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

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins.

PubMed

Hayashi, Shigehiko; Uchida, Yoshihiro; Hasegawa, Taisuke; Higashi, Masahiro; Kosugi, Takahiro; Kamiya, Motoshi

2017-05-05

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins

NASA Astrophysics Data System (ADS)

Hayashi, Shigehiko; Uchida, Yoshihiro; Hasegawa, Taisuke; Higashi, Masahiro; Kosugi, Takahiro; Kamiya, Motoshi

2017-05-01

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

A 4D-optimization concept for scanned ion beam therapy.

PubMed

Graeff, Christian; Lüchtenborg, Robert; Eley, John Gordon; Durante, Marco; Bert, Christoph

2013-12-01

Scanned carbon beam therapy offers advantageous dose distributions and an increased biological effect. Treating moving targets is complex due to sensitivity to range changes and interplay. We propose a 4D treatment planning concept that considers motion during particle number optimization. The target was subdivided into sectors, one for each motion phase of a 4D-CT. Each sector was non-rigidly transformed to its motion phase and there targeted by a dedicated raster field (RST). Therefore, the resulting 4D-RST compensated target motion and range changes. A 4D treatment control system (TCS) was needed for synchronized delivery to the measured patient motion. 4D-optimized plans were simulated for 9 NSCLC lung cancer patients and compared to static irradiation at end-exhale. A prototype TCS was implemented and successfully tested in a film experiment. The 4D-optimized treatment plan resulted in only slightly lower dose coverage of the target compared to static optimization, with V 95% of 97.9% (median, range 96.5-99.4%) vs. 99.3% (98.5-99.8%), with negligible overdose. The conformity number was comparable at 88.2% (85.1-92.5%) vs. 85.2% (79.9-91.2%) for 4D and static, respectively. We implemented and tested a 4D treatment plan optimization method resulting in highly conformal dose delivery. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Supercritical tests of a self-optimizing, variable-Camber wind tunnel model

NASA Technical Reports Server (NTRS)

Levinsky, E. S.; Palko, R. L.

1979-01-01

A testing procedure was used in a 16-foot Transonic Propulsion Wind Tunnel which leads to optimum wing airfoil sections without stopping the tunnel for model changes. Being experimental, the optimum shapes obtained incorporate various three-dimensional and nonlinear viscous and transonic effects not included in analytical optimization methods. The method is a closed-loop, computer-controlled, interactive procedure and employs a Self-Optimizing Flexible Technology wing semispan model that conformally adapts the airfoil section at two spanwise control stations to maximize or minimize various prescribed merit functions subject to both equality and inequality constraints. The model, which employed twelve independent hydraulic actuator systems and flexible skins, was also used for conventional testing. Although six of seven optimizations attempted were at least partially convergent, further improvements in model skin smoothness and hydraulic reliability are required to make the technique fully operational.

The research of conformal optical design

NASA Astrophysics Data System (ADS)

Li, Lin; Li, Yan; Huang, Yi-fan; Du, Bao-lin

2009-07-01

Conformal optical domes are characterized as having external more elongated optical surfaces that are optimized to minimize drag, increased missile velocity and extended operational range. The outer surface of the conformal domes typically deviate greatly from spherical surface descriptions, so the inherent asymmetry of conformal surfaces leads to variations in the aberration content presented to the optical sensor as it is gimbaled across the field of regard, which degrades the sensor's ability to properly image targets of interest and then undermine the overall system performance. Consequently, the aerodynamic advantages of conformal domes cannot be realized in practical systems unless the dynamic aberration correction techniques are developed to restore adequate optical imaging capabilities. Up to now, many optical correction solutions have been researched in conformal optical design, including static aberrations corrections and dynamic aberrations corrections. There are three parts in this paper. Firstly, the combination of static and dynamic aberration correction is introduced. A system for correcting optical aberration created by a conformal dome has an outer surface and an inner surface. The optimization of the inner surface is regard as the static aberration correction; moreover, a deformable mirror is placed at the position of the secondary mirror in the two-mirror all reflective imaging system, which is the dynamic aberration correction. Secondly, the using of appropriate surface types is very important in conformal dome design. Better performing optical systems can result from surface types with adequate degrees of freedom to describe the proper corrector shape. Two surface types and the methods of using them are described, including Zernike polynomial surfaces used in correct elements and user-defined surfaces used in deformable mirror (DM). Finally, the Adaptive optics (AO) correction is presented. In order to correct the dynamical residual aberration in conformal optical design, the SPGD optimization algorithm is operated at each zoom position to calculate the optimized surface shape of the MEMS DM. The communication between MATLAB and Code V established via ActiveX technique is applied in simulation analysis.

Guiding Conformation Space Search with an All-Atom Energy Potential

PubMed Central

Brunette, TJ; Brock, Oliver

2009-01-01

The most significant impediment for protein structure prediction is the inadequacy of conformation space search. Conformation space is too large and the energy landscape too rugged for existing search methods to consistently find near-optimal minima. To alleviate this problem, we present model-based search, a novel conformation space search method. Model-based search uses highly accurate information obtained during search to build an approximate, partial model of the energy landscape. Model-based search aggregates information in the model as it progresses, and in turn uses this information to guide exploration towards regions most likely to contain a near-optimal minimum. We validate our method by predicting the structure of 32 proteins, ranging in length from 49 to 213 amino acids. Our results demonstrate that model-based search is more effective at finding low-energy conformations in high-dimensional conformation spaces than existing search methods. The reduction in energy translates into structure predictions of increased accuracy. PMID:18536015

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

PubMed

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

2016-07-12

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

Adaptive Particle Swarm Optimizer with Varying Acceleration Coefficients for Finding the Most Stable Conformer of Small Molecules.

PubMed

Agrawal, Shikha; Silakari, Sanjay; Agrawal, Jitendra

2015-11-01

A novel parameter automation strategy for Particle Swarm Optimization called APSO (Adaptive PSO) is proposed. The algorithm is designed to efficiently control the local search and convergence to the global optimum solution. Parameters c1 controls the impact of the cognitive component on the particle trajectory and c2 controls the impact of the social component. Instead of fixing the value of c1 and c2 , this paper updates the value of these acceleration coefficients by considering time variation of evaluation function along with varying inertia weight factor in PSO. Here the maximum and minimum value of evaluation function is use to gradually decrease and increase the value of c1 and c2 respectively. Molecular energy minimization is one of the most challenging unsolved problems and it can be formulated as a global optimization problem. The aim of the present paper is to investigate the effect of newly developed APSO on the highly complex molecular potential energy function and to check the efficiency of the proposed algorithm to find the global minimum of the function under consideration. The proposed algorithm APSO is therefore applied in two cases: Firstly, for the minimization of a potential energy of small molecules with up to 100 degrees of freedom and finally for finding the global minimum energy conformation of 1,2,3-trichloro-1-flouro-propane molecule based on a realistic potential energy function. The computational results of all the cases show that the proposed method performs significantly better than the other algorithms. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Optimization for rapid synthesis of silver nanoparticles and its effect on phytopathogenic fungi

NASA Astrophysics Data System (ADS)

Krishnaraj, C.; Ramachandran, R.; Mohan, K.; Kalaichelvan, P. T.

In this present study, silver nanoparticles were synthesized by green chemistry approach using Acalypha indica leaf extract as reducing agents. The reaction medium employed in the synthesis process was optimized to attain better yield, controlled size and stability. Further, the biosynthesized silver nanoparticles were conformed through UV-vis spectrum, XRD and HR-TEM analyses. Different concentration of silver nanoparticles were tested to know the inhibitory effect of fungal plant pathogens namely Alternaria alternata, Sclerotinia sclerotiorum, Macrophomina phaseolina, Rhizoctonia solani, Botrytis cinerea and Curvularia lunata. Interestingly, 15 mg concentration of silver nanoparticles showed excellent inhibitory activity against all the tested pathogens. Thus, the obtained results clearly suggest that silver nanoparticles may have important applications in controlling various plant diseases caused by fungi.

