centres differ from previously explored fragment libraries, but for nearly half of the clusters representative members are commercially available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallography and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.

Convergence of quantum electrodynamics in a curved modification of Minkowski space.

PubMed Central

Segal, I E; Zhou, Z

1994-01-01

The interaction and total hamiltonians for quantum electrodynamics, in the interaction representation, are entirely regular self-adjoint operators in Hilbert space, in the universal covering manifold M of the conformal compactification of Minkowski space Mo. (M is conformally equivalent to the Einstein universe E, in which Mo may be canonically imbedded.) In a fixed Lorentz frame this may be expressed as convergence in a spherical space with suitable periodic boundary conditions in time. The traditional relativistic theory is the formal limit of the present variant as the space curvature vanishes. PMID:11607455

Exploring soft constraints on effective actions

NASA Astrophysics Data System (ADS)

Bianchi, Massimo; Guerrieri, Andrea L.; Huang, Yu-tin; Lee, Chao-Jung; Wen, Congkao

2016-10-01

We study effective actions for simultaneous breaking of space-time and internal symmetries. Novel features arise due to the mixing of Goldstone modes under the broken symmetries which, in contrast to the usual Adler's zero, leads to non-vanishing soft limits. Such scenarios are common for spontaneously broken SCFT's. We explicitly test these soft theorems for N=4 sYM in the Coulomb branch both perturbatively and non-perturbatively. We explore the soft constraints systematically utilizing recursion relations. In the pure dilaton sector of a general CFT, we show that all amplitudes up to order s n ˜ ∂2 n are completely determined in terms of the k-point amplitudes at order s k with k ≤ n. Terms with at most one derivative acting on each dilaton insertion are completely fixed and coincide with those appearing in the conformal DBI, i.e. DBI in AdS. With maximal supersymmetry, the effective actions are further constrained, leading to new non-renormalization theorems. In particular, the effective action is fixed up to eight derivatives in terms of just one unknown four-point coefficient and one more coefficient for ten-derivative terms. Finally, we also study the interplay between scale and conformal invariance in this context.

Analytic solution for the space-time fractional Klein-Gordon and coupled conformable Boussinesq equations

NASA Astrophysics Data System (ADS)

Shallal, Muhannad A.; Jabbar, Hawraz N.; Ali, Khalid K.

2018-03-01

In this paper, we constructed a travelling wave solution for space-time fractional nonlinear partial differential equations by using the modified extended Tanh method with Riccati equation. The method is used to obtain analytic solutions for the space-time fractional Klein-Gordon and coupled conformable space-time fractional Boussinesq equations. The fractional complex transforms and the properties of modified Riemann-Liouville derivative have been used to convert these equations into nonlinear ordinary differential equations.

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

NASA Astrophysics Data System (ADS)

Zhou, Peng; Chen, Xiang; Shang, Zhicai

2009-03-01

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

Density functional theory study of the conformational space of an infinitely long polypeptide chain

NASA Astrophysics Data System (ADS)

Ireta, Joel; Scheffler, Matthias

2009-08-01

The backbone conformational space of infinitely long polyalanine is investigated with density-functional theory and mapping the potential energy surface in terms of (L, θ) cylindrical coordinates. A comparison of the obtained (L, θ) Ramachandran-like plot with results from an extended set of protein structures shows excellent conformity, with the exception of the polyproline II region. It is demonstrated the usefulness of infinitely long polypeptide models for investigating the influence of hydrogen bonding and its cooperative effect on the backbone conformations. The results imply that hydrogen bonding together with long-range electrostatics is the main actuator for most of the structures assumed by protein residues.

Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations

PubMed Central

Lapelosa, Mauro; Gallicchio, Emilio; Levy, Ronald M.

2011-01-01

The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallographic data, which was not used to restrain ligand orientations. The BEDAM method is based on λ -hopping Hamiltonian parallel Replica Exchange (HREM) molecular dynamics conformational sampling, the OPLS-AA/AGBNP2 effective potential, and multi-state free energy estimators (MBAR). Achieving converged and accurate results depends on all of these elements of the calculation. Convergence of the binding free energy is tied to the level of convergence of binding energy distributions at critical intermediate states where bound and unbound states are at equilibrium, and where the rate of binding/unbinding conformational transitions is maximal. This finding mirrors similar observations in the context of order/disorder transitions as for example in protein folding. Insights concerning the physical mechanism of ligand binding and unbinding are obtained. Convergence for the largest FK506 ligand is achieved only after imposing strict conformational restraints, which however require accurate prior structural knowledge of the structure of the complex. The analytical AGBNP2 model is found to underestimate the magnitude of the hydrophobic driving force towards binding in these systems characterized by loosely packed protein-ligand binding interfaces. Rescoring of the binding energies using a numerical surface area model corrects this deficiency. This study illustrates the complex interplay between energy models, exploration of conformational space, and free energy estimators needed to obtain robust estimates from binding free energy calculations. PMID:22368530

The HAMP Signal Relay Domain Adopts Multiple Conformational States through Collective Piston and Tilt Motions

PubMed Central

Zhu, Lizhe; Bolhuis, Peter G.; Vreede, Jocelyne

2013-01-01

The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP. PMID:23468603

Leap-dynamics: efficient sampling of conformational space of proteins and peptides in solution.

PubMed

Kleinjung, J; Bayley, P; Fraternali, F

2000-03-31

A molecular simulation scheme, called Leap-dynamics, that provides efficient sampling of protein conformational space in solution is presented. The scheme is a combined approach using a fast sampling method, imposing conformational 'leaps' to force the system over energy barriers, and molecular dynamics (MD) for refinement. The presence of solvent is approximated by a potential of mean force depending on the solvent accessible surface area. The method has been successfully applied to N-acetyl-L-alanine-N-methylamide (alanine dipeptide), sampling experimentally observed conformations inaccessible to MD alone under the chosen conditions. The method predicts correctly the increased partial flexibility of the mutant Y35G compared to native bovine pancreatic trypsin inhibitor. In particular, the improvement over MD consists of the detection of conformational flexibility that corresponds closely to slow motions identified by nuclear magnetic resonance techniques.

Balancing exploration and exploitation in population-based sampling improves fragment-based de novo protein structure prediction.

PubMed

Simoncini, David; Schiex, Thomas; Zhang, Kam Y J

2017-05-01

Conformational search space exploration remains a major bottleneck for protein structure prediction methods. Population-based meta-heuristics typically enable the possibility to control the search dynamics and to tune the balance between local energy minimization and search space exploration. EdaFold is a fragment-based approach that can guide search by periodically updating the probability distribution over the fragment libraries used during model assembly. We implement the EdaFold algorithm as a Rosetta protocol and provide two different probability update policies: a cluster-based variation (EdaRose c ) and an energy-based one (EdaRose en ). We analyze the search dynamics of our new Rosetta protocols and show that EdaRose c is able to provide predictions with lower C αRMSD to the native structure than EdaRose en and Rosetta AbInitio Relax protocol. Our software is freely available as a C++ patch for the Rosetta suite and can be downloaded from http://www.riken.jp/zhangiru/software/. Our protocols can easily be extended in order to create alternative probability update policies and generate new search dynamics. Proteins 2017; 85:852-858. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Crossing symmetry in alpha space

NASA Astrophysics Data System (ADS)

Hogervorst, Matthijs; van Rees, Balt C.

2017-11-01

We initiate the study of the conformal bootstrap using Sturm-Liouville theory, specializing to four-point functions in one-dimensional CFTs. We do so by decomposing conformal correlators using a basis of eigenfunctions of the Casimir which are labeled by a complex number α. This leads to a systematic method for computing conformal block decompositions. Analyzing bootstrap equations in alpha space turns crossing symmetry into an eigenvalue problem for an integral operator K. The operator K is closely related to the Wilson transform, and some of its eigenfunctions can be found in closed form.

A flexible docking scheme to explore the binding selectivity of PDZ domains.

PubMed

Gerek, Z Nevin; Ozkan, S Banu

2010-05-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 A. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

A flexible docking scheme to explore the binding selectivity of PDZ domains

PubMed Central

Gerek, Z Nevin; Ozkan, S Banu

2010-01-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using RosettaLigand, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately. PMID:20196074

Gluon amplitudes as 2 d conformal correlators

NASA Astrophysics Data System (ADS)

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

2017-10-01

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

Rapid sampling of local minima in protein energy surface and effective reduction through a multi-objective filter

PubMed Central

2013-01-01

Background Many problems in protein modeling require obtaining a discrete representation of the protein conformational space as an ensemble of conformations. In ab-initio structure prediction, in particular, where the goal is to predict the native structure of a protein chain given its amino-acid sequence, the ensemble needs to satisfy energetic constraints. Given the thermodynamic hypothesis, an effective ensemble contains low-energy conformations which are similar to the native structure. The high-dimensionality of the conformational space and the ruggedness of the underlying energy surface currently make it very difficult to obtain such an ensemble. Recent studies have proposed that Basin Hopping is a promising probabilistic search framework to obtain a discrete representation of the protein energy surface in terms of local minima. Basin Hopping performs a series of structural perturbations followed by energy minimizations with the goal of hopping between nearby energy minima. This approach has been shown to be effective in obtaining conformations near the native structure for small systems. Recent work by us has extended this framework to larger systems through employment of the molecular fragment replacement technique, resulting in rapid sampling of large ensembles. Methods This paper investigates the algorithmic components in Basin Hopping to both understand and control their effect on the sampling of near-native minima. Realizing that such an ensemble is reduced before further refinement in full ab-initio protocols, we take an additional step and analyze the quality of the ensemble retained by ensemble reduction techniques. We propose a novel multi-objective technique based on the Pareto front to filter the ensemble of sampled local minima. Results and conclusions We show that controlling the magnitude of the perturbation allows directly controlling the distance between consecutively-sampled local minima and, in turn, steering the exploration towards conformations near the native structure. For the minimization step, we show that the addition of Metropolis Monte Carlo-based minimization is no more effective than a simple greedy search. Finally, we show that the size of the ensemble of sampled local minima can be effectively and efficiently reduced by a multi-objective filter to obtain a simpler representation of the probed energy surface. PMID:24564970

Conformal invariants associated to a measure.

PubMed

Chang, Sun-Yung A; Gursky, Matthew J; Yang, Paul

2006-02-21

In this note, we study some conformal invariants of a Riemannian manifold (M(n), g) equipped with a smooth measure m. In particular, we show that there is a natural definition of the Ricci and scalar curvatures associated to such a space, both of which are conformally invariant. We also adapt the methods of Fefferman and Graham [Fefferman, C. & Graham, C. R. (1985) Astérisque, Numero Hors Serie, 95-116] and Graham, Jenne, Mason, and Sparling [Graham, C. R., Jenne, R., Mason, L. J., & Sparling, G. A. J. (1992) J. London Math. Soc. 46, 557-565] to construct families of conformally covariant operators defined on these spaces. Certain variational problems in this setting are considered, including a generalization of the Einstein-Hilbert action.

IR-UV spectroscopy of jet-cooled 1-indanol: Restriction of the conformational space by hydration

NASA Astrophysics Data System (ADS)

Bouchet, Aude; Altnöder, Jonas; Broquier, Michel; Zehnacker, Anne

2014-11-01

The effect of hydration on a flexible amphiphilic molecule has been studied on the example of 1-hydroxyindan (1-indanol). Studies in jet-cooled conditions by means of resonance-enhanced two-photon ionization and IR-UV double resonance experiments show that the mono-hydrate 1-indanol(H2O) is formed in a dominant isomer, as well as the di-hydrate 1-indanol(H2O)2. 1-Indanol(H2O) favors a cooperative hydrogen bond pattern with -OH⋯O(H)-H⋯π topology, while 1-indanol(H2O)2 forms a cyclic hydrogen bond network with three OH⋯O interactions. The single conformation observed for the hydrates contrasts with the bare molecule which shows two dominant conformations, with the hydroxyl in axial or in equatorial position, respectively. Hydration therefore results in a restriction of the conformational space and conformational locking.

Analysis of the new health management based on health internet of things and cloud computing

NASA Astrophysics Data System (ADS)

Liu, Shaogang

2018-05-01

With the development and application of Internet of things and cloud technology in the medical field, it provides a higher level of exploration space for human health management. By analyzing the Internet of things technology and cloud technology, this paper studies a new form of health management system which conforms to the current social and technical level, and explores its system architecture, system characteristics and application. The new health management platform for networking and cloud can achieve the real-time monitoring and prediction of human health through a variety of sensors and wireless networks based on information and can be transmitted to the monitoring system, and then through the software analysis model, and gives the targeted prevention and treatment measures, to achieve real-time, intelligent health management.

Cyndi: a multi-objective evolution algorithm based method for bioactive molecular conformational generation.

PubMed

Liu, Xiaofeng; Bai, Fang; Ouyang, Sisheng; Wang, Xicheng; Li, Honglin; Jiang, Hualiang

2009-03-31

Conformation generation is a ubiquitous problem in molecule modelling. Many applications require sampling the broad molecular conformational space or perceiving the bioactive conformers to ensure success. Numerous in silico methods have been proposed in an attempt to resolve the problem, ranging from deterministic to non-deterministic and systemic to stochastic ones. In this work, we described an efficient conformation sampling method named Cyndi, which is based on multi-objective evolution algorithm. The conformational perturbation is subjected to evolutionary operation on the genome encoded with dihedral torsions. Various objectives are designated to render the generated Pareto optimal conformers to be energy-favoured as well as evenly scattered across the conformational space. An optional objective concerning the degree of molecular extension is added to achieve geometrically extended or compact conformations which have been observed to impact the molecular bioactivity (J Comput -Aided Mol Des 2002, 16: 105-112). Testing the performance of Cyndi against a test set consisting of 329 small molecules reveals an average minimum RMSD of 0.864 A to corresponding bioactive conformations, indicating Cyndi is highly competitive against other conformation generation methods. Meanwhile, the high-speed performance (0.49 +/- 0.18 seconds per molecule) renders Cyndi to be a practical toolkit for conformational database preparation and facilitates subsequent pharmacophore mapping or rigid docking. The copy of precompiled executable of Cyndi and the test set molecules in mol2 format are accessible in Additional file 1. On the basis of MOEA algorithm, we present a new, highly efficient conformation generation method, Cyndi, and report the results of validation and performance studies comparing with other four methods. The results reveal that Cyndi is capable of generating geometrically diverse conformers and outperforms other four multiple conformer generators in the case of reproducing the bioactive conformations against 329 structures. The speed advantage indicates Cyndi is a powerful alternative method for extensive conformational sampling and large-scale conformer database preparation.

Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

PubMed

Tang, Jun; Jones, Stacey A; Jeffery, Jerry L; Miranda, Sonia R; Galardi, Cristin M; Irlbeck, David M; Brown, Kevin W; McDanal, Charlene B; Han, Nianhe; Gao, Daxin; Wu, Yongyong; Shen, Bin; Liu, Chunyu; Xi, Caiming; Yang, Heping; Li, Rui; Yu, Yajun; Sun, Yufei; Jin, Zhimin; Wang, Erjuan; Johns, Brian A

2014-01-01

A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

Power and Thermal Technologies for Air and Space. Delivery Order 0003: Development of High-Performance Solid Oxide Fuel Cell (SOFC) Technology for Remote Base Applications

DTIC Science & Technology

2007-08-01

In recent years, however, anode supported electrode conformations with thin film electrolytes have been heavily explored because they are capable ...further clarify relationship between interlayer morphology and cell performance will be a subject of a future study. Figure 2. SEM Images of SOFC...CPE B1B CPE B2B RB4B CPE B3B R1 R2 10 and R3, which also exhibited a constant slope over the test range, averaged 0.1 +/- 0.02 and 0.9 +/- 0.01

(φ,ψ)2-motifs: a purely conformation-based, fine-grained enumeration of protein parts at the two-residue level

PubMed Central

Hollingsworth, Scott A.; Lewis, Matthew C.; Berkholz, Donald S.; Wong, Weng-Keen; Karplus, P. Andrew

2011-01-01

A deep understanding of protein structure benefits from the use of a variety of classification strategies that enhance our ability to effectively describe local patterns of conformation. Here, we use a clustering algorithm to analyze 76,533 all-trans segments from protein structures solved at 1.2 Å resolution or better to create a purely φ,ψ-based comprehensive empirical categorization of common conformations adopted by two adjacent φ,ψ-pairs (i.e. (φ,ψ)2-motifs). The clustering algorithm works in an origin-shifted 4-dimensional space based on the two φ,ψ-pairs to yield a parameter-dependent list of (φ,ψ)2-motifs – in order of their prominence. The results are remarkably distinct from and complementary to the standard hydrogen-bond centered view of secondary structure. New insights include an unprecedented level of precision in describing the φ,ψ-angles of both previously known and novel motifs, an ordering of these motifs by their population density, a data-driven recommendation that the standard Cαi…Cαi+3 < 7 Å criteria for defining turns be changed to 6.5 Å, an identification of β-strand and turn capping motifs, and of conformational capping by residues in the polypeptide-II (PII) conformation. We further document that the conformational preferences of a residue are substantially influenced by the conformation of its neighbors, and suggest that accounting for these dependencies will improve protein modeling accuracy. Although the CUEVAS-4D(r10є14) “parts list” presented here is only an initial exploration of the complex (φ,ψ)2-landscape of proteins, it shows there is value to be had from this approach and opens the door to more in-depth characterizations at the (φ,ψ)2-level and at higher dimensions. PMID:22198294

(φ,ψ)₂ motifs: a purely conformation-based fine-grained enumeration of protein parts at the two-residue level.

PubMed

Hollingsworth, Scott A; Lewis, Matthew C; Berkholz, Donald S; Wong, Weng-Keen; Karplus, P Andrew

2012-02-10

A deep understanding of protein structure benefits from the use of a variety of classification strategies that enhance our ability to effectively describe local patterns of conformation. Here, we use a clustering algorithm to analyze 76,533 all-trans segments from protein structures solved at 1.2 Å resolution or better to create a purely φ,ψ-based comprehensive empirical categorization of common conformations adopted by two adjacent φ,ψ pairs (i.e., (φ,ψ)(2) motifs). The clustering algorithm works in an origin-shifted four-dimensional space based on the two φ,ψ pairs to yield a parameter-dependent list of (φ,ψ)(2) motifs, in order of their prominence. The results are remarkably distinct from and complementary to the standard hydrogen-bond-centered view of secondary structure. New insights include an unprecedented level of precision in describing the φ,ψ angles of both previously known and novel motifs, ordering of these motifs by their population density, a data-driven recommendation that the standard C(α(i))…C(α(i+3))<7 Å criteria for defining turns be changed to 6.5 Å, identification of β-strand and turn capping motifs, and identification of conformational capping by residues in polypeptide II conformation. We further document that the conformational preferences of a residue are substantially influenced by the conformation of its neighbors, and we suggest that accounting for these dependencies will improve protein modeling accuracy. Although the CUEVAS-4D(r(10)є(14)) 'parts list' presented here is only an initial exploration of the complex (φ,ψ)(2) landscape of proteins, it shows that there is value to be had from this approach, and it opens the door to more in-depth characterizations at the (φ,ψ)(2) level and at higher dimensions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Boundary kinematic space

DOE PAGES

Karch, Andreas; Sully, James; Uhlemann, Christoph F.; ...

2017-08-10

We extend kinematic space to a simple scenario where the state is not fixed by conformal invariance: the vacuum of a conformal field theory with a boundary (bCFT). We identify the kinematic space associated with the boundary operator product expansion (bOPE) as a subspace of the full kinematic space. In addition, we establish representations of the corresponding bOPE blocks in a dual gravitational description. We show how the new kinematic dictionary and the dynamical data in bOPE allows one to reconstruct the bulk geometry. This is evidence that kinematic space may be a useful construction for understanding bulk physics beyondmore » just kinematics.« less

Boundary kinematic space

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

Karch, Andreas; Sully, James; Uhlemann, Christoph F.

We extend kinematic space to a simple scenario where the state is not fixed by conformal invariance: the vacuum of a conformal field theory with a boundary (bCFT). We identify the kinematic space associated with the boundary operator product expansion (bOPE) as a subspace of the full kinematic space. In addition, we establish representations of the corresponding bOPE blocks in a dual gravitational description. We show how the new kinematic dictionary and the dynamical data in bOPE allows one to reconstruct the bulk geometry. This is evidence that kinematic space may be a useful construction for understanding bulk physics beyondmore » just kinematics.« less

Thickenings and conformal gravity

NASA Astrophysics Data System (ADS)

Lebrun, Claude

1991-07-01

A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason [B-M].

Unveiling Inherent Degeneracies in Determining Population-weighted Ensembles of Inter-domain Orientational Distributions Using NMR Residual Dipolar Couplings: Application to RNA Helix Junction Helix Motifs

PubMed Central

Yang, Shan; Al-Hashimi, Hashim M.

2016-01-01

A growing number of studies employ time-averaged experimental data to determine dynamic ensembles of biomolecules. While it is well known that different ensembles can satisfy experimental data to within error, the extent and nature of these degeneracies, and their impact on the accuracy of the ensemble determination remains poorly understood. Here, we use simulations and a recently introduced metric for assessing ensemble similarity to explore degeneracies in determining ensembles using NMR residual dipolar couplings (RDCs) with specific application to A-form helices in RNA. Various target ensembles were constructed representing different domain-domain orientational distributions that are confined to a topologically restricted (<10%) conformational space. Five independent sets of ensemble averaged RDCs were then computed for each target ensemble and a ‘sample and select’ scheme used to identify degenerate ensembles that satisfy RDCs to within experimental uncertainty. We find that ensembles with different ensemble sizes and that can differ significantly from the target ensemble (by as much as ΣΩ ~ 0.4 where ΣΩ varies between 0 and 1 for maximum and minimum ensemble similarity, respectively) can satisfy the ensemble averaged RDCs. These deviations increase with the number of unique conformers and breadth of the target distribution, and result in significant uncertainty in determining conformational entropy (as large as 5 kcal/mol at T = 298 K). Nevertheless, the RDC-degenerate ensembles are biased towards populated regions of the target ensemble, and capture other essential features of the distribution, including the shape. Our results identify ensemble size as a major source of uncertainty in determining ensembles and suggest that NMR interactions such as RDCs and spin relaxation, on their own, do not carry the necessary information needed to determine conformational entropy at a useful level of precision. The framework introduced here provides a general approach for exploring degeneracies in ensemble determination for different types of experimental data. PMID:26131693

Efficiently sampling conformations and pathways using the concurrent adaptive sampling (CAS) algorithm

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

Ahn, Surl-Hee; Grate, Jay W.; Darve, Eric F.

Molecular dynamics (MD) simulations are useful in obtaining thermodynamic and kinetic properties of bio-molecules but are limited by the timescale barrier, i.e., we may be unable to efficiently obtain properties because we need to run microseconds or longer simulations using femtoseconds time steps. While there are several existing methods to overcome this timescale barrier and efficiently sample thermodynamic and/or kinetic properties, problems remain in regard to being able to sample un- known systems, deal with high-dimensional space of collective variables, and focus the computational effort on slow timescales. Hence, a new sampling method, called the “Concurrent Adaptive Sampling (CAS) algorithm,”more » has been developed to tackle these three issues and efficiently obtain conformations and pathways. The method is not constrained to use only one or two collective variables, unlike most reaction coordinate-dependent methods. Instead, it can use a large number of collective vari- ables and uses macrostates (a partition of the collective variable space) to enhance the sampling. The exploration is done by running a large number of short simula- tions, and a clustering technique is used to accelerate the sampling. In this paper, we introduce the new methodology and show results from two-dimensional models and bio-molecules, such as penta-alanine and triazine polymer« less

Structural basis of regulation and substrate specificity of protein kinase CK2 deduced from the modeling of protein-protein interactions

PubMed Central

Rekha, Nambudiry; Srinivasan, N

2003-01-01

Background Protein Kinase Casein Kinase 2 (PKCK2) is an ubiquitous Ser/Thr kinase expressed in all eukaryotes. It phosphorylates a number of proteins involved in various cellular processes. PKCK2 holoenzyme is catalytically active tetramer, composed of two homologous or identical and constitutively active catalytic (α) and two identical regulatory (β) subunits. The tetramer cannot phosphorylate some substrates that can be phosphorylated by PKCK2α in isolation. The present work explores the structural basis of this feature using computational analysis and modeling. Results We have initially built a model of PKCK2α bound to a substrate peptide with a conformation identical to that of the substrates in the available crystal structures of other kinases complexed with the substrates/ pseudosubstrates. In this model however, the fourth acidic residue in the consensus pattern of the substrate, S/T-X-X-D/E where S/T is the phosphorylation site, did not result in interaction with the active form of PKCK2α and is highly solvent exposed. Interaction of the acidic residue is observed if the substrate peptide adopts conformations as seen in β turn, α helix, or 310 helices. This type of conformation is observed and accommodated well by PKCK2α in calmodulin where the phosphorylation site is at the central helix. PP2A carries sequence patterns for PKCK2α phosphorylation. While the possibility of PP2A being phosphorylated by PKCK2 has been raised in the literature we use the model of PP2A to generate a model of PP2A-PKCK2α complex. PKCK2β undergoes phosphorylation by holoenzyme at the N-terminal region, and is accommodated very well in the limited space available at the substrate-binding site of the holoenzyme while the space is insufficient to accommodate the binding of PP2A or calmodulin in the holoenzyme. Conclusion Charge and shape complimentarity seems to play a role in substrate recognition and binding to PKCK2α, along with the consensus pattern. The detailed conformation of the substrate peptide binding to PKCK2 differs from the conformation of the substrate/pseudo substrate peptide that is bound to other kinases in the crystal structures reported. The ability of holoenzyme to phosphorylate substrate proteins seems to depend on the accessibility of the P-site in limited space available in holoenzyme. PMID:12740046

Dimensionality of Social Influence.

ERIC Educational Resources Information Center

Stricker, Lawrence J.; Jackson, Douglas N.

The research reported in this study explores two problematic avenues of conformity research: (1) the widely assumed generality of diverse measures of group pressure, and (2) the dimensionality of conformity, anticonformity, and independence. These two conformity situations, present and nonpresent norm groups, used two tasks (an objective counting…

Exploration of the kinetic and thermochemical abilities for the free radical scavenging of two quercetin conformers

NASA Astrophysics Data System (ADS)

Mendoza-Wilson, Ana María; Sotelo-Mundo, Rogerio R.; Balandrán-Quintana, René R.; Glossman-Mitnik, Daniel; Sántiz-gómez, Marco a.; García-orozco, karina D.

2010-09-01

Quercetin has a great antioxidant potential due to its large capacity for free radical scavenging. Although it has been found that conformational changes have a profound effect on its chemical properties, there are few studies where conformation is associated with the antioxidant activity. The aim of this investigation was to explore the kinetic and the thermochemical abilities of two quercetin conformers for the free radical scavenging. Quercetin unhydrate (QUH) and quercetin dihydrate (QDH) conformers were studied employing 2,2-diphenyl-1-picrylhydrazyl (DPPH rad ) as in vitro radical model, and catechol and 4-hexyl-resorcinol as reference systems, for identifying the oxidation products. QDH showed to be most effective under conditions of free radical excess, while QUH was most effective when the flavonoid far exceeds the concentration of free radical. It was found, by means of experimental and computational methods, that 4'-OH, 3-OH and 3'-OH are the main reactive sites of both conformers.

Generalized conformal structure, dilaton gravity and SYK

NASA Astrophysics Data System (ADS)

Taylor, Marika

2018-01-01

A theory admits generalized conformal structure if the only scale in the quantum theory is set by a dimensionful coupling. SYK is an example of a theory with generalized conformal structure and in this paper we investigate the consequences of this structure for correlation functions and for the holographic realization of SYK. The Ward identities associated with the generalized conformal structure of SYK are implemented holographically in gravity/multiple scalar theories, which always have a parent AdS3 origin. For questions involving only the graviton/running scalar sector, one can always describe the bulk running in terms of a single scalar but multiple running scalars are in general needed once one includes the bulk fields corresponding to all SYK operators. We then explore chaos in holographic theories with generalized conformal structure. The four point function explored by Maldacena, Shenker and Stanford exhibits exactly the same chaotic behaviour in any such theory as in holographic realizations of conformal theories i.e. the dimensionful coupling scale does not affect the chaotic exponential growth.

Mapping the Conformation Space of Wildtype and Mutant H-Ras with a Memetic, Cellular, and Multiscale Evolutionary Algorithm

PubMed Central

Clausen, Rudy; Ma, Buyong; Nussinov, Ruth; Shehu, Amarda

2015-01-01

An important goal in molecular biology is to understand functional changes upon single-point mutations in proteins. Doing so through a detailed characterization of structure spaces and underlying energy landscapes is desirable but continues to challenge methods based on Molecular Dynamics. In this paper we propose a novel algorithm, SIfTER, which is based instead on stochastic optimization to circumvent the computational challenge of exploring the breadth of a protein’s structure space. SIfTER is a data-driven evolutionary algorithm, leveraging experimentally-available structures of wildtype and variant sequences of a protein to define a reduced search space from where to efficiently draw samples corresponding to novel structures not directly observed in the wet laboratory. The main advantage of SIfTER is its ability to rapidly generate conformational ensembles, thus allowing mapping and juxtaposing landscapes of variant sequences and relating observed differences to functional changes. We apply SIfTER to variant sequences of the H-Ras catalytic domain, due to the prominent role of the Ras protein in signaling pathways that control cell proliferation, its well-studied conformational switching, and abundance of documented mutations in several human tumors. Many Ras mutations are oncogenic, but detailed energy landscapes have not been reported until now. Analysis of SIfTER-computed energy landscapes for the wildtype and two oncogenic variants, G12V and Q61L, suggests that these mutations cause constitutive activation through two different mechanisms. G12V directly affects binding specificity while leaving the energy landscape largely unchanged, whereas Q61L has pronounced, starker effects on the landscape. An implementation of SIfTER is made available at http://www.cs.gmu.edu/~ashehu/?q=OurTools. We believe SIfTER is useful to the community to answer the question of how sequence mutations affect the function of a protein, when there is an abundance of experimental structures that can be exploited to reconstruct an energy landscape that would be computationally impractical to do via Molecular Dynamics. PMID:26325505

Compactification on phase space

NASA Astrophysics Data System (ADS)

Lovelady, Benjamin; Wheeler, James

2016-03-01

A major challenge for string theory is to understand the dimensional reduction required for comparison with the standard model. We propose reducing the dimension of the compactification by interpreting some of the extra dimensions as the energy-momentum portion of a phase-space. Such models naturally arise as generalized quotients of the conformal group called biconformal spaces. By combining the standard Kaluza-Klein approach with such a conformal gauge theory, we may start from the conformal group of an n-dimensional Euclidean space to form a 2n-dimensional quotient manifold with symplectic structure. A pair of involutions leads naturally to two n-dimensional Lorentzian manifolds. For n = 5, this leaves only two extra dimensions, with a countable family of possible compactifications and an SO(5) Yang-Mills field on the fibers. Starting with n=6 leads to 4-dimensional compactification of the phase space. In the latter case, if the two dimensions each from spacetime and momentum space are compactified onto spheres, then there is an SU(2)xSU(2) (left-right symmetric electroweak) field between phase and configuration space and an SO(6) field on the fibers. Such a theory, with minor additional symmetry breaking, could contain all parts of the standard model.

Molecular Dynamic Simulation of Space and Earth-Grown Crystal Structures of Thermostable T1 Lipase Geobacillus zalihae Revealed a Better Structure.

PubMed

Ishak, Siti Nor Hasmah; Aris, Sayangku Nor Ariati Mohamad; Halim, Khairul Bariyyah Abd; Ali, Mohd Shukuri Mohamad; Leow, Thean Chor; Kamarudin, Nor Hafizah Ahmad; Masomian, Malihe; Rahman, Raja Noor Zaliha Raja Abd

2017-09-25

Less sedimentation and convection in a microgravity environment has become a well-suited condition for growing high quality protein crystals. Thermostable T1 lipase derived from bacterium Geobacillus zalihae has been crystallized using the counter diffusion method under space and earth conditions. Preliminary study using YASARA molecular modeling structure program for both structures showed differences in number of hydrogen bond, ionic interaction, and conformation. The space-grown crystal structure contains more hydrogen bonds as compared with the earth-grown crystal structure. A molecular dynamics simulation study was used to provide insight on the fluctuations and conformational changes of both T1 lipase structures. The analysis of root mean square deviation (RMSD), radius of gyration, and root mean square fluctuation (RMSF) showed that space-grown structure is more stable than the earth-grown structure. Space-structure also showed more hydrogen bonds and ion interactions compared to the earth-grown structure. Further analysis also revealed that the space-grown structure has long-lived interactions, hence it is considered as the more stable structure. This study provides the conformational dynamics of T1 lipase crystal structure grown in space and earth condition.

Entanglement entropy of black holes and anti-de Sitter space/conformal-field-theory correspondence.

PubMed

Solodukhin, Sergey N

2006-11-17

A recent proposal by Ryu and Takayanagi for a holographic interpretation of entanglement entropy in conformal field theories dual to supergravity on anti-de Sitter space is generalized to include entanglement entropy of black holes living on the boundary of anti-de Sitter space. The generalized proposal is verified in boundary dimensions d=2 and d=4 for both the uv-divergent and uv-finite terms. In dimension d=4 an expansion of entanglement entropy in terms of size L of the subsystem outside the black hole is considered. A new term in the entropy of dual strongly coupled conformal-field theory, which universally grows as L(2)lnL and is proportional to the value of the obstruction tensor at the black hole horizon, is predicted.

Conformal higher spin theory and twistor space actions

NASA Astrophysics Data System (ADS)

Hähnel, Philipp; McLoughlin, Tristan

2017-12-01

We consider the twistor description of conformal higher spin theories and give twistor space actions for the self-dual sector of theories with spin greater than two that produce the correct flat space-time spectrum. We identify a ghost-free subsector, analogous to the embedding of Einstein gravity with cosmological constant in Weyl gravity, which generates the unique spin-s three-point anti-MHV amplitude consistent with Poincaré invariance and helicity constraints. By including interactions between the infinite tower of higher-spin fields we give a geometric interpretation to the twistor equations of motion as the integrability condition for a holomorphic structure on an infinite jet bundle. Finally, we conjecture anti-self-dual interaction terms which give an implicit definition of a twistor action for the full conformal higher spin theory.

Very special conformal field theories and their holographic duals

NASA Astrophysics Data System (ADS)

Nakayama, Yu

2018-03-01

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

Conformational Entropy of Intrinsically Disordered Proteins from Amino Acid Triads

PubMed Central

Baruah, Anupaul; Rani, Pooja; Biswas, Parbati

2015-01-01

This work quantitatively characterizes intrinsic disorder in proteins in terms of sequence composition and backbone conformational entropy. Analysis of the normalized relative composition of the amino acid triads highlights a distinct boundary between globular and disordered proteins. The conformational entropy is calculated from the dihedral angles of the middle amino acid in the amino acid triad for the conformational ensemble of the globular, partially and completely disordered proteins relative to the non-redundant database. Both Monte Carlo (MC) and Molecular Dynamics (MD) simulations are used to characterize the conformational ensemble of the representative proteins of each group. The results show that the globular proteins span approximately half of the allowed conformational states in the Ramachandran space, while the amino acid triads in disordered proteins sample the entire range of the allowed dihedral angle space following Flory’s isolated-pair hypothesis. Therefore, only the sequence information in terms of the relative amino acid triad composition may be sufficient to predict protein disorder and the backbone conformational entropy, even in the absence of well-defined structure. The predicted entropies are found to agree with those calculated using mutual information expansion and the histogram method. PMID:26138206

Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules.

PubMed

Iuzzolino, Luca; Reilly, Anthony M; McCabe, Patrick; Price, Sarah L

2017-10-10

Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles.

Structural alphabets derived from attractors in conformational space

PubMed Central

2010-01-01

Background The hierarchical and partially redundant nature of protein structures justifies the definition of frequently occurring conformations of short fragments as 'states'. Collections of selected representatives for these states define Structural Alphabets, describing the most typical local conformations within protein structures. These alphabets form a bridge between the string-oriented methods of sequence analysis and the coordinate-oriented methods of protein structure analysis. Results A Structural Alphabet has been derived by clustering all four-residue fragments of a high-resolution subset of the protein data bank and extracting the high-density states as representative conformational states. Each fragment is uniquely defined by a set of three independent angles corresponding to its degrees of freedom, capturing in simple and intuitive terms the properties of the conformational space. The fragments of the Structural Alphabet are equivalent to the conformational attractors and therefore yield a most informative encoding of proteins. Proteins can be reconstructed within the experimental uncertainty in structure determination and ensembles of structures can be encoded with accuracy and robustness. Conclusions The density-based Structural Alphabet provides a novel tool to describe local conformations and it is specifically suitable for application in studies of protein dynamics. PMID:20170534

Transition paths of Met-enkephalin from Markov state modeling of a molecular dynamics trajectory.

PubMed

Banerjee, Rahul; Cukier, Robert I

2014-03-20

Conformational states and their interconversion pathways of the zwitterionic form of the pentapeptide Met-enkephalin (MetEnk) are identified. An explicit solvent molecular dynamics (MD) trajectory is used to construct a Markov state model (MSM) based on dihedral space clustering of the trajectory, and transition path theory (TPT) is applied to identify pathways between open and closed conformers. In the MD trajectory, only four of the eight backbone dihedrals exhibit bistable behavior. Defining a conformer as the string XXXX with X = "+" or "-" denoting, respectively, positive or negative values of a given dihedral angle and obtaining the populations of these conformers shows that only four conformers are highly populated, implying a strong correlation among these dihedrals. Clustering in dihedral space to construct the MSM finds the same four bistable dihedral angles. These state populations are very similar to those found directly from the MD trajectory. TPT is used to obtain pathways, parametrized by committor values, in dihedral state space that are followed in transitioning from closed to open states. Pathway costs are estimated by introducing a kinetics-based procedure that orders pathways from least (shortest) to greater cost paths. The least costly pathways in dihedral space are found to only involve the same XXXX set of dihedral angles, and the conformers accessed in the closed to open transition pathways are identified. For these major pathways, a correlation between reaction path progress (committors) and the end-to-end distance is identified. A dihedral space principal component analysis of the MD trajectory shows that the first three modes capture most of the overall fluctuation, and pick out the same four dihedrals having essentially all the weight in those modes. A MSM based on root-mean-square backbone clustering was also carried out, with good agreement found with dihedral clustering for the static information, but with results that differ significantly for the pathway analysis.

Predicting RNA 3D structure using a coarse-grain helix-centered model

PubMed Central

Kerpedjiev, Peter; Höner zu Siederdissen, Christian; Hofacker, Ivo L.

2015-01-01

A 3D model of RNA structure can provide information about its function and regulation that is not possible with just the sequence or secondary structure. Current models suffer from low accuracy and long running times and either neglect or presume knowledge of the long-range interactions which stabilize the tertiary structure. Our coarse-grained, helix-based, tertiary structure model operates with only a few degrees of freedom compared with all-atom models while preserving the ability to sample tertiary structures given a secondary structure. It strikes a balance between the precision of an all-atom tertiary structure model and the simplicity and effectiveness of a secondary structure representation. It provides a simplified tool for exploring global arrangements of helices and loops within RNA structures. We provide an example of a novel energy function relying only on the positions of stems and loops. We show that coupling our model to this energy function produces predictions as good as or better than the current state of the art tools. We propose that given the wide range of conformational space that needs to be explored, a coarse-grain approach can explore more conformations in less iterations than an all-atom model coupled to a fine-grain energy function. Finally, we emphasize the overarching theme of providing an ensemble of predicted structures, something which our tool excels at, rather than providing a handful of the lowest energy structures. PMID:25904133

Protein stability and dynamics influenced by ligands in extremophilic complexes - a molecular dynamics investigation.

PubMed

Khan, Sara; Farooq, Umar; Kurnikova, Maria

2017-08-22

In this study, we explore the structural and dynamic adaptations of the Tryptophan synthase α-subunit in a ligand bound state in psychrophilic, mesophilic and hyperthermophilic organisms at different temperatures by MD simulations. We quantify the global and local fluctuations in the 40 ns time scale by analyzing the root mean square deviation/fluctuations. The distinct behavior of the active site and loop 6 is observed with the elevation of temperature. Protein stability relies more on electrostatic interactions, and these interactions might be responsible for the stability of varying temperature evolved proteins. The paper also focuses on the effect of temperature on protein dynamics and stability governed by the distinct behavior of the ligand associated with its retention, binding and dissociation over the course of time. The integration of principle component analysis and a free energy landscape was useful in identifying the conformational space accessible to ligand bound homologues and how the presence of the ligand alters the conformational and dynamic properties of the protein.

Anti-AIDS agents 81. Design, synthesis, and structure-activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors.

PubMed

Qian, Keduo; Kuo, Reen-Yun; Chen, Chin-Ho; Huang, Li; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

2010-04-22

In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also designed to better understand the contribution of the C-3' dimethyl group of bevirimat (2), the first-in-class HIV maturation inhibitor, which is currently in phase IIb clinical trials. In addition, another triterpene skeleton, moronic acid (MA, 3), was also employed to study the influence of the backbone and the C-3 modification toward the anti-HIV activity of this compound class. This study enabled us to better understand the structure-activity relationships (SAR) of triterpene-derived anti-HIV agents and led to the design and synthesis of compound 12 (EC(50): 0.0006 microM), which displayed slightly better activity than 2 as a HIV-1 maturation inhibitor.

Subtle Monte Carlo Updates in Dense Molecular Systems.

PubMed

Bottaro, Sandro; Boomsma, Wouter; E Johansson, Kristoffer; Andreetta, Christian; Hamelryck, Thomas; Ferkinghoff-Borg, Jesper

2012-02-14

Although Markov chain Monte Carlo (MC) simulation is a potentially powerful approach for exploring conformational space, it has been unable to compete with molecular dynamics (MD) in the analysis of high density structural states, such as the native state of globular proteins. Here, we introduce a kinetic algorithm, CRISP, that greatly enhances the sampling efficiency in all-atom MC simulations of dense systems. The algorithm is based on an exact analytical solution to the classic chain-closure problem, making it possible to express the interdependencies among degrees of freedom in the molecule as correlations in a multivariate Gaussian distribution. We demonstrate that our method reproduces structural variation in proteins with greater efficiency than current state-of-the-art Monte Carlo methods and has real-time simulation performance on par with molecular dynamics simulations. The presented results suggest our method as a valuable tool in the study of molecules in atomic detail, offering a potential alternative to molecular dynamics for probing long time-scale conformational transitions.

Structural study of piracetam polymorphs and cocrystals: crystallography redetermination and quantum mechanics calculations.