A theoretical and matrix-isolation FT-IR investigation of the conformational landscape of N-acetylcysteine

NASA Astrophysics Data System (ADS)

Boeckx, Bram; Ramaekers, Riet; Maes, Guido

2010-06-01

The conformational landscape of N-acetylcysteine (NAC) has been investigated by a combined experimental matrix-isolation FT-IR and theoretical methodology. This combination is a powerful tool to study the conformational behavior of relatively small molecules. Geometry optimizations at the HF/3-21 level resulted in 438 different geometries with an energy difference smaller than 22 kJ mol -1. Among these, six conformations were detected with a relative energy difference smaller than 10 kJ mol -1 at the DFT(B3LYP)/6-31++G∗∗ level of theory. These were finally subjected to MP2/6-31++G∗∗ optimizations which resulted in five minima. The vibrational and thermodynamical properties of these conformations were calculated at both the DFT and MP2 methodologies. Experimentally NAC was isolated in an argon matrix at 16 K after being sublimated at 323 K. The most stable MP2 form appeared to be dominant in the experimental spectra but the presence of three other conformations with Δ EMP2 < 10 kJ mol -1 was also demonstrated. The experimentally observed abundance of the H-bond containing conformations appeared to be in good accordance with the predicted MP2 value.

Hydration and conformational equilibria of simple hydrophobic and amphiphilic solutes.

PubMed Central

Ashbaugh, H S; Kaler, E W; Paulaitis, M E

1998-01-01

We consider whether the continuum model of hydration optimized to reproduce vacuum-to-water transfer free energies simultaneously describes the hydration free energy contributions to conformational equilibria of the same solutes in water. To this end, transfer and conformational free energies of idealized hydrophobic and amphiphilic solutes in water are calculated from explicit water simulations and compared to continuum model predictions. As benchmark hydrophobic solutes, we examine the hydration of linear alkanes from methane through hexane. Amphiphilic solutes were created by adding a charge of +/-1e to a terminal methyl group of butane. We find that phenomenological continuum parameters fit to transfer free energies are significantly different from those fit to conformational free energies of our model solutes. This difference is attributed to continuum model parameters that depend on solute conformation in water, and leads to effective values for the free energy/surface area coefficient and Born radii that best describe conformational equilibrium. In light of these results, we believe that continuum models of hydration optimized to fit transfer free energies do not accurately capture the balance between hydrophobic and electrostatic contributions that determines the solute conformational state in aqueous solution. PMID:9675177

Inverse 4D conformal planning for lung SBRT using particle swarm optimization

NASA Astrophysics Data System (ADS)

Modiri, A.; Gu, X.; Hagan, A.; Bland, R.; Iyengar, P.; Timmerman, R.; Sawant, A.

2016-08-01

A critical aspect of highly potent regimens such as lung stereotactic body radiation therapy (SBRT) is to avoid collateral toxicity while achieving planning target volume (PTV) coverage. In this work, we describe four dimensional conformal radiotherapy using a highly parallelizable swarm intelligence-based stochastic optimization technique. Conventional lung CRT-SBRT uses a 4DCT to create an internal target volume and then, using forward-planning, generates a 3D conformal plan. In contrast, we investigate an inverse-planning strategy that uses 4DCT data to create a 4D conformal plan, which is optimized across the three spatial dimensions (3D) as well as time, as represented by the respiratory phase. The key idea is to use respiratory motion as an additional degree of freedom. We iteratively adjust fluence weights for all beam apertures across all respiratory phases considering OAR sparing, PTV coverage and delivery efficiency. To demonstrate proof-of-concept, five non-small-cell lung cancer SBRT patients were retrospectively studied. The 4D optimized plans achieved PTV coverage comparable to the corresponding clinically delivered plans while showing significantly superior OAR sparing ranging from 26% to 83% for D max heart, 10%-41% for D max esophagus, 31%-68% for D max spinal cord and 7%-32% for V 13 lung.

Inverse 4D conformal planning for lung SBRT using particle swarm optimization

PubMed Central

Modiri, A; Gu, X; Hagan, A; Bland, R; Iyengar, P; Timmerman, R; Sawant, A

2016-01-01

A critical aspect of highly potent regimens such as lung stereotactic body radiation therapy (SBRT) is to avoid collateral toxicity while achieving planning target volume (PTV) coverage. In this work, we describe four dimensional conformal radiotherapy (4D CRT) using a highly parallelizable swarm intelligence-based stochastic optimization technique. Conventional lung CRT-SBRT uses a 4DCT to create an internal target volume (ITV) and then, using forward-planning, generates a 3D conformal plan. In contrast, we investigate an inverse-planning strategy that uses 4DCT data to create a 4D conformal plan, which is optimized across the three spatial dimensions (3D) as well as time, as represented by the respiratory phase. The key idea is to use respiratory motion as an additional degree of freedom. We iteratively adjust fluence weights for all beam apertures across all respiratory phases considering OAR sparing, PTV coverage and delivery efficiency. To demonstrate proof-of-concept, five non-small-cell lung cancer SBRT patients were retrospectively studied. The 4D optimized plans achieved PTV coverage comparable to the corresponding clinically delivered plans while showing significantly superior OAR sparing ranging from 26% to 83% for Dmax heart, 10% to 41% for Dmax esophagus, 31% to 68% for Dmax spinal cord and 7% to 32% for V13 lung. PMID:27476472

Molecular modeling of calmodulin: a comparison with crystallographic data

NASA Technical Reports Server (NTRS)

McDonald, J. J.; Rein, R.

1989-01-01

Two methods of side-chain placement on a modeled protein have been examined. Two molecular models of calmodulin were constructed that differ in the treatment of side chains prior to optimization of the molecule. A virtual bond analysis program developed by Purisima and Scheraga was used to determine the backbone conformation based on 2.2 angstroms resolution C alpha coordinates for the molecules. In the first model, side chains were initially constructed in an extended conformation. In the second model, a conformational grid search technique was employed. Calcium ions were treated explicitly during energy optimization using CHARMM. The models are compared to a recently published refined crystal structure of calmodulin. The results indicate that the initial choices for side-chains, but also significant effects on the main-chain conformation and supersecondary structure. The conformational differences are discussed. Analysis of these and other methods makes possible the formulation of a methodology for more appropriate side-chain placement in modeled proteins.

Continuous, size and shape-control synthesis of hollow silica nanoparticles enabled by a microreactor-assisted rapid mixing process.

PubMed

He, Yujuan; Kim, Ki-Joong; Chang, Chih-Hung

2017-06-09

Hollow silica nanoparticles (HSNPs) were synthesized using a microreactor-assisted system with a hydrodynamic focusing micromixer. Due to the fast mixing of each precursor in the system, the poly(acrylic acid) (PAA) thermodynamic-locked (TML) conformations were protected from their random aggregations by the immediately initiated growth of silica shells. When altering the mixing time through varying flow rates and flow rate ratios, the different degrees of the aggregation of PAA TML conformations were observed. The globular and necklace-like TML conformations were successfully captured by modifying the PAA concentration at the optimized mixing condition. Uniform HSNPs with an average diameter ∼30 nm were produced from this system. COMSOL numerical models was established to investigate the flow and concentration profiles, and their effects on the formation of PAA templates. Finally, the quality and utility of these uniform HSNPs were demonstrated by the fabrication of antireflective thin films on monocrystalline photovoltaic cells which showed a 3.8% increase in power conversion efficiency.

Continuous, size and shape-control synthesis of hollow silica nanoparticles enabled by a microreactor-assisted rapid mixing process

NASA Astrophysics Data System (ADS)

He, Yujuan; Kim, Ki-Joong; Chang, Chih-Hung

2017-06-01

Hollow silica nanoparticles (HSNPs) were synthesized using a microreactor-assisted system with a hydrodynamic focusing micromixer. Due to the fast mixing of each precursor in the system, the poly(acrylic acid) (PAA) thermodynamic-locked (TML) conformations were protected from their random aggregations by the immediately initiated growth of silica shells. When altering the mixing time through varying flow rates and flow rate ratios, the different degrees of the aggregation of PAA TML conformations were observed. The globular and necklace-like TML conformations were successfully captured by modifying the PAA concentration at the optimized mixing condition. Uniform HSNPs with an average diameter ∼30 nm were produced from this system. COMSOL numerical models was established to investigate the flow and concentration profiles, and their effects on the formation of PAA templates. Finally, the quality and utility of these uniform HSNPs were demonstrated by the fabrication of antireflective thin films on monocrystalline photovoltaic cells which showed a 3.8% increase in power conversion efficiency.