PubMed

Tilborg, Anaëlle; Jacquemin, Denis; Norberg, Bernadette; Perpète, Eric; Michaux, Catherine; Wouters, Johan

2011-12-01

Pharmaceutical compounds are mostly developed as solid dosage forms containing a single-crystal form. It means that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. In this context, piracetam, a pharmaceutical molecule known since the sixties for its nootropic properties, is considered in the present work. This molecule is analyzed using several experimental and theoretical approaches. First, the conformational space of the molecule has been systematically explored by performing a quantum mechanics scan of the two most relevant dihedral angles of the lateral chain. The predicted stable conformations have been compared to all the reported experimental geometries retrieved from the Cambridge Structural Database (CSD) covering polymorphs and cocrystals structures. In parallel, different batches of powders have been recrystallized. Under specific conditions, single crystals of polymorph (III) of piracetam have been obtained, an outcome confirmed by crystallographic analysis. © 2011 International Union of Crystallography. Printed in Singapore – all rights reserved.

Enhanced conformational sampling via novel variable transformations and very large time-step molecular dynamics

NASA Astrophysics Data System (ADS)

Tuckerman, Mark

2006-03-01

One of the computational grand challenge problems is to develop methodology capable of sampling conformational equilibria in systems with rough energy landscapes. If met, many important problems, most notably protein folding, could be significantly impacted. In this talk, two new approaches for addressing this problem will be presented. First, it will be shown how molecular dynamics can be combined with a novel variable transformation designed to warp configuration space in such a way that barriers are reduced and attractive basins stretched. This method rigorously preserves equilibrium properties while leading to very large enhancements in sampling efficiency. Extensions of this approach to the calculation/exploration of free energy surfaces will be discussed. Next, a new very large time-step molecular dynamics method will be introduced that overcomes the resonances which plague many molecular dynamics algorithms. The performance of the methods is demonstrated on a variety of systems including liquid water, long polymer chains simple protein models, and oligopeptides.

Exploring the folding free energy landscape of a β-hairpin miniprotein, chignolin, using multiscale free energy landscape calculation method.

PubMed

Harada, Ryuhei; Kitao, Akio

2011-07-14

The folding process for a β-hairpin miniprotein, chignolin, was investigated by free energy landscape (FEL) calculations using the recently proposed multiscale free energy landscape calculation method (MSFEL). First, coarse-grained molecular dynamics simulations searched a broad conformational space, then multiple independent, all-atom molecular dynamics simulations with explicit solvent determined the detailed local FEL using massively distributed computing. The combination of the two models enabled efficient calculation of the free energy landscapes. The MSFEL analysis showed that chignolin has an intermediate state as well as a misfolded state. The folding process is initiated by the formation of a β-hairpin turn, followed by the formation of contacts in the hydrophobic core between Tyr2 and Trp9. Furthermore, mutation of Tyr2 shifts the population to the misfolded conformation. The results indicate that the hydrophobic core plays an important role in stabilizing the native state of chignolin. © 2011 American Chemical Society

Automatic Selection of Order Parameters in the Analysis of Large Scale Molecular Dynamics Simulations.

PubMed

Sultan, Mohammad M; Kiss, Gert; Shukla, Diwakar; Pande, Vijay S

2014-12-09

Given the large number of crystal structures and NMR ensembles that have been solved to date, classical molecular dynamics (MD) simulations have become powerful tools in the atomistic study of the kinetics and thermodynamics of biomolecular systems on ever increasing time scales. By virtue of the high-dimensional conformational state space that is explored, the interpretation of large-scale simulations faces difficulties not unlike those in the big data community. We address this challenge by introducing a method called clustering based feature selection (CB-FS) that employs a posterior analysis approach. It combines supervised machine learning (SML) and feature selection with Markov state models to automatically identify the relevant degrees of freedom that separate conformational states. We highlight the utility of the method in the evaluation of large-scale simulations and show that it can be used for the rapid and automated identification of relevant order parameters involved in the functional transitions of two exemplary cell-signaling proteins central to human disease states.

Conformational space annealing scheme in the inverse design of functional materials

NASA Astrophysics Data System (ADS)

Kim, Sunghyun; Lee, In-Ho; Lee, Jooyoung; Oh, Young Jun; Chang, Kee Joo

2015-03-01

Recently, the so-called inverse method has drawn much attention, in which specific electronic properties are initially assigned and target materials are subsequently searched. In this work, we develop a new scheme for the inverse design of functional materials, in which the conformational space annealing (CSA) algorithm for global optimization is combined with first-principles density functional calculations. To implement the CSA, we need a series of ingredients, (i) an objective function to minimize, (ii) a 'distance' measure between two conformations, (iii) a local enthalpy minimizer of a given conformation, (iv) ways to combine two parent conformations to generate a daughter one, (v) a special conformation update scheme, and (vi) an annealing method in the 'distance' parameter axis. We show the results of applications for searching for Si crystals with direct band gaps and the lowest-enthalpy phase of boron at a finite pressure and discuss the efficiency of the present scheme. This work is supported by the National Research Foundation of Korea (NRF) under Grant No. NRF-2005-0093845 and by Samsung Science and Technology Foundation under Grant No. SSTFBA1401-08.

Informational and Normative Influences in Conformity from a Neurocomputational Perspective.

PubMed

Toelch, Ulf; Dolan, Raymond J

2015-10-01

We consider two distinct influences that drive conformity behaviour. Whereas informational influences facilitate adaptive and accurate responses, normative influences bias decisions to enhance social acceptance. We explore these influences from a perspective of perceptual and value-based decision-making models and apply these models to classical works on conformity. We argue that an informational account predicts a surprising tendency to conform. Moreover, we detail how normative influences fit into this framework and interact with social influences. Finally, we explore potential neuronal substrates for informational and normative influences based on a consideration of the neurobiological literature, highlighting conceptual shortcomings particularly with regard to a failure to segregate informational and normative influences. Copyright © 2015 Elsevier Ltd. All rights reserved.

Spatial working memory in immersive virtual reality foraging: path organization, traveling distance and search efficiency in humans (Homo sapiens).

PubMed

De Lillo, Carlo; Kirby, Melissa; James, Frances C

2014-05-01

Search and serial recall tasks were used in the present study to characterize the factors affecting the ability of humans to keep track of a set of spatial locations while traveling in an immersive virtual reality foraging environment. The first experiment required the exhaustive exploration of a set of locations following a procedure previously used with other primate and non-primate species to assess their sensitivity to the geometric arrangement of foraging sites. The second experiment assessed the dependency of search performance on search organization by requiring the participants to recall specific trajectories throughout the foraging space. In the third experiment, the distance between the foraging sites was manipulated in order to contrast the effects of organization and traveling distance on recall accuracy. The results show that humans benefit from the use of organized search patterns when attempting to monitor their travel though either a clustered "patchy" space or a matrix of locations. Their ability to recall a series of locations is dependent on whether the order in which they are explored conformed or did not conform to specific organization principles. Moreover, the relationship between search efficiency and search organization is not confounded by effects of traveling distance. These results indicate that in humans, organizational factors may play a large role in their ability to forage efficiently. The extent to which such dependency may pertain to other primates and could be accounted for by visual organization processes is discussed on the basis of previous studies focused on perceptual grouping, search, and serial recall in non-human species. © 2013 Wiley Periodicals, Inc.

A stochastic algorithm for global optimization and for best populations: A test case of side chains in proteins

PubMed Central

Glick, Meir; Rayan, Anwar; Goldblum, Amiram

2002-01-01

The problem of global optimization is pivotal in a variety of scientific fields. Here, we present a robust stochastic search method that is able to find the global minimum for a given cost function, as well as, in most cases, any number of best solutions for very large combinatorial “explosive” systems. The algorithm iteratively eliminates variable values that contribute consistently to the highest end of a cost function's spectrum of values for the full system. Values that have not been eliminated are retained for a full, exhaustive search, allowing the creation of an ordered population of best solutions, which includes the global minimum. We demonstrate the ability of the algorithm to explore the conformational space of side chains in eight proteins, with 54 to 263 residues, to reproduce a population of their low energy conformations. The 1,000 lowest energy solutions are identical in the stochastic (with two different seed numbers) and full, exhaustive searches for six of eight proteins. The others retain the lowest 141 and 213 (of 1,000) conformations, depending on the seed number, and the maximal difference between stochastic and exhaustive is only about 0.15 Kcal/mol. The energy gap between the lowest and highest of the 1,000 low-energy conformers in eight proteins is between 0.55 and 3.64 Kcal/mol. This algorithm offers real opportunities for solving problems of high complexity in structural biology and in other fields of science and technology. PMID:11792838

Conformal array design on arbitrary polygon surface with transformation optics

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

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

2016-06-15

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

Conformal Collineations of the Ricci and Energy-Momentum Tensors in Static Plane Symmetric Space-Times

NASA Astrophysics Data System (ADS)

Akhtar, S. S.; Hussain, T.; Bokhari, A. H.; Khan, F.

2018-04-01

We provide a complete classification of static plane symmetric space-times according to conformal Ricci collineations (CRCs) and conformal matter collineations (CMCs) in both the degenerate and nondegenerate cases. In the case of a nondegenerate Ricci tensor, we find a general form of the vector field generating CRCs in terms of unknown functions of t and x subject to some integrability conditions. We then solve the integrability conditions in different cases depending upon the nature of the Ricci tensor and conclude that the static plane symmetric space-times have a 7-, 10- or 15-dimensional Lie algebra of CRCs. Moreover, we find that these space-times admit an infinite number of CRCs if the Ricci tensor is degenerate. We use a similar procedure to study CMCs in the case of a degenerate or nondegenerate matter tensor. We obtain the exact form of some static plane symmetric space-time metrics that admit nontrivial CRCs and CMCs. Finally, we present some physical applications of our obtained results by considering a perfect fluid as a source of the energy-momentum tensor.

Ab initio conformational analysis of N-formyl ?-alanine amide including electron correlation

NASA Astrophysics Data System (ADS)

Yu, Ching-Hsing; Norman, Mya A.; Schäfer, Lothar; Ramek, Michael; Peeters, Anik; van Alsenoy, Christian

2001-06-01

The conformational properties of N-formyl L-alanine amide (ALA) were investigated using RMP2/6-311G∗∗ ab initio gradient geometry optimization. One hundred forty four structures of ALA were optimized at 30° grid points in its φ(N-C(α)), ψ(C(α)-C‧) conformational space. Using cubic spline functions, the grid structures were then used to construct analytical representations of complete surfaces, in φ,ψ-space, of bond lengths, bond angles, torsional sensitivity and electrostatic atomic charges. Analyses show that, in agreement with previous studies, the right-handed helical conformation, αR, is not a local energy minimum of the potential energy surface of ALA. Comparisons with protein crystallographic data show that the characteristic differences between geometrical trends in dipeptides and proteins, previously found for ab initio dipeptide structures obtained without electron correlation, are also found in the electron-correlated geometries. In contrast to generally accepted features of force fields used in empirical molecular modeling, partial atomic charges obtained by the CHELPG method are found to be not constant, but to vary significantly throughout the φ,ψ-space. By comparing RHF and MP2 structures, the effects of dispersion forces on ALA were studied, revealing molecular contractions for those conformations, in which small adjustments of torsional angles entail large changes in non-bonded distances.

The role of protein homochirality in shaping the energy landscape of folding

PubMed Central

Nanda, Vikas; Andrianarijaona, Aina; Narayanan, Chitra

2007-01-01

The homochirality, or isotacticity, of the natural amino acids facilitates the formation of regular secondary structures such as α-helices and β-sheets. However, many examples exist in nature where novel polypeptide topologies use both l- and d-amino acids. In this study, we explore how stereochemistry of the polypeptide backbone influences basic properties such as compactness and the size of fold space by simulating both lattice and all-atom polypeptide chains. We formulate a rectangular lattice chain model in both two and three dimensions, where monomers are chiral, having the effect of restricting local conformation. Syndiotactic chains with alternating chirality of adjacent monomers have a very large ensemble of accessible conformations characterized predominantly by extended structures. Isotactic chains on the other hand, have far fewer possible conformations and a significant fraction of these are compact. Syndiotactic chains are often unable to access maximally compact states available to their isotactic counterparts of the same length. Similar features are observed in all-atom models of isotactic versus syndiotactic polyalanine. Our results suggest that protein isotacticity has evolved to increase the enthalpy of chain collapse by facilitating compact helical states and to reduce the entropic cost of folding by restricting the size of the unfolded ensemble of competing states. PMID:17600146

A note on φ-analytic conformal vector fields

NASA Astrophysics Data System (ADS)

Deshmukh, Sharief; Bin Turki, Nasser

2017-09-01

Taking clue from the analytic vector fields on a complex manifold, φ-analytic conformal vector fields are defined on a Riemannian manifold (Deshmukh and Al-Solamy in Colloq. Math. 112(1):157-161, 2008). In this paper, we use φ-analytic conformal vector fields to find new characterizations of the n-sphere Sn(c) and the Euclidean space (Rn,<,> ).

Extended Phase-Space Methods for Enhanced Sampling in Molecular Simulations: A Review.

PubMed

Fujisaki, Hiroshi; Moritsugu, Kei; Matsunaga, Yasuhiro; Morishita, Tetsuya; Maragliano, Luca

2015-01-01

Molecular Dynamics simulations are a powerful approach to study biomolecular conformational changes or protein-ligand, protein-protein, and protein-DNA/RNA interactions. Straightforward applications, however, are often hampered by incomplete sampling, since in a typical simulated trajectory the system will spend most of its time trapped by high energy barriers in restricted regions of the configuration space. Over the years, several techniques have been designed to overcome this problem and enhance space sampling. Here, we review a class of methods that rely on the idea of extending the set of dynamical variables of the system by adding extra ones associated to functions describing the process under study. In particular, we illustrate the Temperature Accelerated Molecular Dynamics (TAMD), Logarithmic Mean Force Dynamics (LogMFD), and Multiscale Enhanced Sampling (MSES) algorithms. We also discuss combinations with techniques for searching reaction paths. We show the advantages presented by this approach and how it allows to quickly sample important regions of the free-energy landscape via automatic exploration.

Reversible ratchet effects for vortices in conformal pinning arrays

DOE PAGES

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

2015-05-04

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

Modulation of calmodulin plasticity by the effect of macromolecular crowding.

PubMed

Homouz, Dirar; Sanabria, Hugo; Waxham, M Neal; Cheung, Margaret S

2009-09-04

In vitro biochemical reactions are most often studied in dilute solution, a poor mimic of the intracellular space of eukaryotic cells, which are crowded with mobile and immobile macromolecules. Such crowded conditions exert volume exclusion and other entropic forces that have the potential to impact chemical equilibria and reaction rates. In this article, we used the well-characterized and ubiquitous molecule calmodulin (CaM) and a combination of theoretical and experimental approaches to address how crowding impacts CaM's conformational plasticity. CaM is a dumbbell-shaped molecule that contains four EF hands (two in the N-lobe and two in the C-lobe) that each could bind Ca(2+), leading to stabilization of certain substates that favor interactions with other target proteins. Using coarse-grained molecular simulations, we explored the distribution of CaM conformations in the presence of crowding agents. These predictions, in which crowding effects enhance the population of compact structures, were then confirmed in experimental measurements using fluorescence resonance energy transfer techniques of donor- and acceptor-labeled CaM under normal and crowded conditions. Using protein reconstruction methods, we further explored the folding-energy landscape and examined the structural characteristics of CaM at free-energy basins. We discovered that crowding stabilizes several different compact conformations, which reflects the inherent plasticity in CaM's structure. From these results, we suggest that the EF hands in the C-lobe are flexible and can be thought of as a switch, while those in the N-lobe are stiff, analogous to a rheostat. New combinatorial signaling properties may arise from the product of the differential plasticity of the two distinct lobes of CaM in the presence of crowding. We discuss the implications of these results for modulating CaM's ability to bind Ca(2+) and target proteins.

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

PubMed

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

2018-06-01

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

Long timestep dynamics of peptides by the dynamics driver approach.

PubMed

Derreumaux, P; Schlick, T

1995-04-01

Previous experience with the Langevin/implicit-Euler scheme for dynamics ("LI") on model systems (butane, water) has shown that LI is numerically stable for timesteps in the 5-20 fs range but quenches high-frequency modes. To explore applications to polypeptides, we apply LI to model systems (several dipeptides, a tetrapeptide, and a 13-residue oligoalanine) and also develop a new dynamics driver approach ("DA"). The DA scheme, based on LI, addresses the important issue of proper sampling, which is unlikely to be solved by small-timestep integration methods or implicit methods with intrinsic damping at room temperature, such as LI. Equilibrium averages, time-dependent molecular properties, and sampling trends at room temperature are reported for both LI and DA dynamics simulations, which are then compared to those generated by a standard explicit discretization of the Langevin equation with a 1 fs timestep. We find that LI's quenching effects are severe on both the fast and slow (due to vibrational coupling) frequency modes of all-atom polypeptides and lead to more restricted dynamics at moderate timesteps (40 fs). The DA approach empirically counteracts these damping effects by adding random atomic perturbations to the coordinates at each step (before the minimization of a dynamics function). By restricting the energetic fluctuations and controlling the kinetic energy, we are able with a 60 fs timestep to generate continuous trajectories that sample more of the relevant conformational space and also reproduce reasonably Boltzmann statistics. Although the timescale for transition may be accelerated by the DA approach, the transitional information obtained for the alanine dipeptide and the tetrapeptide is consistent with that obtained by several other theoretical approaches that focus specifically on the determination of pathways. While the trajectory for oligoalanine by the explicit scheme over the nanosecond timeframe remains in the vicinity of the full alpha R-helix starting structure, and a high-temperature (600 degrees K) MD trajectory departs slowly from the alpha helical structure, the DA-generated trajectory for the same CPU time exhibits unfolding and refolding and reveals a range of conformations with an intermediate helix content. Significantly, this range of states is more consistent with spectroscopic experiments on small peptides, as well as the cooperative two-state model for helix-coil transition. The good, near-Boltzmann statistics reported for the smaller systems above, in combination with the interesting oligoalanine results, suggest that DA is a promising tool for efficiently exploring conformational spaces of biomolecules and exploring folding/unfolding processes of polypeptides.

Modelling duality between bound and resonant meson spectra by means of free quantum motions on the de Sitter space-time dS4

NASA Astrophysics Data System (ADS)

Kirchbach, M.; Compean, C. B.

2016-07-01

The real parts of the complex squared energies defined by the resonance poles of the transfer matrix of the Pöschl-Teller barrier, are shown to equal the squared energies of the levels bound within the trigonometric Scarf well potential. By transforming these potentials into parts of the Laplacians describing free quantum motions on the mutually orthogonal open-time-like hyperbolic-, and closed-space-like spherical geodesics on the conformally invariant de Sitter space-time, dS4, the conformal symmetries of these interactions are revealed. On dS4 the potentials under consideration naturally relate to interactions within colorless two-body systems and to cusped Wilson loops. In effect, with the aid of the dS4 space-time as unifying geometry, a conformal symmetry based bijective correspondence (duality) between bound and resonant meson spectra is established at the quantum mechanics level and related to confinement understood as color charge neutrality. The correspondence allows to link the interpretation of mesons as resonance poles of a scattering matrix with their complementary description as states bound by an instantaneous quark interaction and to introduce a conformal symmetry based classification scheme of mesons. As examples representative of such a duality we organize in good agreement with data 71 of the reported light flavor mesons with masses below ˜ 2350 MeV into four conformal families of particles placed on linear f0, π , η , and a0 resonance trajectories, plotted on the ℓ/ M plane. Upon extending the sec2 χ by a properly constructed conformal color dipole potential, shaped after a tangent function, we predict the masses of 12 "missing" mesons. We furthermore notice that the f0 and π trajectories can be viewed as chiral partners, same as the η and a0 trajectories, an indication that chiral symmetry for mesons is likely to be realized in terms of parity doubled conformal multiplets rather than, as usually assumed, only in terms of parity doubled single SO(3) states. We attribute the striking measured meson degeneracies to conformal symmetry dynamics within color neutral two-body systems, and conclude on the usefulness of the de Sitter space-time, dS4, as a tool for modelling strong interactions, on the one side, and on the relevance of hyperbolic and trigonometric potentials in constituent quark models of hadrons, on the other.

Visualizing Structure and Dynamics of Disaccharide Simulations

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

Matthews, J. F.; Beckham, G. T.; Himmel, M. E.

2012-01-01

We examine the effect of several solvent models on the conformational properties and dynamics of disaccharides such as cellobiose and lactose. Significant variation in timescale for large scale conformational transformations are observed. Molecular dynamics simulation provides enough detail to enable insight through visualization of multidimensional data sets. We present a new way to visualize conformational space for disaccharides with Ramachandran plots.

Pilot Non-Conformance to Alerting System Commands

NASA Technical Reports Server (NTRS)

Pritchett, Amy R.; Hansman, R. John

1997-01-01

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

Conformal and projective symmetries in Newtonian cosmology

NASA Astrophysics Data System (ADS)

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

2017-02-01

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

Bootstrapping conformal field theories with the extremal functional method.

PubMed

El-Showk, Sheer; Paulos, Miguel F

2013-12-13

The existence of a positive linear functional acting on the space of (differences between) conformal blocks has been shown to rule out regions in the parameter space of conformal field theories (CFTs). We argue that at the boundary of the allowed region the extremal functional contains, in principle, enough information to determine the dimensions and operator product expansion (OPE) coefficients of an infinite number of operators appearing in the correlator under analysis. Based on this idea we develop the extremal functional method (EFM), a numerical procedure for deriving the spectrum and OPE coefficients of CFTs lying on the boundary (of solution space). We test the EFM by using it to rederive the low lying spectrum and OPE coefficients of the two-dimensional Ising model based solely on the dimension of a single scalar quasiprimary--no Virasoro algebra required. Our work serves as a benchmark for applications to more interesting, less known CFTs in the near future.

Ladder operators for the Klein-Gordon equation with a scalar curvature term

NASA Astrophysics Data System (ADS)

Mück, Wolfgang

2018-01-01

Recently, Cardoso, Houri and Kimura constructed generalized ladder operators for massive Klein-Gordon scalar fields in space-times with conformal symmetry. Their construction requires a closed conformal Killing vector, which is also an eigenvector of the Ricci tensor. Here, a similar procedure is used to construct generalized ladder operators for the Klein-Gordon equation with a scalar curvature term. It is proven that a ladder operator requires the existence of a conformal Killing vector, which must satisfy an additional property. This property is necessary and sufficient for the construction of a ladder operator. For maximally symmetric space-times, the results are equivalent to those of Cardoso, Houri and Kimura.

Directed self-organization of single DNA molecules in a nanoslit via embedded nanopit arrays

PubMed Central

Reisner, Walter; Larsen, Niels B.; Flyvbjerg, Henrik; Tegenfeldt, Jonas O.; Kristensen, Anders

2009-01-01

We show that arrays of nanopit structures etched in a nanoslit can control the positioning and conformation of single DNA molecules in nanofluidic devices. By adjusting the spacing, organization and placement of the nanopits it is possible to immobilize DNA at predetermined regions of a device without additional chemical modification and achieve a high degree of control over local DNA conformation. DNA can be extended between two nanopits and in closely spaced arrays will self-assemble into “connect-the-dots” conformations consisting of locally pinned segments joined by fluctuating linkers. These results have broad implications for nanotechnology fields that require methods for the nanoscale positioning and manipulation of DNA. PMID:19122138

Exploring protein kinase conformation using swarm-enhanced sampling molecular dynamics.

PubMed

Atzori, Alessio; Bruce, Neil J; Burusco, Kepa K; Wroblowski, Berthold; Bonnet, Pascal; Bryce, Richard A

2014-10-27

Protein plasticity, while often linked to biological function, also provides opportunities for rational design of selective and potent inhibitors of their function. The application of computational methods to the prediction of concealed protein concavities is challenging, as the motions involved can be significant and occur over long time scales. Here we introduce the swarm-enhanced sampling molecular dynamics (sesMD) method as a tool to improve sampling of conformational landscapes. In this approach, a swarm of replica simulations interact cooperatively via a set of pairwise potentials incorporating attractive and repulsive components. We apply the sesMD approach to explore the conformations of the DFG motif in the protein p38α mitogen-activated protein kinase. In contrast to multiple MD simulations, sesMD trajectories sample a range of DFG conformations, some of which map onto existing crystal structures. Simulated structures intermediate between the DFG-in and DFG-out conformations are predicted to have druggable pockets of interest for structure-based ligand design.

Domain decomposition methods for nonconforming finite element spaces of Lagrange-type

NASA Technical Reports Server (NTRS)

Cowsar, Lawrence C.

1993-01-01

In this article, we consider the application of three popular domain decomposition methods to Lagrange-type nonconforming finite element discretizations of scalar, self-adjoint, second order elliptic equations. The additive Schwarz method of Dryja and Widlund, the vertex space method of Smith, and the balancing method of Mandel applied to nonconforming elements are shown to converge at a rate no worse than their applications to the standard conforming piecewise linear Galerkin discretization. Essentially, the theory for the nonconforming elements is inherited from the existing theory for the conforming elements with only modest modification by constructing an isomorphism between the nonconforming finite element space and a space of continuous piecewise linear functions.

The Implications of SCORM Conformance for Workplace e-Learning

ERIC Educational Resources Information Center

Witthaus, Gabrielle

2009-01-01

This paper explores the impact that SCORM conformance has had on workplace e-learning. The author describes a project in which she was requested to "repurpose" some materials that had originally been designed for the face-to-face teaching of English as a Foreign Language, into SCORM conformant e-learning materials. The rationale for this request…

Exploratory conformational study of (+)-catechin. Modeling of the polarizability and electric dipole moment.

PubMed

Bentz, Erika N; Pomilio, Alicia B; Lobayan, Rosana M

2014-12-01

The extension of the study of the conformational space of the structure of (+)-catechin at the B3LYP/6-31G(d,p) level of theory is presented in this paper. (+)-Catechin belongs to the family of the flavan-3-ols, which is one of the five largest phenolic groups widely distributed in nature, and whose biological activity and pharmaceutical utility are related to the antioxidant activity due to their ability to scavenge free radicals. The effects of free rotation around all C-O bonds of the OH substituents at different rings are taken into account, obtaining as the most stable conformer, one that had not been previously reported. One hundred seven structures, and a study of the effects of charge delocalization and stereoelectronic effects at the B3LYP/6-311++G(d,p) level are reported by natural bond orbital analysis, streamlining the order of these structures. For further analysis of the structural and molecular properties of this compound in a biological environment, the calculation of polarizabilities, and the study of the electric dipole moment are performed considering the whole conformational space described. The results are analyzed in terms of accumulated knowledge for (4α → 6″, 2α → O → 1″)-phenylflavans and (+)-catechin in previous works, enriching the study of both types of structures, and taking into account the importance of considering the whole conformational space in modeling both the polarizability and the electric dipole moment, also proposing to define a descriptive subspace of only 16 conformers.

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

PubMed

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

2009-11-01

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

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

NASA Astrophysics Data System (ADS)

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

1989-06-01

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

Modulation of the Conformational Dynamics of Apo-Adenylate Kinase through a π-Cation Interaction.

PubMed

Halder, Ritaban; Manna, Rabindra Nath; Chakraborty, Sandipan; Jana, Biman

2017-06-15

Large-scale conformational transition from open to closed state of adenylate kinase (ADK) is essential for its catalytic cycle. Apo-ADK undergoes conformational transition in a way that closely resembles an open-to-closed conformational transition. Here, equilibrium simulations, free-energy simulations, and quantum mechanics/molecular mechanics (QM/MM) calculations in combination with several bioinformatics approaches have been used to explore the molecular origin of this conformational transition in apo-ADK. In addition to its conventional open state, Escherichia coli apo-ADK adopts conformations that resemble a closed-like intermediate, the "half-open-half-closed" (HOHC) state, and a π-cation interaction can account for the stability of this HOHC state. Energetics and the electronic properties of this π-cation interaction have been explored using QM/MM calculations. Upon rescinding the π-cation interaction, the conformational landscape of the apo-ADK changes completely. The apo-ADK population is shifted completely toward the open state. This π-cation interaction is highly conserved in bacterial ADK; the cationic guanidinium moiety of a conserved ARG interacts with the delocalized π-electron cloud of either PHE or TYR. Interestingly, this study demonstrates the modulation of a principal protein dynamics by a conserved specific π-cation interaction across different organisms.

The relative isoperimetric inequality on a conformally parabolic manifold with boundary

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

Kesel'man, Vladimir M

2011-07-31

For an arbitrary noncompact n-dimensional Riemannian manifold with a boundary of conformally parabolic type it is proved that there exists a conformal change of metric such that a relative isoperimetric inequality of the same form as in the closed n-dimensional Euclidean half-space holds on the manifold with the new metric. This isoperimetric inequality is asymptotically sharp. Bibliography: 6 titles.

The protein folding network

NASA Astrophysics Data System (ADS)

Rao, Francesco; Caflisch, Amedeo

2004-03-01

Networks are everywhere. The conformation space of a 20-residue antiparallel beta-sheet peptide [1], sampled by molecular dynamics simulations, is mapped to a network. Conformations are nodes of the network, and the transitions between them are links. As previously found for the World-Wide Web as well as for social and biological networks , the conformation space contains highly connected hubs like the native state which is the most populated free energy basin. Furthermore, the network shows a hierarchical modularity [2] which is consistent with the funnel mechanism of folding [3] and is not observed for a random heteropolymer lacking a native state. Here we show that the conformation space network describes the free energy landscape without requiring projections into arbitrarily chosen reaction coordinates. The network analysis provides a basis for understanding the heterogeneity of the folding transition state and the existence of multiple pathways. [1] P. Ferrara and A. Caflisch, Folding simulations of a three-stranded antiparallel beta-sheet peptide, PNAS 97, 10780-10785 (2000). [2] Ravasz, E. and Barabási, A. L. Hierarchical organization in complex networks. Phys. Rev. E 67, 026112 (2003). [3] Dill, K. and Chan, H From Levinthal to pathways to funnels. Nature Struct. Biol. 4, 10-19 (1997)

RNA unrestrained molecular dynamics ensemble improves agreement with experimental NMR data compared to single static structure: a test case

NASA Astrophysics Data System (ADS)

Beckman, Robert A.; Moreland, David; Louise-May, Shirley; Humblet, Christine

2006-05-01

Nuclear magnetic resonance (NMR) provides structural and dynamic information reflecting an average, often non-linear, of multiple solution-state conformations. Therefore, a single optimized structure derived from NMR refinement may be misleading if the NMR data actually result from averaging of distinct conformers. It is hypothesized that a conformational ensemble generated by a valid molecular dynamics (MD) simulation should be able to improve agreement with the NMR data set compared with the single optimized starting structure. Using a model system consisting of two sequence-related self-complementary ribonucleotide octamers for which NMR data was available, 0.3 ns particle mesh Ewald MD simulations were performed in the AMBER force field in the presence of explicit water and counterions. Agreement of the averaged properties of the molecular dynamics ensembles with NMR data such as homonuclear proton nuclear Overhauser effect (NOE)-based distance constraints, homonuclear proton and heteronuclear 1H-31P coupling constant ( J) data, and qualitative NMR information on hydrogen bond occupancy, was systematically assessed. Despite the short length of the simulation, the ensemble generated from it agreed with the NMR experimental constraints more completely than the single optimized NMR structure. This suggests that short unrestrained MD simulations may be of utility in interpreting NMR results. As expected, a 0.5 ns simulation utilizing a distance dependent dielectric did not improve agreement with the NMR data, consistent with its inferior exploration of conformational space as assessed by 2-D RMSD plots. Thus, ability to rapidly improve agreement with NMR constraints may be a sensitive diagnostic of the MD methods themselves.

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.

Eikonalization of conformal blocks

DOE PAGES

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

2015-09-03

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

Multiscale Molecular Dynamics Simulations of Beta-Amyloid Interactions with Neurons

NASA Astrophysics Data System (ADS)

Qiu, Liming; Vaughn, Mark; Cheng, Kelvin

2012-10-01

Early events of human beta-amyloid protein interactions with cholesterol-containing membranes are critical to understanding the pathogenesis of Alzheimer's disease (AD) and to exploring new therapeutic interventions of AD. Atomistic molecular dynamics (AMD) simulations have been extensively used to study the protein-lipid interaction at high atomic resolutions. However, traditional MD simulations are not efficient in sampling the phase space of complex lipid/protein systems with rugged free energy landscapes. Meanwhile, coarse-grained MD (CGD) simulations are efficient in the phase space sampling but suffered from low spatial resolutions and from the fact that the energy landscapes are not identical to those of the AMD. Here, a multiscale approach was employed to simulate the protein-lipid interactions of beta-amyloid upon its release from proteolysis residing in the neuronal membranes. We utilized a forward (AMD to CGD) and reverse (CGD-AMD) strategy to explore new transmembrane and surface protein configuration and evaluate the stabilization mechanisms by measuring the residue-specific protein-lipid or protein conformations. The detailed molecular interactions revealed in this multiscale MD approach will provide new insights into understanding the early molecular events leading to the pathogenesis of AD.

A scalable and accurate method for classifying protein-ligand binding geometries using a MapReduce approach.

PubMed

Estrada, T; Zhang, B; Cicotti, P; Armen, R S; Taufer, M

2012-07-01

We present a scalable and accurate method for classifying protein-ligand binding geometries in molecular docking. Our method is a three-step process: the first step encodes the geometry of a three-dimensional (3D) ligand conformation into a single 3D point in the space; the second step builds an octree by assigning an octant identifier to every single point in the space under consideration; and the third step performs an octree-based clustering on the reduced conformation space and identifies the most dense octant. We adapt our method for MapReduce and implement it in Hadoop. The load-balancing, fault-tolerance, and scalability in MapReduce allow screening of very large conformation spaces not approachable with traditional clustering methods. We analyze results for docking trials for 23 protein-ligand complexes for HIV protease, 21 protein-ligand complexes for Trypsin, and 12 protein-ligand complexes for P38alpha kinase. We also analyze cross docking trials for 24 ligands, each docking into 24 protein conformations of the HIV protease, and receptor ensemble docking trials for 24 ligands, each docking in a pool of HIV protease receptors. Our method demonstrates significant improvement over energy-only scoring for the accurate identification of native ligand geometries in all these docking assessments. The advantages of our clustering approach make it attractive for complex applications in real-world drug design efforts. We demonstrate that our method is particularly useful for clustering docking results using a minimal ensemble of representative protein conformational states (receptor ensemble docking), which is now a common strategy to address protein flexibility in molecular docking. Copyright © 2012 Elsevier Ltd. All rights reserved.

Triaspartate: a model system for conformationally flexible DDD motifs in proteins.

PubMed

Duitch, Laura; Toal, Siobhan; Measey, Thomas J; Schweitzer-Stenner, Reinhard

2012-05-03

Understanding the interactions that govern turn formation in the unfolded state of proteins is necessary for a complete picture of the role that these turns play in both normal protein folding and functionally relevant yet disordered linear motifs. It is still unclear, however, whether short peptides can adopt stable turn structures in aqueous environments in the absence of any nonlocal interactions. To explore the effect that nearest-neighbor interactions and the local peptide environment have on the turn-forming capability of individual amino acid residues in short peptides, we combined vibrational (IR, Raman, and VCD), UV-CD, and (1)H NMR spectroscopies in order to probe the conformational ensemble of the central aspartic acid residue of the triaspartate peptide (DDD). The study was motivated by the recently discovered turn propensities of aspartic acid in GDG (Hagarman; et al. Chem.-Eur. J. 2011, 17, 6789). We investigated the DDD peptide under both acidic and neutral conditions in order to elucidate the effect that side-chain protonation has on the conformational propensity of the central aspartic acid residue. Amide I' profiles were analyzed in terms of two-dimensional Gaussian distributions representing conformational subdistributions in Ramachandran space. Interestingly, our results show that while the protonated form of the DDD peptide samples various turn-like conformations similar to GDG, deprotonation of the peptide eliminates this propensity for turns, causing the fully ionized peptide to exclusively sample pPII and β-strand-like structures. To further explore the factors stabilizing these more extended conformations in fully ionized DDD, we analyzed the temperature dependence of both the UV-CD spectrum and the (3)J(H(N),H(α)) coupling constants of the two amide protons (N- and C-terminal) in terms of a simple two-state (pPII-β) thermodynamic model. Thus, we were able to obtain the enthalpic and entropic differences between the pPII and β-strand conformations of the central and C-terminal residue. For the central residue, we obtained ΔH(3) = -12.0 kJ/mol and ΔS(3) = -73.8 J/mol·K, resulting in a much larger room-temperature Gibbs free energy of 10.0 kJ/mol, which effectively locks the C-terminal in a β-like conformation. A comparison of the temperature dependence of the chemical shifts reveals that there is indeed some type of protection of the amide protons from solvent in ionized DDD. This finding and several other lines of evidence suggest that both conformations of ionized DDD are stabilized by hydrogen bonding between the carboxylate groups of the central and C-terminal residue and the respective amide protons. These hydrogen bonds can be expected to be eliminated by side-chain protonation and substituted by hydrogen bonds between the N-terminal amide proton and the C-terminal carbonyl group as well as between the central aspartate side chain and the N-terminal amide proton. Hence, our results are indicative of a pH-induced switch in hydrogen-bonding patterns of aspartic acid motifs.

Noise kernels of stochastic gravity in conformally-flat spacetimes

NASA Astrophysics Data System (ADS)

Cho, H. T.; Hu, B. L.

2015-03-01

The central object in the theory of semiclassical stochastic gravity is the noise kernel, which is the symmetric two point correlation function of the stress-energy tensor. Using the corresponding Wightman functions in Minkowski, Einstein and open Einstein spaces, we construct the noise kernels of a conformally coupled scalar field in these spacetimes. From them we show that the noise kernels in conformally-flat spacetimes, including the Friedmann-Robertson-Walker universes, can be obtained in closed analytic forms by using a combination of conformal and coordinate transformations.

Probabilistic sampling of protein conformations: new hope for brute force?

PubMed

Feldman, Howard J; Hogue, Christopher W V

2002-01-01

Protein structure prediction from sequence alone by "brute force" random methods is a computationally expensive problem. Estimates have suggested that it could take all the computers in the world longer than the age of the universe to compute the structure of a single 200-residue protein. Here we investigate the use of a faster version of our FOLDTRAJ probabilistic all-atom protein-structure-sampling algorithm. We have improved the method so that it is now over twenty times faster than originally reported, and capable of rapidly sampling conformational space without lattices. It uses geometrical constraints and a Leonard-Jones type potential for self-avoidance. We have also implemented a novel method to add secondary structure-prediction information to make protein-like amounts of secondary structure in sampled structures. In a set of 100,000 probabilistic conformers of 1VII, 1ENH, and 1PMC generated, the structures with smallest Calpha RMSD from native are 3.95, 5.12, and 5.95A, respectively. Expanding this test to a set of 17 distinct protein folds, we find that all-helical structures are "hit" by brute force more frequently than beta or mixed structures. For small helical proteins or very small non-helical ones, this approach should have a "hit" close enough to detect with a good scoring function in a pool of several million conformers. By fitting the distribution of RMSDs from the native state of each of the 17 sets of conformers to the extreme value distribution, we are able to estimate the size of conformational space for each. With a 0.5A RMSD cutoff, the number of conformers is roughly 2N where N is the number of residues in the protein. This is smaller than previous estimates, indicating an average of only two possible conformations per residue when sterics are accounted for. Our method reduces the effective number of conformations available at each residue by probabilistic bias, without requiring any particular discretization of residue conformational space, and is the fastest method of its kind. With computer speeds doubling every 18 months and parallel and distributed computing becoming more practical, the brute force approach to protein structure prediction may yet have some hope in the near future. Copyright 2001 Wiley-Liss, Inc.

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

NASA Astrophysics Data System (ADS)

Cometta-Morini, Chiara; Loew, Gilda H.

1991-08-01

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

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

NASA Astrophysics Data System (ADS)

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

2017-07-01

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

Twistor Geometry of Null Foliations in Complex Euclidean Space

NASA Astrophysics Data System (ADS)

Taghavi-Chabert, Arman

2017-01-01

We give a detailed account of the geometric correspondence between a smooth complex projective quadric hypersurface Q^n of dimension n ≥ 3, and its twistor space PT, defined to be the space of all linear subspaces of maximal dimension of Q^n. Viewing complex Euclidean space CE^n as a dense open subset of Q^n, we show how local foliations tangent to certain integrable holomorphic totally null distributions of maximal rank on CE^n can be constructed in terms of complex submanifolds of PT. The construction is illustrated by means of two examples, one involving conformal Killing spinors, the other, conformal Killing-Yano 2-forms. We focus on the odd-dimensional case, and we treat the even-dimensional case only tangentially for comparison.

Comparative atomic-scale hydration of the ceramide and phosphocholine headgroup in solution and bilayer environments

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

Gillams, Richard J.; McLain, Sylvia E., E-mail: sylvia.mclain@bioch.ox.ac.uk; Lorenz, Christian D., E-mail: chris.lorenz@kcl.ac.uk

2016-06-14

Previous studies have used neutron diffraction to elucidate the hydration of the ceramide and the phosphatidylcholine headgroup in solution. These solution studies provide bond-length resolution information on the system, but are limited to liquid samples. The work presented here investigates how the hydration of ceramide and phosphatidylcholine headgroups in a solution compares with that found in a lipid bilayer. This work shows that the hydration patterns seen in the solution samples provide valuable insight into the preferential location of hydrating water molecules in the bilayer. There are certain subtle differences in the distribution, which result from a combination of themore » lipid conformation and the lipid-lipid interactions within the bilayer environment. The lipid-lipid interactions in the bilayer will be dependent on the composition of the bilayer, whereas the restricted exploration of conformational space is likely to be applicable in all membrane environments. The generalized description of hydration gathered from the neutron diffraction studies thus provides good initial estimation for the hydration pattern, but this can be further refined for specific systems.« less

Self-Learning Adaptive Umbrella Sampling Method for the Determination of Free Energy Landscapes in Multiple Dimensions

PubMed Central

Wojtas-Niziurski, Wojciech; Meng, Yilin; Roux, Benoit; Bernèche, Simon

2013-01-01

The potential of mean force describing conformational changes of biomolecules is a central quantity that determines the function of biomolecular systems. Calculating an energy landscape of a process that depends on three or more reaction coordinates might require a lot of computational power, making some of multidimensional calculations practically impossible. Here, we present an efficient automatized umbrella sampling strategy for calculating multidimensional potential of mean force. The method progressively learns by itself, through a feedback mechanism, which regions of a multidimensional space are worth exploring and automatically generates a set of umbrella sampling windows that is adapted to the system. The self-learning adaptive umbrella sampling method is first explained with illustrative examples based on simplified reduced model systems, and then applied to two non-trivial situations: the conformational equilibrium of the pentapeptide Met-enkephalin in solution and ion permeation in the KcsA potassium channel. With this method, it is demonstrated that a significant smaller number of umbrella windows needs to be employed to characterize the free energy landscape over the most relevant regions without any loss in accuracy. PMID:23814508

Manipulating and Visualizing Molecular Interactions in Customized Nanoscale Spaces

NASA Astrophysics Data System (ADS)

Stabile, Francis; Henkin, Gil; Berard, Daniel; Shayegan, Marjan; Leith, Jason; Leslie, Sabrina

We present a dynamically adjustable nanofluidic platform for formatting the conformations of and visualizing the interaction kinetics between biomolecules in solution, offering new time resolution and control of the reaction processes. This platform extends convex lens-induced confinement (CLiC), a technique for imaging molecules under confinement, by introducing a system for in situ modification of the chemical environment; this system uses a deep microchannel to diffusively exchange reagents within the nanoscale imaging region, whose height is fixed by a nanopost array. To illustrate, we visualize and manipulate salt-induced, surfactant-induced, and enzyme-induced reactions between small-molecule reagents and DNA molecules, where the conformations of the DNA molecules are formatted by the imposed nanoscale confinement. By using nanofabricated, nonabsorbing, low-background glass walls to confine biomolecules, our nanofluidic platform facilitates quantitative exploration of physiologically and biotechnologically relevant processes at the nanoscale. This device provides new kinetic information about dynamic chemical processes at the single-molecule level, using advancements in the CLiC design including a microchannel-based diffuser and postarray-based dialysis slit.

Exploring the parameter space of the coarse-grained UNRES force field by random search: selecting a transferable medium-resolution force field.

PubMed

He, Yi; Xiao, Yi; Liwo, Adam; Scheraga, Harold A

2009-10-01

We explored the energy-parameter space of our coarse-grained UNRES force field for large-scale ab initio simulations of protein folding, to obtain good initial approximations for hierarchical optimization of the force field with new virtual-bond-angle bending and side-chain-rotamer potentials which we recently introduced to replace the statistical potentials. 100 sets of energy-term weights were generated randomly, and good sets were selected by carrying out replica-exchange molecular dynamics simulations of two peptides with a minimal alpha-helical and a minimal beta-hairpin fold, respectively: the tryptophan cage (PDB code: 1L2Y) and tryptophan zipper (PDB code: 1LE1). Eight sets of parameters produced native-like structures of these two peptides. These eight sets were tested on two larger proteins: the engrailed homeodomain (PDB code: 1ENH) and FBP WW domain (PDB code: 1E0L); two sets were found to produce native-like conformations of these proteins. These two sets were tested further on a larger set of nine proteins with alpha or alpha + beta structure and found to locate native-like structures of most of them. These results demonstrate that, in addition to finding reasonable initial starting points for optimization, an extensive search of parameter space is a powerful method to produce a transferable force field. Copyright 2009 Wiley Periodicals, Inc.

Holograms of Flat Space

NASA Astrophysics Data System (ADS)

Bagchi, Arjun; Grumiller, Daniel

2013-07-01

The holographic principle has a concrete realization in the Anti-de Sitter/Conformal Field Theory (AdS/CFT) correspondence. If this principle is a true fact about quantum gravity then it must also hold beyond AdS/CFT. In this paper, we address specifically holographic field theory duals of gravitational theories in asymptotically flat spacetimes. We present some evidence of our recent conjecture that three-dimensional (3d) conformal Chern-Simons gravity (CSG) with flat space boundary conditions is dual to an extremal CFT.

Role of local sequence in the folding of cellular retinoic abinding protein I: structural propensities of reverse turns.

PubMed

Rotondi, Kenneth S; Gierasch, Lila M

2003-07-08

The experiments described here explore the role of local sequence in the folding of cellular retinoic acid binding protein I (CRABP I). This is a 136-residue, 10-stranded, antiparallel beta-barrel protein with seven beta-hairpins and is a member of the intracellular lipid binding protein (iLBP) family. The relative roles of local and global sequence information in governing the folding of this class of proteins are not well-understood. In question is whether the beta-turns are locally defined by short-range interactions within their sequences, and are thus able to play an active role in reducing the conformational space available to the folding chain, or whether the turns are passive, relying upon global forces to form. Short (six- and seven-residue) peptides corresponding to the seven CRABP I turns were analyzed by circular dichroism and NMR for their tendencies to take up the conformations they adopt in the context of the native protein. The results indicate that two of the peptides, encompassing turns III and IV in CRABP I, have a strong intrinsic bias to form native turns. Intriguingly, these turns are on linked hairpins in CRABP I and represent the best-conserved turns in the iLBP family. These results suggest that local sequence may play an important role in narrowing the conformational ensemble of CRABP I during folding.

Salt bridges: geometrically specific, designable interactions.

PubMed

Donald, Jason E; Kulp, Daniel W; DeGrado, William F

2011-03-01

Salt bridges occur frequently in proteins, providing conformational specificity and contributing to molecular recognition and catalysis. We present a comprehensive analysis of these interactions in protein structures by surveying a large database of protein structures. Salt bridges between Asp or Glu and His, Arg, or Lys display extremely well-defined geometric preferences. Several previously observed preferences are confirmed, and others that were previously unrecognized are discovered. Salt bridges are explored for their preferences for different separations in sequence and in space, geometric preferences within proteins and at protein-protein interfaces, co-operativity in networked salt bridges, inclusion within metal-binding sites, preference for acidic electrons, apparent conformational side chain entropy reduction on formation, and degree of burial. Salt bridges occur far more frequently between residues at close than distant sequence separations, but, at close distances, there remain strong preferences for salt bridges at specific separations. Specific types of complex salt bridges, involving three or more members, are also discovered. As we observe a strong relationship between the propensity to form a salt bridge and the placement of salt-bridging residues in protein sequences, we discuss the role that salt bridges might play in kinetically influencing protein folding and thermodynamically stabilizing the native conformation. We also develop a quantitative method to select appropriate crystal structure resolution and B-factor cutoffs. Detailed knowledge of these geometric and sequence dependences should aid de novo design and prediction algorithms. Copyright © 2010 Wiley-Liss, Inc.

Mapping the conformational free energy of aspartic acid in the gas phase and in aqueous solution.

PubMed

Comitani, Federico; Rossi, Kevin; Ceriotti, Michele; Sanz, M Eugenia; Molteni, Carla

2017-04-14

The conformational free energy landscape of aspartic acid, a proteogenic amino acid involved in a wide variety of biological functions, was investigated as an example of the complexity that multiple rotatable bonds produce even in relatively simple molecules. To efficiently explore such a landscape, this molecule was studied in the neutral and zwitterionic forms, in the gas phase and in water solution, by means of molecular dynamics and the enhanced sampling method metadynamics with classical force-fields. Multi-dimensional free energy landscapes were reduced to bi-dimensional maps through the non-linear dimensionality reduction algorithm sketch-map to identify the energetically stable conformers and their interconnection paths. Quantum chemical calculations were then performed on the minimum free energy structures. Our procedure returned the low energy conformations observed experimentally in the gas phase with rotational spectroscopy [M. E. Sanz et al., Phys. Chem. Chem. Phys. 12, 3573 (2010)]. Moreover, it provided information on higher energy conformers not accessible to experiments and on the conformers in water. The comparison between different force-fields and quantum chemical data highlighted the importance of the underlying potential energy surface to accurately capture energy rankings. The combination of force-field based metadynamics, sketch-map analysis, and quantum chemical calculations was able to produce an exhaustive conformational exploration in a range of significant free energies that complements the experimental data. Similar protocols can be applied to larger peptides with complex conformational landscapes and would greatly benefit from the next generation of accurate force-fields.

Mapping the conformational free energy of aspartic acid in the gas phase and in aqueous solution

NASA Astrophysics Data System (ADS)

Comitani, Federico; Rossi, Kevin; Ceriotti, Michele; Sanz, M. Eugenia; Molteni, Carla

2017-04-01

The conformational free energy landscape of aspartic acid, a proteogenic amino acid involved in a wide variety of biological functions, was investigated as an example of the complexity that multiple rotatable bonds produce even in relatively simple molecules. To efficiently explore such a landscape, this molecule was studied in the neutral and zwitterionic forms, in the gas phase and in water solution, by means of molecular dynamics and the enhanced sampling method metadynamics with classical force-fields. Multi-dimensional free energy landscapes were reduced to bi-dimensional maps through the non-linear dimensionality reduction algorithm sketch-map to identify the energetically stable conformers and their interconnection paths. Quantum chemical calculations were then performed on the minimum free energy structures. Our procedure returned the low energy conformations observed experimentally in the gas phase with rotational spectroscopy [M. E. Sanz et al., Phys. Chem. Chem. Phys. 12, 3573 (2010)]. Moreover, it provided information on higher energy conformers not accessible to experiments and on the conformers in water. The comparison between different force-fields and quantum chemical data highlighted the importance of the underlying potential energy surface to accurately capture energy rankings. The combination of force-field based metadynamics, sketch-map analysis, and quantum chemical calculations was able to produce an exhaustive conformational exploration in a range of significant free energies that complements the experimental data. Similar protocols can be applied to larger peptides with complex conformational landscapes and would greatly benefit from the next generation of accurate force-fields.

Exploring the conformations of polyflavanoids – an approach to understanding the significance of tannins

Treesearch

Richard W. Hemingway

1998-01-01

Reflection on 25 years of research at the USDA Forest Service Laboratory in Pineville, LA suggests that at least a third and possibly closer to half of the research done on polyflavanoids is in one or another way connected with attempts to understand the conformational properties of these compounds. The concentration on definition of the preferred conformations and...

Cosmological signatures of a UV-conformal standard model.

PubMed

Dorsch, Glauber C; Huber, Stephan J; No, Jose Miguel

2014-09-19

Quantum scale invariance in the UV has been recently advocated as an attractive way of solving the gauge hierarchy problem arising in the standard model. We explore the cosmological signatures at the electroweak scale when the breaking of scale invariance originates from a hidden sector and is mediated to the standard model by gauge interactions (gauge mediation). These scenarios, while being hard to distinguish from the standard model at LHC, can give rise to a strong electroweak phase transition leading to the generation of a large stochastic gravitational wave signal in possible reach of future space-based detectors such as eLISA and BBO. This relic would be the cosmological imprint of the breaking of scale invariance in nature.

Going clean: structure and dynamics of peptides in the gas phase and paths to solvation.

PubMed

Baldauf, Carsten; Rossi, Mariana

2015-12-16

The gas phase is an artificial environment for biomolecules that has gained much attention both experimentally and theoretically due to its unique characteristic of providing a clean room environment for the comparison between theory and experiment. In this review we give an overview mainly on first-principles simulations of isolated peptides and the initial steps of their interactions with ions and solvent molecules: a bottom up approach to the complexity of biological environments. We focus on the accuracy of different methods to explore the conformational space, the connections between theory and experiment regarding collision cross section evaluations and (anharmonic) vibrational spectra, and the challenges faced in this field.

From Ramachandran Maps to Tertiary Structures of Proteins.

PubMed

DasGupta, Debarati; Kaushik, Rahul; Jayaram, B

2015-08-27

Sequence to structure of proteins is an unsolved problem. A possible coarse grained resolution to this entails specification of all the torsional (Φ, Ψ) angles along the backbone of the polypeptide chain. The Ramachandran map quite elegantly depicts the allowed conformational (Φ, Ψ) space of proteins which is still very large for the purposes of accurate structure generation. We have divided the allowed (Φ, Ψ) space in Ramachandran maps into 27 distinct conformations sufficient to regenerate a structure to within 5 Å from the native, at least for small proteins, thus reducing the structure prediction problem to a specification of an alphanumeric string, i.e., the amino acid sequence together with one of the 27 conformations preferred by each amino acid residue. This still theoretically results in 27(n) conformations for a protein comprising "n" amino acids. We then investigated the spatial correlations at the two-residue (dipeptide) and three-residue (tripeptide) levels in what may be described as higher order Ramachandran maps, with the premise that the allowed conformational space starts to shrink as we introduce neighborhood effects. We found, for instance, for a tripeptide which potentially can exist in any of the 27(3) "allowed" conformations, three-fourths of these conformations are redundant to the 95% confidence level, suggesting sequence context dependent preferred conformations. We then created a look-up table of preferred conformations at the tripeptide level and correlated them with energetically favorable conformations. We found in particular that Boltzmann probabilities calculated from van der Waals energies for each conformation of tripeptides correlate well with the observed populations in the structural database (the average correlation coefficient is ∼0.8). An alpha-numeric string and hence the tertiary structure can be generated for any sequence from the look-up table within minutes on a single processor and to a higher level of accuracy if secondary structure can be specified. We tested the methodology on 100 small proteins, and in 90% of the cases, a structure within 5 Å is recovered. We thus believe that the method presented here provides the missing link between Ramachandran maps and tertiary structures of proteins. A Web server to convert a tertiary structure to an alphanumeric string and to predict the tertiary structure from the sequence of a protein using the above methodology is created and made freely accessible at http://www.scfbio-iitd.res.in/software/proteomics/rm2ts.jsp.

Hidden supersymmetry and quadratic deformations of the space-time conformal superalgebra

NASA Astrophysics Data System (ADS)

Yates, L. A.; Jarvis, P. D.

2018-04-01

We analyze the structure of the family of quadratic superalgebras, introduced in Jarvis et al (2011 J. Phys. A: Math. Theor. 44 235205), for the quadratic deformations of N  =  1 space-time conformal supersymmetry. We characterize in particular the ‘zero-step’ modules for this case. In such modules, the odd generators vanish identically, and the quadratic superalgebra is realized on a single irreducible representation of the even subalgebra (which is a Lie algebra). In the case under study, the quadratic deformations of N  =  1 space-time conformal supersymmetry, it is shown that each massless positive energy unitary irreducible representation (in the standard classification of Mack), forms such a zero-step module, for an appropriate parameter choice amongst the quadratic family (with vanishing central charge). For these massless particle multiplets therefore, quadratic supersymmetry is unbroken, in that the supersymmetry generators annihilate all physical states (including the vacuum state), while at the same time, superpartners do not exist.

49 CFR 180.213 - Requalification markings.

Code of Federal Regulations, 2013 CFR

2013-10-01

... obliterated, except that, when the space originally provided for requalification dates becomes filled... volumetric expansion test, 10-year volumetric expansion test for UN cylinders and cylinders conforming to § 180.209(f) and (h), or 12-year volumetric expansion test for fire extinguishers conforming to § 173...

49 CFR 180.213 - Requalification markings.

Code of Federal Regulations, 2011 CFR

2011-10-01

... obliterated, except that, when the space originally provided for requalification dates becomes filled... volumetric expansion test, 10-year volumetric expansion test for UN cylinders and cylinders conforming to § 180.209(f) and (h), or 12-year volumetric expansion test for fire extinguishers conforming to § 173...

49 CFR 180.213 - Requalification markings.

Code of Federal Regulations, 2014 CFR

2014-10-01

... obliterated, except that, when the space originally provided for requalification dates becomes filled... volumetric expansion test, 10-year volumetric expansion test for UN cylinders and cylinders conforming to § 180.209(f) and (h), or 12-year volumetric expansion test for fire extinguishers conforming to § 173...

49 CFR 180.213 - Requalification markings.

Code of Federal Regulations, 2012 CFR

2012-10-01

... obliterated, except that, when the space originally provided for requalification dates becomes filled... volumetric expansion test, 10-year volumetric expansion test for UN cylinders and cylinders conforming to § 180.209(f) and (h), or 12-year volumetric expansion test for fire extinguishers conforming to § 173...

NMR Structural Profiling of Transcriptional Intermediates Reveals Riboswitch Regulation by Metastable RNA Conformations.

PubMed

Helmling, Christina; Wacker, Anna; Wolfinger, Michael T; Hofacker, Ivo L; Hengesbach, Martin; Fürtig, Boris; Schwalbe, Harald

2017-02-22

Gene repression induced by the formation of transcriptional terminators represents a prime example for the coupling of RNA synthesis, folding, and regulation. In this context, mapping the changes in available conformational space of transcription intermediates during RNA synthesis is important to understand riboswitch function. A majority of riboswitches, an important class of small metabolite-sensing regulatory RNAs, act as transcriptional regulators, but the dependence of ligand binding and the subsequent allosteric conformational switch on mRNA transcript length has not yet been investigated. We show a strict fine-tuning of binding and sequence-dependent alterations of conformational space by structural analysis of all relevant transcription intermediates at single-nucleotide resolution for the I-A type 2'dG-sensing riboswitch from Mesoplasma florum by NMR spectroscopy. Our results provide a general framework to dissect the coupling of synthesis and folding essential for riboswitch function, revealing the importance of metastable states for RNA-based gene regulation.

Trans-cis molecular photoswitching in interstellar space

NASA Astrophysics Data System (ADS)

Cuadrado, S.; Goicoechea, J. R.; Roncero, O.; Aguado, A.; Tercero, B.; Cernicharo, J.

2016-11-01

As many organic molecules, formic acid (HCOOH) has two conformers (trans and cis). The energy barrier to internal conversion from trans to cis is much higher than the thermal energy available in molecular clouds. Thus, only the most stable conformer (trans) is expected to exist in detectable amounts. We report the first interstellar detection of cis-HCOOH. Its presence in ultraviolet (UV) irradiated gas exclusively (the Orion Bar photodissociation region), with a low trans-to-cis abundance ratio of 2.8 ± 1.0, supports a photoswitching mechanism: a given conformer absorbs a stellar photon that radiatively excites the molecule to electronic states above the interconversion barrier. Subsequent fluorescent decay leaves the molecule in a different conformer form. This mechanism, which we specifically study with ab initio quantum calculations, was not considered in Space before but likely induces structural changes of a variety of interstellar molecules submitted to UV radiation. This paper makes use of observations obtained with the IRAM-30 m telescope. IRAM is supported by INSU/CNRS (France), MPG (Germany), and IGN (Spain).

NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.

PubMed

Güttler, Thomas; Madl, Tobias; Neumann, Piotr; Deichsel, Danilo; Corsini, Lorenzo; Monecke, Thomas; Ficner, Ralf; Sattler, Michael; Görlich, Dirk

2010-11-01

Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Φ) residues, yet CRM1 recognizes them with the same rigid set of five Φ pockets. The different Φ spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an α-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Φ pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly.

Conformal Ablative Thermal Protection System for Planetary and Human Exploration Missions

NASA Technical Reports Server (NTRS)

Beck, R.; Arnold, J.; Gasch, M.; Stackpole, M.; Wercinski, R.; Venkatapathy, E.; Fan, W.; Thornton, J; Szalai, C.

2012-01-01

The Office of Chief Technologist (OCT), NASA has identified the need for research and technology development in part from NASAs Strategic Goal 3.3 of the NASA Strategic Plan to develop and demonstrate the critical technologies that will make NASAs exploration, science, and discovery missions more affordable and more capable. Furthermore, the Game Changing Development Program (GCDP) is a primary avenue to achieve the Agencys 2011 strategic goal to Create the innovative new space technologies for our exploration, science, and economic future. In addition, recently released NASA Space Technology Roadmaps and Priorities, by the National Research Council (NRC) of the National Academy of Sciences stresses the need for NASA to invest in the very near term in specific EDL technologies. The report points out the following challenges (Page 2-38 of the pre-publication copy released on February 1, 2012): Mass to Surface: Develop the ability to deliver more payload to the destination. NASA's future missions will require ever-greater mass delivery capability in order to place scientifically significant instrument packages on distant bodies of interest, to facilitate sample returns from bodies of interest, and to enable human exploration of planets such as Mars. As the maximum mass that can be delivered to an entry interface is fixed for a given launch system and trajectory design, the mass delivered to the surface will require reductions in spacecraft structural mass more efficient, lighter thermal protection systems more efficient lighter propulsion systems and lighter, more efficient deceleration systems. Surface Access: Increase the ability to land at a variety of planetary locales and at a variety of times. Access to specific sites can be achieved via landing at a specific location(s) or transit from a single designated landing location, but it is currently infeasible to transit long distances and through extremely rugged terrain, requiring landing close to the site of interest. The entry environment is not always guaranteed with a direct entry, and improving the entry systems robustness to a variety of environmental conditions could aid in reaching more varied landing sites. The National Research Council (NRC) Space Technology Roadmaps and Priorities report highlights six challenges and they are: 1) Mass to Surface, 2) Surface Access, 3) Precision Landing, 4) Surface Hazard Detection and Avoidance, 5) Safety and Mission Assurance, and 6) Affordability. In order for NASA to meet these challenges, the report recommends immediate focus on Rigid and Flexible Thermal Protection Systems. Rigid TPS systems such as Avcoat or SLA are honeycomb based and PICA is in the form of tiles. The honeycomb systems is manufactured using techniques that require filling of each (3/8 cell) by hand and within a limited amount of time once the ablative compound is mixed, all of the cells have to be filled and the entire heat-shield has to be cured. The tile systems such as PICA pose a different challenge as the mechanical strength characteristic and the manufacturing limitations require large number of small tiles with gap-fillers between the tiles. Recent investments in flexible ablative systems have given rise to the potential for conformal ablative TPS> A conformal TPS over a rigid aeroshell has the potential to solve a number of challenges faced by traditional rigid TPS materials.

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

NASA Astrophysics Data System (ADS)

Kishimoto, Naoki; Waizumi, Hiroki

2017-10-01

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

Hierarchical sampling for metastable conformers determines biomolecular recognition: the case of malectin and diglucosylated N-glycan interactions.

PubMed

Mamidi, Ashalatha Sreshty; Surolia, Avadhesha

2015-01-01

Structural information over the entire course of binding interactions based on the analyses of energy landscapes is described, which provides a framework to understand the events involved during biomolecular recognition. Conformational dynamics of malectin's exquisite selectivity for diglucosylated N-glycan (Dig-N-glycan), a highly flexible oligosaccharide comprising of numerous dihedral torsion angles, are described as an example. For this purpose, a novel approach based on hierarchical sampling for acquiring metastable molecular conformations constituting low-energy minima for understanding the structural features involved in a biologic recognition is proposed. For this purpose, four variants of principal component analysis were employed recursively in both Cartesian space and dihedral angles space that are characterized by free energy landscapes to select the most stable conformational substates. Subsequently, k-means clustering algorithm was implemented for geometric separation of the major native state to acquire a final ensemble of metastable conformers. A comparison of malectin complexes was then performed to characterize their conformational properties. Analyses of stereochemical metrics and other concerted binding events revealed surface complementarity, cooperative and bidentate hydrogen bonds, water-mediated hydrogen bonds, carbohydrate-aromatic interactions including CH-π and stacking interactions involved in this recognition. Additionally, a striking structural transition from loop to β-strands in malectin CRD upon specific binding to Dig-N-glycan is observed. The interplay of the above-mentioned binding events in malectin and Dig-N-glycan supports an extended conformational selection model as the underlying binding mechanism.

Conformal collineations and anisotropic fluids in general relativity

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

Duggal, K.L.; Sharma, R.

1986-10-01

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

Frame covariant nonminimal multifield inflation

NASA Astrophysics Data System (ADS)

Karamitsos, Sotirios; Pilaftsis, Apostolos

2018-02-01

We introduce a frame-covariant formalism for inflation of scalar-curvature theories by adopting a differential geometric approach which treats the scalar fields as coordinates living on a field-space manifold. This ensures that our description of inflation is both conformally and reparameterization covariant. Our formulation gives rise to extensions of the usual Hubble and potential slow-roll parameters to generalized fully frame-covariant forms, which allow us to provide manifestly frame-invariant predictions for cosmological observables, such as the tensor-to-scalar ratio r, the spectral indices nR and nT, their runnings αR and αT, the non-Gaussianity parameter fNL, and the isocurvature fraction βiso. We examine the role of the field space curvature in the generation and transfer of isocurvature modes, and we investigate the effect of boundary conditions for the scalar fields at the end of inflation on the observable inflationary quantities. We explore the stability of the trajectories with respect to the boundary conditions by using a suitable sensitivity parameter. To illustrate our approach, we first analyze a simple minimal two-field scenario before studying a more realistic nonminimal model inspired by Higgs inflation. We find that isocurvature effects are greatly enhanced in the latter scenario and must be taken into account for certain values in the parameter space such that the model is properly normalized to the observed scalar power spectrum PR. Finally, we outline how our frame-covariant approach may be extended beyond the tree-level approximation through the Vilkovisky-De Witt formalism, which we generalize to take into account conformal transformations, thereby leading to a fully frame-invariant effective action at the one-loop level.

Backbone conformational preferences of an intrinsically disordered protein in solution.

PubMed

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

2012-06-01

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

Inherent structure versus geometric metric for state space discretization.

PubMed

Liu, Hanzhong; Li, Minghai; Fan, Jue; Huo, Shuanghong

2016-05-30

Inherent structure (IS) and geometry-based clustering methods are commonly used for analyzing molecular dynamics trajectories. ISs are obtained by minimizing the sampled conformations into local minima on potential/effective energy surface. The conformations that are minimized into the same energy basin belong to one cluster. We investigate the influence of the applications of these two methods of trajectory decomposition on our understanding of the thermodynamics and kinetics of alanine tetrapeptide. We find that at the microcluster level, the IS approach and root-mean-square deviation (RMSD)-based clustering method give totally different results. Depending on the local features of energy landscape, the conformations with close RMSDs can be minimized into different minima, while the conformations with large RMSDs could be minimized into the same basin. However, the relaxation timescales calculated based on the transition matrices built from the microclusters are similar. The discrepancy at the microcluster level leads to different macroclusters. Although the dynamic models established through both clustering methods are validated approximately Markovian, the IS approach seems to give a meaningful state space discretization at the macrocluster level in terms of conformational features and kinetics. © 2016 Wiley Periodicals, Inc.

De novo protein structure prediction by dynamic fragment assembly and conformational space annealing.

PubMed

Lee, Juyong; Lee, Jinhyuk; Sasaki, Takeshi N; Sasai, Masaki; Seok, Chaok; Lee, Jooyoung

2011-08-01

Ab initio protein structure prediction is a challenging problem that requires both an accurate energetic representation of a protein structure and an efficient conformational sampling method for successful protein modeling. In this article, we present an ab initio structure prediction method which combines a recently suggested novel way of fragment assembly, dynamic fragment assembly (DFA) and conformational space annealing (CSA) algorithm. In DFA, model structures are scored by continuous functions constructed based on short- and long-range structural restraint information from a fragment library. Here, DFA is represented by the full-atom model by CHARMM with the addition of the empirical potential of DFIRE. The relative contributions between various energy terms are optimized using linear programming. The conformational sampling was carried out with CSA algorithm, which can find low energy conformations more efficiently than simulated annealing used in the existing DFA study. The newly introduced DFA energy function and CSA sampling algorithm are implemented into CHARMM. Test results on 30 small single-domain proteins and 13 template-free modeling targets of the 8th Critical Assessment of protein Structure Prediction show that the current method provides comparable and complementary prediction results to existing top methods. Copyright © 2011 Wiley-Liss, Inc.

Permuting input for more effective sampling of 3D conformer space

NASA Astrophysics Data System (ADS)

Carta, Giorgio; Onnis, Valeria; Knox, Andrew J. S.; Fayne, Darren; Lloyd, David G.

2006-03-01

SMILES strings and other classic 2D structural formats offer a convenient way to represent molecules as a simplistic connection table, with the inherent advantages of ease of handling and storage. In the context of virtual screening, chemical databases to be screened are often initially represented by canonicalised SMILES strings that can be filtered and pre-processed in a number of ways, resulting in molecules that occupy similar regions of chemical space to active compounds of a therapeutic target. A wide variety of software exists to convert molecules into SMILES format, namely, Mol2smi (Daylight Inc.), MOE (Chemical Computing Group) and Babel (Openeye Scientific Software). Depending on the algorithm employed, the atoms of a SMILES string defining a molecule can be ordered differently. Upon conversion to 3D coordinates they result in the production of ostensibly the same molecule. In this work we show how different permutations of a SMILES string can affect conformer generation, affecting reliability and repeatability of the results. Furthermore, we propose a novel procedure for the generation of conformers, taking advantage of the permutation of the input strings—both SMILES and other 2D formats, leading to more effective sampling of conformation space in output, and also implementing fingerprint and principal component analyses step to post process and visualise the results.

Relativistic anisotropic hydrodynamics

NASA Astrophysics Data System (ADS)

Alqahtani, Mubarak; Nopoush, Mohammad; Strickland, Michael

2018-07-01

In this paper we review recent progress in relativistic anisotropic hydrodynamics. We begin with a pedagogical introduction to the topic which takes into account the advances in our understanding of this topic since its inception. We consider both conformal and non-conformal systems and demonstrate how one can implement a realistic equation of state using a quasiparticle approach. We then consider the inclusion of non-spheroidal (non-ellipsoidal) corrections to leading-order anisotropic hydrodynamics and present the findings of the resulting second-order viscous anisotropic hydrodynamics framework. We compare the results obtained in both the conformal and non-conformal cases with exact solutions to the Boltzmann equation and demonstrate that, in all known cases, anisotropic hydrodynamics best reproduces the exact solutions. Based on this success, we then discuss the phenomenological application of anisotropic hydrodynamics. Along these lines, we review techniques which can be used to convert a momentum-space anisotropic fluid into hadronic degrees of freedom by generalizing the original idea of Cooper-Frye freeze-out to momentum-space anisotropic systems. And, finally, we present phenomenological results of 3 + 1 d quasiparticle anisotropic hydrodynamic simulations and compare them to experimental data produced in 2.76 TeV Pb-Pb collisions at the LHC. Our results indicate that anisotropic hydrodynamics provides a promising framework for describing the dynamics of the momentum-space anisotropic QGP created in heavy-ion collisions.

Equilibrium stochastic dynamics of a Brownian particle in inhomogeneous space: Derivation of an alternative model

NASA Astrophysics Data System (ADS)

Bhattacharyay, A.

2018-03-01

An alternative equilibrium stochastic dynamics for a Brownian particle in inhomogeneous space is derived. Such a dynamics can model the motion of a complex molecule in its conformation space when in equilibrium with a uniform heat bath. The derivation is done by a simple generalization of the formulation due to Zwanzig for a Brownian particle in homogeneous heat bath. We show that, if the system couples to different number of bath degrees of freedom at different conformations then the alternative model gets derived. We discuss results of an experiment by Faucheux and Libchaber which probably has indicated possible limitation of the Boltzmann distribution as equilibrium distribution of a Brownian particle in inhomogeneous space and propose experimental verification of the present theory using similar methods.

Research on conformal dome of Karman-curve shape

NASA Astrophysics Data System (ADS)

Zhang, Yunqiang; Chang, Jun; Niu, Yajun

2018-01-01

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

Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling

NASA Astrophysics Data System (ADS)

Pérez-Castillo, Yunierkis; Froeyen, Matheus; Cabrera-Pérez, Miguel Ángel; Nowé, Ann

2011-04-01

Bacterial β-ketoacyl-acyl carrier protein synthase III (FabH) has become an attractive target for the development of new antibacterial agents which can overcome the increased resistance of these pathogens to antibiotics in clinical use. Despite several efforts have been dedicated to find inhibitors for this enzyme, it is not a straightforward task, mainly due its high flexibility which makes difficult the structure-based design of FabH inhibitors. Here, we present for the first time a Molecular Dynamics (MD) study of the E. colil FabH enzyme to explore its conformational space. We compare the flexibility of this enzyme for the unliganded protein and an enzyme-inhibitor complex and find a correspondence between our modeling results and the experimental evidence previously reported for this enzyme. Furthermore, through a 100 ns MD simulation of the unliganded enzyme we extract useful information related to the concerted motions that take place along the principal components of displacement. We also establish a relation between the presence of water molecules in the oxyanion hole with the conformational stability of structural important loops. Representative conformations of the binding pocket along the whole trajectory of the unliganded protein are selected through cluster analysis and we find that they contain a conformational diversity which is not provided by the X-ray structures of ecFabH. As a proof of this last hypothesis, we use a set of 10 FabH inhibitors and show that they cannot be correctly modeled in any available X-ray structure, while by using our set of conformations extracted from the MD simulations, this task can be accomplish. Finally, we show the ability of short MD simulations for the refinement of the docking binding poses and for MM-PBSA calculations to predict stable protein-inhibitor complexes in this enzyme.

Modeling activated states of GPCRs: the rhodopsin template.

PubMed

Niv, Masha Y; Skrabanek, Lucy; Filizola, Marta; Weinstein, Harel

2006-01-01

Activation of G Protein-Coupled Receptors (GPCRs) is an allosteric mechanism triggered by ligand binding and resulting in conformational changes transduced by the transmembrane domain. Models of the activated forms of GPCRs have become increasingly necessary for the development of a clear understanding of signal propagation into the cell. Experimental evidence points to a multiplicity of conformations related to the activation of the receptor, rendered important physiologically by the suggestion that different conformations may be responsible for coupling to different signaling pathways. In contrast to the inactive state of rhodopsin (RHO) for which several high quality X-ray structures are available, the structure-related information for the active states of rhodopsin and all other GPCRs is indirect. We have collected and stored such information in a repository we maintain for activation-specific structural data available for rhodopsin-like GPCRs, http://www.physiology.med.cornell.edu/GPCRactivation/gpcrindex.html . Using these data as structural constraints, we have applied Simulated Annealing Molecular Dynamics to construct a number of different active state models of RHO starting from the known inactive structure. The common features of the models indicate that TM3 and TM5 play an important role in activation, in addition to the well-established rearrangement of TM6. Some of the structural changes observed in these models occur in regions that were not involved in the constraints, and have not been previously tested experimentally; they emerge as interesting candidates for further experimental exploration of the conformational space of activated GPCRs. We show that none of the normal modes calculated from the inactive structure has a dominant contribution along the path of conformational rearrangement from inactive to the active forms of RHO in the models. This result may differentiate rhodopsin from other GPCRs, and the reasons for this difference are discussed in the context of the structural properties and the physiological function of the protein.

Pilot Non-Conformance to Alerting System Commands During Closely Spaced Parallel Approaches

NASA Technical Reports Server (NTRS)

Pritchett, Amy Ruth; Hansman, R. John; Corker, Kevin (Technical Monitor)

1997-01-01

Cockpit alerting systems monitor potentially hazardous situations, both inside and outside the aircraft. When a hazard is projected to occur, the alerting system displays alerts and/or command decisions to the pilot. However, pilots have been observed to not conform to alerting system commands by delaying their response or by not following the automatic commands exactly. This non-conformance to the automatic alerting system can reduce its benefit. Therefore, a need exists to understand the causes and effects of pilot non-conformance in order to develop automatic alerting systems whose commands the pilots are more likely to follow. These considerations were examined through flight simulator evaluations of the collision avoidance task during closely spaced parallel approaches. This task provided a useful case-study because the effects of non-conformance can be significant, given the time-critical nature of the task. A preliminary evaluation of alerting systems identified non-conformance in over 40% of the cases and a corresponding drop in collision avoidance performance. A follow-on experiment found subjects' alerting and maneuver selection criteria were consistent with different strategies than those used by automatic systems, indicating the pilot may potentially disagree with the alerting system if the pilot attempts to verify automatic alerts and commanded avoidance maneuvers. A final experiment found supporting automatic alerts with the explicit display of its underlying criteria resulted in more consistent subject reactions. In light of these experimental results, a general discussion of pilot non-conformance is provided. Contributing factors in pilot non-conformance include a lack of confidence in the automatic system and mismatches between the alerting system's commands and the pilots' own decisions based on the information available to them. The effects of non-conformance on system performance are discussed. Possible methods of reconciling mismatches are given, and design considerations for alerting systems which alleviate the problem of non-conformance are provided.

Conformational and functional analysis of molecular dynamics trajectories by Self-Organising Maps

PubMed Central

2011-01-01

Background Molecular dynamics (MD) simulations are powerful tools to investigate the conformational dynamics of proteins that is often a critical element of their function. Identification of functionally relevant conformations is generally done clustering the large ensemble of structures that are generated. Recently, Self-Organising Maps (SOMs) were reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data mining problems. We present a novel strategy to analyse and compare conformational ensembles of protein domains using a two-level approach that combines SOMs and hierarchical clustering. Results The conformational dynamics of the α-spectrin SH3 protein domain and six single mutants were analysed by MD simulations. The Cα's Cartesian coordinates of conformations sampled in the essential space were used as input data vectors for SOM training, then complete linkage clustering was performed on the SOM prototype vectors. A specific protocol to optimize a SOM for structural ensembles was proposed: the optimal SOM was selected by means of a Taguchi experimental design plan applied to different data sets, and the optimal sampling rate of the MD trajectory was selected. The proposed two-level approach was applied to single trajectories of the SH3 domain independently as well as to groups of them at the same time. The results demonstrated the potential of this approach in the analysis of large ensembles of molecular structures: the possibility of producing a topological mapping of the conformational space in a simple 2D visualisation, as well as of effectively highlighting differences in the conformational dynamics directly related to biological functions. Conclusions The use of a two-level approach combining SOMs and hierarchical clustering for conformational analysis of structural ensembles of proteins was proposed. It can easily be extended to other study cases and to conformational ensembles from other sources. PMID:21569575

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

PubMed

Lungu, Claudiu N; Diudea, Mircea V

2018-01-01

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

A New Paradigm for Robotic Rovers

NASA Astrophysics Data System (ADS)

Clark, P. E.; Curtis, S. A.; Rilee, M. L.

We are in the process of developing rovers with extreme mobility needed to explore remote, rugged terrain. We call these systems Tetrahedral Explorer Technologies (TETs). Architecture is based on conformable tetrahedra, the simplest space-filling form, as building blocks, single or networked, where apices act as nodes from which struts reversibly deploy. The tetrahedral framework acts as a simple skeletal muscular structure. We have already prototyped a simple robotic walker from a single reconfigurable tetrahedron capable of tumbling and a more evolved 12Tetrahedral Walker, the Autonomous Landed Investigator (ALI), which has interior nodes for payload, more continuous motion, and is commandable through a user friendly interface. ALI is an EMS level mission concept which would allow autonomous in situ exploration of the lunar poles within the next decade. ALI would consist of one or more 12tetrahedral walkers capable of rapid locomotion with the many degrees of freedom and equipped for navigation in the unilluminated, inaccessible and thus largely unexplored rugged terrains where lunar resources are likely to be found: the Polar Regions. ALI walkers would act as roving reconnaissance teams for unexplored regions, analyzing samples along the way.

Recursive Techniques for Computing Gluon Scattering in Anti-de-Sitter Space

NASA Astrophysics Data System (ADS)

Shyaka, Claude; Kharel, Savan

2016-03-01

The anti-de Sitter/conformal field theory correspondence is a relationship between two kinds of physical theories. On one side of the duality are special type of quantum (conformal) field theories known as the Yang-Mills theory. These quantum field theories are known to be equivalent to theories of gravity in Anti-de Sitter (AdS) space. The physical observables in the theory are the correlation functions that live in the boundary of AdS space. In general correlation functions are computed using configuration space and the expressions are extremely complicated. Using momentum basis and recursive techniques developed by Raju, we extend tree level correlation functions for four and five-point correlation functions in Yang-Mills theory in Anti-de Sitter space. In addition, we show that for certain external helicity, the correlation functions have simple analytic structure. Finally, we discuss how one can generalize these results to n-point functions. Hendrix college odyssey Grant.

BP-Dock: A Flexible Docking Scheme for Exploring Protein–Ligand Interactions Based on Unbound Structures

PubMed Central

Bolia, Ashini; Gerek, Z. Nevin; Ozkan, S. Banu

2016-01-01

Molecular docking serves as an important tool in modeling protein–ligand interactions. However, it is still challenging to incorporate overall receptor flexibility, especially backbone flexibility, in docking due to the large conformational space that needs to be sampled. To overcome this problem, we developed a novel flexible docking approach, BP-Dock (Backbone Perturbation-Dock) that can integrate both backbone and side chain conformational changes induced by ligand binding through a multi-scale approach. In the BP-Dock method, we mimic the nature of binding-induced events as a first-order approximation by perturbing the residues along the protein chain with a small Brownian kick one at a time. The response fluctuation profile of the chain upon these perturbations is computed using the perturbation response scanning method. These response fluctuation profiles are then used to generate binding-induced multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, we applied our approach on a large and diverse data set using unbound structures as receptors. We also compared the BP-Dock results with bound and unbound docking, where overall receptor flexibility was not taken into account. Our results highlight the importance of modeling backbone flexibility in docking for recapitulating the experimental binding affinities, especially when an unbound structure is used. With BP-Dock, we can generate a wide range of binding site conformations realized in nature even in the absence of a ligand that can help us to improve the accuracy of unbound docking. We expect that our fast and efficient flexible docking approach may further aid in our understanding of protein–ligand interactions as well as virtual screening of novel targets for rational drug design. PMID:24380381

Correlation Functions in Two-Dimensional Critical Systems with Conformal Symmetry

NASA Astrophysics Data System (ADS)

Flores, Steven Miguel

This thesis presents a study of certain conformal field theory (CFT) correlation functions that describe physical observables in conform ally invariant two-dimensional critical systems. These are typically continuum limits of critical lattice models in a domain within the complex plane and with a boundary. Certain clusters, called boundary clusters, anchor to the boundary of the domain, and many of their features are governed by a conformally invariant probability measure. For example, percolaion is an example of a critical lattice model, and when it is confined to a domain with a boundary, connected clusters of activated bonds that touch that boundary are the boundary clusters. This thesis is concerned with how the boundary clusters interact with each other according to that measure. One question that it considers are "how likely are these clusters to repel each other or to connect with one another in a certain topological configuration?" Chapter one non-rigorously derives an already well-known elliptic system of differential equations closely tied to this matter by using standard techniques of CFT, chapters two and three rigorously infer certain properties concerning the solution space of this system, and chapter four uses some of those results to predict an answer to this question. This thesis also considers local variations of this question such as "what regions of the domain do the perimeters of the boundary clusters explore," and "how often will several boundary clusters connect at just a single, specified point in the domain?" Chapter five predicts precise answers to these questions. All of these answers are quantitative predictions that we verify via high-precision computer simulation. Chapters four and five also present these simulation results. Further material that supplements chapter one is included in two appendices.

Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

PubMed Central

Jo, Sunhwan; Bahar, Ivet; Roux, Benoît

2014-01-01

Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results. PMID:24699246

Application of Optimization Techniques to Design of Unconventional Rocket Nozzle Configurations

NASA Technical Reports Server (NTRS)

Follett, W.; Ketchum, A.; Darian, A.; Hsu, Y.