Knowledge-Based Methods To Train and Optimize Virtual Screening Ensembles

PubMed Central

2016-01-01

Ensemble docking can be a successful virtual screening technique that addresses the innate conformational heterogeneity of macromolecular drug targets. Yet, lacking a method to identify a subset of conformational states that effectively segregates active and inactive small molecules, ensemble docking may result in the recommendation of a large number of false positives. Here, three knowledge-based methods that construct structural ensembles for virtual screening are presented. Each method selects ensembles by optimizing an objective function calculated using the receiver operating characteristic (ROC) curve: either the area under the ROC curve (AUC) or a ROC enrichment factor (EF). As the number of receptor conformations, N, becomes large, the methods differ in their asymptotic scaling. Given a set of small molecules with known activities and a collection of target conformations, the most resource intense method is guaranteed to find the optimal ensemble but scales as O(2N). A recursive approximation to the optimal solution scales as O(N2), and a more severe approximation leads to a faster method that scales linearly, O(N). The techniques are generally applicable to any system, and we demonstrate their effectiveness on the androgen nuclear hormone receptor (AR), cyclin-dependent kinase 2 (CDK2), and the peroxisome proliferator-activated receptor δ (PPAR-δ) drug targets. Conformations that consisted of a crystal structure and molecular dynamics simulation cluster centroids were used to form AR and CDK2 ensembles. Multiple available crystal structures were used to form PPAR-δ ensembles. For each target, we show that the three methods perform similarly to one another on both the training and test sets. PMID:27097522

The molecular matching problem

NASA Technical Reports Server (NTRS)

Kincaid, Rex K.

1993-01-01

Molecular chemistry contains many difficult optimization problems that have begun to attract the attention of optimizers in the Operations Research community. Problems including protein folding, molecular conformation, molecular similarity, and molecular matching have been addressed. Minimum energy conformations for simple molecular structures such as water clusters, Lennard-Jones microclusters, and short polypeptides have dominated the literature to date. However, a variety of interesting problems exist and we focus here on a molecular structure matching (MSM) problem.

Technical Note: A novel leaf sequencing optimization algorithm which considers previous underdose and overdose events for MLC tracking radiotherapy

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

Wisotzky, Eric, E-mail: eric.wisotzky@charite.de, E-mail: eric.wisotzky@ipk.fraunhofer.de; O’Brien, Ricky; Keall, Paul J., E-mail: paul.keall@sydney.edu.au

2016-01-15

Purpose: Multileaf collimator (MLC) tracking radiotherapy is complex as the beam pattern needs to be modified due to the planned intensity modulation as well as the real-time target motion. The target motion cannot be planned; therefore, the modified beam pattern differs from the original plan and the MLC sequence needs to be recomputed online. Current MLC tracking algorithms use a greedy heuristic in that they optimize for a given time, but ignore past errors. To overcome this problem, the authors have developed and improved an algorithm that minimizes large underdose and overdose regions. Additionally, previous underdose and overdose events aremore » taken into account to avoid regions with high quantity of dose events. Methods: The authors improved the existing MLC motion control algorithm by introducing a cumulative underdose/overdose map. This map represents the actual projection of the planned tumor shape and logs occurring dose events at each specific regions. These events have an impact on the dose cost calculation and reduce recurrence of dose events at each region. The authors studied the improvement of the new temporal optimization algorithm in terms of the L1-norm minimization of the sum of overdose and underdose compared to not accounting for previous dose events. For evaluation, the authors simulated the delivery of 5 conformal and 14 intensity-modulated radiotherapy (IMRT)-plans with 7 3D patient measured tumor motion traces. Results: Simulations with conformal shapes showed an improvement of L1-norm up to 8.5% after 100 MLC modification steps. Experiments showed comparable improvements with the same type of treatment plans. Conclusions: A novel leaf sequencing optimization algorithm which considers previous dose events for MLC tracking radiotherapy has been developed and investigated. Reductions in underdose/overdose are observed for conformal and IMRT delivery.« less

Optimizing pKa computation in proteins with pH adapted conformations.

PubMed

Kieseritzky, Gernot; Knapp, Ernst-Walter

2008-05-15

pK(A) in proteins are determined by electrostatic energy computations using a small number of optimized protein conformations derived from crystal structures. In these protein conformations hydrogen positions and geometries of salt bridges on the protein surface were determined self-consistently with the protonation pattern at three pHs (low, ambient, and high). Considering salt bridges at protein surfaces is most relevant, since they open at low and high pH. In the absence of these conformational changes, computed pK(A)(comp) of acidic (basic) groups in salt bridges underestimate (overestimate) experimental pK(A)(exp), dramatically. The pK(A)(comp) for 15 different proteins with 185 known pK(A)(exp) yield an RMSD of 1.12, comparable with two other methods. One of these methods is fully empirical with many adjustable parameters. The other is also based on electrostatic energy computations using many non-optimized side chain conformers but employs larger dielectric constants at short distances of charge pairs that diminish their electrostatic interactions. These empirical corrections that account implicitly for additional conformational flexibility were needed to describe the energetics of salt bridges appropriately. This is not needed in the present approach. The RMSD of the present approach improves if one considers only strongly shifted pK(A)(exp) in contrast to the other methods under these conditions. Our method allows interpreting pK(A)(comp) in terms of pH dependent hydrogen bonding pattern and salt bridge geometries. A web service is provided to perform pK(A) computations. 2007 Wiley-Liss, Inc.

Essential role of conformational selection in ligand binding.

PubMed

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

2014-02-01

Two competing and mutually exclusive mechanisms of ligand recognition - conformational selection and induced fit - have dominated our interpretation of ligand binding in biological macromolecules for almost six decades. Conformational selection posits the pre-existence of multiple conformations of the macromolecule from which the ligand selects the optimal one. Induced fit, on the other hand, postulates the existence of conformational rearrangements of the original conformation into an optimal one that are induced by binding of the ligand. In the former case, conformational transitions precede the binding event; in the latter, conformational changes follow the binding step. Kineticists have used a facile criterion to distinguish between the two mechanisms based on the dependence of the rate of relaxation to equilibrium, kobs, on the ligand concentration, [L]. A value of kobs decreasing hyperbolically with [L] has been seen as diagnostic of conformational selection, while a value of kobs increasing hyperbolically with [L] has been considered diagnostic of induced fit. However, this simple conclusion is only valid under the rather unrealistic assumption of conformational transitions being much slower than binding and dissociation events. In general, induced fit only produces values of kobs that increase with [L] but conformational selection is more versatile and is associated with values of kobs that increase with, decrease with or are independent of [L]. The richer repertoire of kinetic properties of conformational selection applies to kinetic mechanisms with single or multiple saturable relaxations and explains the behavior of nearly all experimental systems reported in the literature thus far. Conformational selection is always sufficient and often necessary to account for the relaxation kinetics of ligand binding to a biological macromolecule and is therefore an essential component of any binding mechanism. On the other hand, induced fit is never necessary and only sufficient in a few cases. Therefore, the long assumed importance and preponderance of induced fit as a mechanism of ligand binding should be reconsidered. © 2013 Elsevier B.V. All rights reserved.

Methodologies in the modeling of combined chemo-radiation treatments

NASA Astrophysics Data System (ADS)

Grassberger, C.; Paganetti, H.

2016-11-01

The variety of treatment options for cancer patients has increased significantly in recent years. Not only do we combine radiation with surgery and chemotherapy, new therapeutic approaches such as immunotherapy and targeted therapies are starting to play a bigger role. Physics has made significant contributions to radiation therapy treatment planning and delivery. In particular, treatment plan optimization using inverse planning techniques has improved dose conformity considerably. Furthermore, medical physics is often the driving force behind tumor control and normal tissue complication modeling. While treatment optimization and outcome modeling does focus mainly on the effects of radiation, treatment modalities such as chemotherapy are treated independently or are even neglected entirely. This review summarizes the published efforts to model combined modality treatments combining radiation and chemotherapy. These models will play an increasing role in optimizing cancer therapy not only from a radiation and drug dosage standpoint, but also in terms of spatial and temporal optimization of treatment schedules.