1996-01-01

Several current rocket engine concepts such as the bell-annular tri-propellant engine, and the linear aerospike being proposed for the X-33 require unconventional three dimensional rocket nozzles which must conform to rectangular or sector shaped envelopes to meet integration constraints. These types of nozzles exist outside the current experience database, therefore, the application of efficient design methods for these propulsion concepts is critical to the success of launch vehicle programs. The objective of this work is to optimize several different nozzle configurations, including two- and three-dimensional geometries. Methodology includes coupling computational fluid dynamic (CFD) analysis to genetic algorithms and Taguchi methods as well as implementation of a streamline tracing technique. Results of applications are shown for several geometeries including: three dimensional thruster nozzles with round or super elliptic throats and rectangualar exits, two- and three-dimensional thrusters installed within a bell nozzle, and three dimensional thrusters with round throats and sector shaped exits. Due to the novel designs considered for this study, there is little experience which can be used to guide the effort and limit the design space. With a nearly infinite parameter space to explore, simple parametric design studies cannot possibly search the entire design space within the time frame required to impact the design cycle. For this reason, robust and efficient optimization methods are required to explore and exploit the design space to achieve high performance engine designs. Five case studies which examine the application of various techniques in the engineering environment are presented in this paper.

An investigation into Ca-DNA conformation as a function of relative humidity

NASA Astrophysics Data System (ADS)

Smith, Megan Schwenker

Raman spectroscopy experiments on CaDNA free-standing, highly-ordered wet-spun films containing various concentrations of CaCl2 show that CaDNA does not adopt the A conformation and reveals a maximum of DNA in the B conformation at 80% relative humidity. Swelling experiments on these same films give information as to the intermolecular spacing between molecules. Finally, a proof of principle measurement of the activation enthalpy of guanosine is also given.

Correlated motion of protein subdomains and large-scale conformational flexibility of RecA protein filament

NASA Astrophysics Data System (ADS)

Yu, Garmay; A, Shvetsov; D, Karelov; D, Lebedev; A, Radulescu; M, Petukhov; V, Isaev-Ivanov

2012-02-01

Based on X-ray crystallographic data available at Protein Data Bank, we have built molecular dynamics (MD) models of homologous recombinases RecA from E. coli and D. radiodurans. Functional form of RecA enzyme, which is known to be a long helical filament, was approximated by a trimer, simulated in periodic water box. The MD trajectories were analyzed in terms of large-scale conformational motions that could be detectable by neutron and X-ray scattering techniques. The analysis revealed that large-scale RecA monomer dynamics can be described in terms of relative motions of 7 subdomains. Motion of C-terminal domain was the major contributor to the overall dynamics of protein. Principal component analysis (PCA) of the MD trajectories in the atom coordinate space showed that rotation of C-domain is correlated with the conformational changes in the central domain and N-terminal domain, that forms the monomer-monomer interface. Thus, even though C-terminal domain is relatively far from the interface, its orientation is correlated with large-scale filament conformation. PCA of the trajectories in the main chain dihedral angle coordinate space implicates a co-existence of a several different large-scale conformations of the modeled trimer. In order to clarify the relationship of independent domain orientation with large-scale filament conformation, we have performed analysis of independent domain motion and its implications on the filament geometry.

Construction of all N=4 conformal supergravities.

PubMed

Butter, Daniel; Ciceri, Franz; de Wit, Bernard; Sahoo, Bindusar

2017-02-24

All N=4 conformal supergravities in four space-time dimensions are constructed. These are the only N=4 supergravity theories whose actions are invariant under off-shell supersymmetry. They are encoded in terms of a holomorphic function that is homogeneous of zeroth degree in scalar fields that parametrize an SU(1,1)/U(1) coset space. When this function equals a constant the Lagrangian is invariant under continuous SU(1,1) transformations. The construction of these higher-derivative invariants also opens the door to various applications for nonconformal theories.

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

PubMed Central

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

2013-01-01

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

Prediction of conformationally dependent atomic multipole moments in carbohydrates

PubMed Central

Cardamone, Salvatore

2015-01-01

The conformational flexibility of carbohydrates is challenging within the field of computational chemistry. This flexibility causes the electron density to change, which leads to fluctuating atomic multipole moments. Quantum Chemical Topology (QCT) allows for the partitioning of an “atom in a molecule,” thus localizing electron density to finite atomic domains, which permits the unambiguous evaluation of atomic multipole moments. By selecting an ensemble of physically realistic conformers of a chemical system, one evaluates the various multipole moments at defined points in configuration space. The subsequent implementation of the machine learning method kriging delivers the evaluation of an analytical function, which smoothly interpolates between these points. This allows for the prediction of atomic multipole moments at new points in conformational space, not trained for but within prediction range. In this work, we demonstrate that the carbohydrates erythrose and threose are amenable to the above methodology. We investigate how kriging models respond when the training ensemble incorporating multiple energy minima and their environment in conformational space. Additionally, we evaluate the gains in predictive capacity of our models as the size of the training ensemble increases. We believe this approach to be entirely novel within the field of carbohydrates. For a modest training set size of 600, more than 90% of the external test configurations have an error in the total (predicted) electrostatic energy (relative to ab initio) of maximum 1 kJ mol−1 for open chains and just over 90% an error of maximum 4 kJ mol−1 for rings. © 2015 Wiley Periodicals, Inc. PMID:26547500

Prediction of conformationally dependent atomic multipole moments in carbohydrates.

PubMed

Cardamone, Salvatore; Popelier, Paul L A

2015-12-15

The conformational flexibility of carbohydrates is challenging within the field of computational chemistry. This flexibility causes the electron density to change, which leads to fluctuating atomic multipole moments. Quantum Chemical Topology (QCT) allows for the partitioning of an "atom in a molecule," thus localizing electron density to finite atomic domains, which permits the unambiguous evaluation of atomic multipole moments. By selecting an ensemble of physically realistic conformers of a chemical system, one evaluates the various multipole moments at defined points in configuration space. The subsequent implementation of the machine learning method kriging delivers the evaluation of an analytical function, which smoothly interpolates between these points. This allows for the prediction of atomic multipole moments at new points in conformational space, not trained for but within prediction range. In this work, we demonstrate that the carbohydrates erythrose and threose are amenable to the above methodology. We investigate how kriging models respond when the training ensemble incorporating multiple energy minima and their environment in conformational space. Additionally, we evaluate the gains in predictive capacity of our models as the size of the training ensemble increases. We believe this approach to be entirely novel within the field of carbohydrates. For a modest training set size of 600, more than 90% of the external test configurations have an error in the total (predicted) electrostatic energy (relative to ab initio) of maximum 1 kJ mol(-1) for open chains and just over 90% an error of maximum 4 kJ mol(-1) for rings. © 2015 Wiley Periodicals, Inc.

Beyond the Bend: Exploring the Conformational Landscape of Decyl, Undecyl, and Dodecylbenzene

NASA Astrophysics Data System (ADS)

Hewett, Daniel M.; Zwier, Timothy S.

2017-06-01

Alkylbenzenes are important components in the combustion process: they make up 20-30% of petroleum fuels and are intermediates on the pathway to soot formation. Understanding their conformational preferences is a vital step in understanding the processes by which fuels begin their journey from small, simple hydrocarbons into the large, graphitic masses of soot. Previous work done in our group, in collaboration with the Sibert group, found that the smallest alkylbenzene which folds its chain back over the ring is octylbenzene. The population of the lone folded structure in octylbenzene is low; however, theory predicts a rapid stabilization of the folded conformations relative to more extended structures as the chain length is increased, suggesting a likely shift in population towards folded structures. This talk will focus on our exploration of this possibility by discussing the UV excitation and single conformation IR spectra of decyl, undecyl, and dodecylbenzene, where increasing chain length allows for multiple stable folded configurations.

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

NASA Astrophysics Data System (ADS)

Yamamoto, Takashi; Kimikawa, Yuichi

1992-10-01

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

[Can the local energy minimization refine the PDB structures of different resolution universally?].

PubMed

Godzi, M G; Gromova, A P; Oferkin, I V; Mironov, P V

2009-01-01

The local energy minimization was statistically validated as the refinement strategy for PDB structure pairs of different resolution. Thirteen pairs of structures with the only difference in resolution were extracted from PDB, and the structures of 11 identical proteins obtained by different X-ray diffraction techniques were represented. The distribution of RMSD value was calculated for these pairs before and after the local energy minimization of each structure. The MMFF94 field was used for energy calculations, and the quasi-Newton method was used for local energy minimization. By comparison of these two RMSD distributions, the local energy minimization was proved to statistically increase the structural differences in pairs so that it cannot be used for refinement purposes. To explore the prospects of complex refinement strategies based on energy minimization, randomized structures were obtained by moving the initial PDB structures as far as the minimized structures had been moved in a multidimensional space of atomic coordinates. For these randomized structures, the RMSD distribution was calculated and compared with that for minimized structures. The significant differences in their mean values proved the energy surface of the protein to have only few minima near the conformations of different resolution obtained by X-ray diffraction for PDB. Some other results obtained by exploring the energy surface near these conformations are also presented. These results are expected to be very useful for the development of new protein refinement strategies based on energy minimization.

Exploring the conformational changes of the ATP binding site of gyrase B from Escherichia coli complexed with different established inhibitors by using molecular dynamics simulation: protein-ligand interactions in the light of the alanine scanning and free energy decomposition methods.

PubMed

Saíz-Urra, Liane; Cabrera, Miguel Angel; Froeyen, Matheus

2011-02-01

Currently, bacterial diseases cause a death toll around 2 million people a year encouraging the search for new antimicrobial agents. DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A(2)B(2). GyrA is involved in DNA breakage and reunion and GyrB catalyzes the hydrolysis of ATP. The GyrB subunit from Escherichia coli has been investigated, namely the ATP binding pocket both considering the protein without ligands and bound with the inhibitors clorobiocin, novobiocin and 5'-adenylyl-β-γ-imidodiphosphate. The stability of the systems was studied by molecular dynamics simulation with the further analysis of the time dependent root-mean-square coordinate deviation (RMSD) from the initial structure, and temperature factors. Moreover, exploration of the conformational space of the systems during the MD simulation was carried out by a clustering data mining technique using the average-linkage algorithm. Recognizing the key residues in the binding site of the enzyme that are involved in the binding mode with the aforementioned inhibitors was investigated by using two techniques: free energy decomposition and computational alanine scanning. The results from these simulations highlight the important residues in the ATP binding site and can be useful in the design process of potential new inhibitors. Copyright © 2010 Elsevier Inc. All rights reserved.

Prediction of RNA secondary structures: from theory to models and real molecules

NASA Astrophysics Data System (ADS)

Schuster, Peter

2006-05-01

RNA secondary structures are derived from RNA sequences, which are strings built form the natural four letter nucleotide alphabet, {AUGC}. These coarse-grained structures, in turn, are tantamount to constrained strings over a three letter alphabet. Hence, the secondary structures are discrete objects and the number of sequences always exceeds the number of structures. The sequences built from two letter alphabets form perfect structures when the nucleotides can form a base pair, as is the case with {GC} or {AU}, but the relation between the sequences and structures differs strongly from the four letter alphabet. A comprehensive theory of RNA structure is presented, which is based on the concepts of sequence space and shape space, being a space of structures. It sets the stage for modelling processes in ensembles of RNA molecules like evolutionary optimization or kinetic folding as dynamical phenomena guided by mappings between the two spaces. The number of minimum free energy (mfe) structures is always smaller than the number of sequences, even for two letter alphabets. Folding of RNA molecules into mfe energy structures constitutes a non-invertible mapping from sequence space onto shape space. The preimage of a structure in sequence space is defined as its neutral network. Similarly the set of suboptimal structures is the preimage of a sequence in shape space. This set represents the conformation space of a given sequence. The evolutionary optimization of structures in populations is a process taking place in sequence space, whereas kinetic folding occurs in molecular ensembles that optimize free energy in conformation space. Efficient folding algorithms based on dynamic programming are available for the prediction of secondary structures for given sequences. The inverse problem, the computation of sequences for predefined structures, is an important tool for the design of RNA molecules with tailored properties. Simultaneous folding or cofolding of two or more RNA molecules can be modelled readily at the secondary structure level and allows prediction of the most stable (mfe) conformations of complexes together with suboptimal states. Cofolding algorithms are important tools for efficient and highly specific primer design in the polymerase chain reaction (PCR) and help to explain the mechanisms of small interference RNA (si-RNA) molecules in gene regulation. The evolutionary optimization of RNA structures is illustrated by the search for a target structure and mimics aptamer selection in evolutionary biotechnology. It occurs typically in steps consisting of short adaptive phases interrupted by long epochs of little or no obvious progress in optimization. During these quasi-stationary epochs the populations are essentially confined to neutral networks where they search for sequences that allow a continuation of the adaptive process. Modelling RNA evolution as a simultaneous process in sequence and shape space provides answers to questions of the optimal population size and mutation rates. Kinetic folding is a stochastic process in conformation space. Exact solutions are derived by direct simulation in the form of trajectory sampling or by solving the master equation. The exact solutions can be approximated straightforwardly by Arrhenius kinetics on barrier trees, which represent simplified versions of conformational energy landscapes. The existence of at least one sequence forming any arbitrarily chosen pair of structures is granted by the intersection theorem. Folding kinetics is the key to understanding and designing multistable RNA molecules or RNA switches. These RNAs form two or more long lived conformations, and conformational changes occur either spontaneously or are induced through binding of small molecules or other biopolymers. RNA switches are found in nature where they act as elements in genetic and metabolic regulation. The reliability of RNA secondary structure prediction is limited by the accuracy with which the empirical parameters can be determined and by principal deficiencies, for example by the lack of energy contributions resulting from tertiary interactions. In addition, native structures may be determined by folding kinetics rather than by thermodynamics. We address the first problem by considering base pair probabilities or base pairing entropies, which are derived from the partition function of conformations. A high base pair probability corresponding to a low pairing entropy is taken as an indicator of a high reliability of prediction. Pseudoknots are discussed as an example of a tertiary interaction that is highly important for RNA function. Moreover, pseudoknot formation is readily incorporated into structure prediction algorithms. Some examples of experimental data on RNA secondary structures that are readily explained using the landscape concept are presented. They deal with (i) properties of RNA molecules with random sequences, (ii) RNA molecules from restricted alphabets, (iii) existence of neutral networks, (iv) shape space covering, (v) riboswitches and (vi) evolution of non-coding RNAs as an example of evolution restricted to neutral networks.

3DNALandscapes: a database for exploring the conformational features of DNA.

PubMed

Zheng, Guohui; Colasanti, Andrew V; Lu, Xiang-Jun; Olson, Wilma K

2010-01-01

3DNALandscapes, located at: http://3DNAscapes.rutgers.edu, is a new database for exploring the conformational features of DNA. In contrast to most structural databases, which archive the Cartesian coordinates and/or derived parameters and images for individual structures, 3DNALandscapes enables searches of conformational information across multiple structures. The database contains a wide variety of structural parameters and molecular images, computed with the 3DNA software package and known to be useful for characterizing and understanding the sequence-dependent spatial arrangements of the DNA sugar-phosphate backbone, sugar-base side groups, base pairs, base-pair steps, groove structure, etc. The data comprise all DNA-containing structures--both free and bound to proteins, drugs and other ligands--currently available in the Protein Data Bank. The web interface allows the user to link, report, plot and analyze this information from numerous perspectives and thereby gain insight into DNA conformation, deformability and interactions in different sequence and structural contexts. The data accumulated from known, well-resolved DNA structures can serve as useful benchmarks for the analysis and simulation of new structures. The collective data can also help to understand how DNA deforms in response to proteins and other molecules and undergoes conformational rearrangements.

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.

New insights into the folding of a β-sheet miniprotein in a reduced space of collective hydrogen bond variables: application to a hydrodynamic analysis of the folding flow.

PubMed

Kalgin, Igor V; Caflisch, Amedeo; Chekmarev, Sergei F; Karplus, Martin

2013-05-23

A new analysis of the 20 μs equilibrium folding/unfolding molecular dynamics simulations of the three-stranded antiparallel β-sheet miniprotein (beta3s) in implicit solvent is presented. The conformation space is reduced in dimensionality by introduction of linear combinations of hydrogen bond distances as the collective variables making use of a specially adapted principal component analysis (PCA); i.e., to make structured conformations more pronounced, only the formed bonds are included in determining the principal components. It is shown that a three-dimensional (3D) subspace gives a meaningful representation of the folding behavior. The first component, to which eight native hydrogen bonds make the major contribution (four in each beta hairpin), is found to play the role of the reaction coordinate for the overall folding process, while the second and third components distinguish the structured conformations. The representative points of the trajectory in the 3D space are grouped into conformational clusters that correspond to locally stable conformations of beta3s identified in earlier work. A simplified kinetic network based on the three components is constructed, and it is complemented by a hydrodynamic analysis. The latter, making use of "passive tracers" in 3D space, indicates that the folding flow is much more complex than suggested by the kinetic network. A 2D representation of streamlines shows there are vortices which correspond to repeated local rearrangement, not only around minima of the free energy surface but also in flat regions between minima. The vortices revealed by the hydrodynamic analysis are apparently not evident in folding pathways generated by transition-path sampling. Making use of the fact that the values of the collective hydrogen bond variables are linearly related to the Cartesian coordinate space, the RMSD between clusters is determined. Interestingly, the transition rates show an approximate exponential correlation with distance in the hydrogen bond subspace. Comparison with the many published studies shows good agreement with the present analysis for the parts that can be compared, supporting the robust character of our understanding of this "hydrogen atom" of protein folding.

Unique Aspects of the Structure and Dynamics of Elementary Iβ Cellulose Microfibrils Revealed by Computational Simulations1[OPEN

PubMed Central

Oehme, Daniel P.; Downton, Matthew T.; Doblin, Monika S.; Wagner, John; Gidley, Michael J.; Bacic, Antony

2015-01-01

The question of how many chains an elementary cellulose microfibril contains is critical to understanding the molecular mechanism(s) of cellulose biosynthesis and regulation. Given the hexagonal nature of the cellulose synthase rosette, it is assumed that the number of chains must be a multiple of six. We present molecular dynamics simulations on three different models of Iβ cellulose microfibrils, 18, 24, and 36 chains, to investigate their structure and dynamics in a hydrated environment. The 36-chain model stays in a conformational space that is very similar to the initial crystalline phase, while the 18- and 24-chain models sample a conformational space different from the crystalline structure yet similar to conformations observed in recent high-temperature molecular dynamics simulations. Major differences in the conformations sampled between the different models result from changes to the tilt of chains in different layers, specifically a second stage of tilt, increased rotation about the O2-C2 dihedral, and a greater sampling of non-TG exocyclic conformations, particularly the GG conformation in center layers and GT conformation in solvent-exposed exocyclic groups. With a reinterpretation of nuclear magnetic resonance data, specifically for contributions made to the C6 peak, data from the simulations suggest that the 18- and 24-chain structures are more viable models for an elementary cellulose microfibril, which also correlates with recent scattering and diffraction experimental data. These data inform biochemical and molecular studies that must explain how a six-particle cellulose synthase complex rosette synthesizes microfibrils likely comprised of either 18 or 24 chains. PMID:25786828

Force-momentum-based self-guided Langevin dynamics: A rapid sampling method that approaches the canonical ensemble

NASA Astrophysics Data System (ADS)

Wu, Xiongwu; Brooks, Bernard R.

2011-11-01

The self-guided Langevin dynamics (SGLD) is a method to accelerate conformational searching. This method is unique in the way that it selectively enhances and suppresses molecular motions based on their frequency to accelerate conformational searching without modifying energy surfaces or raising temperatures. It has been applied to studies of many long time scale events, such as protein folding. Recent progress in the understanding of the conformational distribution in SGLD simulations makes SGLD also an accurate method for quantitative studies. The SGLD partition function provides a way to convert the SGLD conformational distribution to the canonical ensemble distribution and to calculate ensemble average properties through reweighting. Based on the SGLD partition function, this work presents a force-momentum-based self-guided Langevin dynamics (SGLDfp) simulation method to directly sample the canonical ensemble. This method includes interaction forces in its guiding force to compensate the perturbation caused by the momentum-based guiding force so that it can approximately sample the canonical ensemble. Using several example systems, we demonstrate that SGLDfp simulations can approximately maintain the canonical ensemble distribution and significantly accelerate conformational searching. With optimal parameters, SGLDfp and SGLD simulations can cross energy barriers of more than 15 kT and 20 kT, respectively, at similar rates for LD simulations to cross energy barriers of 10 kT. The SGLDfp method is size extensive and works well for large systems. For studies where preserving accessible conformational space is critical, such as free energy calculations and protein folding studies, SGLDfp is an efficient approach to search and sample the conformational space.

The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions.

PubMed Central

Ri, Y; Ballesteros, J A; Abrams, C K; Oh, S; Verselis, V K; Weinstein, H; Bargiello, T A

1999-01-01

We have explored the role of a proline residue located at position 87 in the second transmembrane segment (TM2) of gap junctions in the mechanism of voltage-dependent gating of connexin32 (Cx32). Substitution of this proline (denoted Cx32P87) with residues G, A, or V affects channel function in a progressive manner consistent with the expectation that a proline kink (PK) motif exists in the second transmembrane segment (TM2) of this connexin. Mutations of the preceding threonine residue T86 to S, A, C, V, N, or L shift the conductance-voltage relation of wild-type Cx32, such that the mutated channels close at smaller transjunctional voltages. The observed shift in voltage dependence is consistent with a reduction in the open probability of the mutant hemichannels at a transjunctional voltage (Vj) of 0 mV. In both cases in which kinetics were examined, the time constants for reaching steady state were faster for T86N and T86A than for wild type at comparable voltages, suggesting that the T86 mutations cause the energetic destabilization of the open state relative to the other states of the channel protein. The structural underpinnings of the observed effects were explored with Monte Carlo simulations. The conformational space of TM2 helices was found to differ for the T86A, V, N, and L mutants, which produce a less bent helix ( approximately 20 degrees bend angle) compared to the wild type, which has a approximately 37 degrees bend angle. The greater bend angle of the wild-type helix reflects the propensity of the T86 residue to hydrogen bond with the backbone carbonyl of amino acid residue I82. The relative differences in propensity for hydrogen bonding of the mutants relative to the wild-type threonine residue in the constructs we studied (T86A, V, N, L, S, and C) correlate with the shift in the conductance-voltage relation observed for T86 mutations. The data are consistent with a structural model in which the open conformation of the Cx32 channel corresponds to a more bent TM2 helix, and the closed conformation corresponds to a less bent helix. We propose that the modulation of the hydrogen-bonding potential of the T86 residue alters the bend angle of the PK motif and mediates conformational changes between open and closed channel states. PMID:10354417

Update on Conformal Ablative Thermal Protection System for Planetary and Human Exploration Missions

NASA Astrophysics Data System (ADS)

Beck, R. A. S.; Arnold, J. O.; Gasch, M. J.; Stackpoole, M. M.; Venkatapathy, E.

2014-06-01

In FY13, more advanced testing and modeling of the new NASA conformal ablative TPS material was performed. Most notable were the 3- and 4-point bending tests and the aerothermal testing on seams and joints in shear. The material outperformed PICA.

The bridging conformations of double-end anchored polymer-surfactants destabilize a hydrogel of lipid membranes

NASA Astrophysics Data System (ADS)

Slack, N. L.; Davidson, P.; Chibbaro, M. A.; Jeppesen, C.; Eiselt, P.; Warriner, H. E.; Schmidt, H.-W.; Pincus, P.; Safinya, C. R.

2001-10-01

Double-end-anchored poly-ethylene-glycol-surfactants (DEA-PEG-surfactants) induce the gelation of lyotropic lamellar Lα phases stabilized by undulation forces. The physical hydrogel (Lα,g) derives its viscoelasticity from the proliferation of defects at a mesoscopic level. The DEA-PEG-surfactants assume both looping and bridging conformations. The existence of novel bridging conformations is indicated by the coexistence of two lamellar phases and the limited swelling of the Lα and Lα,g phases. Modeling of the polymer decorated membranes demonstrates the existence of bridging and yields a rapidly decreasing density of bridging conformations with increasing interlayer spacing.

Enhanced sampling of molecular dynamics simulation of peptides and proteins by double coupling to thermal bath.

PubMed

Chen, Changjun; Huang, Yanzhao; Xiao, Yi

2013-01-01

Low sampling efficiency in conformational space is the well-known problem for conventional molecular dynamics. It greatly increases the difficulty for molecules to find the transition path to native state, and costs amount of CPU time. To accelerate the sampling, in this paper, we re-couple the critical degrees of freedom in the molecule to environment temperature, like dihedrals in generalized coordinates or nonhydrogen atoms in Cartesian coordinate. After applying to ALA dipeptide model, we find that this modified molecular dynamics greatly enhances the sampling behavior in the conformational space and provides more information about the state-to-state transition, while conventional molecular dynamics fails to do so. Moreover, from the results of 16 independent 100 ns simulations by the new method, it shows that trpzip2 has one-half chances to reach the naive state in all the trajectories, which is greatly higher than conventional molecular dynamics. Such an improvement would provide a potential way for searching the conformational space or predicting the most stable states of peptides and proteins.

New 'phase' of quantum gravity.

PubMed

Wang, Charles H-T

2006-12-15

The emergence of loop quantum gravity over the past two decades has stimulated a great resurgence of interest in unifying general relativity and quantum mechanics. Among a number of appealing features of this approach is the intuitive picture of quantum geometry using spin networks and powerful mathematical tools from gauge field theory. However, the present form of loop quantum gravity suffers from a quantum ambiguity, owing to the presence of a free (Barbero-Immirzi) parameter. Following the recent progress on conformal decomposition of gravitational fields, we present a new phase space for general relativity. In addition to spin-gauge symmetry, the new phase space also incorporates conformal symmetry making the description parameter free. The Barbero-Immirzi ambiguity is shown to occur only if the conformal symmetry is gauge fixed prior to quantization. By withholding its full symmetries, the new phase space offers a promising platform for the future development of loop quantum gravity. This paper aims to provide an exposition, at a reduced technical level, of the above theoretical advances and their background developments. Further details are referred to cited references.

StructMap: Elastic Distance Analysis of Electron Microscopy Maps for Studying Conformational Changes.

PubMed

Sanchez Sorzano, Carlos Oscar; Alvarez-Cabrera, Ana Lucia; Kazemi, Mohsen; Carazo, Jose María; Jonić, Slavica

2016-04-26

Single-particle electron microscopy (EM) has been shown to be very powerful for studying structures and associated conformational changes of macromolecular complexes. In the context of analyzing conformational changes of complexes, distinct EM density maps obtained by image analysis and three-dimensional (3D) reconstruction are usually analyzed in 3D for interpretation of structural differences. However, graphic visualization of these differences based on a quantitative analysis of elastic transformations (deformations) among density maps has not been done yet due to a lack of appropriate methods. Here, we present an approach that allows such visualization. This approach is based on statistical analysis of distances among elastically aligned pairs of EM maps (one map is deformed to fit the other map), and results in visualizing EM maps as points in a lower-dimensional distance space. The distances among points in the new space can be analyzed in terms of clusters or trajectories of points related to potential conformational changes. The results of the method are shown with synthetic and experimental EM maps at different resolutions. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Rotational Spectrum and Conformational Analysis of N-methyl-2-aminoethanol: Insights into the Shape of Adrenergic Neurotransmitters

NASA Astrophysics Data System (ADS)

Calabrese, Camilla; Maris, Assimo; Evangelisti, Luca; Piras, Anna; Parravicini, Valentina; Melandri, Sonia

2018-02-01

Abstract We describe an experimental and quantum chemical study for the accurate determination of the conformational space of small molecular systems governed by intramolecular non-covalent interactions. The model systems investigated belong to the biological relevant aminoalcohol’s family, and include 2-aminophenylethanol, 2-methylaminophenylethanol, noradrenaline, adrenaline 2-aminoethanol and N-methyl-2-aminoethanol. For the latter molecule, the rotational spectrum in the 6-18 and 59.6-74.4 GHz ranges was recorded in the isolated conditions of a free jet expansion. Based on the analysis of the rotational spectra, two different conformational species and 11 isotopologues were observed and their spectroscopic constants, including 14N-nuclear hyperfine coupling constants and methyl internal rotation barriers, were determined. From the experimental data a structural determination was obtained, which was also used to benchmark accurate quantum chemical calculations on the whole conformational space. Atom in molecules and non-covalent interactions theories allowed the characterization of the position of the intramolecular non-covalent interactions and the energies involved, highlighting the subtle balance responsible of the stabilization of all the molecular systems.

Inherent Structure versus Geometric Metric for State Space Discretization

PubMed Central

Liu, Hanzhong; Li, Minghai; Fan, Jue; Huo, Shuanghong

2016-01-01

Inherent structure (IS) and geometry-based clustering methods are commonly used for analyzing molecular dynamics trajectories. ISs are obtained by minimizing the sampled conformations into local minima on potential/effective energy surface. The conformations that are minimized into the same energy basin belong to one cluster. We investigate the influence of the applications of these two methods of trajectory decomposition on our understanding of the thermodynamics and kinetics of alanine tetrapeptide. We find that at the micro cluster level, the IS approach and root-mean-square deviation (RMSD) based clustering method give totally different results. Depending on the local features of energy landscape, the conformations with close RMSDs can be minimized into different minima, while the conformations with large RMSDs could be minimized into the same basin. However, the relaxation timescales calculated based on the transition matrices built from the micro clusters are similar. The discrepancy at the micro cluster level leads to different macro clusters. Although the dynamic models established through both clustering methods are validated approximately Markovian, the IS approach seems to give a meaningful state space discretization at the macro cluster level. PMID:26915811

Exploring the biological consequences of conformational changes in aspartame models containing constrained analogues of phenylalanine.

PubMed

Mollica, Adriano; Mirzaie, Sako; Costante, Roberto; Carradori, Simone; Macedonio, Giorgia; Stefanucci, Azzurra; Dvoracsko, Szabolcs; Novellino, Ettore

2016-12-01

The dipeptide aspartame (Asp-Phe-OMe) is a sweetener widely used in replacement of sucrose by food industry. 2',6'-Dimethyltyrosine (DMT) and 2',6'-dimethylphenylalanine (DMP) are two synthetic phenylalanine-constrained analogues, with a limited freedom in χ-space due to the presence of methyl groups in position 2',6' of the aromatic ring. These residues have shown to increase the activity of opioid peptides, such as endomorphins improving the binding to the opioid receptors. In this work, DMT and DMP have been synthesized following a diketopiperazine-mediated route and the corresponding aspartame derivatives (Asp-DMT-OMe and Asp-DMP-OMe) have been evaluated in vivo and in silico for their activity as synthetic sweeteners.

A comparison of design variables for control theory based airfoil optimization

NASA Technical Reports Server (NTRS)

Reuther, James; Jameson, Antony

1995-01-01

This paper describes the implementation of optimization techniques based on control theory for airfoil design. In our previous work in the area it was shown that control theory could be employed to devise effective optimization procedures for two-dimensional profiles by using either the potential flow or the Euler equations with either a conformal mapping or a general coordinate system. We have also explored three-dimensional extensions of these formulations recently. The goal of our present work is to demonstrate the versatility of the control theory approach by designing airfoils using both Hicks-Henne functions and B-spline control points as design variables. The research also demonstrates that the parameterization of the design space is an open question in aerodynamic design.

Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight.

PubMed

Purohit, Rituraj

2014-01-01

KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.

Conformally non-flat spacetime representing dense compact objects

NASA Astrophysics Data System (ADS)

Singh, Ksh. Newton; Bhar, Piyali; Rahaman, Farook; Pant, Neeraj; Rahaman, Mansur

2017-06-01

A new conformally non-flat interior spacetime embedded in five-dimensional (5D) pseudo Euclidean space is explored in this paper. We proceed our calculation with the assumption of spherically symmetric anisotropic matter distribution and Karmarkar condition (necessary condition for class one). This solution is free from geometrical singularity and well-behaved in all respects. We ansatz a new type of metric potential g11 and solve for the metric potential g00 via Karmarkar condition. Further, all the physical parameters are determined from Einstein’s field equations using the two metric potentials. All the constants of integration are determined using boundary conditions. Due to its conformally non-flat character, it can represent bounded configurations. Therefore, we have used it to model two compact stars Vela X-1 and Cyg X-2. Indeed, the obtained masses and radii of these two objects from our solution are well matched with those observed values given in [T. Gangopadhyay et al., Mon. Not. R. Astron. Soc. 431, 3216 (2013)] and [J. Casares et al., Mon. Not. R. Astron. Soc. 401, 2517 (2010)]. The equilibrium of the models is investigated from generalized TOV-equation. We have adopted [L. Herrera’s, Phys. Lett. A 165, 206 (1992)] method and static stability criterion of Harisson-Zeldovich-Novikov [B. K. Harrison et al., Gravitational Theory and Gravitational Collapse (University of Chicago Press, 1965); Ya. B. Zeldovich and I. D. Novikov, Relativistic Astrophysics, Vol. 1, Stars and Relativity (University of Chicago Press, 1971)] to analyze the stability of the models.

Encounter complexes and dimensionality reduction in protein-protein association.

PubMed

Kozakov, Dima; Li, Keyong; Hall, David R; Beglov, Dmitri; Zheng, Jiefu; Vakili, Pirooz; Schueler-Furman, Ora; Paschalidis, Ioannis Ch; Clore, G Marius; Vajda, Sandor

2014-04-08

An outstanding challenge has been to understand the mechanism whereby proteins associate. We report here the results of exhaustively sampling the conformational space in protein-protein association using a physics-based energy function. The agreement between experimental intermolecular paramagnetic relaxation enhancement (PRE) data and the PRE profiles calculated from the docked structures shows that the method captures both specific and non-specific encounter complexes. To explore the energy landscape in the vicinity of the native structure, the nonlinear manifold describing the relative orientation of two solid bodies is projected onto a Euclidean space in which the shape of low energy regions is studied by principal component analysis. Results show that the energy surface is canyon-like, with a smooth funnel within a two dimensional subspace capturing over 75% of the total motion. Thus, proteins tend to associate along preferred pathways, similar to sliding of a protein along DNA in the process of protein-DNA recognition. DOI: http://dx.doi.org/10.7554/eLife.01370.001.

Encounter complexes and dimensionality reduction in protein–protein association

PubMed Central

Kozakov, Dima; Li, Keyong; Hall, David R; Beglov, Dmitri; Zheng, Jiefu; Vakili, Pirooz; Schueler-Furman, Ora; Paschalidis, Ioannis Ch; Clore, G Marius; Vajda, Sandor

2014-01-01

An outstanding challenge has been to understand the mechanism whereby proteins associate. We report here the results of exhaustively sampling the conformational space in protein–protein association using a physics-based energy function. The agreement between experimental intermolecular paramagnetic relaxation enhancement (PRE) data and the PRE profiles calculated from the docked structures shows that the method captures both specific and non-specific encounter complexes. To explore the energy landscape in the vicinity of the native structure, the nonlinear manifold describing the relative orientation of two solid bodies is projected onto a Euclidean space in which the shape of low energy regions is studied by principal component analysis. Results show that the energy surface is canyon-like, with a smooth funnel within a two dimensional subspace capturing over 75% of the total motion. Thus, proteins tend to associate along preferred pathways, similar to sliding of a protein along DNA in the process of protein-DNA recognition. DOI: http://dx.doi.org/10.7554/eLife.01370.001 PMID:24714491

SIMS: A Hybrid Method for Rapid Conformational Analysis

PubMed Central

Gipson, Bryant; Moll, Mark; Kavraki, Lydia E.

2013-01-01

Proteins are at the root of many biological functions, often performing complex tasks as the result of large changes in their structure. Describing the exact details of these conformational changes, however, remains a central challenge for computational biology due the enormous computational requirements of the problem. This has engendered the development of a rich variety of useful methods designed to answer specific questions at different levels of spatial, temporal, and energetic resolution. These methods fall largely into two classes: physically accurate, but computationally demanding methods and fast, approximate methods. We introduce here a new hybrid modeling tool, the Structured Intuitive Move Selector (sims), designed to bridge the divide between these two classes, while allowing the benefits of both to be seamlessly integrated into a single framework. This is achieved by applying a modern motion planning algorithm, borrowed from the field of robotics, in tandem with a well-established protein modeling library. sims can combine precise energy calculations with approximate or specialized conformational sampling routines to produce rapid, yet accurate, analysis of the large-scale conformational variability of protein systems. Several key advancements are shown, including the abstract use of generically defined moves (conformational sampling methods) and an expansive probabilistic conformational exploration. We present three example problems that sims is applied to and demonstrate a rapid solution for each. These include the automatic determination of “active” residues for the hinge-based system Cyanovirin-N, exploring conformational changes involving long-range coordinated motion between non-sequential residues in Ribose-Binding Protein, and the rapid discovery of a transient conformational state of Maltose-Binding Protein, previously only determined by Molecular Dynamics. For all cases we provide energetic validations using well-established energy fields, demonstrating this framework as a fast and accurate tool for the analysis of a wide range of protein flexibility problems. PMID:23935893

Stereotype Threat, Gender-Role Conformity, and New Zealand Adolescent Males in Choirs

ERIC Educational Resources Information Center

Watson, Penelope; Rubie-Davies, Christine Margaret; Hattie, John Allan

2017-01-01

Choirs have been stereotypically gendered feminine in many national contexts. When gender-role conformity has been expected in such settings, male choral participation and performance has often been rendered gender incongruent and consequently threatening. Gender stereotype threat was explored as a factor which might instigate a potentially…

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

PubMed

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

2018-05-21

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

Evaluation of an expert system for fault detection, isolation, and recovery in the manned maneuvering unit

NASA Technical Reports Server (NTRS)

Rushby, John; Crow, Judith

1990-01-01

The authors explore issues in the specification, verification, and validation of artificial intelligence (AI) based software, using a prototype fault detection, isolation and recovery (FDIR) system for the Manned Maneuvering Unit (MMU). They use this system as a vehicle for exploring issues in the semantics of C-Language Integrated Production System (CLIPS)-style rule-based languages, the verification of properties relating to safety and reliability, and the static and dynamic analysis of knowledge based systems. This analysis reveals errors and shortcomings in the MMU FDIR system and raises a number of issues concerning software engineering in CLIPs. The authors came to realize that the MMU FDIR system does not conform to conventional definitions of AI software, despite the fact that it was intended and indeed presented as an AI system. The authors discuss this apparent disparity and related questions such as the role of AI techniques in space and aircraft operations and the suitability of CLIPS for critical applications.

Design of ultrasensitive probes for human neutrophil elastase through hybrid combinatorial substrate library profiling

PubMed Central

Kasperkiewicz, Paulina; Poreba, Marcin; Snipas, Scott J.; Parker, Heather; Winterbourn, Christine C.; Salvesen, Guy S.; Drag, Marcin

2014-01-01

The exploration of protease substrate specificity is generally restricted to naturally occurring amino acids, limiting the degree of conformational space that can be surveyed. We substantially enhanced this by incorporating 102 unnatural amino acids to explore the S1–S4 pockets of human neutrophil elastase. This approach provides hybrid natural and unnatural amino acid sequences, and thus we termed it the Hybrid Combinatorial Substrate Library. Library results were validated by the synthesis of individual tetrapeptide substrates, with the optimal substrate demonstrating more than three orders of magnitude higher catalytic efficiency than commonly used substrates of elastase. This optimal substrate was converted to an activity-based probe that demonstrated high selectivity and revealed the specific presence of active elastase during the process of neutrophil extracellular trap formation. We propose that this approach can be successfully used for any type of endopeptidase to deliver high activity and selectivity in substrates and probes. PMID:24550277

Monitoring of the Conformational Space of Dipeptides by Generative Topographic Mapping.

PubMed

Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre

2018-01-01

This work describes a procedure to build generative topographic maps (GTM) as 2D representation of the conformational space (CS) of dipeptides. GTMs with excellent propensities to support highly predictive landscapes of various conformational properties were reported for three dipeptides (AA, KE and KR). CS monitoring via GTMproceeds through the projection of conformer ensembles on the map, producing cumulated responsibility (CR) vectors characteristic of the CS areas covered by the ensemble. Overlap of the CS areas visited by two distinct simulations can be expressed by the Tanimoto coefficient Tc of the associated CRs. This idea was used to monitor the reproducibility of the stochastic evolutionary conformer generation process implemented in S4MPLE. It could be shown that conformers produced by <500 S4MPLE runs reproducibly cover the relevant CS zone at given setup of the driving force field. The propensity of a simulation to visit the native CS zone can thus be quantitatively estimated, as the Tc score with respect to the "native" CR, as defined by the ensemble of dipeptide geometries extracted from PDB proteins. It could be shown that low-energy CS regions were indeed found to fall within the native zone. The Tc overlap score behaved as a smooth function of force field parameters. This opens the perspective of a novel force field parameter tuning procedure, bound to simultaneously optimize the behavior of the in Silico simulations for every possible dipeptide. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Crystal structure, matrix-isolation FTIR, and UV-induced conformational isomerization of 3-quinolinecarboxaldehyde.

PubMed

Kuş, Nihal; Henriques, Marta Sofia; Paixão, José António; Lapinski, Leszek; Fausto, Rui

2014-09-25

The crystal structure of 3-quinolinecarboxaldehyde (3QC) has been solved, and the compound has been shown to crystallize in the space group P21/c (monoclinic) with a = 6.306(4), b = 18.551(11), c = 6.999(4) Å, β = 106.111(13)°, and Z = 4. The crystals were found to exhibit pseudomerohedral twinning with a twin law corresponding to a two-fold rotation around the monoclinic (100) reciprocal lattice axis (or [4 0 1] in direct space). Individual molecules adopt the syn conformation in the crystal, with the oxygen atom of the aldehyde substituent directed toward the same side of the ring nitrogen atom. In the gas phase, the compound exists in two nearly isoenergetic conformers (syn and anti), which could be successfully trapped in solid argon at 10 K, and their infrared spectra are registered and interpreted. Upon in situ irradiation of matrix-isolated 3QC with UV light (λ > 315 nm), significant reduction of the population of the less stable anti conformer was observed, while that of the conformational ground state (syn conformer) increased, indicating occurrence of the anti → syn isomerization. Upon irradiation at higher energy (λ > 235 nm), the syn → anti reverse photoreaction was observed. Interpretation of the structural, spectroscopic, and photochemical experimental data received support from quantum chemical theoretical results obtained at both DFT/B3LYP (including TD-DFT investigation of excited states) and MP2 levels, using the 6-311++G(d,p) basis set.

Conformal, Transparent Printed Antenna Developed for Communication and Navigation Systems

NASA Technical Reports Server (NTRS)

Lee, Richard Q.; Simons, Rainee N.

1999-01-01

Conformal, transparent printed antennas have advantages over conventional antennas in terms of space reuse and aesthetics. Because of their compactness and thin profile, these antennas can be mounted on video displays for efficient integration in communication systems such as palmtop computers, digital telephones, and flat-panel television displays. As an array of multiple elements, the antenna subsystem may save weight by reusing space (via vertical stacking) on photovoltaic arrays or on Earth-facing sensors. Also, the antenna could go unnoticed on automobile windshields or building windows, enabling satellite uplinks and downlinks or other emerging high-frequency communications.

Detection and characterization of nonspecific, sparsely-populated binding modes in the early stages of complexation

PubMed Central

Cardone, A.; Bornstein, A.; Pant, H. C.; Brady, M.; Sriram, R.; Hassan, S. A.

2015-01-01

A method is proposed to study protein-ligand binding in a system governed by specific and non-specific interactions. Strong associations lead to narrow distributions in the proteins configuration space; weak and ultra-weak associations lead instead to broader distributions, a manifestation of non-specific, sparsely-populated binding modes with multiple interfaces. The method is based on the notion that a discrete set of preferential first-encounter modes are metastable states from which stable (pre-relaxation) complexes at equilibrium evolve. The method can be used to explore alternative pathways of complexation with statistical significance and can be integrated into a general algorithm to study protein interaction networks. The method is applied to a peptide-protein complex. The peptide adopts several low-population conformers and binds in a variety of modes with a broad range of affinities. The system is thus well suited to analyze general features of binding, including conformational selection, multiplicity of binding modes, and nonspecific interactions, and to illustrate how the method can be applied to study these problems systematically. The equilibrium distributions can be used to generate biasing functions for simulations of multiprotein systems from which bulk thermodynamic quantities can be calculated. PMID:25782918

Comparison of Multiple Molecular Dynamics Trajectories Calculated for the Drug-Resistant HIV-1 Integrase T66I/M154I Catalytic Domain

PubMed Central

Brigo, Alessandro; Lee, Keun Woo; Iurcu Mustata, Gabriela; Briggs, James M.

2005-01-01

HIV-1 integrase (IN) is an essential enzyme for the viral replication and an interesting target for the design of new pharmaceuticals for multidrug therapy of AIDS. Single and multiple mutations of IN at residues T66, S153, or M154 confer degrees of resistance to several inhibitors that prevent the enzyme from performing its normal strand transfer activity. Four different conformations of IN were chosen from a prior molecular dynamics (MD) simulation on the modeled IN T66I/M154I catalytic core domain as starting points for additional MD studies. The aim of this article is to understand the dynamic features that may play roles in the catalytic activity of the double mutant enzyme in the absence of any inhibitor. Moreover, we want to verify the influence of using different starting points on the MD trajectories and associated dynamical properties. By comparison of the trajectories obtained from these MD simulations we have demonstrated that the starting point does not affect the conformational space explored by this protein and that the time of the simulation is long enough to achieve convergence for this system. PMID:15764656

Crystal structures reveal an induced-fit binding of a substrate-like Aza-peptide epoxide to SARS coronavirus main peptidase.

PubMed

Lee, Ting-Wai; Cherney, Maia M; Liu, Jie; James, Karen Ellis; Powers, James C; Eltis, Lindsay D; James, Michael N G

2007-02-23

The SARS coronavirus main peptidase (SARS-CoV M(pro)) plays an essential role in the life-cycle of the virus and is a primary target for the development of anti-SARS agents. Here, we report the crystal structure of M(pro) at a resolution of 1.82 Angstroms, in space group P2(1) at pH 6.0. In contrast to the previously reported structure of M(pro) in the same space group at the same pH, the active sites and the S1 specificity pockets of both protomers in the structure of M(pro) reported here are in the catalytically competent conformation, suggesting their conformational flexibility. We report two crystal structures of M(pro) having an additional Ala at the N terminus of each protomer (M(+A(-1))(pro)), both at a resolution of 2.00 Angstroms, in space group P4(3)2(1)2: one unbound and one bound by a substrate-like aza-peptide epoxide (APE). In the unbound form, the active sites and the S1 specificity pockets of both protomers of M(+A(-1))(pro) are observed in a collapsed (catalytically incompetent) conformation; whereas they are in an open (catalytically competent) conformation in the APE-bound form. The observed conformational flexibility of the active sites and the S1 specificity pockets suggests that these parts of M(pro) exist in dynamic equilibrium. The structural data further suggest that the binding of APE to M(pro) follows an induced-fit model. The substrate likely also binds in an induced-fit manner in a process that may help drive the catalytic cycle.

New Perspectives for Hadron Phenomenology:The Effects of Final-State Interactions and Near-Conformal Effective QCD Couplings

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

Brodsky, S

2003-10-24

The effective QCD charge extracted from {tau} decay is remarkably constant at small momenta, implying the near-conformal behavior of hadronic interactions at small momentum transfer. The correspondence of large-N{sub c} supergravity theory in higher-dimensional anti-de Sitter spaces with gauge theory in physical space-time also has interesting implications for hadron phenomenology in the conformal limit, such as constituent counting rules for hard exclusive processes. The utility of light-front quantization and lightfront Fock wavefunctions for analyzing such phenomena and representing the dynamics of QCD bound states is reviewed. I also discuss the novel effects of initial- and final-state interactions in hard QCDmore » inclusive processes, including Bjorken-scaling single-spin asymmetries and the leading-twist diffractive and shadowing contributions to deep inelastic lepton-proton scattering.« less

New Skeletal-Space-Filling Models

ERIC Educational Resources Information Center

Clarke, Frank H.

1977-01-01

Describes plastic, skeletal molecular models that are color-coded and can illustrate both the conformation and overall shape of small molecules. They can also be converted to space-filling counterparts by the additions of color-coded polystyrene spheres. (MLH)

Conformal Transformations and Conformal Killing Fields

NASA Astrophysics Data System (ADS)

Definition 1.1 A semi-Riemannian manifold is a pair (M,g) consisting of a differentiate (i.e. C∞) manifold M and a differentiable tensor field g which assigns to each point a ∈ M a non-degenerate and symmetric bilinear form on the tangent space TaM: g_a :T_a M × T_a M to R.

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

PubMed

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

2012-12-13

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

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

PubMed

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

2010-02-01

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

Unique aspects of the structure and dynamics of elementary Iβ cellulose microfibrils revealed by computational simulations.

PubMed

Oehme, Daniel P; Downton, Matthew T; Doblin, Monika S; Wagner, John; Gidley, Michael J; Bacic, Antony

2015-05-01

The question of how many chains an elementary cellulose microfibril contains is critical to understanding the molecular mechanism(s) of cellulose biosynthesis and regulation. Given the hexagonal nature of the cellulose synthase rosette, it is assumed that the number of chains must be a multiple of six. We present molecular dynamics simulations on three different models of Iβ cellulose microfibrils, 18, 24, and 36 chains, to investigate their structure and dynamics in a hydrated environment. The 36-chain model stays in a conformational space that is very similar to the initial crystalline phase, while the 18- and 24-chain models sample a conformational space different from the crystalline structure yet similar to conformations observed in recent high-temperature molecular dynamics simulations. Major differences in the conformations sampled between the different models result from changes to the tilt of chains in different layers, specifically a second stage of tilt, increased rotation about the O2-C2 dihedral, and a greater sampling of non-TG exocyclic conformations, particularly the GG conformation in center layers and GT conformation in solvent-exposed exocyclic groups. With a reinterpretation of nuclear magnetic resonance data, specifically for contributions made to the C6 peak, data from the simulations suggest that the 18- and 24-chain structures are more viable models for an elementary cellulose microfibril, which also correlates with recent scattering and diffraction experimental data. These data inform biochemical and molecular studies that must explain how a six-particle cellulose synthase complex rosette synthesizes microfibrils likely comprised of either 18 or 24 chains. © 2015 American Society of Plant Biologists. All Rights Reserved.

Holographic derivation of entanglement entropy from the anti-de Sitter space/conformal field theory correspondence.

PubMed

Ryu, Shinsei; Takayanagi, Tadashi

2006-05-12

A holographic derivation of the entanglement entropy in quantum (conformal) field theories is proposed from anti-de Sitter/conformal field theory (AdS/CFT) correspondence. We argue that the entanglement entropy in d + 1 dimensional conformal field theories can be obtained from the area of d dimensional minimal surfaces in AdS(d+2), analogous to the Bekenstein-Hawking formula for black hole entropy. We show that our proposal agrees perfectly with the entanglement entropy in 2D CFT when applied to AdS(3). We also compare the entropy computed in AdS(5)XS(5) with that of the free N=4 super Yang-Mills theory.

Anti-de Sitter-space/conformal-field-theory Casimir energy for rotating black holes.

PubMed

Gibbons, G W; Perry, M J; Pope, C N

2005-12-02

We show that, if one chooses the Einstein static universe as the metric on the conformal boundary of Kerr-anti-de Sitter spacetime, then the Casimir energy of the boundary conformal field theory can easily be determined. The result is independent of the rotation parameters, and the total boundary energy then straightforwardly obeys the first law of thermodynamics. Other choices for the metric on the conformal boundary will give different, more complicated, results. As an application, we calculate the Casimir energy for free self-dual tensor multiplets in six dimensions and compare it with that of the seven-dimensional supergravity dual. They differ by a factor of 5/4.

A multifractal analysis of equilibrium measures for conformal expanding maps and Moran-like geometric constructions

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

Pesin, Y.; Weiss, H.

1997-01-01

In this paper we establish the complete multifractal formalism for equilibrium measures for Holder continuous conformal expanding maps and expanding Markov Moran-like geometric constructions. Examples include Markov maps of an interval, beta transformations of an interval, rational maps with hyperbolic Julia sets, and conformal total endomorphisms. We also construct a Holder continuous homeomorphism of a compact metric space with an ergodic invariant measure of positive entropy for which the dimension spectrum is not convex, and hence the multifractal formalism fails.

Conformational Asymmetry and Quasicrystal Approximants in Linear Diblock Copolymers

NASA Astrophysics Data System (ADS)

Schulze, Morgan W.; Lewis, Ronald M.; Lettow, James H.; Hickey, Robert J.; Gillard, Timothy M.; Hillmyer, Marc A.; Bates, Frank S.

2017-05-01

Small angle x-ray scattering experiments on three model low molar mass diblock copolymer systems containing minority polylactide and majority hydrocarbon blocks demonstrate that conformational asymmetry stabilizes the Frank-Kasper σ phase. Differences in block flexibility compete with space filling at constant density inducing the formation of polyhedral shaped particles that assemble into this low symmetry ordered state with local tetrahedral coordination. These results confirm predictions from self-consistent field theory that establish the origins of symmetry breaking in the ordering of block polymer melts subjected to compositional and conformational asymmetry.

Conformal structure of massless scalar amplitudes beyond tree level

NASA Astrophysics Data System (ADS)

Banerjee, Nabamita; Banerjee, Shamik; Bhatkar, Sayali Atul; Jain, Sachin

2018-04-01

We show that the one-loop on-shell four-point scattering amplitude of massless ϕ 4 scalar field theory in 4D Minkowski space time, when Mellin transformed to the Celestial sphere at infinity, transforms covariantly under the global conformal group (SL(2, ℂ)) on the sphere. The unitarity of the four-point scalar amplitudes is recast into this Mellin basis. We show that the same conformal structure also appears for the two-loop Mellin amplitude. Finally we comment on some universal structure for all loop four-point Mellin amplitudes specific to this theory.

Symmetric factorization of the conformation tensor in viscoelastic fluid models

NASA Astrophysics Data System (ADS)

Thomases, Becca; Balci, Nusret; Renardy, Michael; Doering, Charles

2010-11-01

The positive definite symmetric polymer conformation tensor possesses a unique symmetric square root that satisfies a closed evolution equation in the Oldroyd-B and FENE-P models of viscoelastic fluid flow. When expressed in terms of the velocity field and the symmetric square root of the conformation tensor, these models' equations of motion formally constitute an evolution in a Hilbert space with a total energy functional that defines a norm. Moreover, this formulation is easily implemented in direct numerical simulations resulting in significant practical advantages in terms of both accuracy and stability.

Cofactor-binding sites in proteins of deviating sequence: comparative analysis and clustering in torsion angle, cavity, and fold space.

PubMed

Stegemann, Björn; Klebe, Gerhard

2012-02-01

Small molecules are recognized in protein-binding pockets through surface-exposed physicochemical properties. To optimize binding, they have to adopt a conformation corresponding to a local energy minimum within the formed protein-ligand complex. However, their conformational flexibility makes them competent to bind not only to homologous proteins of the same family but also to proteins of remote similarity with respect to the shape of the binding pockets and folding pattern. Considering drug action, such observations can give rise to unexpected and undesired cross reactivity. In this study, datasets of six different cofactors (ADP, ATP, NAD(P)(H), FAD, and acetyl CoA, sharing an adenosine diphosphate moiety as common substructure), observed in multiple crystal structures of protein-cofactor complexes exhibiting sequence identity below 25%, have been analyzed for the conformational properties of the bound ligands, the distribution of physicochemical properties in the accommodating protein-binding pockets, and the local folding patterns next to the cofactor-binding site. State-of-the-art clustering techniques have been applied to group the different protein-cofactor complexes in the different spaces. Interestingly, clustering in cavity (Cavbase) and fold space (DALI) reveals virtually the same data structuring. Remarkable relationships can be found among the different spaces. They provide information on how conformations are conserved across the host proteins and which distinct local cavity and fold motifs recognize the different portions of the cofactors. In those cases, where different cofactors are found to be accommodated in a similar fashion to the same fold motifs, only a commonly shared substructure of the cofactors is used for the recognition process. Copyright © 2011 Wiley Periodicals, Inc.

A New Exploration of the Torsional Energy Surface of N-Pentane Using Molecular Modeling Software

ERIC Educational Resources Information Center

Galembeck, Sergio E.; Caramori, Giovanni F.; Romero, Jose Ricardo

2005-01-01

The torsional potential energy surface of a chemical compounds, the accessible conformations at a specified temperature and the transition states that connect these confirmations establishes many chemical properties such as dynamic behavior, reactivity and biological activity. A conformational search of n-pentane is presented using computational…

Vacillating between Opposing Conceptions of Personhood: Individualism and Conformism in Turkish Educational Practices

ERIC Educational Resources Information Center

Ceyhan, Muge Ayan

2009-01-01

Based on one and a half years of participant observation at Bakis School, this article aims to explore two different sets of educational practices, one which seemingly promotes sameness, obedience and conformity, and the other difference, entrepreneurialism and individualism. By way of discussing the shifting cultural values, beliefs and…

Characterizing Conformational Dynamics of Proteins Using Evolutionary Couplings.

PubMed

Feng, Jiangyan; Shukla, Diwakar

2018-01-25

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

Mechanism for Active Membrane Fusion Triggering by Morbillivirus Attachment Protein

PubMed Central

Ader, Nadine; Brindley, Melinda; Avila, Mislay; Örvell, Claes; Horvat, Branka; Hiltensperger, Georg; Schneider-Schaulies, Jürgen; Vandevelde, Marc; Zurbriggen, Andreas; Plemper, Richard K.

2013-01-01

The paramyxovirus entry machinery consists of two glycoproteins that tightly cooperate to achieve membrane fusion for cell entry: the tetrameric attachment protein (HN, H, or G, depending on the paramyxovirus genus) and the trimeric fusion protein (F). Here, we explore whether receptor-induced conformational changes within morbillivirus H proteins promote membrane fusion by a mechanism requiring the active destabilization of prefusion F or by the dissociation of prefusion F from intracellularly preformed glycoprotein complexes. To properly probe F conformations, we identified anti-F monoclonal antibodies (MAbs) that recognize conformation-dependent epitopes. Through heat treatment as a surrogate for H-mediated F triggering, we demonstrate with these MAbs that the morbillivirus F trimer contains a sufficiently high inherent activation energy barrier to maintain the metastable prefusion state even in the absence of H. This notion was further validated by exploring the conformational states of destabilized F mutants and stabilized soluble F variants combined with the use of a membrane fusion inhibitor (3g). Taken together, our findings reveal that the morbillivirus H protein must lower the activation energy barrier of metastable prefusion F for fusion triggering. PMID:23077316

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

PubMed

Fadrná, Eva; Koca, Jaroslav

2003-04-01

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

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

PubMed

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

2017-06-29

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

High-resolution comparative modeling with RosettaCM.

PubMed

Song, Yifan; DiMaio, Frank; Wang, Ray Yu-Ruei; Kim, David; Miles, Chris; Brunette, Tj; Thompson, James; Baker, David

2013-10-08

We describe an improved method for comparative modeling, RosettaCM, which optimizes a physically realistic all-atom energy function over the conformational space defined by homologous structures. Given a set of sequence alignments, RosettaCM assembles topologies by recombining aligned segments in Cartesian space and building unaligned regions de novo in torsion space. The junctions between segments are regularized using a loop closure method combining fragment superposition with gradient-based minimization. The energies of the resulting models are optimized by all-atom refinement, and the most representative low-energy model is selected. The CASP10 experiment suggests that RosettaCM yields models with more accurate side-chain and backbone conformations than other methods when the sequence identity to the templates is greater than ∼15%. Copyright © 2013 Elsevier Ltd. All rights reserved.

Emission behaviors of unsymmetrical 1,3-diaryl-β-diketones: A model perfectly disclosing the effect of molecular conformation on luminescence of organic solids

NASA Astrophysics Data System (ADS)

Cheng, Xiao; Li, Feng; Han, Shenghua; Zhang, Yufei; Jiao, Chuanjun; Wei, Jinbei; Ye, Kaiqi; Wang, Yue; Zhang, Hongyu

2015-03-01

A series of unsymmetrical 1,3-diaryl-β-diketones 1-6 displaying molecular conformation-dependent fluorescence quantum yields have been synthesized. Crystals with planar molecular conformation such as 1, 2, 3 and 4 are highly fluorescent (φf: 39-53%), and the one holding slightly twisted conformation (5) is moderately luminescent (φf = 17%), while crystal 6 possessing heavily bent structure is completely nonluminous (φf ~ 0). The distinct fluorescence efficiencies are ascribed to their different molecular conformations, since all the crystals hold the same crystal system, space group and crystal packing structures. Additionally, the fluorescent crystals 1-5 display low threshold amplified spontaneous emission (ASE) with small full widths at half-maximum (FWHM: 3-7 nm), indicating their potential as candidates for organic crystal lasing devices.

``Sequence space soup'' of proteins and copolymers

NASA Astrophysics Data System (ADS)

Chan, Hue Sun; Dill, Ken A.

1991-09-01

To study the protein folding problem, we use exhaustive computer enumeration to explore ``sequence space soup,'' an imaginary solution containing the ``native'' conformations (i.e., of lowest free energy) under folding conditions, of every possible copolymer sequence. The model is of short self-avoiding chains of hydrophobic (H) and polar (P) monomers configured on the two-dimensional square lattice. By exhaustive enumeration, we identify all native structures for every possible sequence. We find that random sequences of H/P copolymers will bear striking resemblance to known proteins: Most sequences under folding conditions will be approximately as compact as known proteins, will have considerable amounts of secondary structure, and it is most probable that an arbitrary sequence will fold to a number of lowest free energy conformations that is of order one. In these respects, this simple model shows that proteinlike behavior should arise simply in copolymers in which one monomer type is highly solvent averse. It suggests that the structures and uniquenesses of native proteins are not consequences of having 20 different monomer types, or of unique properties of amino acid monomers with regard to special packing or interactions, and thus that simple copolymers might be designable to collapse to proteinlike structures and properties. A good strategy for designing a sequence to have a minimum possible number of native states is to strategically insert many P monomers. Thus known proteins may be marginally stable due to a balance: More H residues stabilize the desired native state, but more P residues prevent simultaneous stabilization of undesired native states.

Swellix: a computational tool to explore RNA conformational space.

PubMed

Sloat, Nathan; Liu, Jui-Wen; Schroeder, Susan J

2017-11-21

The sequence of nucleotides in an RNA determines the possible base pairs for an RNA fold and thus also determines the overall shape and function of an RNA. The Swellix program presented here combines a helix abstraction with a combinatorial approach to the RNA folding problem in order to compute all possible non-pseudoknotted RNA structures for RNA sequences. The Swellix program builds on the Crumple program and can include experimental constraints on global RNA structures such as the minimum number and lengths of helices from crystallography, cryoelectron microscopy, or in vivo crosslinking and chemical probing methods. The conceptual advance in Swellix is to count helices and generate all possible combinations of helices rather than counting and combining base pairs. Swellix bundles similar helices and includes improvements in memory use and efficient parallelization. Biological applications of Swellix are demonstrated by computing the reduction in conformational space and entropy due to naturally modified nucleotides in tRNA sequences and by motif searches in Human Endogenous Retroviral (HERV) RNA sequences. The Swellix motif search reveals occurrences of protein and drug binding motifs in the HERV RNA ensemble that do not occur in minimum free energy or centroid predicted structures. Swellix presents significant improvements over Crumple in terms of efficiency and memory use. The efficient parallelization of Swellix enables the computation of sequences as long as 418 nucleotides with sufficient experimental constraints. Thus, Swellix provides a practical alternative to free energy minimization tools when multiple structures, kinetically determined structures, or complex RNA-RNA and RNA-protein interactions are present in an RNA folding problem.

Characterizing protein conformations by correlation analysis of coarse-grained contact matrices.

PubMed

Lindsay, Richard J; Siess, Jan; Lohry, David P; McGee, Trevor S; Ritchie, Jordan S; Johnson, Quentin R; Shen, Tongye

2018-01-14

We have developed a method to capture the essential conformational dynamics of folded biopolymers using statistical analysis of coarse-grained segment-segment contacts. Previously, the residue-residue contact analysis of simulation trajectories was successfully applied to the detection of conformational switching motions in biomolecular complexes. However, the application to large protein systems (larger than 1000 amino acid residues) is challenging using the description of residue contacts. Also, the residue-based method cannot be used to compare proteins with different sequences. To expand the scope of the method, we have tested several coarse-graining schemes that group a collection of consecutive residues into a segment. The definition of these segments may be derived from structural and sequence information, while the interaction strength of the coarse-grained segment-segment contacts is a function of the residue-residue contacts. We then perform covariance calculations on these coarse-grained contact matrices. We monitored how well the principal components of the contact matrices is preserved using various rendering functions. The new method was demonstrated to assist the reduction of the degrees of freedom for describing the conformation space, and it potentially allows for the analysis of a system that is approximately tenfold larger compared with the corresponding residue contact-based method. This method can also render a family of similar proteins into the same conformational space, and thus can be used to compare the structures of proteins with different sequences.

Characterizing protein conformations by correlation analysis of coarse-grained contact matrices

NASA Astrophysics Data System (ADS)

Lindsay, Richard J.; Siess, Jan; Lohry, David P.; McGee, Trevor S.; Ritchie, Jordan S.; Johnson, Quentin R.; Shen, Tongye

2018-01-01

We have developed a method to capture the essential conformational dynamics of folded biopolymers using statistical analysis of coarse-grained segment-segment contacts. Previously, the residue-residue contact analysis of simulation trajectories was successfully applied to the detection of conformational switching motions in biomolecular complexes. However, the application to large protein systems (larger than 1000 amino acid residues) is challenging using the description of residue contacts. Also, the residue-based method cannot be used to compare proteins with different sequences. To expand the scope of the method, we have tested several coarse-graining schemes that group a collection of consecutive residues into a segment. The definition of these segments may be derived from structural and sequence information, while the interaction strength of the coarse-grained segment-segment contacts is a function of the residue-residue contacts. We then perform covariance calculations on these coarse-grained contact matrices. We monitored how well the principal components of the contact matrices is preserved using various rendering functions. The new method was demonstrated to assist the reduction of the degrees of freedom for describing the conformation space, and it potentially allows for the analysis of a system that is approximately tenfold larger compared with the corresponding residue contact-based method. This method can also render a family of similar proteins into the same conformational space, and thus can be used to compare the structures of proteins with different sequences.

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

NASA Astrophysics Data System (ADS)

Dian, Brian; Clarkson, Jasper; Zwier, Timothy

2003-03-01

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

CCProf: exploring conformational change profile of proteins

PubMed Central

Chang, Che-Wei; Chou, Chai-Wei; Chang, Darby Tien-Hao

2016-01-01

In many biological processes, proteins have important interactions with various molecules such as proteins, ions or ligands. Many proteins undergo conformational changes upon these interactions, where regions with large conformational changes are critical to the interactions. This work presents the CCProf platform, which provides conformational changes of entire proteins, named conformational change profile (CCP) in the context. CCProf aims to be a platform where users can study potential causes of novel conformational changes. It provides 10 biological features, including conformational change, potential binding target site, secondary structure, conservation, disorder propensity, hydropathy propensity, sequence domain, structural domain, phosphorylation site and catalytic site. All these information are integrated into a well-aligned view, so that researchers can capture important relevance between different biological features visually. The CCProf contains 986 187 protein structure pairs for 3123 proteins. In addition, CCProf provides a 3D view in which users can see the protein structures before and after conformational changes as well as binding targets that induce conformational changes. All information (e.g. CCP, binding targets and protein structures) shown in CCProf, including intermediate data are available for download to expedite further analyses. Database URL: http://zoro.ee.ncku.edu.tw/ccprof/ PMID:27016699

Null conformal Killing-Yano tensors and Birkhoff theorem

NASA Astrophysics Data System (ADS)

Ferrando, Joan Josep; Sáez, Juan Antonio

2016-04-01

We study the space-times admitting a null conformal Killing-Yano tensor whose divergence defines a Killing vector. We analyze the similarities and differences with the recently studied non null case (Ferrando and Sáez in Gen Relativ Gravit 47:1911, 2015). The results by Barnes concerning the Birkhoff theorem for the case of null orbits are analyzed and generalized.

Spacecraft materials guide. [including: encapsulants and conformal coatings; optical materials; lubrication; and, bonding and joining processes

NASA Technical Reports Server (NTRS)

Staugaitis, C. L. (Editor)

1975-01-01

Materials which have demonstrated their suitability for space application are summarized. Common, recurring problems in encapsulants and conformal coatings, optical materials, lubrication, and bonding and joining are noted. The subjects discussed include: low density and syntactic foams, electrical encapsulants; optical glasses, interference filter, mirrors; oils, greases, lamillar lubricants; and, soldering and brazing processes.

Dual of the Janus solution: An interface conformal field theory

NASA Astrophysics Data System (ADS)

Clark, A. B.; Freedman, D. Z.; Karch, A.; Schnabl, M.

2005-03-01

We propose and study a specific gauge theory dual of the smooth, nonsupersymmetric (and apparently stable) Janus solution of Type IIB supergravity found in Bak et al. [J. High Energy Phys., JHEPFG, 1029-8479 05 (2003) 072]. The dual field theory is N=4 SYM theory on two half-spaces separated by a planar interface with different coupling constants in each half-space. We assume that the position dependent coupling multiplies the operator L' which is the fourth descendent of the primary TrX{IXJ} and closely related to the N=4 Lagrangian density. At the classical level supersymmetry is broken explicitly, but SO(3,2) conformal symmetry is preserved. We use conformal perturbation theory to study various correlation functions to first and second order in the discontinuity of g2YM, confirming quantum level conformal symmetry. Certain quantities such as the vacuum expectation value are protected to all orders in g2YMN, and we find perfect agreement between the weak coupling value in the gauge theory and the strong coupling gravity result. SO(3,2) symmetry requires vanishing vacuum energy, =0, and this is confirmed in first order in the discontinuity.

Anomalies, conformal manifolds, and spheres

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

Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar

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

Anomalies, conformal manifolds, and spheres

NASA Astrophysics Data System (ADS)

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

2016-03-01

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

Equilibrium Molecular Thermodynamics from Kirkwood Sampling

PubMed Central

2015-01-01

We present two methods for barrierless equilibrium sampling of molecular systems based on the recently proposed Kirkwood method (J. Chem. Phys.2009, 130, 134102). Kirkwood sampling employs low-order correlations among internal coordinates of a molecule for random (or non-Markovian) sampling of the high dimensional conformational space. This is a geometrical sampling method independent of the potential energy surface. The first method is a variant of biased Monte Carlo, where Kirkwood sampling is used for generating trial Monte Carlo moves. Using this method, equilibrium distributions corresponding to different temperatures and potential energy functions can be generated from a given set of low-order correlations. Since Kirkwood samples are generated independently, this method is ideally suited for massively parallel distributed computing. The second approach is a variant of reservoir replica exchange, where Kirkwood sampling is used to construct a reservoir of conformations, which exchanges conformations with the replicas performing equilibrium sampling corresponding to different thermodynamic states. Coupling with the Kirkwood reservoir enhances sampling by facilitating global jumps in the conformational space. The efficiency of both methods depends on the overlap of the Kirkwood distribution with the target equilibrium distribution. We present proof-of-concept results for a model nine-atom linear molecule and alanine dipeptide. PMID:25915525

Anomalies, conformal manifolds, and spheres

DOE PAGES

Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar; ...

2016-03-04

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

New optical solitons of space-time conformable fractional perturbed Gerdjikov-Ivanov equation by sine-Gordon equation method

NASA Astrophysics Data System (ADS)

Yaşar, Elif; Yıldırım, Yakup; Yaşar, Emrullah

2018-06-01

This paper devotes to conformable fractional space-time perturbed Gerdjikov-Ivanov (GI) equation which appears in nonlinear fiber optics and photonic crystal fibers (PCF). We consider the model with full nonlinearity in order to give a generalized flavor. The sine-Gordon equation approach is carried out to model equation for retrieving the dark, bright, dark-bright, singular and combined singular optical solitons. The constraint conditions are also reported for guaranteeing the existence of these solitons. We also present some graphical simulations of the solutions for better understanding the physical phenomena of the behind the considered model.

Characterization of an Integral Thermal Protection and Cryogenic Insulation Material for Advanced Space Transportation Vehicles

NASA Technical Reports Server (NTRS)

Salerno, L. J.; White, S. M.; Helvensteijn, B. P. M.

2000-01-01

NASA's planned advanced space transportation vehicles will benefit from the use of integral/conformal cryogenic propellant tanks which will reduce the launch weight and lower the earth-to-orbit costs considerably. To implement the novel concept of integral/conformal tanks requires developing an equally novel concept in thermal protection materials. Providing insulation against reentry heating and preserving propellant mass can no longer be considered separate problems to be handled by separate materials. A new family of materials, Superthermal Insulation (STI), has been conceiving and investigated by NASA's Ames Research Center to simultaneously provide both thermal protection and cryogenic insulation in a single, integral material.

Thermally tunable grating using thermo-responsive magnetic fluid

NASA Astrophysics Data System (ADS)

Zaibudeen, A. W.; Philip, John

2017-04-01

We report a thermally tunable grating prepared using poly(N-isopropylacrylamide) and super paramagnetic iron oxide nanoparticles. The array spacing is reversibly tuned by varying the temperature between 5 and 38 °C. Here, the ability of thermo-responsive polymer brushes to alter their conformation at an interface is exploited to control the grating spacing in nanoscale. The underlying mechanism for the temperature dependent conformational changes are studied by measuring the subtle intermolecular forces between the polymer covered interfaces. It is observed that the interparticle forces are repulsive and exponentially decaying with distance. The thermo-responsive grating is simple to use and offers a wide range of applications.

New Insights into the Folding of a β-Sheet Miniprotein in a Reduced Space of Collective Hydrogen Bond Variables: Application to a Hydrodynamic Analysis of the Folding Flow

PubMed Central

Kalgin, Igor V.; Caflisch, Amedeo; Chekmarev, Sergei F.; Karplus, Martin

2013-01-01

A new analysis of the 20 μs equilibrium folding/unfolding molecular dynamics simulations of the three-stranded antiparallel β-sheet miniprotein (beta3s) in implicit solvent is presented. The conformation space is reduced in dimensionality by introduction of linear combinations of hydrogen bond distances as the collective variables making use of a specially adapted Principal Component Analysis (PCA); i.e., to make structured conformations more pronounced, only the formed bonds are included in determining the principal components. It is shown that a three-dimensional (3D) subspace gives a meaningful representation of the folding behavior. The first component, to which eight native hydrogen bonds make the major contribution (four in each beta hairpin), is found to play the role of the reaction coordinate for the overall folding process, while the second and third components distinguish the structured conformations. The representative points of the trajectory in the 3D space are grouped into conformational clusters that correspond to locally stable conformations of beta3s identified in earlier work. A simplified kinetic network based on the three components is constructed and it is complemented by a hydrodynamic analysis. The latter, making use of “passive tracers” in 3D space, indicates that the folding flow is much more complex than suggested by the kinetic network. A 2D representation of streamlines shows there are vortices which correspond to repeated local rearrangement, not only around minima of the free energy surface, but also in flat regions between minima. The vortices revealed by the hydrodynamic analysis are apparently not evident in folding pathways generated by transition-path sampling. Making use of the fact that the values of the collective hydrogen bond variables are linearly related to the Cartesian coordinate space, the RMSD between clusters is determined. Interestingly, the transition rates show an approximate exponential correlation with distance in the hydrogen bond subspace. Comparison with the many published studies shows good agreement with the present analysis for the parts that can be compared, supporting the robust character of our understanding of this “hydrogen atom” of protein folding. PMID:23621790

Revealing Abrupt and Spontaneous Ruptures of Protein Native Structure under picoNewton Compressive Force Manipulation.

PubMed

Chowdhury, S Roy; Cao, Jin; He, Yufan; Lu, H Peter

2018-03-27

Manipulating protein conformations for exploring protein structure-function relationship has shown great promise. Although protein conformational changes under pulling force manipulation have been extensively studied, protein conformation changes under a compressive force have not been explored quantitatively. The latter is even more biologically significant and relevant in revealing protein functions in living cells associated with protein crowdedness, distribution fluctuations, and cell osmotic stress. Here we report our experimental observations on abrupt ruptures of protein native structures under compressive force, demonstrated and studied by single-molecule AFM-FRET spectroscopic nanoscopy. Our results show that the protein ruptures are abrupt and spontaneous events occurred when the compressive force reaches a threshold of 12-75 pN, a force amplitude accessible from thermal fluctuations in a living cell. The abrupt ruptures are sensitive to local environment, likely a general and important pathway of protein unfolding in living cells.

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

PubMed

Yonezawa, Yasushige

2014-05-01

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

Protein Allostery and Conformational Dynamics.

PubMed

Guo, Jingjing; Zhou, Huan-Xiang

2016-06-08

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

43 CFR 3482.2 - Action on plans.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Exploration and Resource Recovery and Protection Plans § 3482.2 Action on plans. (a)(1) Exploration plans. The.... The authorized officer may impose additional conditions to conform to the rules of this part. In... with the approval terms of the exploration plan. (2) Resource recovery and protection plans. No...

43 CFR 3482.2 - Action on plans.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Exploration and Resource Recovery and Protection Plans § 3482.2 Action on plans. (a)(1) Exploration plans. The.... The authorized officer may impose additional conditions to conform to the rules of this part. In... with the approval terms of the exploration plan. (2) Resource recovery and protection plans. No...

43 CFR 3482.2 - Action on plans.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Exploration and Resource Recovery and Protection Plans § 3482.2 Action on plans. (a)(1) Exploration plans. The.... The authorized officer may impose additional conditions to conform to the rules of this part. In... with the approval terms of the exploration plan. (2) Resource recovery and protection plans. No...

Virtual Environments in Scientific Visualization

NASA Technical Reports Server (NTRS)

Bryson, Steve; Lisinski, T. A. (Technical Monitor)

1994-01-01

Virtual environment technology is a new way of approaching the interface between computers and humans. Emphasizing display and user control that conforms to the user's natural ways of perceiving and thinking about space, virtual environment technologies enhance the ability to perceive and interact with computer generated graphic information. This enhancement potentially has a major effect on the field of scientific visualization. Current examples of this technology include the Virtual Windtunnel being developed at NASA Ames Research Center. Other major institutions such as the National Center for Supercomputing Applications and SRI International are also exploring this technology. This talk will be describe several implementations of virtual environments for use in scientific visualization. Examples include the visualization of unsteady fluid flows (the virtual windtunnel), the visualization of geodesics in curved spacetime, surface manipulation, and examples developed at various laboratories.

Dynamics of supersonic microparticle impact on elastomers revealed by real–time multi–frame imaging

PubMed Central

Veysset, David; Hsieh, Alex J.; Kooi, Steven; Maznev, Alexei A.; Masser, Kevin A.; Nelson, Keith A.

2016-01-01

Understanding high–velocity microparticle impact is essential for many fields, from space exploration to medicine and biology. Investigations of microscale impact have hitherto been limited to post–mortem analysis of impacted specimens, which does not provide direct information on the impact dynamics. Here we report real–time multi–frame imaging studies of the impact of 7 μm diameter glass spheres traveling at 700–900 m/s on elastomer polymers. With a poly(urethane urea) (PUU) sample, we observe a hyperelastic impact phenomenon not seen on the macroscale: a microsphere undergoes a full conformal penetration into the specimen followed by a rebound which leaves the specimen unscathed. The results challenge the established interpretation of the behaviour of elastomers under high–velocity impact. PMID:27156501

Equivalence of emergent de Sitter spaces from conformal field theory

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

Asplund, Curtis T.; Callebaut, Nele; Zukowski, Claire

Recently, two groups have made distinct proposals for a de Sitter space that is emergent from conformal field theory (CFT). The first proposal is that, for two-dimensional holographic CFTs, the kinematic space of geodesics on a space-like slice of the asymptotically anti-de Sitter bulk is two-dimensional de Sitter space (dS 2), with a metric that can be derived from the entanglement entropy of intervals in the CFT. In the second proposal, de Sitter dynamics emerges naturally from the first law of entanglement entropy for perturbations around the vacuum state of CFTs. We provide support for the equivalence of these twomore » emergent spacetimes in the vacuum case and beyond. In particular, we study the kinematic spaces of nontrivial solutions of 3d gravity, including the BTZ black string, BTZ black hole, and conical singularities. We argue that the resulting spaces are generically globally hyperbolic spacetimes that support dynamics given boundary conditions at future infinity. For the BTZ black string, corresponding to a thermal state of the CFT, we show that both prescriptions lead to an emergent hyperbolic patch of dS 2. As a result, we offer a general method for relating kinematic space and the auxiliary de Sitter space that is valid in the vacuum and thermal cases.« less

Approaching Pharmacological Space: Events and Components.

PubMed

Vistoli, Giulio; Pedretti, Alessandro; Mazzolari, Angelica; Testa, Bernard

2018-01-01

With a view to introducing the concept of pharmacological space and its potential applications in investigating and predicting the toxic mechanisms of xenobiotics, this opening chapter describes the logical relations between conformational behavior, physicochemical properties and binding spaces, which are seen as the three key elements composing the pharmacological space. While the concept of conformational space is routinely used to encode molecular flexibility, the concepts of property spaces and, particularly, of binding spaces are more innovative. Indeed, their descriptors can find fruitful applications (a) in describing the dynamic adaptability a given ligand experiences when inserted into a specific environment, and (b) in parameterizing the flexibility a ligand retains when bound to a biological target. Overall, these descriptors can conveniently account for the often disregarded entropic factors and as such they prove successful when inserted in ligand- or structure-based predictive models. Notably, and although binding space parameters can clearly be derived from MD simulations, the chapter will illustrate how docking calculations, despite their static nature, are able to evaluate ligand's flexibility by analyzing several poses for each ligand. Such an approach, which represents the founding core of the binding space concept, can find various applications in which the related descriptors show an impressive enhancing effect on the statistical performances of the resulting predictive models.

Equivalence of emergent de Sitter spaces from conformal field theory

DOE PAGES

Asplund, Curtis T.; Callebaut, Nele; Zukowski, Claire

2016-09-27

Recently, two groups have made distinct proposals for a de Sitter space that is emergent from conformal field theory (CFT). The first proposal is that, for two-dimensional holographic CFTs, the kinematic space of geodesics on a space-like slice of the asymptotically anti-de Sitter bulk is two-dimensional de Sitter space (dS 2), with a metric that can be derived from the entanglement entropy of intervals in the CFT. In the second proposal, de Sitter dynamics emerges naturally from the first law of entanglement entropy for perturbations around the vacuum state of CFTs. We provide support for the equivalence of these twomore » emergent spacetimes in the vacuum case and beyond. In particular, we study the kinematic spaces of nontrivial solutions of 3d gravity, including the BTZ black string, BTZ black hole, and conical singularities. We argue that the resulting spaces are generically globally hyperbolic spacetimes that support dynamics given boundary conditions at future infinity. For the BTZ black string, corresponding to a thermal state of the CFT, we show that both prescriptions lead to an emergent hyperbolic patch of dS 2. As a result, we offer a general method for relating kinematic space and the auxiliary de Sitter space that is valid in the vacuum and thermal cases.« less

The Development of SCORM-Conformant Learning Content Based on the Learning Cycle Using Participatory Design

ERIC Educational Resources Information Center

Su, C. Y.; Chiu, C. H.; Wang, T. I.

2010-01-01

This study incorporates the 5E learning cycle strategy to design and develop Sharable Content Object Reference Model-conformant materials for elementary science education. The 5E learning cycle that supports the constructivist approach has been widely applied in science education. The strategy consists of five phases: engagement, exploration,…

Doing Gender for Different Reasons: Why Gender Conformity Positively and Negatively Predicts Self-Esteem

ERIC Educational Resources Information Center

Good, Jessica J.; Sanchez, Diana T.

2010-01-01

Past research has shown that valuing gender conformity is associated with both positive and negative consequences for self-esteem and positive affect. The current research (women, n= 226; men, n= 175) explored these conflicting findings by separating out investing in societal gender ideals from personally valuing one's gender identity ("private…

Conformationally constrained farnesoid X receptor (FXR) agonists: alternative replacements of the stilbene.

PubMed

Akwabi-Ameyaw, Adwoa; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

2011-10-15

To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency. Copyright © 2011 Elsevier Ltd. All rights reserved.

Generalized essential energy space random walks to more effectively accelerate solute sampling in aqueous environment

NASA Astrophysics Data System (ADS)

Lv, Chao; Zheng, Lianqing; Yang, Wei

2012-01-01

Molecular dynamics sampling can be enhanced via the promoting of potential energy fluctuations, for instance, based on a Hamiltonian modified with the addition of a potential-energy-dependent biasing term. To overcome the diffusion sampling issue, which reveals the fact that enlargement of event-irrelevant energy fluctuations may abolish sampling efficiency, the essential energy space random walk (EESRW) approach was proposed earlier. To more effectively accelerate the sampling of solute conformations in aqueous environment, in the current work, we generalized the EESRW method to a two-dimension-EESRW (2D-EESRW) strategy. Specifically, the essential internal energy component of a focused region and the essential interaction energy component between the focused region and the environmental region are employed to define the two-dimensional essential energy space. This proposal is motivated by the general observation that in different conformational events, the two essential energy components have distinctive interplays. Model studies on the alanine dipeptide and the aspartate-arginine peptide demonstrate sampling improvement over the original one-dimension-EESRW strategy; with the same biasing level, the present generalization allows more effective acceleration of the sampling of conformational transitions in aqueous solution. The 2D-EESRW generalization is readily extended to higher dimension schemes and employed in more advanced enhanced-sampling schemes, such as the recent orthogonal space random walk method.