Optimization and Simulation of Plastic Injection Process using Genetic Algorithm and Moldflow

NASA Astrophysics Data System (ADS)

Martowibowo, Sigit Yoewono; Kaswadi, Agung

2017-03-01

The use of plastic-based products is continuously increasing. The increasing demands for thinner products, lower production costs, yet higher product quality has triggered an increase in the number of research projects on plastic molding processes. An important branch of such research is focused on mold cooling system. Conventional cooling systems are most widely used because they are easy to make by using conventional machining processes. However, the non-uniform cooling processes are considered as one of their weaknesses. Apart from the conventional systems, there are also conformal cooling systems that are designed for faster and more uniform plastic mold cooling. In this study, the conformal cooling system is applied for the production of bowl-shaped product made of PP AZ564. Optimization is conducted to initiate machine setup parameters, namely, the melting temperature, injection pressure, holding pressure and holding time. The genetic algorithm method and Moldflow were used to optimize the injection process parameters at a minimum cycle time. It is found that, an optimum injection molding processes could be obtained by setting the parameters to the following values: T M = 180 °C; P inj = 20 MPa; P hold = 16 MPa and t hold = 8 s, with a cycle time of 14.11 s. Experiments using the conformal cooling system yielded an average cycle time of 14.19 s. The studied conformal cooling system yielded a volumetric shrinkage of 5.61% and the wall shear stress was found at 0.17 MPa. The difference between the cycle time obtained through simulations and experiments using the conformal cooling system was insignificant (below 1%). Thus, combining process parameters optimization and simulations by using genetic algorithm method with Moldflow can be considered as valid.

A conformal mapping based fractional order approach for sub-optimal tuning of PID controllers with guaranteed dominant pole placement

NASA Astrophysics Data System (ADS)

Saha, Suman; Das, Saptarshi; Das, Shantanu; Gupta, Amitava

2012-09-01

A novel conformal mapping based fractional order (FO) methodology is developed in this paper for tuning existing classical (Integer Order) Proportional Integral Derivative (PID) controllers especially for sluggish and oscillatory second order systems. The conventional pole placement tuning via Linear Quadratic Regulator (LQR) method is extended for open loop oscillatory systems as well. The locations of the open loop zeros of a fractional order PID (FOPID or PIλDμ) controller have been approximated in this paper vis-à-vis a LQR tuned conventional integer order PID controller, to achieve equivalent integer order PID control system. This approach eases the implementation of analog/digital realization of a FOPID controller with its integer order counterpart along with the advantages of fractional order controller preserved. It is shown here in the paper that decrease in the integro-differential operators of the FOPID/PIλDμ controller pushes the open loop zeros of the equivalent PID controller towards greater damping regions which gives a trajectory of the controller zeros and dominant closed loop poles. This trajectory is termed as "M-curve". This phenomena is used to design a two-stage tuning algorithm which reduces the existing PID controller's effort in a significant manner compared to that with a single stage LQR based pole placement method at a desired closed loop damping and frequency.

Soft, Conformal Bioelectronics for a Wireless Human-Wheelchair Interface

PubMed Central

Mishra, Saswat; Norton, James J. S.; Lee, Yongkuk; Lee, Dong Sup; Agee, Nicolas; Chen, Yanfei; Chun, Youngjae; Yeo, Woon-Hong

2017-01-01

There are more than 3 million people in the world whose mobility relies on wheelchairs. Recent advancement on engineering technology enables more intuitive, easy-to-use rehabilitation systems. A human-machine interface that uses non-invasive, electrophysiological signals can allow a systematic interaction between human and devices; for example, eye movement-based wheelchair control. However, the existing machine-interface platforms are obtrusive, uncomfortable, and often cause skin irritations as they require a metal electrode affixed to the skin with a gel and acrylic pad. Here, we introduce a bioelectronic system that makes dry, conformal contact to the skin. The mechanically comfortable sensor records high-fidelity electrooculograms, comparable to the conventional gel electrode. Quantitative signal analysis and infrared thermographs show the advantages of the soft biosensor for an ergonomic human-machine interface. A classification algorithm with an optimized set of features shows the accuracy of 94% with five eye movements. A Bluetooth-enabled system incorporating the soft bioelectronics demonstrates a precise, hands-free control of a robotic wheelchair via electrooculograms. PMID:28152485

HRD Motif as the Central Hub of the Signaling Network for Activation Loop Autophosphorylation in Abl Kinase.

PubMed

La Sala, Giuseppina; Riccardi, Laura; Gaspari, Roberto; Cavalli, Andrea; Hantschel, Oliver; De Vivo, Marco

2016-11-08

A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. First, only the open conformation of the Abl kinase domain's activation loop (A-loop) favors ATP binding to the catalytic cleft. In this regard, the trans-autophosphorylation of the Y412 residue, which is located along the A-loop, favors the stability of the open conformation, in turn enhancing Abl activity. Another key factor for full Abl activity is the formation of active conformations of the catalytic DFG motif in the Abl kinase domain. Furthermore, binding of the SH2 domain to the N-lobe of the Abl kinase was recently demonstrated to have a long-range allosteric effect on the stabilization of the A-loop open state. Intriguingly, these distinct structural factors imply a complex signal transmission network for controlling the A-loop's flexibility and conformational preference for optimal Abl function. However, the exact dynamical features of this signal transmission network structure remain unclear. Here, we report on microsecond-long molecular dynamics coupled with enhanced sampling simulations of multiple Abl model systems, in the presence or absence of the SH2 domain and with the DFG motif flipped in two ways (in or out conformation). Through comparative analysis, our simulations augment the interpretation of the existing Abl experimental data, revealing a dynamical network of interactions that interconnect SH2 domain binding with A-loop plasticity and Y412 autophosphorylation in Abl. This signaling network engages the DFG motif and, importantly, other conserved structural elements of the kinase domain, namely, the EPK-ELK H-bond network and the HRD motif. Our results show that the signal propagation for modulating the A-loop spatial localization is highly dependent on the HRD motif conformation, which thus acts as the central hub of this (allosteric) signaling network controlling Abl activation and function.

SU-E-T-562: Motion Tracking Optimization for Conformal Arc Radiotherapy Plans: A QUASAR Phantom Based Study

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

Xu, Z; Wang, I; Yao, R

Purpose: This study is to use plan parameters optimization (Dose rate, collimator angle, couch angle, initial starting phase) to improve the performance of conformal arc radiotherapy plans with motion tracking by increasing the plan performance score (PPS). Methods: Two types of 3D conformal arc plans were created based on QUASAR respiratory motion phantom with spherical and cylindrical targets. Sinusoidal model was applied to the MLC leaves to generate motion tracking plans. A MATLAB program was developed to calculate PPS of each plan (ranges from 0–1) and optimize plan parameters. We first selected the dose rate for motion tracking plans andmore » then used simulated annealing algorithm to search for the combination of the other parameters that resulted in the plan of the maximal PPS. The optimized motion tracking plan was delivered by Varian Truebeam Linac. In-room cameras and stopwatch were used for starting phase selection and synchronization between phantom motion and plan delivery. Gaf-EBT2 dosimetry films were used to measure the dose delivered to the target in QUASAR phantom. Dose profiles and Truebeam trajectory log files were used for plan delivery performance evaluation. Results: For spherical target, the maximal PPS (PPSsph) of the optimized plan was 0.79: (Dose rate: 500MU/min, Collimator: 90°, Couch: +10°, starting phase: 0.83π). For cylindrical target, the maximal PPScyl was 0.75 (Dose rate: 300MU/min, Collimator: 87°, starting phase: 0.97π) with couch at 0°. Differences of dose profiles between motion tracking plans (with the maximal and the minimal PPS) and 3D conformal plans were as follows: PPSsph=0.79: %ΔFWHM: 8.9%, %Dmax: 3.1%; PPSsph=0.52: %ΔFWHM: 10.4%, %Dmax: 6.1%. PPScyl=0.75: %ΔFWHM: 4.7%, %Dmax: 3.6%; PPScyl=0.42: %ΔFWHM: 12.5%, %Dmax: 9.6%. Conclusion: By achieving high plan performance score through parameters optimization, we can improve target dose conformity of motion tracking plan by decreasing total MLC leaf travel distance and leaf speed.« less

Comparative structural and vibrational study of the four lowest energy conformers of serotonin

NASA Astrophysics Data System (ADS)

Jha, Omkant; Yadav, T. K.; Yadav, R. A.