A comparison of two conformal mapping techniques applied to an aerobrake body

NASA Technical Reports Server (NTRS)

Hommel, Mark J.

1987-01-01

Conformal mapping is a classical technique which has been utilized for solving problems in aerodynamics and hydrodynamics. Conformal mapping has been successfully applied in the construction of grids around airfoils, engine inlets and other aircraft configurations. Conformal mapping techniques were applied to an aerobrake body having an axis of symmetry. Two different approaches were utilized: (1) Karman-Trefftz transformation; and (2) Point Wise Schwarz Christoffel transformation. In both cases, the aerobrake body was mapped onto a near circle, and a grid was generated in the mapped plane. The mapped body and grid were then mapped back into physical space and the properties of the associated grids were examined. Advantages and disadvantages of both approaches are discussed.

The Rotational Spectrum of Complex Organic Molecules: 2(N)-METHYLAMINOETHANOL

NASA Astrophysics Data System (ADS)

Melandri, S.; Maris, A.; Calabrese, C.

2013-06-01

The detection of molecules in space, is based on their spectroscopic features and high resolution spectral data is needed to allow an unambiguous identification of them. Many of the molecules detected in space are complex organic molecules containing chains of carbon atoms and which therefore show a high degree of molecular flexibility. The high number of low energy conformations and the presence of large amplitude motions on shallow potential energy surfaces are peculiar to this kind of systems. The presence of a high number of stable conformers - often interconverting through small energy barriers - usually gives rise to very complex spectra, which represent a challenge for spectroscopic and computational methods. We report the rotational study of methylaminoethanol (MAE) performed by Free Jet Absorption Microwave Spectrocopy (FJAMW). For this species it has proved essential to compute the complete potential energy surfaces related to the low amplitude modes. This has been calculated at the B3LYP/6-311++G** level of theory while the stable geometries have been characterized MP2/6-311++G**. The interest in the conformational properties of MAE is twofold: in the first place, aminoethanol and thus also MAE can be considered precursors of aminoacids in the interstellar medium and secondly, the MAE side chain is present in important biological molecules such as adrenaline. The conformational preferences of MAE are dominated by the intramolecular hydrogen bond between the OH and NH2 groups and its flexibility and asymmetry generate a very high number of conformers. 24 stable conformations have been predicted and two conformers were observed by FJAMW spectroscopy with our 60-72 GHz spectrometer. With respect to a previous study we have extended the observed frequency range, partly reassigned the rotational spectrum of one of the conformers and determined the nuclear quadrupole constants. The search for higher energy conformers has also been undertaken. S. Charnley, in Proceedings of the workshop: The bridge between the Big Bang and Biology, CNR, Italy 1999. R. E. Penn and L. W. Buxton J. Mol. Spectrosc. {56} 229 1975.

"Outlines" of History: Measured Spaces and Kinesthetics

ERIC Educational Resources Information Center

Morris, Ronald Vaughan

2008-01-01

What would happen if social studies student used spaces marked out on the floor and physical movement to learn social studies? Would such a lesson conform with the Vision of Powerful Teaching and Learning in the Social Studies? Students get out of their chairs and away from their desks to perform events within a defined space elsewhere in the room…

Rotational Spectrum, Conformational Composition, Intramolecular Hydrogen Bonding, and Quantum Chemical Calculations of Mercaptoacetonitrile (HSCH2C≡N), a Compound of Potential Astrochemical Interest.

PubMed

Møllendal, Harald; Samdal, Svein; Guillemin, Jean-Claude

2016-03-31

The microwave spectra of mercaptoacetonitrile (HSCH2C≡N) and one deuterated species (DSCH2C≡N) were investigated in the 7.5-124 GHz spectral interval. The spectra of two conformers denoted SC and AP were assigned. The H-S-C-C chain of atoms is synclinal in SC and anti-periplanar in AP. The ground state of SC is split into two substates separated by a comparatively small energy difference resulting in closely spaced transitions with equal intensities. Several transitions of the parent species of SC deviate from Watson's Hamiltonian. Only slight improvements were obtained using a Hamiltonian that takes coupling between the two substates into account. Deviations from Watson's Hamiltonian were also observed for the parent species of AP. However, the spectrum of the deuterated species, which was investigated only for the SC conformer, fits satisfactorily to Watson's Hamiltonian. Relative intensity measurements found SC to be lower in energy than AP by 3.8(3) kJ/mol. The strength of the intramolecular hydrogen bond between the thiol and cyano groups was estimated to be ∼2.1 kJ/mol. The microwave work was augmented by quantum chemical calculations at CCSD and MP2 levels using basis sets of minimum triple-ζ quality. Mercaptoacetonitrile has astrochemical interest, and the spectra presented herein should be useful for a potential identification of this compound in the interstellar medium. Three different ways of generating mercaptoacetonitrile from compounds already found in the interstellar medium were explored by quantum chemical calculations.

14 CFR 183.51 - ODA Unit personnel.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false ODA Unit personnel. 183.51 Section 183.51 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) ADMINISTRATIVE... compliance, determine conformity, determine airworthiness, issue certificates or issue approvals; or (c) A...

14 CFR 183.51 - ODA Unit personnel.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false ODA Unit personnel. 183.51 Section 183.51 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) ADMINISTRATIVE... compliance, determine conformity, determine airworthiness, issue certificates or issue approvals; or (c) A...

14 CFR 183.51 - ODA Unit personnel.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false ODA Unit personnel. 183.51 Section 183.51 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) ADMINISTRATIVE... compliance, determine conformity, determine airworthiness, issue certificates or issue approvals; or (c) A...

14 CFR 183.51 - ODA Unit personnel.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false ODA Unit personnel. 183.51 Section 183.51 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) ADMINISTRATIVE... compliance, determine conformity, determine airworthiness, issue certificates or issue approvals; or (c) A...

14 CFR 183.51 - ODA Unit personnel.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false ODA Unit personnel. 183.51 Section 183.51 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) ADMINISTRATIVE... compliance, determine conformity, determine airworthiness, issue certificates or issue approvals; or (c) A...

Correlation Functions of σ Fields with Values in a Hyperbolic Space

NASA Astrophysics Data System (ADS)

Haba, Z.

It is shown that the functional integral for a σ field with values in the Poincare upper half-plane (and some other hyperbolic spaces) can be performed explicitly resulting in a conformal invariant noncanonical field theory in two dimensions.

Inverse bootstrapping conformal field theories

NASA Astrophysics Data System (ADS)

Li, Wenliang

2018-01-01

We propose a novel approach to study conformal field theories (CFTs) in general dimensions. In the conformal bootstrap program, one usually searches for consistent CFT data that satisfy crossing symmetry. In the new method, we reverse the logic and interpret manifestly crossing-symmetric functions as generating functions of conformal data. Physical CFTs can be obtained by scanning the space of crossing-symmetric functions. By truncating the fusion rules, we are able to concentrate on the low-lying operators and derive some approximate relations for their conformal data. It turns out that the free scalar theory, the 2d minimal model CFTs, the ϕ 4 Wilson-Fisher CFT, the Lee-Yang CFTs and the Ising CFTs are consistent with the universal relations from the minimal fusion rule ϕ 1 × ϕ 1 = I + ϕ 2 + T , where ϕ 1 , ϕ 2 are scalar operators, I is the identity operator and T is the stress tensor.

An improved reaction path optimization method using a chain of conformations

NASA Astrophysics Data System (ADS)

Asada, Toshio; Sawada, Nozomi; Nishikawa, Takuya; Koseki, Shiro

2018-05-01

The efficient fast path optimization (FPO) method is proposed to optimize the reaction paths on energy surfaces by using chains of conformations. No artificial spring force is used in the FPO method to ensure the equal spacing of adjacent conformations. The FPO method is applied to optimize the reaction path on two model potential surfaces. The use of this method enabled the optimization of the reaction paths with a drastically reduced number of optimization cycles for both potentials. It was also successfully utilized to define the MEP of the isomerization of the glycine molecule in water by FPO method.

Light-front holographic QCD and emerging confinement

DOE PAGES

Brodsky, Stanley J.; de Téramond, Guy F.; Dosch, Hans Günter; ...

2015-05-21

In this study we explore the remarkable connections between light-front dynamics, its holographic mapping to gravity in a higher-dimensional anti-de Sitter (AdS) space, and conformal quantum mechanics. This approach provides new insights into the origin of a fundamental mass scale and the physics underlying confinement dynamics in QCD in the limit of massless quarks. The result is a relativistic light-front wave equation for arbitrary spin with an effective confinement potential derived from a conformal action and its embedding in AdS space. This equation allows for the computation of essential features of hadron spectra in terms of a single scale. Themore » light-front holographic methods described here give a precise interpretation of holographic variables and quantities in AdS space in terms of light-front variables and quantum numbers. This leads to a relation between the AdS wave functions and the boost-invariant light-front wave functions describing the internal structure of hadronic bound-states in physical spacetime. The pion is massless in the chiral limit and the excitation spectra of relativistic light-quark meson and baryon bound states lie on linear Regge trajectories with identical slopes in the radial and orbital quantum numbers. In the light-front holographic approach described here currents are expressed as an infinite sum of poles, and form factors as a product of poles. At large q 2 the form factor incorporates the correct power-law fall-off for hard scattering independent of the specific dynamics and is dictated by the twist. At low q 2 the form factor leads to vector dominance. The approach is also extended to include small quark masses. We briefly review in this report other holographic approaches to QCD, in particular top-down and bottom-up models based on chiral symmetry breaking. We also include a discussion of open problems and future applications.« less

Mechanical Computing in Microelectromechanical Systems (MEMS)

DTIC Science & Technology

2003-03-01

New York: John Wiley and Sons, Inc., 1968. 25. Helvajian , H . and S. Janson, Microengineering Aerospace Systems, ch. Micro- engineering Space Systems...sacrificial layer. (g)Strip remaining resist. ( h ) Deposit a structural layer(conformal deposition is shown). (i) Deposit resist. (j) Expose resist...layer is then deposited, and assuming a conformal process, the structural layer will follow the topography of the sacrificial layer (Figure 2.9( h

Calcium-energized motor protein forisome controls damage in phloem: potential applications as biomimetic "smart" material.

PubMed

Srivastava, Vineet Kumar; Tuteja, Renu; Tuteja, Narendra

2015-06-01

Forisomes are ATP independent, mechanically active proteins from the Fabaceae family (also called Leguminosae). These proteins are located in sieve tubes of phloem and function to prevent loss of nutrient-rich photoassimilates, upon mechanical injury/wounding. Forisomes are SEO (sieve element occlusion) gene family proteins that have recently been shown to be involved in wound sealing mechanism. Recent findings suggest that forisomes could act as an ideal model to study self assembly mechanism for the development of nanotechnological devices like microinstruments, the microfluidic system frequently used in space exploration missions. Technology enabling improvement in micro instruments has been identified as a key technology by NASA in future space exploration missions. Forisomes are designated as biomimetic smart materials which are calcium-energized motor proteins. Since forisomes are biomolecules from plant systems it can be doctored through genetic engineering. In contrast, "smart" materials which are not derived from plants are difficult to modify in their properties. Current levels of understanding about forisomes conformational shifts with respect to calcium ions and pH changes requires supplement of future advances with relation to its 3D structure to understand self assembly processes. In plant systems it forms blood clots in the form of occlusions to prevent nutrient fluid leakage and thus proves to be a unique damage control system of phloem tissue.

On the ambiguity of conformational states: A B&S-LEUS simulation study of the helical conformations of decaalanine in water

NASA Astrophysics Data System (ADS)

Bieler, Noah S.; Hünenberger, Philippe H.

2015-04-01

Estimating the relative stabilities of different conformational states of a (bio-)molecule using molecular dynamics simulations involves two challenging problems: the conceptual problem of how to define the states of interest and the technical problem of how to properly sample these states, along with achieving a sufficient number of interconversion transitions. In this study, the two issues are addressed in the context of a decaalanine peptide in water, by considering the 310-, α-, and π-helical states. The simulations rely on the ball-and-stick local-elevation umbrella-sampling (B&S-LEUS) method. In this scheme, the states are defined as hyperspheres (balls) in a (possibly high dimensional) collective-coordinate space and connected by hypercylinders (sticks) to ensure transitions. A new object, the pipe, is also introduced here to handle curvilinear pathways. Optimal sampling within the so-defined space is ensured by confinement and (one-dimensional) memory-based biasing potentials associated with the three different kinds of objects. The simulation results are then analysed in terms of free energies using reweighting, possibly relying on two distinct sets of collective coordinates for the state definition and analysis. The four possible choices considered for these sets are Cartesian coordinates, hydrogen-bond distances, backbone dihedral angles, or pairwise sums of successive backbone dihedral angles. The results concerning decaalanine underline that the concept of conformational state may be extremely ambiguous, and that its tentative absolute definition as a free-energy basin remains subordinated to the choice of a specific analysis space. For example, within the force-field employed and depending on the analysis coordinates selected, the 310-helical state may refer to weakly overlapping collections of conformations, differing by as much as 25 kJ mol-1 in terms of free energy. As another example, the π-helical state appears to correspond to a free-energy basin for three choices of analysis coordinates, but to be unstable with the fourth one. The problem of conformational-state definition may become even more intricate when comparison with experiment is involved, where the state definition relies on spectroscopic or functional observables.

On the ambiguity of conformational states: A B&S-LEUS simulation study of the helical conformations of decaalanine in water.

PubMed

Bieler, Noah S; Hünenberger, Philippe H

2015-04-28

Estimating the relative stabilities of different conformational states of a (bio-)molecule using molecular dynamics simulations involves two challenging problems: the conceptual problem of how to define the states of interest and the technical problem of how to properly sample these states, along with achieving a sufficient number of interconversion transitions. In this study, the two issues are addressed in the context of a decaalanine peptide in water, by considering the 310-, α-, and π-helical states. The simulations rely on the ball-and-stick local-elevation umbrella-sampling (B&S-LEUS) method. In this scheme, the states are defined as hyperspheres (balls) in a (possibly high dimensional) collective-coordinate space and connected by hypercylinders (sticks) to ensure transitions. A new object, the pipe, is also introduced here to handle curvilinear pathways. Optimal sampling within the so-defined space is ensured by confinement and (one-dimensional) memory-based biasing potentials associated with the three different kinds of objects. The simulation results are then analysed in terms of free energies using reweighting, possibly relying on two distinct sets of collective coordinates for the state definition and analysis. The four possible choices considered for these sets are Cartesian coordinates, hydrogen-bond distances, backbone dihedral angles, or pairwise sums of successive backbone dihedral angles. The results concerning decaalanine underline that the concept of conformational state may be extremely ambiguous, and that its tentative absolute definition as a free-energy basin remains subordinated to the choice of a specific analysis space. For example, within the force-field employed and depending on the analysis coordinates selected, the 310-helical state may refer to weakly overlapping collections of conformations, differing by as much as 25 kJ mol(-1) in terms of free energy. As another example, the π-helical state appears to correspond to a free-energy basin for three choices of analysis coordinates, but to be unstable with the fourth one. The problem of conformational-state definition may become even more intricate when comparison with experiment is involved, where the state definition relies on spectroscopic or functional observables.

AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking.

PubMed

Ben-Shimon, Avraham; Niv, Masha Y

2015-05-05

The huge conformational space stemming from the inherent flexibility of peptides is among the main obstacles to successful and efficient computational modeling of protein-peptide interactions. Current peptide docking methods typically overcome this challenge using prior knowledge from the structure of the complex. Here we introduce AnchorDock, a peptide docking approach, which automatically targets the docking search to the most relevant parts of the conformational space. This is done by precomputing the free peptide's structure and by computationally identifying anchoring spots on the protein surface. Next, a free peptide conformation undergoes anchor-driven simulated annealing molecular dynamics simulations around the predicted anchoring spots. In the challenging task of a completely blind docking test, AnchorDock produced exceptionally good results (backbone root-mean-square deviation ≤ 2.2Å, rank ≤15) for 10 of 13 unbound cases tested. The impressive performance of AnchorDock supports a molecular recognition pathway that is driven via pre-existing local structural elements. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides.

PubMed

Schwochert, Joshua; Lao, Yongtong; Pye, Cameron R; Naylor, Matthew R; Desai, Prashant V; Gonzalez Valcarcel, Isabel C; Barrett, Jaclyn A; Sawada, Geri; Blanco, Maria-Jesus; Lokey, R Scott

2016-08-11

Cyclic peptide (CP) natural products provide useful model systems for mapping "beyond-Rule-of-5" (bRo5) space. We identified the phepropeptins as natural product CPs with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural CPs whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.

Conformational Flexibility of Human Casein Kinase Catalytic Subunit Explored by Metadynamics

PubMed Central

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-01-01

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

Physical and geometrical aspects of de sitter interior of a gravastar

NASA Astrophysics Data System (ADS)

Morawiec, Pawel Jan

The principal motivation for the investigations reported in this thesis is the gravastar model for physical black holes. According to this model the final state of the gravitational collapse of cold super-dense stars with the mass greater than some critical value is a non-singular object called a gravastar. This thesis presents results related to the various aspects of the de Sitter interior of a gravastar. The main object of the research was a generalized rotating interior of a gravastar. It was shown that the rotation, characterized by the vorticity, is localized on the vortex line. The metric under considerations is the de Sitter metric, however in some variant of the oblate spheroidal coordinates. Additionally a cosmic string on the rotation axis is present. This new result is the de Sitter version of the Mazur string, which was obtained from the four dimensional Levi-Civita metric as the generalization of the three-dimensional cosmic string by Adler and Jackiw. Also, using analogy between rotation in the superfluid and the magnetic field we gave another example of the Cosmic No Hair Theorem, this time "no magnetic fields in de Sitter space". But we also have shown that when the de Sitter event horizon is replaced by a thin shell (with a finite thickness), as it is in the gravastar model, the non-vanishing magnetic field could be present. To our knowledge these are new results. In this thesis we have studied behavior of the massless Dirac field as an example of a matter field in the de Sitter spacetime in the vicinity of an event horizon. We found convenient to work in the frame of the optical geometry of the de Sitter space as it is related to the metric in the static coordinates through a conformal Weyl rescaling and the dynamics of the massless Dirac fields is conformally invariant. The fact that the spatial part of the metric in the optical geometry of de Sitter space is the constant negative curvature Lobachevski space (the Euclidean ant-de Sitter space) suggested the existenc of the emerging de Sitter quantum field theory and conformal field theory correspondence on the de Sitter event horizon. We have studied implications of this conjecture. According to the AdS/CFT correspondence prescription the functional integral over the matter fields described by the action with the properly chosen boundary terms defining the so called partition function as the functional of the boundary values of the matter fields is also the generating functional for the correlation functions in the conformal field theory on the boundary of AdS space. In the case of the optical geometry of the de Sitter space the boundary is the event horizon that is the boundary of its Lobachevski spatial part times time. We have chosen the action for the massless Dirac fields in the optical de Sitter geometry with appropriate surface term and subsequently we have evaluated the real time partition function as the functional of the carefully defined boundary values of the Dirac field. It turns out that this partition functional can be, indeed, interpreted as the generating functional of the real time conformal field theory correlation functions of the fermionic operators, dual to the fermionic fields on the boundary. This means that the conformal field theory correlation functions are evaluated as the vacuum expectation values of the chronologically ordered fermionic operator. This result demonstrates the emergence of the de Sitter/Conformal field theory correspondence on the de Sitter horizon. The presence of the negative curvature Lobachevski geometry in the spatial part of the optical geometry of the de Sitter space, is responsible for the effective one-dimensional behavior of the matter degrees of freedom and of the emergence of the de Sitter/Conformal field theory correspondence on the event horizon. Although we have demonstrated the existence of this correspondence for the fermionic fields only, we anticipate this result to be valid generally.

Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics

PubMed Central

Zheng, Liangzhen; Mu, Yuguang

2016-01-01

Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship. However, no apo-form (non-ligand bound) of PR LBD model has been proposed either by experiments or computational methods so far. In this study, we explored the structural dynamics of PR LBD using molecular dynamics simulations and advanced sampling tools in both ligand-bound and the apo-forms. Resolved by the simulation study, helix 11, helix 12 and loop 895–908 (the loop between these two helices) are quite flexible in antagonistic conformation. Several residues, such as Arg899 and Glu723, could form salt-bridging interaction between helix 11 and helix 3, and are important for the PR LBD dynamics. And we also propose that helix 12 in apo-form PR LBD, not like other NR LBDs, such as human estrogen receptor α (ERα) LBD, may not adopt a totally extended conformation. With the aid of umbrella sampling and metadynamics simulations, several stable conformations of apo-form PR LBD have been sampled, which may work as critical structural models for further large scale virtual screening study to discover novel PR ligands for therapeutic application. PMID:27824891

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. © 2016 Wiley Periodicals, Inc.

A population-based evolutionary search approach to the multiple minima problem in de novo protein structure prediction

PubMed Central

2013-01-01

Background Elucidating the native structure of a protein molecule from its sequence of amino acids, a problem known as de novo structure prediction, is a long standing challenge in computational structural biology. Difficulties in silico arise due to the high dimensionality of the protein conformational space and the ruggedness of the associated energy surface. The issue of multiple minima is a particularly troublesome hallmark of energy surfaces probed with current energy functions. In contrast to the true energy surface, these surfaces are weakly-funneled and rich in comparably deep minima populated by non-native structures. For this reason, many algorithms seek to be inclusive and obtain a broad view of the low-energy regions through an ensemble of low-energy (decoy) conformations. Conformational diversity in this ensemble is key to increasing the likelihood that the native structure has been captured. Methods We propose an evolutionary search approach to address the multiple-minima problem in decoy sampling for de novo structure prediction. Two population-based evolutionary search algorithms are presented that follow the basic approach of treating conformations as individuals in an evolving population. Coarse graining and molecular fragment replacement are used to efficiently obtain protein-like child conformations from parents. Potential energy is used both to bias parent selection and determine which subset of parents and children will be retained in the evolving population. The effect on the decoy ensemble of sampling minima directly is measured by additionally mapping a conformation to its nearest local minimum before considering it for retainment. The resulting memetic algorithm thus evolves not just a population of conformations but a population of local minima. Results and conclusions Results show that both algorithms are effective in terms of sampling conformations in proximity of the known native structure. The additional minimization is shown to be key to enhancing sampling capability and obtaining a diverse ensemble of decoy conformations, circumventing premature convergence to sub-optimal regions in the conformational space, and approaching the native structure with proximity that is comparable to state-of-the-art decoy sampling methods. The results are shown to be robust and valid when using two representative state-of-the-art coarse-grained energy functions. PMID:24565020

DICOM: key concepts--part I.

PubMed

Kabachinski, Jeff

2005-01-01

In this issue and next, we're investigating different sections of the DICOM Standard to get a grip on what it's all about. The bottom line is to facilitate communication and DICOM addresses all the technical aspects to allow complying OEMs to talk to one another. In part 2, IT World completes its overview on DICOM by exploring UID, networking with DICOM, conformance, and conformance statements.

Quiet Please! There's a Lady on the Stage--Boys, Gender and Sexuality Non-Conformity and Class

ERIC Educational Resources Information Center

McInnes, David; Couch, Murray

2004-01-01

In this paper we do two things. Initially, we explore the experience of gender and sexuality non-conformity for boys in school. Here, the designation sissy boy is interpreted through shame dynamics produced in part by the linguistic violence of designation. From this we consider the development of what we call epistemophilic resolutions--the…

From conformal blocks to path integrals in the Vaidya geometry

NASA Astrophysics Data System (ADS)

Anous, Tarek; Hartman, Thomas; Rovai, Antonin; Sonner, Julian

2017-09-01

Correlators in conformal field theory are naturally organized as a sum over conformal blocks. In holographic theories, this sum must reorganize into a path integral over bulk fields and geometries. We explore how these two sums are related in the case of a point particle moving in the background of a 3d collapsing black hole. The conformal block expansion is recast as a sum over paths of the first-quantized particle moving in the bulk geometry. Off-shell worldlines of the particle correspond to subdominant contributions in the Euclidean conformal block expansion, but these same operators must be included in order to correctly reproduce complex saddles in the Lorentzian theory. During thermalization, a complex saddle dominates under certain circumstances; in this case, the CFT correlator is not given by the Virasoro identity block in any channel, but can be recovered by summing heavy operators. This effectively converts the conformal block expansion in CFT from a sum over intermediate states to a sum over channels that mimics the bulk path integral.

Triple helical DNA in a duplex context and base pair opening

PubMed Central

Esguerra, Mauricio; Nilsson, Lennart; Villa, Alessandra

2014-01-01

It is fundamental to explore in atomic detail the behavior of DNA triple helices as a means to understand the role they might play in vivo and to better engineer their use in genetic technologies, such as antigene therapy. To this aim we have performed atomistic simulations of a purine-rich antiparallel triple helix stretch of 10 base triplets flanked by canonical Watson–Crick double helices. At the same time we have explored the thermodynamic behavior of a flipping Watson–Crick base pair in the context of the triple and double helix. The third strand can be accommodated in a B-like duplex conformation. Upon binding, the double helix changes shape, and becomes more rigid. The triple-helical region increases its major groove width mainly by oversliding in the negative direction. The resulting conformations are somewhere between the A and B conformations with base pairs remaining almost perpendicular to the helical axis. The neighboring duplex regions maintain a B DNA conformation. Base pair opening in the duplex regions is more probable than in the triplex and binding of the Hoogsteen strand does not influence base pair breathing in the neighboring duplex region. PMID:25228466

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

PubMed

Zhang, Zhe; Ehmann, Uwe; Zacharias, Martin

2017-05-01

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

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight

PubMed Central

Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels. PMID:28817602

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

PubMed

Regad, Leslie; Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

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.

Correspondence between nonrelativistic anti-de Sitter space and conformal field theory, and aging-gravity duality.

PubMed

Minic, Djordje; Pleimling, Michel

2008-12-01

We point out that the recent discussion of nonrelativistic anti-de Sitter space and conformal field theory correspondence has a direct application in nonequilibrium statistical physics, a fact which has not been emphasized in the recent literature on the subject. In particular, we propose a duality between aging in systems far from equilibrium characterized by the dynamical exponent z=2 and gravity in a specific background. The key ingredient in our proposal is the recent geometric realization of the Schrödinger group. We also discuss the relevance of the proposed correspondence for the more general aging phenomena in systems where the value of the dynamical exponent is different from 2.

Conformal Cryogenic Tank Trade Study for Reusable Launch Vehicles

NASA Technical Reports Server (NTRS)

Rivers, H. Kevin

1999-01-01

Future reusable launch vehicles may be lifting bodies with non-circular cross section like the proposed Lockheed-Martin VentureStar(tm). Current designs for the cryogenic tanks of these vehicles are dual-lobed and quad-lobed tanks which are packaged more efficiently than circular tanks, but still have low packaging efficiencies with large gaps existing between the vehicle outer mold line and the outer surfaces of the tanks. In this study, tanks that conform to the outer mold line of a non-circular vehicle were investigated. Four structural concepts for conformal cryogenic tanks and a quad-lobed tank concept were optimized for minimum weight designs. The conformal tank concepts included a sandwich tank stiffened with axial tension webs, a sandwich tank stiffened with transverse tension webs, a sandwich tank stiffened with rings and tension ties, and a sandwich tank stiffened with orthogrid stiffeners and tension ties. For each concept, geometric parameters (such as ring frame spacing, the number and spacing of tension ties or webs, and tank corner radius) and internal pressure loads were varied and the structure was optimized using a finite-element-based optimization procedure. Theoretical volumetric weights were calculated by dividing the weight of the barrel section of the tank concept and its associated frames, webs and tension ties by the volume it circumscribes. This paper describes the four conformal tank concepts and the design assumptions utilized in their optimization. The conformal tank optimization results included theoretical weights, trends and comparisons between the concepts, are also presented, along with results from the optimization of a quad-lobed tank. Also, the effects of minimum gauge values and non-optimum weights on the weight of the optimized structure are described in this paper.

Enhanced conformational sampling using enveloping distribution sampling.

PubMed

Lin, Zhixiong; van Gunsteren, Wilfred F

2013-10-14

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

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

PubMed

Tamura, Koichi; Hayashi, Shigehiko

2015-07-14

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

Fermionic halos at finite temperature in AdS/CFT

NASA Astrophysics Data System (ADS)

Argüelles, Carlos R.; Grandi, Nicolás E.

2018-05-01

We explore the gravitational backreaction of a system consisting in a very large number of elementary fermions at finite temperature, in asymptotically AdS space. We work in the hydrodynamic approximation, and solve the Tolman-Oppenheimer-Volkoff equations with a perfect fluid whose equation of state takes into account both the relativistic effects of the fermionic constituents, as well as its finite temperature effects. We find a novel dense core-diluted halo structure for the density profiles in the AdS bulk, similarly as recently reported in flat space, for the case of astrophysical dark matter halos in galaxies. We further study the critical equilibrium configurations above which the core undergoes gravitational collapse towards a massive black hole, and calculate the corresponding critical central temperatures, for two qualitatively different central regimes of the fermions: the diluted-Fermi case, and the degenerate case. As a probe for the dual CFT, we construct the holographic two-point correlator of a scalar operator with large conformal dimension in the worldline limit, and briefly discuss on the boundary CFT effects at the critical points.

Dynamics of partially folded and unfolded proteins investigated with quasielastic neutron spectroscopy

NASA Astrophysics Data System (ADS)

Stadler, Andreas M.

2018-05-01

Molecular dynamics in proteins animate and play a vital role for biologically relevant processes of these biomacromolecules. Quasielastic incoherent neutron scattering (QENS) is a well-suited experimental method to study protein dynamics from the picosecond to several nanoseconds and in the Ångström length-scale. In QENS experiments of protein solutions hydrogens act as reporters for the motions of methyl groups or amino acids to which they are bound. Neutron Spin-Echo spectroscopy (NSE) offers the highest energy resolution in the field of neutron spectroscopy and allows the study of slow collective motions in proteins up to several hundred nanoseconds and in the nanometer length-scale. In the following manuscript I will review recent studies that stress the relevance of molecular dynamics for protein folding and for conformational transitions of intrinsically disordered proteins (IDPs). During the folding collapse the protein is exploring its accessible conformational space via molecular motions. A large flexibility of partially folded and unfolded proteins, therefore, is mandatory for rapid protein folding. IDPs are a special case as they are largely unstructured under physiological conditions. A large flexibility is a characteristic property of IDPs as it allows, for example, the interaction with various binding partners or the rapid response to different conditions.

The liquid⟷amorphous transition and the high pressure phase diagram of carbon

NASA Astrophysics Data System (ADS)

Robinson, David R.; Wilson, Mark

2013-04-01

The phase diagram of carbon is mapped to high pressure using a computationally-tractable potential model. The use of a relatively simple (Tersoff-II) potential model allows a large range of phase space to be explored. The coexistence (melting) curve for the diamond crystal/liquid dyad is mapped directly by modelling the solid/liquid interfaces. The melting curve is found to be re-entrant and belongs to a conformal class of diamond/liquid coexistence curves. On supercooling the liquid a phase transition to a tetrahedral amorphous form (ta-C) is observed. The liquid ⟷ amorphous coexistence curve is mapped onto the pT plane and is found to also be re-entrant. The entropy changes for both melting and the amorphous ⟶ liquid transitions are obtained from the respective coexistence curves and the associated changes in molar volume. The structural change on amorphization is analysed at different points on the coexistence curve including for transitions that are both isochoric and isocoordinate (no change in nearest-neighbour coordination number). The conformal nature of the melting curve is highlighted with respect to the known behaviour of Si. The relationship of the observed liquid/amorphous coexistence curve to the Si low- and high-density amorphous (LDA/HDA) transition is discussed.

God of the hinge: treating LGBTQIA patients.

PubMed

Boland, Annie

2017-11-01

This paper looks at systems of gender within the context of analysis. It explores the unique challenges of individuation faced by transsexual, transgender, gender queer, gender non-conforming, cross-dressing and intersex patients. To receive patients generously we need to learn how a binary culture produces profound and chronic trauma. These patients wrestle with being who they are whilst simultaneously receiving negative projections and feeling invisible. While often presenting with the struggles of gender conforming individuals, understanding the specifically gendered aspect of their identity is imperative. An analyst's unconscious bias may lead to iatrogenic shaming. The author argues that rigorous, humble inquiry into the analyst's transphobia can be transformative for patient, analyst, and the work itself. Analysis may, then, provide gender-variant patients with their first remembered and numinous experience of authentic connection to self. Conjuring the image of a hinge, securely placed in the neutral region of a third space, creates a transpositive analytic temenos. Invoking the spirit of the Trickster in the construction of this matrix supports the full inclusion of gender-variant patients. Nuanced attunement scaffolds mirroring and the possibility of play. Being mindful that gender is sturdy and delicate as well as mercurial and defined enriches the analyst's listening. © 2017, The Society of Analytical Psychology.

Atropisomerism about aryl-Csp(3) bonds: the electronic and steric influence of ortho-substituents on conformational exchange in cannabidiol and linderatin derivatives.

PubMed

Berber, Hatice; Lameiras, Pedro; Denhez, Clément; Antheaume, Cyril; Clayden, Jonathan

2014-07-03

Terpenylation reactions of substituted phenols were used to prepare cannabidiol and linderatin derivatives, and their structure and conformational behavior in solution were investigated by NMR and, for some representative examples, by DFT. VT-NMR spectra and DFT calculations were used to determine the activation energies of the conformational change arising from restricted rotation about the aryl-Csp(3) bond that lead to two unequally populated rotameric epimers. The NBO calculation was applied to explain the electronic stabilization of one conformer over another by donor-acceptor charge transfer interactions. Conformational control arises from a combination of stereoelectronic and steric effects between substituents in close contact with each other on the two rings of the endocyclic epoxide atropisomers. This study represents the first exploration of the stereoelectronic origins of atropisomerism around C(sp(2))-C(sp(3)) single bonds through theoretical calculations.

Surface Design Based on Discrete Conformal Transformations

NASA Astrophysics Data System (ADS)

Duque, Carlos; Santangelo, Christian; Vouga, Etienne

Conformal transformations are angle-preserving maps from one domain to another. Although angles are preserved, the lengths between arbitrary points are not generally conserved. As a consequence there is always a given amount of distortion associated to any conformal map. Different uses of such transformations can be found in various fields, but have been used by us to program non-uniformly swellable gel sheets to buckle into prescribed three dimensional shapes. In this work we apply circle packings as a kind of discrete conformal map in order to find conformal maps from the sphere to the plane that can be used as nearly uniform swelling patterns to program non-Euclidean sheets to buckle into spheres. We explore the possibility of tuning the area distortion to fit the experimental range of minimum and maximum swelling by modifying the boundary of the planar domain through the introduction of different cutting schemes.

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

PubMed

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

2017-09-09

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

Discovering Conformational Sub-States Relevant to Protein Function

PubMed Central

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

2011-01-01

Background Internal motions enable proteins to explore a range of conformations, even in the vicinity of native state. The role of conformational fluctuations in the designated function of a protein is widely debated. Emerging evidence suggests that sub-groups within the range of conformations (or sub-states) contain properties that may be functionally relevant. However, low populations in these sub-states and the transient nature of conformational transitions between these sub-states present significant challenges for their identification and characterization. Methods and Findings To overcome these challenges we have developed a new computational technique, quasi-anharmonic analysis (QAA). QAA utilizes higher-order statistics of protein motions to identify sub-states in the conformational landscape. Further, the focus on anharmonicity allows identification of conformational fluctuations that enable transitions between sub-states. QAA applied to equilibrium simulations of human ubiquitin and T4 lysozyme reveals functionally relevant sub-states and protein motions involved in molecular recognition. In combination with a reaction pathway sampling method, QAA characterizes conformational sub-states associated with cis/trans peptidyl-prolyl isomerization catalyzed by the enzyme cyclophilin A. In these three proteins, QAA allows identification of conformational sub-states, with critical structural and dynamical features relevant to protein function. Conclusions Overall, QAA provides a novel framework to intuitively understand the biophysical basis of conformational diversity and its relevance to protein function. PMID:21297978

Validating a Coarse-Grained Potential Energy Function through Protein Loop Modelling

PubMed Central

MacDonald, James T.; Kelley, Lawrence A.; Freemont, Paul S.

2013-01-01

Coarse-grained (CG) methods for sampling protein conformational space have the potential to increase computational efficiency by reducing the degrees of freedom. The gain in computational efficiency of CG methods often comes at the expense of non-protein like local conformational features. This could cause problems when transitioning to full atom models in a hierarchical framework. Here, a CG potential energy function was validated by applying it to the problem of loop prediction. A novel method to sample the conformational space of backbone atoms was benchmarked using a standard test set consisting of 351 distinct loops. This method used a sequence-independent CG potential energy function representing the protein using -carbon positions only and sampling conformations with a Monte Carlo simulated annealing based protocol. Backbone atoms were added using a method previously described and then gradient minimised in the Rosetta force field. Despite the CG potential energy function being sequence-independent, the method performed similarly to methods that explicitly use either fragments of known protein backbones with similar sequences or residue-specific /-maps to restrict the search space. The method was also able to predict with sub-Angstrom accuracy two out of seven loops from recently solved crystal structures of proteins with low sequence and structure similarity to previously deposited structures in the PDB. The ability to sample realistic loop conformations directly from a potential energy function enables the incorporation of additional geometric restraints and the use of more advanced sampling methods in a way that is not possible to do easily with fragment replacement methods and also enable multi-scale simulations for protein design and protein structure prediction. These restraints could be derived from experimental data or could be design restraints in the case of computational protein design. C++ source code is available for download from http://www.sbg.bio.ic.ac.uk/phyre2/PD2/. PMID:23824634

No more CKY two-forms in the NHEK

NASA Astrophysics Data System (ADS)

Mitsuka, Yoshihiro; Moutsopoulos, George

2012-02-01

We show that in the near-horizon limit of a Kerr-NUT-AdS black hole, the space of conformal Killing-Yano two-forms does not enhance and remains of dimension 2. The same holds for an analogous polar limit in the case of extremal NUT charge. We also derive the conformal Killing-Yano p-form equation for any background in an arbitrary dimension in the form of parallel transport.

Spherically symmetric conformal gravity and ''gravitational bubbles''

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

Berezin, V.A.; Dokuchaev, V.I.; Eroshenko, Yu.N., E-mail: berezin@inr.ac.ru, E-mail: dokuchaev@inr.ac.ru, E-mail: eroshenko@inr.ac.ru

2016-01-01

The general structure of the spherically symmetric solutions in the Weyl conformal gravity is described. The corresponding Bach equations are derived for the special type of metrics, which can be considered as the representative of the general class. The complete set of the pure vacuum solutions is found. It consists of two classes. The first one contains the solutions with constant two-dimensional curvature scalar of our specific metrics, and the representatives are the famous Robertson-Walker metrics. One of them we called the ''gravitational bubbles'', which is compact and with zero Weyl tensor. Thus, we obtained the pure vacuum curved space-timesmore » (without any material sources, including the cosmological constant) what is absolutely impossible in General Relativity. Such a phenomenon makes it easier to create the universe from ''nothing''. The second class consists of the solutions with varying curvature scalar. We found its representative as the one-parameter family. It appears that it can be conformally covered by the thee-parameter Mannheim-Kazanas solution. We also investigated the general structure of the energy-momentum tensor in the spherical conformal gravity and constructed the vectorial equation that reveals clearly some features of non-vacuum solutions. Two of them are explicitly written, namely, the metrics à la Vaidya, and the electrovacuum space-time metrics.« less

A random forest learning assisted "divide and conquer" approach for peptide conformation search.

PubMed

Chen, Xin; Yang, Bing; Lin, Zijing

2018-06-11

Computational determination of peptide conformations is challenging as it is a problem of finding minima in a high-dimensional space. The "divide and conquer" approach is promising for reliably reducing the search space size. A random forest learning model is proposed here to expand the scope of applicability of the "divide and conquer" approach. A random forest classification algorithm is used to characterize the distributions of the backbone φ-ψ units ("words"). A random forest supervised learning model is developed to analyze the combinations of the φ-ψ units ("grammar"). It is found that amino acid residues may be grouped as equivalent "words", while the φ-ψ combinations in low-energy peptide conformations follow a distinct "grammar". The finding of equivalent words empowers the "divide and conquer" method with the flexibility of fragment substitution. The learnt grammar is used to improve the efficiency of the "divide and conquer" method by removing unfavorable φ-ψ combinations without the need of dedicated human effort. The machine learning assisted search method is illustrated by efficiently searching the conformations of GGG/AAA/GGGG/AAAA/GGGGG through assembling the structures of GFG/GFGG. Moreover, the computational cost of the new method is shown to increase rather slowly with the peptide length.

Fluorine Substitution in Neurotransmitters: Microwave Spectroscopy and Modelling of the Conformational Space and Non Bonding Interactions

NASA Astrophysics Data System (ADS)

Melandri, S.; Maris, A.; Merloni, A.

2011-06-01

Fluorine substitution in molecules is a common practice in bio-organic chemistry in order to modulate physicochemical properties and biological activity of molecules and an increasing number of drugs on the market contain fluorine, the presence of which is often of major importance to modify pharmacokinetics properties and molecular activity. The rationale for such a strategy is that fluorine is generally a stronger electron acceptor than the other halogen atoms and its size is intermediate between that of hydrogen and oxygen. We have studied two fluorinated analogs of 2-phenylethylamine (PEA), the prototype molecule for adrenergic neurotransmitters, namely: 4-Fluoro (4FPEA) and 2-Fluoro-2-phenylethylamine (2FPEA) by Molecular Beam Fourier Transform Microwave Spectroscopy in the frequency range 6-18 GHz and ab initio calculations at the MP2/6311++G** level. The aim is to obtain information on the spatial arrangement of the ethylamine side chain and the effects of fluorination on the energy landscape. The conformational space is dominated by low energy gauche conformations stabilized by weak interactions between the aminic hydrogens and the electron cloud of the benzene ring and anti conformations higher in energy. In 2FPEA the presence of the fluorine atom almost duplicate the number of possible conformation with respect to 4FPEA. We observed two conformers of 4FPEA and five conformers of 2FPEA which have been classified with the guide provided by accurate ab initio calculations. The identification of the conformational species was helped by the analysis of the quadrupole hyperfine pattern which is greatly influenced by the orientation of the amino group and acts as a fingerprint for each conformation. The orientation of the dipole moment within the principal axis frame and the order of stability of the different conformations are other independent pieces of evidence for the unambiguous assignment and identification of the conformers. The order of stability was found to be altered in both molecules with respect to the prototype PEA molecule, especially in the case of 2FPEA where we observe a stabilization of some of the anti forms and great destabilization of some of the gauche forms. These observations are in agreement with the results of the theoretical calculation and can be rationalized in terms of the effect of the fluorine atom on the electron density of the molecule and in particular on the electron cloud on the benzene ring.