2017-02-01

A computational investigation of all possible lowest energy conformers of serotonin was carried out at the B3LYP/6-311 ++G** level. Out of the 14 possible lowest energy conformers, the first 4 conformers were investigated thoroughly for the optimized geometries, fundamental frequencies, the potential energy distributions, APT and natural charges, natural bond orbital (NBO) analysis, MEP, Contour map, total density array, HOMO, LUMO energies. The second third and fourth conformers are energetically at higher temperatures of 78, 94 and 312 K respectively with respect to the first one. Bond angles and bond lengths do not show significant variations while the dihedral angles vary significantly in going from one conformer to the other. Some of the vibrational modes of the indole moiety are conformation dependent to some extent whereas most of the normal modes of vibration of amino-ethyl side chain vary significantly in going from one conformer to conformer. The MEP for the four conformers suggested that the sites of the maximum positive and negative ESP change on changing the conformation. The charges at some atomic sites also change significantly from conformer to conformer.

A risk analysis approach applied to field surveillance in utility meters in legal metrology

NASA Astrophysics Data System (ADS)

Rodrigues Filho, B. A.; Nonato, N. S.; Carvalho, A. D.

2018-03-01

Field surveillance represents the level of control in metrological supervision responsible for checking the conformity of measuring instruments in-service. Utility meters represent the majority of measuring instruments produced by notified bodies due to self-verification in Brazil. They play a major role in the economy once electricity, gas and water are the main inputs to industries in their production processes. Then, to optimize the resources allocated to control these devices, the present study applied a risk analysis in order to identify among the 11 manufacturers notified to self-verification, the instruments that demand field surveillance.

Precise side-chain conformation analysis of L-phenylalanine in α-helical polypeptide by quantum-chemical calculation and 13C CP-MAS NMR measurement

NASA Astrophysics Data System (ADS)

Niimura, Subaru; Suzuki, Junya; Kurosu, Hiromichi; Yamanobe, Takeshi; Shoji, Akira

2010-04-01

To clarify the positive role of side-chain conformation in the stability of protein secondary structure (main-chain conformation), we successfully calculated the optimization structure of a well-defined α-helical octadecapeptide composed of L-alanine (Ala) and L-phenylalanine (Phe) residues, H-(Ala) 8-Phe-(Ala) 9-OH, based on the molecular orbital calculation with density functional theory (DFT/B3LYP/6-31G(d)). From the total energy and the precise secondary structural parameters such as main-chain dihedral angles and hydrogen-bond parameters of the optimized structure, we confirmed that the conformational stability of an α-helix is affected dominantly by the side-chain conformation ( χ1) of the Phe residue in this system: model A ( T form: around 180° of χ1) is most stable in α-helix and model B ( G + form: around -60° of χ1) is next stable, but model C ( G - form: around 60° of χ1) is less stable. In addition, we demonstrate that the stable conformation of poly( L-phenylalanine) is an α-helix with the side-chain T form, by comparison of the carbonyl 13C chemical shift measured by 13C CP-MAS NMR and the calculated one.

Behavior of the E-E' Bonds (E, E' = S and Se) in Glutathione Disulfide and Derivatives Elucidated by Quantum Chemical Calculations with the Quantum Theory of Atoms-in-Molecules Approach.

PubMed

Hayashi, Satoko; Tsubomoto, Yutaka; Nakanishi, Waro

2018-02-17

The nature of the E-E' bonds (E, E' = S and Se) in glutathione disulfide ( 1 ) and derivatives 2 - 3 , respectively, was elucidated by applying quantum theory of atoms-in-molecules (QTAIM) dual functional analysis (QTAIM-DFA), to clarify the basic contribution of E-E' in the biological redox process, such as the glutathione peroxidase process. Five most stable conformers a - e were obtained, after applying the Monte-Carlo method then structural optimizations. In QTAIM-DFA, total electron energy densities H b ( r c ) are plotted versus H b ( r c ) - V b ( r c )/2 at bond critical points (BCPs), where V b ( r c ) are potential energy densities at BCPs. Data from the fully optimized structures correspond to the static nature. Those containing perturbed structures around the fully optimized one in the plot represent the dynamic nature of interactions. The behavior of E-E' was examined carefully. Whereas E-E' in 1a - 3e were all predicted to have the weak covalent nature of the shared shell interactions, two different types of S-S were detected in 1 , depending on the conformational properties. Contributions from the intramolecular non-covalent interactions to stabilize the conformers were evaluated. An inverse relationship was observed between the stability of a conformer and the strength of E-E' in the conformer, of which reason was discussed.

Definition of the supraclavicular and infraclavicular nodes: implications for three-dimensional CT-based conformal radiation therapy.

PubMed

Madu, C N; Quint, D J; Normolle, D P; Marsh, R B; Wang, E Y; Pierce, L J

2001-11-01

To delineate with computed tomography (CT) the anatomic regions containing the supraclavicular (SCV) and infraclavicular (IFV) nodal groups, to define the course of the brachial plexus, to estimate the actual radiation dose received by these regions in a series of patients treated in the traditional manner, and to compare these doses to those received with an optimized dosimetric technique. Twenty patients underwent contrast material-enhanced CT for the purpose of radiation therapy planning. CT scans were used to study the location of the SCV and IFV nodal regions by using outlining of readily identifiable anatomic structures that define the nodal groups. The brachial plexus was also outlined by using similar methods. Radiation therapy doses to the SCV and IFV were then estimated by using traditional dose calculations and optimized planning. A repeated measures analysis of covariance was used to compare the SCV and IFV depths and to compare the doses achieved with the traditional and optimized methods. Coverage by the 90% isodose surface was significantly decreased with traditional planning versus conformal planning as the depth to the SCV nodes increased (P < .001). Significantly decreased coverage by using the 90% isodose surface was demonstrated for traditional planning versus conformal planning with increasing IFV depth (P = .015). A linear correlation was found between brachial plexus depth and SCV depth up to 7 cm. Conformal optimized planning provided improved dosimetric coverage compared with standard techniques.

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.

Guaranteed Discrete Energy Optimization on Large Protein Design Problems.

PubMed

Simoncini, David; Allouche, David; de Givry, Simon; Delmas, Céline; Barbe, Sophie; Schiex, Thomas

2015-12-08

In Computational Protein Design (CPD), assuming a rigid backbone and amino-acid rotamer library, the problem of finding a sequence with an optimal conformation is NP-hard. In this paper, using Dunbrack's rotamer library and Talaris2014 decomposable energy function, we use an exact deterministic method combining branch and bound, arc consistency, and tree-decomposition to provenly identify the global minimum energy sequence-conformation on full-redesign problems, defining search spaces of size up to 10(234). This is achieved on a single core of a standard computing server, requiring a maximum of 66GB RAM. A variant of the algorithm is able to exhaustively enumerate all sequence-conformations within an energy threshold of the optimum. These proven optimal solutions are then used to evaluate the frequencies and amplitudes, in energy and sequence, at which an existing CPD-dedicated simulated annealing implementation may miss the optimum on these full redesign problems. The probability of finding an optimum drops close to 0 very quickly. In the worst case, despite 1,000 repeats, the annealing algorithm remained more than 1 Rosetta unit away from the optimum, leading to design sequences that could differ from the optimal sequence by more than 30% of their amino acids.

Rapid Optimal SPH Particle Distributions in Spherical Geometries For Creating Astrophysical Initial Conditions

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

Raskin, Cody; Owen, J. Michael

Creating spherical initial conditions in smoothed particle hydrodynamics simulations that are spherically conformal is a difficult task. Here in this paper, we describe two algorithmic methods for evenly distributing points on surfaces that when paired can be used to build three-dimensional spherical objects with optimal equipartition of volume between particles, commensurate with an arbitrary radial density function. We demonstrate the efficacy of our method against stretched lattice arrangements on the metrics of hydrodynamic stability, spherical conformity, and the harmonic power distribution of gravitational settling oscillations. We further demonstrate how our method is highly optimized for simulating multi-material spheres, such asmore » planets with core–mantle boundaries.« less

Rapid Optimal SPH Particle Distributions in Spherical Geometries For Creating Astrophysical Initial Conditions

DOE PAGES

Raskin, Cody; Owen, J. Michael

2016-03-24

Creating spherical initial conditions in smoothed particle hydrodynamics simulations that are spherically conformal is a difficult task. Here in this paper, we describe two algorithmic methods for evenly distributing points on surfaces that when paired can be used to build three-dimensional spherical objects with optimal equipartition of volume between particles, commensurate with an arbitrary radial density function. We demonstrate the efficacy of our method against stretched lattice arrangements on the metrics of hydrodynamic stability, spherical conformity, and the harmonic power distribution of gravitational settling oscillations. We further demonstrate how our method is highly optimized for simulating multi-material spheres, such asmore » planets with core–mantle boundaries.« less

RAPID OPTIMAL SPH PARTICLE DISTRIBUTIONS IN SPHERICAL GEOMETRIES FOR CREATING ASTROPHYSICAL INITIAL CONDITIONS

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

Raskin, Cody; Owen, J. Michael

2016-04-01

Creating spherical initial conditions in smoothed particle hydrodynamics simulations that are spherically conformal is a difficult task. Here, we describe two algorithmic methods for evenly distributing points on surfaces that when paired can be used to build three-dimensional spherical objects with optimal equipartition of volume between particles, commensurate with an arbitrary radial density function. We demonstrate the efficacy of our method against stretched lattice arrangements on the metrics of hydrodynamic stability, spherical conformity, and the harmonic power distribution of gravitational settling oscillations. We further demonstrate how our method is highly optimized for simulating multi-material spheres, such as planets with core–mantlemore » boundaries.« less

Proof of Principle of Ocular sparing in dogs with sinonasal tumors treated with intensity-modulated radiation therapy

PubMed Central

Lawrence, Jessica A.; Forrest, Lisa J.; Turek, Michelle M.; Miller, Paul E.; Mackie, T. Rockwell; Jaradat, Hazim A.; Vail, David M.; Dubielzig, Richard R.; Chappell, Richard; Mehta, Minesh P.

2010-01-01

Intensity modulated radiation therapy (IMRT) allows optimization of radiation dose delivery to complex tumor volumes with rapid dose drop-off to surrounding normal tissues. A prospective study was performed to evaluate the concept of conformal avoidance using IMRT in canine sinonasal cancer. The potential of IMRT to improve clinical outcome with respect to acute and late ocular toxicity was evaluated. Thirty-one dogs with sinonasal cancer were treated definitively with IMRT using helical tomotherapy and/or dynamic multileaf collimator (DMLC) delivery. Ocular toxicity was evaluated prospectively and compared to a comparable group of historical controls treated with conventional two-dimensional radiotherapy (2D-RT) techniques. Treatment plans were devised for each dog using helical tomotherapy and DMLC that achieved the target dose to the planning treatment volume and limited critical normal tissues to the prescribed dose-volume constraints. Overall acute and late toxicities were limited and minor, detectable by an experienced observer. This was in contrast to the profound ocular morbidity observed in the historical control group treated with 2D-RT. Overall median survival for IMRT treated and 2D treated dogs was 420 days and 411 days, respectively. Compared with conventional techniques, IMRT reduced dose delivered to eyes and resulted in bilateral ocular sparing in the dogs reported herein. These data provide proof-of-principle that conformal avoidance radiotherapy can be delivered through high conformity IMRT, resulting in decreased normal tissue toxicity as compared to historical controls treated with 2D-RT. PMID:20973393

Modification and optimization of the united-residue (UNRES) potential-energy function for canonical simulations. I. Temperature dependence of the effective energy function and tests of the optimization method with single training proteins

PubMed Central

Liwo, Adam; Khalili, Mey; Czaplewski, Cezary; Kalinowski, Sebastian; Ołdziej, Stanisław; Wachucik, Katarzyna; Scheraga, Harold A.

2011-01-01

We report the modification and parameterization of the united-residue (UNRES) force field for energy-based protein-structure prediction and protein-folding simulations. We tested the approach on three training proteins separately: 1E0L (β), 1GAB (α), and 1E0G (α + β). Heretofore, the UNRES force field had been designed and parameterized to locate native-like structures of proteins as global minima of their effective potential-energy surfaces, which largely neglected the conformational entropy because decoys composed of only lowest-energy conformations were used to optimize the force field. Recently, we developed a mesoscopic dynamics procedure for UNRES, and applied it with success to simulate protein folding pathways. How ever, the force field turned out to be largely biased towards α-helical structures in canonical simulations because the conformational entropy had been neglected in the parameterization. We applied the hierarchical optimization method developed in our earlier work to optimize the force field, in which the conformational space of a training protein is divided into levels each corresponding to a certain degree of native-likeness. The levels are ordered according to increasing native-likeness; level 0 corresponds to structures with no native-like elements and the highest level corresponds to the fully native-like structures. The aim of optimization is to achieve the order of the free energies of levels, decreasing as their native-likeness increases. The procedure is iterative, and decoys of the training protein(s) generated with the energy-function parameters of the preceding iteration are used to optimize the force field in a current iteration. We applied the multiplexing replica exchange molecular dynamics (MREMD) method, recently implemented in UNRES, to generate decoys; with this modification, conformational entropy is taken into account. Moreover, we optimized the free-energy gaps between levels at temperatures corresponding to a predominance of folded or unfolded structures, as well as to structures at the putative folding-transition temperature, changing the sign of the gaps at the transition temperature. This enabled us to obtain force fields characterized by a single peak in the heat capacity at the transition temperature. Furthermore, we introduced temperature dependence to the UNRES force field; this is consistent with the fact that it is a free-energy and not a potential-energy function. PMID:17201450

Conformal phased surfaces for wireless powering of bioelectronic microdevices

PubMed Central

Agrawal, Devansh R.; Tanabe, Yuji; Weng, Desen; Ma, Andrew; Hsu, Stephanie; Liao, Song-Yan; Zhen, Zhe; Zhu, Zi-Yi; Sun, Chuanbowen; Dong, Zhenya; Yang, Fengyuan; Tse, Hung Fat; Poon, Ada S. Y.; Ho, John S.

2017-01-01

Wireless powering could enable the long-term operation of advanced bioelectronic devices within the human body. Although both enhanced powering depth and device miniaturization can be achieved by shaping the field pattern within the body, existing electromagnetic structures do not provide the spatial phase control required to synthesize such patterns. Here, we describe the design and operation of conformal electromagnetic structures, termed phased surfaces, that interface with non-planar body surfaces and optimally modulate the phase response to enhance the performance of wireless powering. We demonstrate that the phased surfaces can wirelessly transfer energy across anatomically heterogeneous tissues in large animal models, powering miniaturized semiconductor devices (<12 mm3) deep within the body (>4 cm). As an illustration of in vivo operation, we wirelessly regulated cardiac rhythm by powering miniaturized stimulators at multiple endocardial sites in a porcine animal model. PMID:29226018

Allosteric transcriptional regulation via changes in the overall topology of the core promoter

DOE PAGES

Philips, Steven J.; Canalizo-Hernandez, Monica; Yildirim, Ilyas; ...