Self-dual Skyrmions on the spheres S2 N +1

NASA Astrophysics Data System (ADS)

Amari, Y.; Ferreira, L. A.

2018-04-01

We construct self-dual sectors for scalar field theories on a (2 N +2 )-dimensional Minkowski space-time with the target space being the 2 N +1 -dimensional sphere S2 N +1. The construction of such self-dual sectors is made possible by the introduction of an extra functional in the action that renders the static energy and the self-duality equations conformally invariant on the (2 N +1 )-dimensional spatial submanifold. The conformal and target-space symmetries are used to build an ansatz that leads to an infinite number of exact self-dual solutions with arbitrary values of the topological charge. The five-dimensional case is discussed in detail, where it is shown that two types of theories admit self-dual sectors. Our work generalizes the known results in the three-dimensional case that lead to an infinite set of self-dual Skyrmion solutions.

Concomitant and conformational polymorphism in 4‧-(isoquinolyl-2,2‧:6‧,2″-terpyridine and 4‧-(4-quinolyl)-2,2‧:6‧,2″-terpyridine

NASA Astrophysics Data System (ADS)

Njogu, Eric M.; Nyamori, Vincent O.; Omondi, Bernard

2018-02-01

The occurrence of concomitant polymorphism in 4‧-(isoquinolyl)-2,2‧:6‧,2″-terpyridine, 1a and 1b (2-quinterpy) and conformational polymorphism in 4‧-(4-quinolyl)-2,2‧:6‧,2″-terpyridine (4-quinterpy) has been identified to due to crystallization process and solvent, respectively. Crystallization of 2-quinterpy in acetone yielded the concomitant polymorphs 1a and 1b which crystallize in the monoclinic P21/c and the orthorhombic Pna21 space groups, respectively. The polymorph 2a was grown from bulk 4-quinterpy in dimethyl sulfoxide, crystallizes in the monoclinic P21/c space group, while 2b grown from acetonitrile or even acetone crystallizes in the monoclinic system but in P21/n space group.

Renormalization of position space amplitudes in a massless QFT

NASA Astrophysics Data System (ADS)

Todorov, Ivan

2017-03-01

Ultraviolet renormalization of position space massless Feynman amplitudes has been shown to yield associate homogeneous distributions. Their degree is determined by the degree of divergence while their order—the highest power of logarithm in the dilation anomaly—is given by the number of (sub)divergences. In the present paper we review these results and observe that (convergent) integration over internal vertices does not alter the total degree of (superficial) ultraviolet divergence. For a conformally invariant theory internal integration is also proven to preserve the order of associate homogeneity. The renormalized 4-point amplitudes in the φ4 theory (in four space-time dimensions) are written as (non-analytic) translation invariant functions of four complex variables with calculable conformal anomaly. Our conclusion concerning the (off-shell) infrared finiteness of the ultraviolet renormalized massless φ4 theory agrees with the old result of Lowenstein and Zimmermann [23].

Defense Space Acquisitions: Too Early to Determine if Recent Changes Will Resolve Persistent Fragmentation in Management and Oversight

DTIC Science & Technology

2016-07-27

effectively respond to these threats has increased the importance of focused leadership in national security space. In Senate Report 114-49 accompanying...review the effectiveness of the current DOD space acquisition and oversight model and to evaluate what changes, if any, could be considered to... effectively consolidate space leadership. Some of these responsibilities include reviewing all service budgets for conformity with national security

AdS/CFT, Black Holes, And Fuzzballs

NASA Astrophysics Data System (ADS)

Zadeh, Ida G.

In this thesis we investigate two different aspects of the AdS/CFT correspondence. We first investigate the holographic AdS/CMT correspondence. Gravitational backgrounds in d + 2 dimensions have been proposed as holographic duals to Lifshitz-like theories describing critical phenomena in d + 1 dimensions with critical exponent z ≥ 1. We numerically explore a dilaton-Einstein-Maxwell model admitting such backgrounds as solutions. We show how to embed these solutions into AdS space for a range of values of z and d. We next investigate the AdS3/CFT2 correspondence and focus on the microscopic CFT description of the D1--D5 system on T4 x S1. In the context of the fuzzball programme, we investigate deforming the CFT away from the orbifold point and study lifting of the low-lying string states. We start by considering general 2D orbifold CFTs of the form M N/SN, with M a target space manifold and SN the symmetric group. The Lunin-Mathur covering space technique provides a way to compute correlators in these orbifold theories, and we generalize this technique in two ways. First, we consider excitations of twist operators by modes of fields that are not twisted by that operator, and show how to account for these excitations when computing correlation functions in the covering space. Second, we consider non-twist sector operators and show how to include the effects of these insertions in the covering space. Using the generalization of the Lunin-Mathur symmetric orbifold technology and conformal perturbation theory, we initiate a program to compute the anomalous dimensions of low-lying string states in the D1--D5 superconformal field theory. Our method entails finding four-point functions involving a string operator O of interest and the deformation operator, taking coincidence limits to identify which other operators mix with O, subtracting conformal families of these operators, and computing their mixing coefficients. We find evidence of operator mixing at first order in the deformation parameter, which means that the string state acquires an anomalous dimension. After diagonalization this will mean that anomalous dimensions of some string states in the D1--D5 SCFT must decrease away from the orbifold point while others increase. Finally, we summarize our results and discuss some future directions of research.

Can a continuum solvent model reproduce the free energy landscape of a -hairpin folding in water?

NASA Astrophysics Data System (ADS)

Zhou, Ruhong; Berne, Bruce J.

2002-10-01

The folding free energy landscape of the C-terminal -hairpin of protein G is explored using the surface-generalized Born (SGB) implicit solvent model, and the results are compared with the landscape from an earlier study with explicit solvent model. The OPLSAA force field is used for the -hairpin in both implicit and explicit solvent simulations, and the conformational space sampling is carried out with a highly parallel replica-exchange method. Surprisingly, we find from exhaustive conformation space sampling that the free energy landscape from the implicit solvent model is quite different from that of the explicit solvent model. In the implicit solvent model some nonnative states are heavily overweighted, and more importantly, the lowest free energy state is no longer the native -strand structure. An overly strong salt-bridge effect between charged residues (E42, D46, D47, E56, and K50) is found to be responsible for this behavior in the implicit solvent model. Despite this, we find that the OPLSAA/SGB energies of all the nonnative structures are higher than that of the native structure; thus the OPLSAA/SGB energy is still a good scoring function for structure prediction for this -hairpin. Furthermore, the -hairpin population at 282 K is found to be less than 40% from the implicit solvent model, which is much smaller than the 72% from the explicit solvent model and 80% from experiment. On the other hand, both implicit and explicit solvent simulations with the OPLSAA force field exhibit no meaningful helical content during the folding process, which is in contrast to some very recent studies using other force fields.

Can a continuum solvent model reproduce the free energy landscape of a β-hairpin folding in water?

PubMed Central

Zhou, Ruhong; Berne, Bruce J.

2002-01-01

The folding free energy landscape of the C-terminal β-hairpin of protein G is explored using the surface-generalized Born (SGB) implicit solvent model, and the results are compared with the landscape from an earlier study with explicit solvent model. The OPLSAA force field is used for the β-hairpin in both implicit and explicit solvent simulations, and the conformational space sampling is carried out with a highly parallel replica-exchange method. Surprisingly, we find from exhaustive conformation space sampling that the free energy landscape from the implicit solvent model is quite different from that of the explicit solvent model. In the implicit solvent model some nonnative states are heavily overweighted, and more importantly, the lowest free energy state is no longer the native β-strand structure. An overly strong salt-bridge effect between charged residues (E42, D46, D47, E56, and K50) is found to be responsible for this behavior in the implicit solvent model. Despite this, we find that the OPLSAA/SGB energies of all the nonnative structures are higher than that of the native structure; thus the OPLSAA/SGB energy is still a good scoring function for structure prediction for this β-hairpin. Furthermore, the β-hairpin population at 282 K is found to be less than 40% from the implicit solvent model, which is much smaller than the 72% from the explicit solvent model and ≈80% from experiment. On the other hand, both implicit and explicit solvent simulations with the OPLSAA force field exhibit no meaningful helical content during the folding process, which is in contrast to some very recent studies using other force fields. PMID:12242327

Can a continuum solvent model reproduce the free energy landscape of a beta -hairpin folding in water?

PubMed

Zhou, Ruhong; Berne, Bruce J

2002-10-01

The folding free energy landscape of the C-terminal beta-hairpin of protein G is explored using the surface-generalized Born (SGB) implicit solvent model, and the results are compared with the landscape from an earlier study with explicit solvent model. The OPLSAA force field is used for the beta-hairpin in both implicit and explicit solvent simulations, and the conformational space sampling is carried out with a highly parallel replica-exchange method. Surprisingly, we find from exhaustive conformation space sampling that the free energy landscape from the implicit solvent model is quite different from that of the explicit solvent model. In the implicit solvent model some nonnative states are heavily overweighted, and more importantly, the lowest free energy state is no longer the native beta-strand structure. An overly strong salt-bridge effect between charged residues (E42, D46, D47, E56, and K50) is found to be responsible for this behavior in the implicit solvent model. Despite this, we find that the OPLSAA/SGB energies of all the nonnative structures are higher than that of the native structure; thus the OPLSAA/SGB energy is still a good scoring function for structure prediction for this beta-hairpin. Furthermore, the beta-hairpin population at 282 K is found to be less than 40% from the implicit solvent model, which is much smaller than the 72% from the explicit solvent model and approximately equal 80% from experiment. On the other hand, both implicit and explicit solvent simulations with the OPLSAA force field exhibit no meaningful helical content during the folding process, which is in contrast to some very recent studies using other force fields.

Probing the conformational dynamics of photosystem I in unconfined and confined spaces.

PubMed

Das, Gaurav; Chattoraj, Shyamtanu; Nandi, Somen; Mondal, Prasenjit; Saha, Abhijit; Bhattacharyya, Kankan; Ghosh, Surajit

2017-12-20

The fluorescence dynamics of Photosystem I (PSI) in bulk water and inside a confined environment like a liposome have been investigated using time resolved confocal microscopy. In bulk water, PSI exhibits a major emission peak at ∼680 nm, while in the liposome it exhibits a markedly blue shifted emission maximum at ∼485 nm. This is indicative of conformational changes due to entrapment and emergence of a stressed conformation of PSI inside the liposome. The observed time constants for the fluorescence lifetime of PSI inside the liposome are significantly high as opposed to PSI in bulk water. More interestingly, the fluorescence intensity of PSI in bulk water exhibits strong fluctuations with many high intensity jumps and these are anti-correlated with the fluorescence lifetime of PSI. In contrast, inside the liposome, no such anti-correlated behaviour is observed. We further demonstrated that PSI exhibits at least two conformational states in bulk water, whereas a single conformation is observed inside the liposome, indicating the conformational rigidity and locking of the PSI complex inside a liposome.

Visualization of SV2A conformations in situ by the use of Protein Tomography

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

Lynch, Berkley A.; Matagne, Alain; Braennstroem, Annika

2008-10-31

The synaptic vesicle protein 2A (SV2A), the brain-binding site of the anti-epileptic drug levetiracetam (LEV), has been characterized by Protein Tomography{sup TM}. We identified two major conformations of SV2A in mouse brain tissue: first, a compact, funnel-structure with a pore-like opening towards the cytoplasm; second, a more open, V-shaped structure with a cleft-like opening towards the intravesicular space. The large differences between these conformations suggest a high degree of flexibility and support a valve-like mechanism consistent with the postulated transporter role of SV2A. These two conformations are represented both in samples treated with LEV, and in saline-treated samples, which indicatesmore » that LEV binding does not cause a large-scale conformational change of SV2A, or lock a specific conformational state of the protein. This study provides the first direct structural data on SV2A, and supports a transporter function suggested by sequence homology to MFS class of transporter proteins.« less

Second-order hydrodynamics and universality in non-conformal holographic fluids

NASA Astrophysics Data System (ADS)

Kleinert, Philipp; Probst, Jonas

2016-12-01

We study second-order hydrodynamic transport in strongly coupled non-conformal field theories with holographic gravity duals in asymptotically anti-de Sitter space. We first derive new Kubo formulae for five second-order transport coefficients in non-conformal fluids in (3 + 1) dimensions. We then apply them to holographic RG flows induced by scalar operators of dimension Δ = 3. For general background solutions of the dual bulk geometry, we find explicit expressions for the five transport coefficients at infinite coupling and show that a specific combination, tilde{H}=2η {τ}_{π }-2(κ -{κ}^{ast})-{λ}_2 , always vanishes. We prove analytically that the Haack-Yarom identity H = 2 ητ π - 4λ1 - λ2 = 0, which is known to be true for conformal holographic fluids at infinite coupling, also holds when taking into account leading non-conformal corrections. The numerical results we obtain for two specific families of RG flows suggest that H vanishes regardless of conformal symmetry. Our work provides further evidence that the Haack-Yarom identity H = 0 may be universally satisfied by strongly coupled fluids.

"This Was My Hell": The Violence Experienced by Gender Non-Conforming Youth in US High Schools

ERIC Educational Resources Information Center

Wyss, Shannon E.

2004-01-01

This paper explores the experiences of harassment and violence endured by seven gender non-conforming youth in US high schools. Based on a larger research project, it opens an inquiry into the school-based lives of gender-variant teens, a group heretofore ignored by most academics and educators. Breaking violence down into two main types (physical…

Intergroup Contact, Attitudes toward Homosexuality, and the Role of Acceptance of Gender Non-Conformity in Young Adolescents

ERIC Educational Resources Information Center

Collier, Kate L.; Bos, Henny M. W.; Sandfort, Theo G. M.

2012-01-01

This study explored how contact with gay and lesbian persons affects adolescents' attitudes toward them, and whether this association is mediated or moderated by one's acceptance of gender non-conformity. We analyzed survey responses from 456 Dutch adolescents aged 12-15 who reported having no same-sex attractions. Data were collected in 2008 at 8…

14 CFR 1260.74 - Property use, disposition, and vesting of title.

Code of Federal Regulations, 2012 CFR

2012-01-01

... demonstrates that the equipment will be used exclusively for research activities. (b) Vesting of title to... title. 1260.74 Section 1260.74 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION..., and vesting of title. (a) Approval for acquisition of property shall conform to the following...

14 CFR 1260.74 - Property use, disposition, and vesting of title.

Code of Federal Regulations, 2010 CFR

2010-01-01

... demonstrates that the equipment will be used exclusively for research activities. (b) Vesting of title to... title. 1260.74 Section 1260.74 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION..., and vesting of title. (a) Approval for acquisition of property shall conform to the following...

14 CFR 1260.74 - Property use, disposition, and vesting of title.

Code of Federal Regulations, 2011 CFR

2011-01-01

... demonstrates that the equipment will be used exclusively for research activities. (b) Vesting of title to... title. 1260.74 Section 1260.74 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION..., and vesting of title. (a) Approval for acquisition of property shall conform to the following...

14 CFR 21.500 - Approval of engines and propellers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Approval of engines and propellers. 21.500 Section 21.500 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... propeller— (a) Conforms to its U.S. type certificate and is in condition for safe operation; and (b) Has...

Argyres-Douglas theories and S-duality

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

Buican, Matthew; Giacomelli, Simone; Nishinaka, Takahiro

We generalize S-duality to N=2 superconformal field theories (SCFTs) with Coulomb branch operators of non-integer scaling dimension. As simple examples, we find minimal generalizations of the S-dualities discovered in SU(2) gauge theory with four fundamental flavors by Seiberg and Witten and in SU(3) gauge theory with six fundamental flavors by Argyres and Seiberg. Our constructions start by weakly gauging diagonal SU(2) and SU(3) flavor symmetry subgroups of two copies of a particular rank-one Argyres-Douglas theory (along with sufficient numbers of hypermultiplets to guarantee conformality of the gauging). Here, as we explore the resulting conformal manifold of the SU(2) SCFT, wemore » find an action of S-duality on the parameters of the theory that is reminiscent of Spin(8) triality. On the other hand, as we explore the conformal manifold of the SU(3) theory, we find that an exotic rank-two SCFT emerges in a dual SU(2) description.« less

Structural investigation of cellobiose dehydrogenase IIA: Insights from small angle scattering into intra- and intermolecular electron transfer mechanisms

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

Bodenheimer, Annette M.; O'Dell, William B.; Oliver, Ryan C.

Background: Cellobiose dehydrogenases have gained interest due to their potential applications in sectors from biofuel production to biomedical devices. The CDHIIA variant is comprised of a cytochrome domain (CYT), a dehydrogenase domain (DH), and a carbohydrate-binding module (CBM) that are connected by two flexible linkers. Upon cellobiose oxidation at the DH, intramolecular electron transfer (IaET) occurs from the DH to the CYT. In vivo, CDHIIA CYT subsequently performs intermolecular electron transfer (IeET) to a lytic polysaccharide monooxygenase (LPMO). The relevant solution-state CDH domain conformations for IaET and IeET have not been fully characterized.Methods: Small-angle X-ray and neutron scattering measurements ofmore » oxidized CDHIIA from Myriococcum thermophilum and Neurospora crassa were performed to investigate the structural landscape explored in solution by MtCDHIIA and NcCDHIIA in response to cations, pH, and the presence of an electron acceptor, LPMO9D from N. crassa.Results: The scattering data complemented by modeling show that, under oxidizing conditions, MtCDHIIA undergoes global conformational rearrangement in the presence of Ca2+. Oxidized NcCDHIIA exhibits conformational changes upon pH variation and, in the presence of NcLPMO9D, primarily adopts a compact conformation.Conclusions: These results demonstrate different conformational responses of oxidized MtCDHIIA and NcCDHIIA to changes in environment. The results also reveal a shift in the oxidized NcCDHIIA conformational landscape toward interdomain compaction upon co-incubation with NcLPMO9D.General significance: The present study is the first report on the structural landscapes explored in solution by oxidized cellobiose dehydrogenases under various cation concentrations, pH conditions and in the presence of an electron-accepting LPMO.« less

Structural investigation of cellobiose dehydrogenase IIA: Insights from small angle scattering into intra- and intermolecular electron transfer mechanisms

DOE PAGES

Bodenheimer, Annette M.; O'Dell, William B.; Oliver, Ryan C.; ...

2018-01-31

Background: Cellobiose dehydrogenases have gained interest due to their potential applications in sectors from biofuel production to biomedical devices. The CDHIIA variant is comprised of a cytochrome domain (CYT), a dehydrogenase domain (DH), and a carbohydrate-binding module (CBM) that are connected by two flexible linkers. Upon cellobiose oxidation at the DH, intramolecular electron transfer (IaET) occurs from the DH to the CYT. In vivo, CDHIIA CYT subsequently performs intermolecular electron transfer (IeET) to a lytic polysaccharide monooxygenase (LPMO). The relevant solution-state CDH domain conformations for IaET and IeET have not been fully characterized.Methods: Small-angle X-ray and neutron scattering measurements ofmore » oxidized CDHIIA from Myriococcum thermophilum and Neurospora crassa were performed to investigate the structural landscape explored in solution by MtCDHIIA and NcCDHIIA in response to cations, pH, and the presence of an electron acceptor, LPMO9D from N. crassa.Results: The scattering data complemented by modeling show that, under oxidizing conditions, MtCDHIIA undergoes global conformational rearrangement in the presence of Ca2+. Oxidized NcCDHIIA exhibits conformational changes upon pH variation and, in the presence of NcLPMO9D, primarily adopts a compact conformation.Conclusions: These results demonstrate different conformational responses of oxidized MtCDHIIA and NcCDHIIA to changes in environment. The results also reveal a shift in the oxidized NcCDHIIA conformational landscape toward interdomain compaction upon co-incubation with NcLPMO9D.General significance: The present study is the first report on the structural landscapes explored in solution by oxidized cellobiose dehydrogenases under various cation concentrations, pH conditions and in the presence of an electron-accepting LPMO.« less

Temperature-dependent conformational variation of chromophoric dissolved organic matter and its consequent interaction with phenanthrene.

PubMed

Chen, Wei; Liu, Xiao-Yang; Yu, Han-Qing

2017-03-01

Temperature variation caused by climate change, seasonal variation and geographic locations affects the physicochemical compositions of chromophoric dissolved organic matter (CDOM), resulting in difference in the fates of CDOM-related environmental pollutants. Exploration into the thermal induced structural transition of CDOM can help to better understand their environmental impacts, but information on this aspect is still lacking. Through integrating fluorescence excitation-emission matrix coupled parallel factor analysis with synchronous fluorescence two-dimensional correlation spectroscopy, this study provides an in-depth insight into the temperature-dependent conformational transitions of CDOM and their impact on its hydrophobic interaction with persistent organic pollutants (with phenanthrene as an example) in water. The fluorescence components in CDOM change linearly to water temperature with different extents and different temperature regions. The thermal induced transition priority in CDOM is protein-like component → fulvic-like component → humic-like component. Furthermore, the impact of thermal-induced conformational transition of CDOM on its hydrophobic interaction with phenanthrene is observed and explored. The fluorescence-based analytic results reveal that the conjugation degree of the aromatic groups in the fulvic- and humic-like substances, and the unfolding of the secondary structure in the protein-like substances with aromatic structure, contribute to the conformation variation. This integrated approach jointly enhances the characterization of temperature-dependent conformational variation of CDOM, and provides a promising way to elucidate the environmental behaviours of CDOM. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

PubMed

Xie, Min; Qi, Yajing; Hu, Yongjun

2011-04-14

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

Renormalization, conformal ward identities and the origin of a conformal anomaly pole

NASA Astrophysics Data System (ADS)

Corianò, Claudio; Maglio, Matteo Maria

2018-06-01

We investigate the emergence of a conformal anomaly pole in conformal field theories in the case of the TJJ correlator. We show how it comes to be generated in dimensional renormalization, using a basis of 13 form factors (the F-basis), where only one of them requires renormalization (F13), extending previous studies. We then combine recent results on the structure of the non-perturbative solutions of the conformal Ward identities (CWI's) for the TJJ in momentum space, expressed in terms of a minimal set of 4 form factors (A-basis), with the properties of the F-basis, and show how the singular behaviour of the corresponding form factors in both basis can be related. The result proves the centrality of such massless effective interactions induced by the anomaly, which have recently found realization in solid state, in the theory of topological insulators and of Weyl semimetals. This pattern is confirmed in massless abelian and nonabelian theories (QED and QCD) investigated at one-loop.

Some general aspects of torsional sensitivity and the GG-effect

NASA Astrophysics Data System (ADS)

Yu, C.-H.; Schäfer, L.; Ramek, M.; Miller, D. M.; Teppen, B. J.

1999-08-01

The geometries of 28 compounds of type X-C1-C2-C3-Y, with X,Y=CH 3, F, Cl, OH, NH 2, COH, and COOH, were fully optimized by ab initio HF/4-21G calculations at 30° grid points in their respective φ(X-C1-C2-C3), ψ(C1-C2-C3-Y)-torsional spaces. The results make it possible to construct parameter surfaces and their gradients in φ, ψ-space. The magnitude of the gradient, |∇ P|=[( ∂P/ ∂φ) 2+( ∂P/ ∂ψ) 2] 1/2, of a structural parameter P (a bond length, bond angle, or non-bonded distance) in φ, ψ-torsional space is a measure of torsional sensitivity (TS); i.e. a measure of the extent to which bond lengths, bond angles, and non-bonded distances change at a point in φ, ψ-space with backbone torsional angles. It is found that TS is not constant throughout the conformational space of a molecule, but varies in a characteristic way. It seems that, regardless of the nature of X or Y, extended forms are typically in regions of low TS; puckered conformations, of high TS. Conformations with two sequential gauche torsional angles (GG sequences) are characterized by high TS of 1,5-non-bonded distances concomitant with relatively low TS of other internal coordinates. This property of GG sequences is the source of a stabilizing and cooperative energy increment that is not afforded by other torsional sequences, such as trans- trans or trans- gauche. A structural data base, consisting of thousands of HF/4-21G structures of X-C-C-Y and X-C-C-C-Y systems has been assembled and is available on a CD.

Higher symmetries of the Schrödinger operator in Newton-Cartan geometry

NASA Astrophysics Data System (ADS)

Gundry, James

2017-03-01

We establish several relationships between the non-relativistic conformal symmetries of Newton-Cartan geometry and the Schrödinger equation. In particular we discuss the algebra sch(d) of vector fields conformally-preserving a flat Newton-Cartan spacetime, and we prove that its curved generalisation generates the symmetry group of the covariant Schrödinger equation coupled to a Newtonian potential and generalised Coriolis force. We provide intrinsic Newton-Cartan definitions of Killing tensors and conformal Schrödinger-Killing tensors, and we discuss their respective links to conserved quantities and to the higher symmetries of the Schrödinger equation. Finally we consider the role of conformal symmetries in Newtonian twistor theory, where the infinite-dimensional algebra of holomorphic vector fields on twistor space corresponds to the symmetry algebra cnc(3) on the Newton-Cartan spacetime.

Conformational flexibility and packing plausibility of repaglinide polymorphs

NASA Astrophysics Data System (ADS)

Rani, Dimpy; Goyal, Parnika; Chadha, Renu

2018-04-01

The present manuscript highlights the structural insight into the repaglinide polymorphs. The experimental screening for the possible crystal forms were carried out using various solvents, which generated three forms. The crystal structure of Form II and III was determined using PXRD pattern whereas structural analysis of Form I has already been reported. Form I, II and II was found to exist in P212121, PNA21 and P21/c space groups respectively. Conformational analysis was performed to account the conformational flexibility of RPG. The obtained conformers were further utilized to obtain the information about the crystal packing pattern of RPG polymorphs by polymorph prediction module. The lattice energy landscape, depicting the relationship between lattice energy and density of the polymorphs has been obtained for various possible polymorphs. The experimentally isolated polymorphs were successfully fitted into lattice energy landscape.

Thermally and vibrationally induced conformational isomerizations, infrared spectra, and photochemistry of gallic acid in low-temperature matrices

NASA Astrophysics Data System (ADS)

Justino, Licínia L. G.; Reva, Igor; Fausto, Rui

2016-07-01

Near-infrared (near-IR) narrowband selective vibrational excitation and annealing of gallic acid (3,4,5-trihydroxybenzoic acid) isolated in cryogenic matrices were used to induce interconversions between its most stable conformers. The isomerizations were probed by infrared spectroscopy. An extensive set of quantum chemical calculations, carried out at the DFT(B3LYP)/6-311++G(d,p) level of approximation, was used to undertake a detailed analysis of the ground state potential energy surface of the molecule. This investigation of the molecule conformational space allowed extracting mechanistic insights into the observed annealing- or near-IR-induced isomerization processes. The infrared spectra of the two most stable conformers of gallic acid in N2, Xe, and Ar matrices were fully assigned. Finally, the UV-induced photochemistry of the matrix isolated compound was investigated.

Vibrational cross-angles in condensed molecules: a structural tool.

PubMed

Chen, Hailong; Zhang, Yufan; Li, Jiebo; Liu, Hongjun; Jiang, De-En; Zheng, Junrong

2013-09-05

The fluctuations of three-dimensional molecular conformations of a molecule in different environments play critical roles in many important chemical and biological processes. X-ray diffraction (XRD) techniques and nuclear magnetic resonance (NMR) methods are routinely applied to monitor the molecular conformations in condensed phases. However, some special requirements of the methods have prevented them from exploring many molecular phenomena at the current stage. Here, we introduce another method to resolve molecular conformations based on an ultrafast MIR/T-Hz multiple-dimensional vibrational spectroscopic technique. The model molecule (4'-methyl-2'-nitroacetanilide, MNA) is prepared in two of its crystalline forms and liquid samples. Two polarized ultrafast infrared pulses are then used to determine the cross-angles of vibrational transition moment directions by exciting one vibrational band and detecting the induced response on another vibrational band of the molecule. The vibrational cross-angles are then converted into molecular conformations with the aid of calculations. The molecular conformations determined by the method are supported by X-ray diffraction and molecular dynamics simulation results. The experimental results suggest that thermodynamic interactions with solvent molecules are not altering the molecular conformations of MNA in the solutions to control their ultimate conformations in the crystals.

Neural Basis of Two Kinds of Social Influence: Obedience and Conformity

PubMed Central

Xie, Ying; Chen, Mingliang; Lai, Hongxia; Zhang, Wuke; Zhao, Zhen; Anwar, Ch. Mahmood

2016-01-01

Event-related potentials (ERPs) were used in this study to explore the neural mechanism of obedience and conformity on the model of online book purchasing. Participants were asked to decide as quickly as possible whether to buy a book based on limited information including its title, keywords and number of positive and negative reviews. Obedience was induced by forcing participants to buy books which received mostly negative reviews. In contrast, conformity was aroused by majority influence (caused by positive and negative comments). P3 and N2, two kinds of ERP components related to social cognitive process, were measured and recorded with electroencephalogram (EEG) test. The results show that compared with conformity decisions, obedience decisions induced greater cognitive conflicts. In ERP measurements, greater amplitudes of N2 component were observed in the context of obedience. However, consistency level did not make a difference on P3 peak latency for both conformity and obedience. This shows that classification process is implicit in both conformity and obedience decision-making. In addition, for both conformity and obedience decisions, augmented P3 was observed when the reviews consistency (either negative or positive) was higher. PMID:26941632

Conformational flexibility of human casein kinase catalytic subunit explored by metadynamics.

PubMed

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-03-04

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the γ phosphate from ATP to serine and threonine residues on protein substrates. In a number of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2α catalytic subunit. This variability reflects a high flexibility for two regions of CK2α: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, we present a computational study simulating the equilibrium between three conformations involving these regions. Simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provides a reference pathway describing the conformational changes being studied, based on analysis of free energy surfaces. The free energies of the three conformations were found to be close and the paths proposed had low activation barriers. Our results indicate that these conformations can exist in water. This information should be useful when designing inhibitors specific to one conformation. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Equivalent equations of motion for gravity and entropy

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

Czech, Bartlomiej; Lamprou, Lampros; McCandlish, Samuel

We demonstrate an equivalence between the wave equation obeyed by the entanglement entropy of CFT subregions and the linearized bulk Einstein equation in Anti-de Sitter space. In doing so, we make use of the formalism of kinematic space and fields on this space. We show that the gravitational dynamics are equivalent to a gauge invariant wave-equation on kinematic space and that this equation arises in natural correspondence to the conformal Casimir equation in the CFT.

Equivalent equations of motion for gravity and entropy

DOE PAGES

Czech, Bartlomiej; Lamprou, Lampros; McCandlish, Samuel; ...

2017-02-01

We demonstrate an equivalence between the wave equation obeyed by the entanglement entropy of CFT subregions and the linearized bulk Einstein equation in Anti-de Sitter space. In doing so, we make use of the formalism of kinematic space and fields on this space. We show that the gravitational dynamics are equivalent to a gauge invariant wave-equation on kinematic space and that this equation arises in natural correspondence to the conformal Casimir equation in the CFT.

TET Explorers: Pushing back the frontiers of Science

NASA Astrophysics Data System (ADS)

Curtis, S. A.; Clark, P. E.; Garvin, J. B.; Rilee, M. L.; Dorband, J. E.; Cheung, C. Y.; Sams, J. E.

2005-12-01

We are in the process of developing Tetrahedral Explorer Technologies (TETs) for the extreme mobility needed to explore remote, rugged terrain. TET architecture is based on the tetrahedron as building block, acting singly or interconnected, where apices act as nodes from which struts reversibly deploy. Conformable tetrahedra are the simplest space-filling form the way triangles are the simplest plane-filling facets. The tetrahedral framework acts as a simple skeletal muscular structure. Reconfigurable architecture is essential in exploration because reaching features of the greatest potential interest requires crossing a wide range of terrains. Thus, areas of interest are relatively inaccessible to permanently appendaged vehicles. For example, morphology and geochemistry of interior basins, walls, and ejecta blankets of impact structures must all be studied to understand the nature of an impact event. The crater floor might be relatively flat and navigable, while typical crater walls are variably sloping, and dominated by unconsolidated debris. To be totally functional, structures must form pseudo-appendages varying in size, rate, and manner of deployment (gait). We have already prototyped a simple robotic walker from a single reconfigurable tetrahedron capable of tumbling and are simulating and building a prototype of the more evolved 12Tetrahedral Walker (Autonomous Lunar Investigator) which has interior nodes for payload, more continuous motion, and is commandable through a user friendly interface. Our current applications consist of a more differentiated architecture to form detachable, reconfigurable, reshapable linearly extendable bodies (Class W or Worm), ranging from arms terminating in opposable digits (Class S or Spider) to act as manual assistant subsystems on rovers, to autonomous pseudo-hominid clamberers (Class M or Mammal), with extensions terminating in a wider range of sensors. We are now simulating Class W and Class S gaits and will be building a prototype rover arm. Ultimately, complex continuous n-tetrahedral structures, more advanced versions of Class A, will have deployable outer skin, and even higher degrees of freedom. Combined high and low level intelligence through an extended neural interface will allow `shape shifting' for required function, from surface-conformable lander to amorphous rover to concave surface formation for antenna function. Such architecture will consist of reusable, reconfigurable, mobile, and self-repairing structures, capable of acting as a multi-functional infrastructure. TET systems will act as robotic adjuncts to human explorers, enabling access to otherwise inaccessible resources essential to sustaining human presence.

Bosonization in Space-Time

NASA Astrophysics Data System (ADS)

Stone, Michael

The following sections are included: * Introduction * Free Fermi Fields * Free Bosons * The Bosonization Rules * A Quantum Pythagoras Theorem * Appendix 1A. Complex Coordinates * Appendix IB. Conformal Symmetry * References

Thermodynamical properties of hairy black holes in n spacetime dimensions

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

Nadalini, Mario; Vanzo, Luciano; Zerbini, Sergio

The issue concerning the existence of exact black hole solutions in the presence of a nonvanishing cosmological constant and scalar fields is reconsidered. With regard to this, in investigating no-hair theorem violations, exact solutions of gravity having as a source an interacting and conformally coupled scalar field are revisited in arbitrary dimensional nonasymptotically flat space-times. New and known hairy black hole solutions are discussed. The thermodynamical properties associated with these solutions are investigated and the invariance of the black hole entropy with respect to different conformal frames is proved. The issue of the positivity of the entropy is discussed andmore » resolved for the case of black holes immersed in de Sitter space.« less

Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) for Conformational Space Search of Peptide and Miniprotein

PubMed Central

Hao, Ge-Fei; Xu, Wei-Fang; Yang, Sheng-Gang; Yang, Guang-Fu

2015-01-01

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. PMID:26492886

QUENCHING OF STAR FORMATION IN SLOAN DIGITAL SKY SURVEY GROUPS: CENTRALS, SATELLITES, AND GALACTIC CONFORMITY

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

Knobel, Christian; Lilly, Simon J.; Woo, Joanna

2015-02-10

We re-examine the fraction of low-redshift Sloan Digital Sky Survey satellites and centrals in which star formation has been quenched, using the environment quenching efficiency formalism that separates out the dependence of stellar mass. We show that the centrals of the groups containing the satellites are responding to the environment in the same way as their satellites (at least for stellar masses above 10{sup 10.3} M {sub ☉}), and that the well-known differences between satellites and the general set of centrals arise because the latter are overwhelmingly dominated by isolated galaxies. The widespread concept of ''satellite quenching'' as the causemore » of environmental effects in the galaxy population can therefore be generalized to ''group quenching''. We then explore the dependence of the quenching efficiency of satellites on overdensity, group-centric distance, halo mass, the stellar mass of the satellite, and the stellar mass and specific star formation rate (sSFR) of its central, trying to isolate the effect of these often interdependent variables. We emphasize the importance of the central sSFR in the quenching efficiency of the associated satellites, and develop the meaning of this ''galactic conformity'' effect in a probabilistic description of the quenching of galaxies. We show that conformity is strong, and that it varies strongly across parameter space. Several arguments then suggest that environmental quenching and mass quenching may be different manifestations of the same underlying process. The marked difference in the apparent mass dependencies of environment quenching and mass quenching which produces distinctive signatures in the mass functions of centrals and satellites will arise naturally, since, for satellites at least, the distributions of the environmental variables that we investigate in this work are essentially independent of the stellar mass of the satellite.« less

Ensemble-based characterization of unbound and bound states on protein energy landscape

PubMed Central

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

2013-01-01

Physicochemical description of numerous cell processes is fundamentally based on the energy landscapes of protein molecules involved. Although the whole energy landscape is difficult to reconstruct, increased attention to particular targets has provided enough structures for mapping functionally important subspaces associated with the unbound and bound protein structures. The subspace mapping produces a discrete representation of the landscape, further called energy spectrum. We compiled and characterized ensembles of bound and unbound conformations of six small proteins and explored their spectra in implicit solvent. First, the analysis of the unbound-to-bound changes points to conformational selection as the binding mechanism for four proteins. Second, results show that bound and unbound spectra often significantly overlap. Moreover, the larger the overlap the smaller the root mean square deviation (RMSD) between the bound and unbound conformational ensembles. Third, the center of the unbound spectrum has a higher energy than the center of the corresponding bound spectrum of the dimeric and multimeric states for most of the proteins. This suggests that the unbound states often have larger entropy than the bound states. Fourth, the exhaustively long minimization, making small intrarotamer adjustments (all-atom RMSD ≤ 0.7 Å), dramatically reduces the distance between the centers of the bound and unbound spectra as well as the spectra extent. It condenses unbound and bound energy levels into a thin layer at the bottom of the energy landscape with the energy spacing that varies between 0.8–4.6 and 3.5–10.5 kcal/mol for the unbound and bound states correspondingly. Finally, the analysis of protein energy fluctuations showed that protein vibrations itself can excite the interstate transitions, including the unbound-to-bound ones. PMID:23526684

Generating intrinsically disordered protein conformational ensembles from a Markov chain

NASA Astrophysics Data System (ADS)

Cukier, Robert I.

2018-03-01

Intrinsically disordered proteins (IDPs) sample a diverse conformational space. They are important to signaling and regulatory pathways in cells. An entropy penalty must be payed when an IDP becomes ordered upon interaction with another protein or a ligand. Thus, the degree of conformational disorder of an IDP is of interest. We create a dichotomic Markov model that can explore entropic features of an IDP. The Markov condition introduces local (neighbor residues in a protein sequence) rotamer dependences that arise from van der Waals and other chemical constraints. A protein sequence of length N is characterized by its (information) entropy and mutual information, MIMC, the latter providing a measure of the dependence among the random variables describing the rotamer probabilities of the residues that comprise the sequence. For a Markov chain, the MIMC is proportional to the pair mutual information MI which depends on the singlet and pair probabilities of neighbor residue rotamer sampling. All 2N sequence states are generated, along with their probabilities, and contrasted with the probabilities under the assumption of independent residues. An efficient method to generate realizations of the chain is also provided. The chain entropy, MIMC, and state probabilities provide the ingredients to distinguish different scenarios using the terminologies: MoRF (molecular recognition feature), not-MoRF, and not-IDP. A MoRF corresponds to large entropy and large MIMC (strong dependence among the residues' rotamer sampling), a not-MoRF corresponds to large entropy but small MIMC, and not-IDP corresponds to low entropy irrespective of the MIMC. We show that MorFs are most appropriate as descriptors of IDPs. They provide a reasonable number of high-population states that reflect the dependences between neighbor residues, thus classifying them as IDPs, yet without very large entropy that might lead to a too high entropy penalty.

Calcium powered phloem protein of SEO gene family "Forisome" functions in wound sealing and act as biomimetic smart materials.

PubMed

Srivastava, Vineet Kumar; Tuteja, Narendra

2014-01-01

Forisomes protein belongs to SEO gene family and is unique to Fabaceae family. These proteins are located in sieve tubes of phloem and function to prevent loss of nutrient-rich photoassimilates, upon mechanical injury/wounding. Forisome protein is also known as ATP independent, mechanically active proteins. Despite the wealth of information role of forisome in plants are not yet fully understood. Recent reports suggest that forisomes protein can act as ideal model to study self assembly mechanism for development of nanotechnological devices like microfluidic system application in space exploration mission. Improvement in micro instrument is highly demanding and has been a key technology by NASA in future space exploration missions. Based on its physical parameters, forisome are found to be ideal biomimetic materials for micro fluidic system because the conformational shifts can be replicated in vitro and are fully reversible over large number of cycles. By the use of protein engineering forisome recombinant protein can be tailored. Due to its unique ability to convert chemical energy into mechanical energy forisome has received much attention. For nanotechnological application and handling biomolecules such as DNA, RNA, protein and cell as a whole microfluidic system will be the most powerful technology. The discovery of new biomimetic smart materials has been a key factor in development of space science and its requirements in such a challenging environment. The field of microfludic, particularly in terms of development of its components along with identification of new biomimetic smart materials, deserves more attention. More biophysical investigation is required to characterize it to make it more suitable under parameters of performance.

Calcium powered phloem protein of SEO gene family "Forisome" functions in wound sealing and act as biomimetic smart materials.

PubMed

Srivastava, Vineet Kumar; Tuteja, Narendra

2014-06-06

Forisomes protein belongs to SEO gene family and is unique to Fabaceae family. These proteins are located in sieve tubes of phloem and function to prevent loss of nutrient-rich photoassimilates, upon mechanical injury/wounding. Forisome protein is also known as ATP independent, mechanically active proteins. Despite the wealth of information role of forisome in plants are not yet fully understood. Recent reports suggest that forisomes protein can act as ideal model to study self assembly mechanism for development of nanotechnological devices like microfluidic system application in space exploration mission. Improvement in micro instrument is highly demanding and has been a key technology by NASA in future space exploration missions. Based on its physical parameters, forisome are found to be ideal biomimetic materials for micro fluidic system because the conformational shifts can be replicated in vitro and are fully reversible over large number of cycles. By the use of protein engineering forisome recombinant protein can be tailored. Due to its unique ability to convert chemical energy into mechanical energy forisome has received much attention. For nanotechnological application and handling biomolecules such as DNA, RNA, protein and cell as a whole microfluidic system will be the most powerful technology. The discovery of new biomimetic smart materials has been a key factor in development of space science and its requirements in such a challenging environment. The field of microfludic, particularly in terms of development of its components along with identification of new biomimetic smart materials, deserves more attention. More biophysical investigation is required to characterize it to make it more suitable under parameters of performance.