2015-08-21

Many transcriptional activators act at a distance from core promoter elements and work by recruiting RNA polymerase through protein-protein interactions. We show here how the prokaryotic regulatory protein CueR both represses and activates transcription by differentially modulating local DNA structure within the promoter. Structural studies reveal that the repressor state slightly bends the promoter DNA, precluding optimal RNA polymerase-promoter recognition. Upon binding a metal ion in the allosteric site, CueR switches into an activator conformation. It maintains all protein-DNA contacts but introduces torsional stresses that kink and undertwist the promoter, stabilizing an A-DNA-like conformation. Finally, these factors switch on andmore » off transcription by exerting dynamic control of DNA stereochemistry, reshaping the core promoter and making it a better or worse substrate for polymerase.« less

Influence of measuring algorithm on shape accuracy in the compensating turning of high gradient thin-wall parts

NASA Astrophysics Data System (ADS)

Wang, Tao; Wang, Guilin; Zhu, Dengchao; Li, Shengyi

2015-02-01

In order to meet the requirement of aerodynamics, the infrared domes or windows with conformal and thin-wall structure becomes the development trend of high-speed aircrafts in the future. But these parts usually have low stiffness, the cutting force will change along with the axial position, and it is very difficult to meet the requirement of shape accuracy by single machining. Therefore, on-machine measurement and compensating turning are used to control the shape errors caused by the fluctuation of cutting force and the change of stiffness. In this paper, on the basis of ultra precision diamond lathe, a contact measuring system with five DOFs is developed to achieve on-machine measurement of conformal thin-wall parts with high accuracy. According to high gradient surface, the optimizing algorithm is designed on the distribution of measuring points by using the data screening method. The influence rule of sampling frequency is analyzed on measuring errors, the best sampling frequency is found out based on planning algorithm, the effect of environmental factors and the fitting errors are controlled within lower range, and the measuring accuracy of conformal dome is greatly improved in the process of on-machine measurement. According to MgF2 conformal dome with high gradient, the compensating turning is implemented by using the designed on-machine measuring algorithm. The shape error is less than PV 0.8μm, greatly superior compared with PV 3μm before compensating turning, which verifies the correctness of measuring algorithm.

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

NASA Astrophysics Data System (ADS)

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

1993-03-01

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

A computational study of open-chain epothilone analogue

NASA Astrophysics Data System (ADS)

Kamel, Karol; Rusinska-Roszak, Danuta

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

Comparing conformal, arc radiotherapy and helical tomotherapy in craniospinal irradiation planning.

PubMed

Myers, Pamela A; Mavroidis, Panayiotis; Papanikolaou, Nikos; Stathakis, Sotirios

2014-09-08

Currently, radiotherapy treatment plan acceptance is based primarily on dosimetric performance measures. However, use of radiobiological analysis to assess benefit in terms of tumor control and harm in terms of injury to normal tissues can be advantageous. For pediatric craniospinal axis irradiation (CSI) patients, in particular, knowing the technique that will optimize the probabilities of benefit versus injury can lead to better long-term outcomes. Twenty-four CSI pediatric patients (median age 10) were retrospectively planned with three techniques: three-dimensional conformal radiation therapy (3D CRT), volumetric-modulated arc therapy (VMAT), and helical tomotherapy (HT). VMAT plans consisted of one superior and one inferior full arc, and tomotherapy plans were created using a 5.02cm field width and helical pitch of 0.287. Each plan was normalized to 95% of target volume (whole brain and spinal cord) receiving prescription dose 23.4Gy in 13 fractions. Using an in-house MATLAB code and DVH data from each plan, the three techniques were evaluated based on biologically effective uniform dose (D=), the complication-free tumor control probability (P+), and the width of the therapeutically beneficial range. Overall, 3D CRT and VMAT plans had similar values of D= (24.1 and 24.2 Gy), while HT had a D= slightly lower (23.6 Gy). The average values of the P+ index were 64.6, 67.4, and 56.6% for 3D CRT, VMAT, and HT plans, respectively, with the VMAT plans having a statistically significant increase in P+. Optimal values of D= were 28.4, 33.0, and 31.9 Gy for 3D CRT, VMAT, and HT plans, respectively. Although P+ values that correspond to the initial dose prescription were lower for HT, after optimizing the D= prescription level, the optimal P+ became 94.1, 99.5, and 99.6% for 3D CRT, VMAT, and HT, respectively, with the VMAT and HT plans having statistically significant increases in P+. If the optimal dose level is prescribed using a radiobiological evaluation method, as opposed to a purely dosimetric one, the two IMRT techniques, VMAT and HT, will yield largest overall benefit to CSI patients by maximizing tumor control and limiting normal tissue injury. Using VMAT or HT may provide these pediatric patients with better long-term outcomes after radiotherapy.

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

PubMed

Boeckx, Bram; Maes, Guido

2012-02-01

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

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

NASA Astrophysics Data System (ADS)

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

2014-10-01

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

Quality assurance for high dose rate brachytherapy treatment planning optimization: using a simple optimization to verify a complex optimization

NASA Astrophysics Data System (ADS)

Deufel, Christopher L.; Furutani, Keith M.

2014-02-01

As dose optimization for high dose rate brachytherapy becomes more complex, it becomes increasingly important to have a means of verifying that optimization results are reasonable. A method is presented for using a simple optimization as quality assurance for the more complex optimization algorithms typically found in commercial brachytherapy treatment planning systems. Quality assurance tests may be performed during commissioning, at regular intervals, and/or on a patient specific basis. A simple optimization method is provided that optimizes conformal target coverage using an exact, variance-based, algebraic approach. Metrics such as dose volume histogram, conformality index, and total reference air kerma agree closely between simple and complex optimizations for breast, cervix, prostate, and planar applicators. The simple optimization is shown to be a sensitive measure for identifying failures in a commercial treatment planning system that are possibly due to operator error or weaknesses in planning system optimization algorithms. Results from the simple optimization are surprisingly similar to the results from a more complex, commercial optimization for several clinical applications. This suggests that there are only modest gains to be made from making brachytherapy optimization more complex. The improvements expected from sophisticated linear optimizations, such as PARETO methods, will largely be in making systems more user friendly and efficient, rather than in finding dramatically better source strength distributions.

SU-E-J-86: Functional Conformal Planning for Stereotactic Body Radiation Therapy with CT-Pulmonary Ventilation Imaging

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

Kurosawa, T; Moriya, S; Sato, M

2015-06-15

Purpose: To evaluate the functional planning using CT-pulmonary ventilation imaging for conformal SBRT. Methods: The CT-pulmonary ventilation image was generated using the Jacobian metric in the in-house program with the NiftyReg software package. Using the ventilation image, the normal lung was split into three lung regions for functionality (high, moderate and low). The anatomical plan (AP) and functional plan (FP) were made for ten lung SBRT patients. For the AP, the beam angles were optimized with the dose-volume constraints for the normal lung sparing and the PTV coverage. For the FP, the gantry angles were also optimized with the additionalmore » constraint for high functional lung. The MLC aperture shapes were adjusted to the PTV with the additional 5 mm margin. The dosimetric parameters for PTV, the functional volumes, spinal cord and so on were compared in both plans. Results: Compared to the AP, the FP showed better dose sparing for high- and moderate-functional lungs with similar PTV coverage while not taking care of the low functional lung (High:−12.9±9.26% Moderate: −2.0±7.09%, Low: +4.1±12.2%). For the other normal organs, the FP and AP showed similar dose sparing in the eight patients. However, the FP showed that the maximum doses for spinal cord were increased with the significant increment of 16.4Gy and 21.0Gy in other two patients, respectively. Because the beam direction optimizer chose the unexpected directions passing through the spinal cord. Conclusion: Even the functional conformal SBRT can selectively reduce high- and moderatefunctional lung while keeping the PTV coverage. However, it would be careful that the optimizer would choose unexpected beam angles and the dose sparing for the other normal organs can be worse. Therefore, the planner needs to control the dose-volume constraints and also limit the beam angles in order to achieve the expected dose sparing and coverage.« less

Molecular mechanics approach for design and conformational studies of macrocyclic ligands

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

Rohini,; Akbar, Rifat; Kanungo, B. K., E-mail: b.kanungo@gmail.com

2015-08-28

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

PubChem3D: conformer ensemble accuracy

PubMed Central

2013-01-01

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

Stereotactic Body Radiotherapy in the Management of Oligometastatic Disease.