Calcium powered phloem protein of SEO gene family “Forisome” functions in wound sealing and act as biomimetic smart materials

PubMed Central

Srivastava, Vineet Kumar; Tuteja, Narendra

2014-01-01

Forisomes protein belongs to SEO gene family and is unique to Fabaceae family. These proteins are located in sieve tubes of phloem and function to prevent loss of nutrient-rich photoassimilates, upon mechanical injury/wounding. Forisome protein is also known as ATP independent, mechanically active proteins. Despite the wealth of information role of forisome in plants are not yet fully understood. Recent reports suggest that forisomes protein can act as ideal model to study self assembly mechanism for development of nanotechnological devices like microfluidic system application in space exploration mission. Improvement in micro instrument is highly demanding and has been a key technology by NASA in future space exploration missions. Based on its physical parameters, forisome are found to be ideal biomimetic materials for micro fluidic system because the conformational shifts can be replicated in vitro and are fully reversible over large number of cycles. By the use of protein engineering forisome recombinant protein can be tailored. Due to its unique ability to convert chemical energy into mechanical energy forisome has received much attention. For nanotechnological application and handling biomolecules such as DNA, RNA, protein and cell as a whole microfluidic system will be the most powerful technology. The discovery of new biomimetic smart materials has been a key factor in development of space science and its requirements in such a challenging environment. The field of microfludic, particularly in terms of development of its components along with identification of new biomimetic smart materials, deserves more attention. More biophysical investigation is required to characterize it to make it more suitable under parameters of performance. PMID:25763691

Systematic Improvement of Potential-Derived Atomic Multipoles and Redundancy of the Electrostatic Parameter Space.

PubMed

Jakobsen, Sofie; Jensen, Frank

2014-12-09

We assess the accuracy of force field (FF) electrostatics at several levels of approximation from the standard model using fixed partial charges to conformational specific multipole fits including up to quadrupole moments. Potential-derived point charges and multipoles are calculated using least-squares methods for a total of ∼1000 different conformations of the 20 natural amino acids. Opposed to standard charge fitting schemes the procedure presented in the current work employs fitting points placed on a single isodensity surface, since the electrostatic potential (ESP) on such a surface determines the ESP at all points outside this surface. We find that the effect of multipoles beyond partial atomic charges is of the same magnitude as the effect due to neglecting conformational dependency (i.e., polarizability), suggesting that the two effects should be included at the same level in FF development. The redundancy at both the partial charge and multipole levels of approximation is quantified. We present an algorithm which stepwise reduces or increases the dimensionality of the charge or multipole parameter space and provides an upper limit of the ESP error that can be obtained at a given truncation level. Thereby, we can identify a reduced set of multipole moments corresponding to ∼40% of the total number of multipoles. This subset of parameters provides a significant improvement in the representation of the ESP compared to the simple point charge model and close to the accuracy obtained using the complete multipole parameter space. The selection of the ∼40% most important multipole sites is highly transferable among different conformations, and we find that quadrupoles are of high importance for atoms involved in π-bonding, since the anisotropic electric field generated in such regions requires a large degree of flexibility.

The construction of general basis functions in reweighting ensemble dynamics simulations: Reproduce equilibrium distribution in complex systems from multiple short simulation trajectories

NASA Astrophysics Data System (ADS)

Zhang, Chuan-Biao; Ming, Li; Xin, Zhou

2015-12-01

Ensemble simulations, which use multiple short independent trajectories from dispersive initial conformations, rather than a single long trajectory as used in traditional simulations, are expected to sample complex systems such as biomolecules much more efficiently. The re-weighted ensemble dynamics (RED) is designed to combine these short trajectories to reconstruct the global equilibrium distribution. In the RED, a number of conformational functions, named as basis functions, are applied to relate these trajectories to each other, then a detailed-balance-based linear equation is built, whose solution provides the weights of these trajectories in equilibrium distribution. Thus, the sufficient and efficient selection of basis functions is critical to the practical application of RED. Here, we review and present a few possible ways to generally construct basis functions for applying the RED in complex molecular systems. Especially, for systems with less priori knowledge, we could generally use the root mean squared deviation (RMSD) among conformations to split the whole conformational space into a set of cells, then use the RMSD-based-cell functions as basis functions. We demonstrate the application of the RED in typical systems, including a two-dimensional toy model, the lattice Potts model, and a short peptide system. The results indicate that the RED with the constructions of basis functions not only more efficiently sample the complex systems, but also provide a general way to understand the metastable structure of conformational space. Project supported by the National Natural Science Foundation of China (Grant No. 11175250).

From conformal blocks to path integrals in the Vaidya geometry

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

Anous, Tarek; Hartman, Thomas; Rovai, Antonin

Correlators in conformal field theory are naturally organized as a sum over conformal blocks. In holographic theories, this sum must reorganize into a path integral over bulk fields and geometries. We explore how these two sums are related in the case of a point particle moving in the background of a 3d collapsing black hole. The conformal block expansion is recast as a sum over paths of the first-quantized particle moving in the bulk geometry. Off-shell worldlines of the particle correspond to subdominant contributions in the Euclidean conformal block expansion, but these same operators must be included in order tomore » correctly reproduce complex saddles in the Lorentzian theory. During thermalization, a complex saddle dominates under certain circumstances; in this case, the CFT correlator is not given by the Virasoro identity block in any channel, but can be recovered by summing heavy operators. This effectively converts the conformal block expansion in CFT from a sum over intermediate states to a sum over channels that mimics the bulk path integral.« less

Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates

PubMed Central

Tuszynski, Jack A.; Gallo, Diego; Morbiducci, Umberto; Danani, Andrea

2016-01-01

The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Whereas recent NMR studies have demonstrated that different JD conformations exist, the likelihood of JD achievable conformational states in solution is still an open issue. Marked differences in the available NMR models are located in the hairpin region, supporting the idea that JD has a flexible hairpin in dynamic equilibrium between open and closed states. In this work we have carried out an investigation on the JD conformational arrangement by means of both classical molecular dynamics (MD) and Metadynamics employing essential coordinates as collective variables. We provide a representation of the free energy landscape characterizing the transition pathway from a JD open-like structure to a closed-like conformation. Findings of our in silico study strongly point to the closed-like conformation as the most likely for a Josephin Domain in water. PMID:26745628

From conformal blocks to path integrals in the Vaidya geometry

DOE PAGES

Anous, Tarek; Hartman, Thomas; Rovai, Antonin; ...

2017-09-04

Correlators in conformal field theory are naturally organized as a sum over conformal blocks. In holographic theories, this sum must reorganize into a path integral over bulk fields and geometries. We explore how these two sums are related in the case of a point particle moving in the background of a 3d collapsing black hole. The conformal block expansion is recast as a sum over paths of the first-quantized particle moving in the bulk geometry. Off-shell worldlines of the particle correspond to subdominant contributions in the Euclidean conformal block expansion, but these same operators must be included in order tomore » correctly reproduce complex saddles in the Lorentzian theory. During thermalization, a complex saddle dominates under certain circumstances; in this case, the CFT correlator is not given by the Virasoro identity block in any channel, but can be recovered by summing heavy operators. This effectively converts the conformal block expansion in CFT from a sum over intermediate states to a sum over channels that mimics the bulk path integral.« less

Solitons, τ-functions and hamiltonian reduction for non-Abelian conformal affine Toda theories

NASA Astrophysics Data System (ADS)

Ferreira, L. A.; Miramontes, J. Luis; Guillén, Joaquín Sánchez

1995-02-01

We consider the Hamiltonian reduction of the "two-loop" Wess-Zumino-Novikov-Witten model (WZNW) based on an untwisted affine Kac-Moody algebra G. The resulting reduced models, called Generalized Non-Abelian Conformal Affine Toda (G-CAT), are conformally invariant and a wide class of them possesses soliton solutions; these models constitute non-Abelian generalizations of the conformal affine Toda models. Their general solution is constructed by the Leznov-Saveliev method. Moreover, the dressing transformations leading to the solutions in the orbit of the vacuum are considered in detail, as well as the τ-functions, which are defined for any integrable highest weight representation of G, irrespectively of its particular realization. When the conformal symmetry is spontaneously broken, the G-CAT model becomes a generalized affine Toda model, whose soliton solutions are constructed. Their masses are obtained exploring the spontaneous breakdown of the conformal symmetry, and their relation to the fundamental particle masses is discussed. We also introduce what we call the two-loop Virasoro algebra, describing extended symmetries of the two-loop WZNW models.

Are Educational Governance Reforms in a Post-Conflict Society Conforming to Global Standards? Examining the Application of Education Convergence Theory in an Internationally Supervised and Politicized Context

ERIC Educational Resources Information Center

Komatsu, Taro

2016-01-01

This article examines whether and to what extent educational reforms in a post-conflict society conform to "global (regional) standards," and explores the meaning of inconsistencies observed in the process of global reform transfer. Among the nations of the world, nowhere is the influence of external forces on educational reforms more…

Structural polymorphism of a cytosine-rich DNA sequence forming i-motif structure: Exploring pH based biosensors.

PubMed

Ahmed, Saami; Kaushik, Mahima; Chaudhary, Swati; Kukreti, Shrikant

2018-05-01

Sequence recognition and conformational polymorphism enable DNA to emerge out as a substantial tool in fabricating the devices within nano-dimensions. These DNA associated nano devices work on the principle of conformational switches, which can be facilitated by many factors like sequence of DNA/RNA strand, change in pH or temperature, enzyme or ligand interactions etc. Thus, controlling these DNA conformational changes to acquire the desired function is significant for evolving DNA hybridization biosensor, used in genetic screening and molecular diagnosis. For exploring this conformational switching ability of cytosine-rich DNA oligonucleotides as a function of pH for their potential usage as biosensors, this study has been designed. A C-rich stretch of DNA sequence (5'-TCCCCCAATTAATTCCCCCA-3'; SG20c) has been investigated using UV-Thermal denaturation, poly-acrylamide gel electrophoresis and CD spectroscopy. The SG20c sequence is shown to adopt various topologies of i-motif structure at low pH. This pH dependent transition of SG20c from unstructured single strand to unimolecular and bimolecular i-motif structures can further be exploited for its utilization as switching on/off pH-based biosensors. Copyright © 2018. Published by Elsevier B.V.

Exploring the free energy landscape of a model β-hairpin peptide and its isoform.

PubMed

Narayanan, Chitra; Dias, Cristiano L

2014-10-01

Secondary structural transitions from α-helix to β-sheet conformations are observed in several misfolding diseases including Alzheimer's and Parkinson's. Determining factors contributing favorably to the formation of each of these secondary structures is therefore essential to better understand these disease states. β-hairpin peptides form basic components of anti-parallel β-sheets and are suitable model systems for characterizing the fundamental forces stabilizing β-sheets in fibrillar structures. In this study, we explore the free energy landscape of the model β-hairpin peptide GB1 and its E2 isoform that preferentially adopts α-helical conformations at ambient conditions. Umbrella sampling simulations using all-atom models and explicit solvent are performed over a large range of end-to-end distances. Our results show the strong preference of GB1 and the E2 isoform for β-hairpin and α-helical conformations, respectively, consistent with previous studies. We show that the unfolded states of GB1 are largely populated by misfolded β-hairpin structures which differ from each other in the position of the β-turn. We discuss the energetic factors contributing favorably to the formation of α-helix and β-hairpin conformations in these peptides and highlight the energetic role of hydrogen bonds and non-bonded interactions. © 2014 Wiley Periodicals, Inc.

Spontaneous Breaking of Scale Invariance in U(N) Chern-Simons Gauge Theories in Three Dimensions

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

Bardeen, William A.

2015-09-24

I explore the existence of a massive phase in a conformally invariant U(N) Chern-Simons gauge theories in D = 3 with matter fields in the fundamental representation. These models have attracted recent attention as being dual, in the conformal phase, to theories of higher spin gravity on AdS 4. Using the 0t Hooft large N expansion, exact solutions are obtained for scalar current correlators in the massive phase where the conformal symmetry is spontaneously broken. A massless dilaton appears as a composite state, and its properties are discussed. Solutions exist for matters field that are either bosons or fermions.

Spontaneous Breaking of Scale Invariance in U(N) Chern-Simons Gauge Theories in Three Dimensions

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

Bardeen, William

2014-10-24

I explore the existence of a massive phase in a conformally invariant U(N) Chern-Simons gauge theories in D = 3 with matter fields in the fundamental representation. These models have attracted recent attention as being dual, in the conformal phase, to theories of higher spin gravity on AdS 4. Using the 1t Hooft large N expansion, exact solutions are obtained for scalar current correlators in the massive phase where the conformal symmetry is spontaneously broken. A massless dilaton appears as a composite state, and its properties are discussed. Solutions exist for matters field that are either bosons or fermions.

Structural alterations of thin actin filaments in muscle contraction by synchrotron X-ray fiber diffraction.

PubMed

Wakabayashi, Katsuzo; Sugimoto, Yasunobu; Takezawa, Yasunori; Ueno, Yutaka; Minakata, Shiho; Oshima, Kanji; Matsuo, Tatsuhito; Kobayashi, Takakazu

2007-01-01

Strong evidence has been accumulated that the conformational changes of the thin actin filaments are occurring and playing an important role in the entire process of muscle contraction. The conformational changes and the mechanical properties of the thin actin filaments we have found by X-ray fiber diffraction on skeletal muscle contraction are explored. Recent studies on the conformational changes of regulatory proteins bound to actin filaments upon activation and in the force generation process are also described. Finally, the roles of structural alterations and dynamics of the actin filaments are discussed in conjunction with the regulation mechanism and the force generation mechanism.

Conformational Change of Bacteriorhodopsin Quantitatively Monitored by Microcantilever Sensors

PubMed Central

Braun, Thomas; Backmann, Natalija; Vögtli, Manuel; Bietsch, Alexander; Engel, Andreas; Lang, Hans-Peter; Gerber, Christoph; Hegner, Martin

2006-01-01

Bacteriorhodopsin proteoliposomes were used as a model system to explore the applicability of micromechanical cantilever arrays to detect conformational changes in membrane protein patches. The three main results of our study concern: 1), reliable functionalization of micromechanical cantilever arrays with proteoliposomes using ink jet spotting; 2), successful detection of the prosthetic retinal removal (bleaching) from the bacteriorhodopsin protein by measuring the induced nanomechanical surface stress change; and 3), the quantitative response thereof, which depends linearly on the amount of removed retinal. Our results show this technique to be a potential tool to measure membrane protein-based receptor-ligand interactions and conformational changes. PMID:16443650

Anagostic interactions in chiral separation. Polymorphism in a [Co(II)(L)] complex: Crystallographic and theoretical studies

NASA Astrophysics Data System (ADS)

Awwadi, Firas F.; Hodali, Hamdallah A.

2018-02-01

Syntheses and crystal structures of two polymorphs of the complex [Co(II)(L)], where H2L = 2,2'-[cis-1,2-diaminocyclohexanediylbis (nitrilo-methylidyne)]bis (5-dimethyl-amino]phenol, have been studied. The two polymorphs concomitantly crystallized by vapour diffusion of solvent. The first polymorph (I) crystallized as a racemate in the centrosymmetric tetragonal I41/a space group. The second polymorph (II) crystallized in the chiral orthorhombic space group P212121. The chiral conformers of symmetrical cis-1,2-disubstituted cyclohexane molecules cannot be resolved in the liquid or gas phases, due to the rapid ring inversion. In the present study, the two chiral conformers are present in crystals of polymorph I, whereas, only one chiral conformer is present in crystals of polymorph II. Crystal structure analysis indicated that the formation of two different polymorphs of [Co(II)(L)] complex can be rationalized based on Csbnd H⋯Co anagostic interactions. Density Functional Theory (DFT) calculations indicated that Csbnd H⋯Co interactions are due to HOMO-LUMO interactions.

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

PubMed

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

1990-08-01

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

14 CFR § 1260.74 - Property use, disposition, and vesting of title.

Code of Federal Regulations, 2014 CFR

2014-01-01

... demonstrates that the equipment will be used exclusively for research activities. (b) Vesting of title to... title. § 1260.74 Section § 1260.74 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION..., and vesting of title. (a) Approval for acquisition of property shall conform to the following...

Fast, clash-free RNA conformational morphing using molecular junctions

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

Heliou, Amelie; Budday, Dominik; Fonseca, Rasmus

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

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

Twistor theory at fifty: from contour integrals to twistor strings

NASA Astrophysics Data System (ADS)

Atiyah, Michael; Dunajski, Maciej; Mason, Lionel J.

2017-10-01

We review aspects of twistor theory, its aims and achievements spanning the last five decades. In the twistor approach, space-time is secondary with events being derived objects that correspond to compact holomorphic curves in a complex threefold-the twistor space. After giving an elementary construction of this space, we demonstrate how solutions to linear and nonlinear equations of mathematical physics-anti-self-duality equations on Yang-Mills or conformal curvature-can be encoded into twistor cohomology. These twistor correspondences yield explicit examples of Yang-Mills and gravitational instantons, which we review. They also underlie the twistor approach to integrability: the solitonic systems arise as symmetry reductions of anti-self-dual (ASD) Yang-Mills equations, and Einstein-Weyl dispersionless systems are reductions of ASD conformal equations. We then review the holomorphic string theories in twistor and ambitwistor spaces, and explain how these theories give rise to remarkable new formulae for the computation of quantum scattering amplitudes. Finally, we discuss the Newtonian limit of twistor theory and its possible role in Penrose's proposal for a role of gravity in quantum collapse of a wave function.

Twistor theory at fifty: from contour integrals to twistor strings.

PubMed

Atiyah, Michael; Dunajski, Maciej; Mason, Lionel J

2017-10-01

We review aspects of twistor theory, its aims and achievements spanning the last five decades. In the twistor approach, space-time is secondary with events being derived objects that correspond to compact holomorphic curves in a complex threefold-the twistor space. After giving an elementary construction of this space, we demonstrate how solutions to linear and nonlinear equations of mathematical physics-anti-self-duality equations on Yang-Mills or conformal curvature-can be encoded into twistor cohomology. These twistor correspondences yield explicit examples of Yang-Mills and gravitational instantons, which we review. They also underlie the twistor approach to integrability: the solitonic systems arise as symmetry reductions of anti-self-dual (ASD) Yang-Mills equations, and Einstein-Weyl dispersionless systems are reductions of ASD conformal equations. We then review the holomorphic string theories in twistor and ambitwistor spaces, and explain how these theories give rise to remarkable new formulae for the computation of quantum scattering amplitudes. Finally, we discuss the Newtonian limit of twistor theory and its possible role in Penrose's proposal for a role of gravity in quantum collapse of a wave function.

Towards a large-scale scalable adaptive heart model using shallow tree meshes

NASA Astrophysics Data System (ADS)

Krause, Dorian; Dickopf, Thomas; Potse, Mark; Krause, Rolf

2015-10-01

Electrophysiological heart models are sophisticated computational tools that place high demands on the computing hardware due to the high spatial resolution required to capture the steep depolarization front. To address this challenge, we present a novel adaptive scheme for resolving the deporalization front accurately using adaptivity in space. Our adaptive scheme is based on locally structured meshes. These tensor meshes in space are organized in a parallel forest of trees, which allows us to resolve complicated geometries and to realize high variations in the local mesh sizes with a minimal memory footprint in the adaptive scheme. We discuss both a non-conforming mortar element approximation and a conforming finite element space and present an efficient technique for the assembly of the respective stiffness matrices using matrix representations of the inclusion operators into the product space on the so-called shallow tree meshes. We analyzed the parallel performance and scalability for a two-dimensional ventricle slice as well as for a full large-scale heart model. Our results demonstrate that the method has good performance and high accuracy.

High Order Numerical Simulation of Waves Using Regular Grids and Non-conforming Interfaces

DTIC Science & Technology

2013-10-06

SECURITY CLASSIFICATION OF: We study the propagation of waves over large regions of space with smooth, but not necessarily constant, material...of space with smooth, but not necessarily constant, material characteristics, separated into sub-domains by interfaces of arbitrary shape. We...Abstract We study the propagation of waves over large regions of space with smooth, but not necessarily constant, material characteristics, separated into

Exploring RNA structure and dynamics through enhanced sampling simulations.

PubMed

Mlýnský, Vojtěch; Bussi, Giovanni

2018-04-01

RNA function is intimately related to its structural dynamics. Molecular dynamics simulations are useful for exploring biomolecular flexibility but are severely limited by the accessible timescale. Enhanced sampling methods allow this timescale to be effectively extended in order to probe biologically relevant conformational changes and chemical reactions. Here, we review the role of enhanced sampling techniques in the study of RNA systems. We discuss the challenges and promises associated with the application of these methods to force-field validation, exploration of conformational landscapes and ion/ligand-RNA interactions, as well as catalytic pathways. Important technical aspects of these methods, such as the choice of the biased collective variables and the analysis of multi-replica simulations, are examined in detail. Finally, a perspective on the role of these methods in the characterization of RNA dynamics is provided. Copyright © 2018 Elsevier Ltd. All rights reserved.

Constrained Maximum Likelihood Estimation of Relative Abundances of Protein Conformation in a Heterogeneous Mixture from Small Angle X-Ray Scattering Intensity Measurements

PubMed Central

Onuk, A. Emre; Akcakaya, Murat; Bardhan, Jaydeep P.; Erdogmus, Deniz; Brooks, Dana H.; Makowski, Lee

2015-01-01

In this paper, we describe a model for maximum likelihood estimation (MLE) of the relative abundances of different conformations of a protein in a heterogeneous mixture from small angle X-ray scattering (SAXS) intensities. To consider cases where the solution includes intermediate or unknown conformations, we develop a subset selection method based on k-means clustering and the Cramér-Rao bound on the mixture coefficient estimation error to find a sparse basis set that represents the space spanned by the measured SAXS intensities of the known conformations of a protein. Then, using the selected basis set and the assumptions on the model for the intensity measurements, we show that the MLE model can be expressed as a constrained convex optimization problem. Employing the adenylate kinase (ADK) protein and its known conformations as an example, and using Monte Carlo simulations, we demonstrate the performance of the proposed estimation scheme. Here, although we use 45 crystallographically determined experimental structures and we could generate many more using, for instance, molecular dynamics calculations, the clustering technique indicates that the data cannot support the determination of relative abundances for more than 5 conformations. The estimation of this maximum number of conformations is intrinsic to the methodology we have used here. PMID:26924916

Witten diagrams revisited: the AdS geometry of conformal blocks

DOE PAGES

Hijano, Eliot; Kraus, Per; Perlmutter, Eric; ...

2016-01-25

Here, we develop a new method for decomposing blocks. The steps involved are elementary, requiring no explicit integration, and operate directly in position space. Central to this construction is an appealingly simple answer to the question: what object in AdS computes a conformal block? The answer is a "geodesic Witten diagram", which is essentially an ordinary exchange Witten diagram, except that the cubic vertices are not integrated over all of AdS, but only over bulk geodesics connecting the boundary operators. In particular, we also consider the case of four-point functions of scalar operators, and show how to easily reproduce existingmore » results for the relevant conformal blocks in arbitrary dimension.« less

Solving the Nonlocality Riddle by Conformal Quantum Geometrodynamics

NASA Astrophysics Data System (ADS)

Santamato, Enrico; de Martini, Francesco

2012-01-01

Since the 1935 proposal by Einstein, Podolsky and Rosen the riddle of nonlocality, today demonstrated by the violation of Bell's inequalities within innumerable experiments, has been a cause of concern and confusion within the debate over the foundations of quantum mechanics. The present paper tackles the problem by a nonrelativistic approach based on conformal differential geometry applied to the solution of the dynamical problem of two entangled spin 1/2 particles. It is found that the quantum nonlocality may be understood on the basis of a conformal quantum geometrodynamics acting necessarily on the full "configuration space" of the entangled particles. At the end, the violation of the Bell inequalities is demonstrated without making recourse to the common nonlocality paradigm.

Single-Molecule Studies of Hyaluronic Acid Conformation

NASA Astrophysics Data System (ADS)

Innes-Gold, Sarah; Berezney, John; Saleh, Omar

Hyaluronic acid (HA) is a charged linear polysaccharide abundant in extracellular spaces. Its solution conformation and mechanical properties help define the environment outside of cells, play key roles in cell motility and adhesion processes, and are of interest for the development of HA biomaterials. Intra-chain hydrogen bonds and electrostatic repulsion contribute to HAs physical structure, but the nature of this structure, as well as its dependence on solution electrostatics, are not well-understood. To address this problem, we have investigated HA conformation and mechanical properties under a range of solution conditions systematically designed to affect charge screening or hydrogen bonding. We used magnetic tweezers to apply biological-scale stretching forces to individual HA chains under varying solution conditions.

Distinguishing Signatures of Multipathway Conformational Transitions

NASA Astrophysics Data System (ADS)

Pierse, Christopher A.; Dudko, Olga K.

2017-02-01

The folding and binding of biomolecules into functional conformations are thought to be commonly mediated by multiple pathways rather than a unique route. Yet even in experiments where one can "see" individual conformational transitions, their stochastic nature generally precludes one from determining whether the transitions occurred through one or multiple pathways. We establish model-free, observable signatures in the response of macromolecules to force that unambiguously identify multiple pathways—even when the pathways themselves cannot be resolved. The unified analytical description reveals that, through multiple pathways, the response of molecules to external forces can be shaped in diverse ways, resulting in a rich design space for a tailored biological function already at the single-molecule level.

Single-molecule FRET reveals the energy landscape of the full-length SAM-I riboswitch.

PubMed

Manz, Christoph; Kobitski, Andrei Yu; Samanta, Ayan; Keller, Bettina G; Jäschke, Andres; Nienhaus, G Ulrich

2017-11-01

S-adenosyl-L-methionine (SAM) ligand binding induces major structural changes in SAM-I riboswitches, through which gene expression is regulated via transcription termination. Little is known about the conformations and motions governing the function of the full-length Bacillus subtilis yitJ SAM-I riboswitch. Therefore, we have explored its conformational energy landscape as a function of Mg 2+ and SAM ligand concentrations using single-molecule Förster resonance energy transfer (smFRET) microscopy and hidden Markov modeling analysis. We resolved four conformational states both in the presence and the absence of SAM and determined their Mg 2+ -dependent fractional populations and conformational dynamics, including state lifetimes, interconversion rate coefficients and equilibration timescales. Riboswitches with terminator and antiterminator folds coexist, and SAM binding only gradually shifts the populations toward terminator states. We observed a pronounced acceleration of conformational transitions upon SAM binding, which may be crucial for off-switching during the brief decision window before expression of the downstream gene.

1H, 13C and 19F NMR studies on fluorinated ethers

NASA Astrophysics Data System (ADS)

Balonga, P. E.; Kowalewski, V. J.; Contreras, R. H.

The enflurane and ethoxyflurane 1H, 13C and 19F NMR spectra are examined—including sign determination of FF and FH couplings—and considered in the light of previously reported results for methoxyflurane. Conformational differences between methoxyflurane and the former two molecules are indicated by through space FH coupling constants and by the nonequivalence of geminal fluorine nuclei. Populations of conformers about the CC bond are estimated.

Production development of organic nonflammable spacecraft potting, encapsulating and conformal coating compounds. Volume 4: Executive summary

NASA Technical Reports Server (NTRS)

Lieberman, S. L.

1974-01-01

The necessity of having nonflammable versions of potting and encapsulating compounds and conformal coatings for space vehicles is discussed. The formulation, EPOCAST 87517 A/B, was found to have the best balance of thermal, electrical, mechanical, physical, and chemical properties of those evaluated. The requirements which this formulation did not meet are listed, and other formulations which were evaluated are summarized. Recommendations for improving EPOCAST 87517 A/B are included.

Hierarchical multifunctional composites by conformally coating aligned carbon nanotube arrays with conducting polymer.

PubMed

Vaddiraju, Sreeram; Cebeci, Hülya; Gleason, Karen K; Wardle, Brian L

2009-11-01

A novel method for the fabrication of carbon nanotube (CNT)-conducting polymer composites is demonstrated by conformally coating extremely high aspect ratio vertically aligned-CNT (A-CNT) arrays with conducting polymer via oxidative chemical vapor deposition (oCVD). A mechanical densification technique is employed that allows the spacing of the A-CNTs to be controlled, yielding a range of inter-CNT distances between 20 and 70 nm. Using this morphology control, oCVD is shown to conformally coat 8-nm-diameter CNTs having array heights up to 1 mm (an aspect ratio of 10(5)) at all inter-CNT spacings. Three phase CNT-conducting polymer nanocomposites are then fabricated by introducing an insulating epoxy via capillary-driven wetting. CNT morphology is maintained during processing, allowing quantification of direction-dependent (nonisotropic) composite properties. Electrical conductivity occurs primarily along the CNT axial direction, such that the conformal conducting polymer has little effect on the activation energy required for charge conduction. In contrast, the conducting polymer coating enhanced the conductivity in the radial direction by lowering the activation energy required for the creation of mobile charge carriers, in agreement with variable-range-hopping models. The fabrication strategy introduced here can be used to create many multifunctional materials and devices (e.g., direction-tailorable hydrophobic and highly conducting materials), including a new four-phase advanced fiber composite architecture.

Multifunctional Cytochrome c: Learning New Tricks from an Old Dog.

PubMed

Alvarez-Paggi, Damián; Hannibal, Luciana; Castro, María A; Oviedo-Rouco, Santiago; Demicheli, Veronica; Tórtora, Veronica; Tomasina, Florencia; Radi, Rafael; Murgida, Daniel H

2017-11-08

Cytochrome c (cyt c) is a small soluble heme protein characterized by a relatively flexible structure, particularly in the ferric form, such that it is able to sample a broad conformational space. Depending on the specific conditions, interactions, and cellular localization, different conformations may be stabilized, which differ in structure, redox properties, binding affinities, and enzymatic activity. The primary function is electron shuttling in oxidative phosphorylation, and is exerted by the so-called native cyt c in the intermembrane mitochondrial space of healthy cells. Under pro-apoptotic conditions, however, cyt c gains cardiolipin peroxidase activity, translocates into the cytosol to engage in the intrinsic apoptotic pathway, and enters the nucleus where it impedes nucleosome assembly. Other reported functions include cytosolic redox sensing and involvement in the mitochondrial oxidative folding machinery. Moreover, post-translational modifications such as nitration, phosphorylation, and sulfoxidation of specific amino acids induce alternative conformations with differential properties, at least in vitro. Similar structural and functional alterations are elicited by biologically significant electric fields and by naturally occurring mutations of human cyt c that, along with mutations at the level of the maturation system, are associated with specific diseases. Here, we summarize current knowledge and recent advances in understanding the different structural, dynamic, and thermodynamic factors that regulate the primary electron transfer function, as well as alternative functions and conformations of cyt c. Finally, we present recent technological applications of this moonlighting protein.

A Twist on Facial Selectivity of Hydride Reductions of Cyclic Ketones: Twist-Boat Conformers in Cyclohexanone, Piperidone, and Tropinone Reactions

PubMed Central

2015-01-01

The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin–Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted N-acylpiperidones with a small hydride reagent (LiAlH4) but not with a bulky hydride (lithium triisopropylborohydride). PMID:25372509

Space and Time Resolved Detection of Platelet Activation and von Willebrand Factor Conformational Changes in Deep Suspensions.

PubMed

Biasetti, Jacopo; Sampath, Kaushik; Cortez, Angel; Azhir, Alaleh; Gilad, Assaf A; Kickler, Thomas S; Obser, Tobias; Ruggeri, Zaverio M; Katz, Joseph

2017-01-01

Tracking cells and proteins' phenotypic changes in deep suspensions is critical for the direct imaging of blood-related phenomena in in vitro replica of cardiovascular systems and blood-handling devices. This paper introduces fluorescence imaging techniques for space and time resolved detection of platelet activation, von Willebrand factor (VWF) conformational changes, and VWF-platelet interaction in deep suspensions. Labeled VWF, platelets, and VWF-platelet strands are suspended in deep cuvettes, illuminated, and imaged with a high-sensitivity EM-CCD camera, allowing detection using an exposure time of 1 ms. In-house postprocessing algorithms identify and track the moving signals. Recombinant VWF-eGFP (rVWF-eGFP) and VWF labeled with an FITC-conjugated polyclonal antibody are employed. Anti-P-Selectin FITC-conjugated antibodies and the calcium-sensitive probe Indo-1 are used to detect activated platelets. A positive correlation between the mean number of platelets detected per image and the percentage of activated platelets determined through flow cytometry is obtained, validating the technique. An increase in the number of rVWF-eGFP signals upon exposure to shear stress demonstrates the technique's ability to detect breakup of self-aggregates. VWF globular and unfolded conformations and self-aggregation are also observed. The ability to track the size and shape of VWF-platelet strands in space and time provides means to detect pro- and antithrombotic processes.

Simultaneous escaping of explicit and hidden free energy barriers: application of the orthogonal space random walk strategy in generalized ensemble based conformational sampling.

PubMed

Zheng, Lianqing; Chen, Mengen; Yang, Wei

2009-06-21

To overcome the pseudoergodicity problem, conformational sampling can be accelerated via generalized ensemble methods, e.g., through the realization of random walks along prechosen collective variables, such as spatial order parameters, energy scaling parameters, or even system temperatures or pressures, etc. As usually observed, in generalized ensemble simulations, hidden barriers are likely to exist in the space perpendicular to the collective variable direction and these residual free energy barriers could greatly abolish the sampling efficiency. This sampling issue is particularly severe when the collective variable is defined in a low-dimension subset of the target system; then the "Hamiltonian lagging" problem, which reveals the fact that necessary structural relaxation falls behind the move of the collective variable, may be likely to occur. To overcome this problem in equilibrium conformational sampling, we adopted the orthogonal space random walk (OSRW) strategy, which was originally developed in the context of free energy simulation [L. Zheng, M. Chen, and W. Yang, Proc. Natl. Acad. Sci. U.S.A. 105, 20227 (2008)]. Thereby, generalized ensemble simulations can simultaneously escape both the explicit barriers along the collective variable direction and the hidden barriers that are strongly coupled with the collective variable move. As demonstrated in our model studies, the present OSRW based generalized ensemble treatments show improved sampling capability over the corresponding classical generalized ensemble treatments.

Multiple loop conformations of peptides predicted by molecular dynamics simulations are compatible with nuclear magnetic resonance.

PubMed

Carstens, Heiko; Renner, Christian; Milbradt, Alexander G; Moroder, Luis; Tavan, Paul

2005-03-29

The affinity and selectivity of protein-protein interactions can be fine-tuned by varying the size, flexibility, and amino acid composition of involved surface loops. As a model for such surface loops, we study the conformational landscape of an octapeptide, whose flexibility is chemically steered by a covalent ring closure integrating an azobenzene dye into and by a disulfide bridge additionally constraining the peptide backbone. Because the covalently integrated azobenzene dyes can be switched by light between a bent cis state and an elongated trans state, six cyclic peptide models of strongly different flexibilities are obtained. The conformational states of these peptide models are sampled by NMR and by unconstrained molecular dynamics (MD) simulations. Prototypical conformations and the free-energy landscapes in the high-dimensional space spanned by the phi/psi angles at the peptide backbone are obtained by clustering techniques from the MD trajectories. Multiple open-loop conformations are shown to be predicted by MD particularly in the very flexible cases and are shown to comply with the NMR data despite the fact that such open-loop conformations are missing in the refined NMR structures.

Conformity and statistical tolerancing

NASA Astrophysics Data System (ADS)

Leblond, Laurent; Pillet, Maurice

2018-02-01

Statistical tolerancing was first proposed by Shewhart (Economic Control of Quality of Manufactured Product, (1931) reprinted 1980 by ASQC), in spite of this long history, its use remains moderate. One of the probable reasons for this low utilization is undoubtedly the difficulty for designers to anticipate the risks of this approach. The arithmetic tolerance (worst case) allows a simple interpretation: conformity is defined by the presence of the characteristic in an interval. Statistical tolerancing is more complex in its definition. An interval is not sufficient to define the conformance. To justify the statistical tolerancing formula used by designers, a tolerance interval should be interpreted as the interval where most of the parts produced should probably be located. This tolerance is justified by considering a conformity criterion of the parts guaranteeing low offsets on the latter characteristics. Unlike traditional arithmetic tolerancing, statistical tolerancing requires a sustained exchange of information between design and manufacture to be used safely. This paper proposes a formal definition of the conformity, which we apply successively to the quadratic and arithmetic tolerancing. We introduce a concept of concavity, which helps us to demonstrate the link between tolerancing approach and conformity. We use this concept to demonstrate the various acceptable propositions of statistical tolerancing (in the space decentring, dispersion).

Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: the myoglobin case.

PubMed

Papaleo, Elena; Mereghetti, Paolo; Fantucci, Piercarlo; Grandori, Rita; De Gioia, Luca

2009-01-01

Several molecular dynamics (MD) simulations were used to sample conformations in the neighborhood of the native structure of holo-myoglobin (holo-Mb), collecting trajectories spanning 0.22 micros at 300 K. Principal component (PCA) and free-energy landscape (FEL) analyses, integrated by cluster analysis, which was performed considering the position and structures of the individual helices of the globin fold, were carried out. The coherence between the different structural clusters and the basins of the FEL, together with the convergence of parameters derived by PCA indicates that an accurate description of the Mb conformational space around the native state was achieved by multiple MD trajectories spanning at least 0.14 micros. The integration of FEL, PCA, and structural clustering was shown to be a very useful approach to gain an overall view of the conformational landscape accessible to a protein and to identify representative protein substates. This method could be also used to investigate the conformational and dynamical properties of Mb apo-, mutant, or delete versions, in which greater conformational variability is expected and, therefore identification of representative substates from the simulations is relevant to disclose structure-function relationship.

Electrochemical removal of material from metallic work

DOEpatents

Csakvary, Tibor; Fromson, Robert E.

1980-05-13

Deburring, polishing, surface forming and the like are carried out by electrochemical machining with conformable electrode means including an electrically conducting and an insulating web. The surface of the work to be processed is covered by a deformable electrically insulating web or cloth which is perforated and conforms with the work. The web is covered by a deformable perforated electrically conducting screen electrode which also conforms with, and is insulated from, the work by the insulating web. An electrolyte is conducted through the electrode and insulating web and along the work through a perforated elastic member which engages the electrode under pressure pressing the electrode and web against the work. High current under low voltage is conducted betwen the electrode and work through the insulator, removing material from the work. Under the pressure of the elastic member, the electrode and insulator continue to conform with the work and the spacing between the electrode and work is maintained constant.

Plan-graph Based Heuristics for Conformant Probabilistic Planning

NASA Technical Reports Server (NTRS)

Ramakrishnan, Salesh; Pollack, Martha E.; Smith, David E.

2004-01-01

In this paper, we introduce plan-graph based heuristics to solve a variation of the conformant probabilistic planning (CPP) problem. In many real-world problems, it is the case that the sensors are unreliable or take too many resources to provide knowledge about the environment. These domains are better modeled as conformant planning problems. POMDP based techniques are currently the most successful approach for solving CPP but have the limitation of state- space explosion. Recent advances in deterministic and conformant planning have shown that plan-graphs can be used to enhance the performance significantly. We show that this enhancement can also be translated to CPP. We describe our process for developing the plan-graph heuristics and estimating the probability of a partial plan. We compare the performance of our planner PVHPOP when used with different heuristics. We also perform a comparison with a POMDP solver to show over a order of magnitude improvement in performance.

Thermally and vibrationally induced conformational isomerizations, infrared spectra, and photochemistry of gallic acid in low-temperature matrices

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

Justino, Licínia L. G., E-mail: liciniaj@ci.uc.pt; Reva, Igor; Fausto, Rui

2016-07-07

Near-infrared (near-IR) narrowband selective vibrational excitation and annealing of gallic acid (3,4,5-trihydroxybenzoic acid) isolated in cryogenic matrices were used to induce interconversions between its most stable conformers. The isomerizations were probed by infrared spectroscopy. An extensive set of quantum chemical calculations, carried out at the DFT(B3LYP)/6-311++G(d,p) level of approximation, was used to undertake a detailed analysis of the ground state potential energy surface of the molecule. This investigation of the molecule conformational space allowed extracting mechanistic insights into the observed annealing- or near-IR-induced isomerization processes. The infrared spectra of the two most stable conformers of gallic acid in N{sub 2},more » Xe, and Ar matrices were fully assigned. Finally, the UV-induced photochemistry of the matrix isolated compound was investigated.« less

On the origin of fluorescence in bacteriophytochrome infrared fluorescent proteins

PubMed Central

Samma, Alex A.; Johnson, Chelsea K.; Song, Shuang; Alvarez, Samuel

2010-01-01

Tsien (Science, 2009, 324, 804-807) has recently reported the creation of the first infrared fluorescent protein (IFP). It was engineered from bacterial phytochrome by removing the PHY and histidine kinase-related domains, by optimizing the protein to prevent dimerization and by limiting the biliverdins conformational freedom, especially around its D ring. We have used database analyses and molecular dynamics simulations with freely rotating chromophoric dihedrals in order to model the dihedral freedom available to the biliverdin D ring in the excited state; to show that the tetrapyrrole ligands in phytochromes are flexible and can adopt many conformations, however their conformational space is limited/defined by the chemospatial characteristics of the protein cavity. Our simulations confirm that the reduced accessibility to conformations geared to an excited state proton transfer may be responsible for the fluorescence in IFP, just as has been suggested by Kennis (PNAS, 2010, 107, 9170-9175) for fluorescent bacteriophytochrome from Rhodopseudomonas palustris. PMID:21047084

Stochastic quantization of conformally coupled scalar in AdS

NASA Astrophysics Data System (ADS)

Jatkar, Dileep P.; Oh, Jae-Hyuk

2013-10-01

We explore the relation between stochastic quantization and holographic Wilsonian renormalization group flow further by studying conformally coupled scalar in AdS d+1. We establish one to one mapping between the radial flow of its double trace deformation and stochastic 2-point correlation function. This map is shown to be identical, up to a suitable field re-definition of the bulk scalar, to the original proposal in arXiv:1209.2242.

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

PubMed

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

2015-06-28

The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

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

NASA Astrophysics Data System (ADS)

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

2015-06-01

The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

Steric interactions determine side-chain conformations in protein cores.

PubMed

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

2016-09-01

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

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

PubMed Central

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

2008-01-01

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

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

Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo

The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use inmore » combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.« less

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

PubMed

Shao, Qiang

2016-10-26

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