PubMed

Ahmed, Kamran A; Torres-Roca, Javier F

2016-01-01

The treatment of oligometastatic disease has become common as imaging techniques have advanced and the management of systemic disease has improved. Use of highly targeted, hypofractionated regimens of stereotactic body radiotherapy (SBRT) is now a primary management option for patients with oligometastatic disease. The properties of SBRT are summarized and the results of retrospective and prospective studies of SBRT use in the management of oligometastases are reviewed. Future directions of SBRT, including optimizing dose and fractionation schedules, are also discussed. SBRT can deliver highly conformal, dosed radiation treatments for ablative tumors in a few treatment sessions. Phase 1/2 trials and retrospective institutional results support use of SBRT as a treatment option for oligometastatic disease metastasized to the lung, liver, and spine, and SBRT offers adequate toxicity profiles with good rates of local control. Future directions will involve optimizing dose and fractionation schedules for select histologies to improve rates of local control while limiting toxicity to normal structures. SBRT offers an excellent management option for patients with oligometastases. However, additional research is still needed to optimize dose and fractionation schedules.

TH-AB-BRB-04: Quality Assurance for Advanced Digital Linac Implementations

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

Yu, V.

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

TH-AB-BRB-00: Research Opportunities with Digital Linear Accelerators

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

NONE

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

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

PubMed Central

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

2013-01-01

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

Comparison of the helical tomotherapy against the multileaf collimator-based intensity-modulated radiotherapy and 3D conformal radiation modalities in lung cancer radiotherapy

PubMed Central

Mavroidis, P; Shi, C; Plataniotis, G A; Delichas, M G; Costa Ferreira, B; Rodriguez, S; Lind, B K; Papanikolaou, N

2011-01-01

Objectives The aim of this study was to compare three-dimensional (3D) conformal radiotherapy and the two different forms of IMRT in lung cancer radiotherapy. Methods Cases of four lung cancer patients were investigated by developing a 3D conformal treatment plan, a linac MLC-based step-and-shoot IMRT plan and an HT plan for each case. With the use of the complication-free tumour control probability (P+) index and the uniform dose concept as the common prescription point of the plans, the different treatment plans were compared based on radiobiological measures. Results The applied plan evaluation method shows the MLC-based IMRT and the HT treatment plans are almost equivalent over the clinically useful dose prescription range; however, the 3D conformal plan inferior. At the optimal dose levels, the 3D conformal treatment plans give an average P+ of 48.1% for a effective uniform dose to the internal target volume (ITV) of 62.4 Gy, whereas the corresponding MLC-based IMRT treatment plans are more effective by an average ΔP+ of 27.0% for a Δ effective uniform dose of 16.3 Gy. Similarly, the HT treatment plans are more effective than the 3D-conformal plans by an average ΔP+ of 23.8% for a Δ effective uniform dose of 11.6 Gy. Conclusion A radiobiological treatment plan evaluation can provide a closer association of the delivered treatment with the clinical outcome by taking into account the dose–response relations of the irradiated tumours and normal tissues. The use of P – effective uniform dose diagrams can complement the traditional tools of evaluation to compare and effectively evaluate different treatment plans. PMID:20858664

Alignment-independent technique for 3D QSAR analysis

NASA Astrophysics Data System (ADS)

Wilkes, Jon G.; Stoyanova-Slavova, Iva B.; Buzatu, Dan A.

2016-04-01

Molecular biochemistry is controlled by 3D phenomena but structure-activity models based on 3D descriptors are infrequently used for large data sets because of the computational overhead for determining molecular conformations. A diverse dataset of 146 androgen receptor binders was used to investigate how different methods for defining molecular conformations affect the performance of 3D-quantitative spectral data activity relationship models. Molecular conformations tested: (1) global minimum of molecules' potential energy surface; (2) alignment-to-templates using equal electronic and steric force field contributions; (3) alignment using contributions "Best-for-Each" template; (4) non-energy optimized, non-aligned (2D > 3D). Aggregate predictions from models were compared. Highest average coefficients of determination ranged from R Test 2 = 0.56 to 0.61. The best model using 2D > 3D (imported directly from ChemSpider) produced R Test 2 = 0.61. It was superior to energy-minimized and conformation-aligned models and was achieved in only 3-7 % of the time required using the other conformation strategies. Predictions averaged from models built on different conformations achieved a consensus R Test 2 = 0.65. The best 2D > 3D model was analyzed for underlying structure-activity relationships. For the compound strongest binding to the androgen receptor, 10 substructural features contributing to binding were flagged. Utility of 2D > 3D was compared for two other activity endpoints, each modeling a medium sized data set. Results suggested that large scale, accurate predictions using 2D > 3D SDAR descriptors may be produced for interactions involving endocrine system nuclear receptors and other data sets in which strongest activities are produced by fairly inflexible substrates.

Model based LV-reconstruction in bi-plane x-ray angiography

NASA Astrophysics Data System (ADS)

Backfrieder, Werner; Carpella, Martin; Swoboda, Roland; Steinwender, Clemens; Gabriel, Christian; Leisch, Franz

2005-04-01

Interventional x-ray angiography is state of the art in diagnosis and therapy of severe diseases of the cardiovascular system. Diagnosis is based on contrast enhanced dynamic projection images of the left ventricle. A new model based algorithm for three dimensional reconstruction of the left ventricle from bi-planar angiograms was developed. Parametric super ellipses are deformed until their projection profiles optimally fit measured ventricular projections. Deformation is controlled by a simplex optimization procedure. A resulting optimized parameter set builds the initial guess for neighboring slices. A three dimensional surface model of the ventricle is built from stacked contours. The accuracy of the algorithm has been tested with mathematical phantom data and clinical data. Results show conformance with provided projection data and high convergence speed makes the algorithm useful for clinical application. Fully three dimensional reconstruction of the left ventricle has a high potential for improvements of clinical findings in interventional cardiology.

A small molecule chemical chaperone optimizes its unfolded state contraction and denaturant like properties

NASA Astrophysics Data System (ADS)

Sharma, Sunny; Sarkar, Suparna; Paul, Simanta Sarani; Roy, Syamal; Chattopadhyay, Krishnananda

2013-12-01

Protein aggregation is believed to occur through the formation of misfolded conformations. It is expected that, in order to minimize aggregation, an effective small molecule chaperone would destabilize these intermediates. To study the mechanism of a chemical chaperone, we have designed a series of mutant proteins in which a tryptophan residue experiences different local environments and solvent exposures. We show that these mutants correspond to a series of conformationally altered proteins with varying degree of misfolding stress and aggregation propensities. Using arginine as a model small molecule, we show that a combination of unfolded state contraction and denaturant like properties results in selective targeting and destabilization of the partially folded proteins. In comparison, the effect of arginine towards the folded like control mutant, which is not aggregation prone, is significantly less. Other small molecules, lacking either of the above two properties, do not offer any specificity towards the misfolded proteins.

A Latent Class Regression Analysis of Men's Conformity to Masculine Norms and Psychological Distress

ERIC Educational Resources Information Center

Wong, Y. Joel; Owen, Jesse; Shea, Munyi

2012-01-01

How are specific dimensions of masculinity related to psychological distress in specific groups of men? To address this question, the authors used latent class regression to assess the optimal number of latent classes that explained differential relationships between conformity to masculine norms and psychological distress in a racially diverse…

Stereotactic radiosurgery versus stereotactic radiotherapy for patients with vestibular schwannoma: a Leksell Gamma Knife Society 2000 debate.

PubMed

Linskey, M E

2000-12-01

By definition, the term "radiosurgery" refers to the delivery of a therapeutic radiation dose in a single fraction, not simply the use of stereotaxy. Multiple-fraction delivery is better termed "stereotactic radiotherapy." There are compelling radiobiological principles supporting the biological superiority of single-fraction radiation for achieving an optimal therapeutic response for the slowly proliferating, late-responding, tissue of a schwannoma. It is axiomatic that complication avoidance requires precise three-dimensional conformality between treatment and tumor volumes. This degree of conformality can only be achieved through complex multiisocenter planning. Alternative radiosurgery devices are generally limited to delivering one to four isocenters in a single treatment session. Although they can reproduce dose plans similar in conformality to early gamma knife dose plans by using a similar number of isocenters, they cannot reproduce the conformality of modern gamma knife plans based on magnetic resonance image-targeted localization and five to 30 isocenters. A disturbing trend is developing in which institutions without nongamma knife radiosurgery (GKS) centers are championing and/or shifting to hypofractionated stereotactic radiotherapy for vestibular schwannomas. This trend appears to be driven by a desire to reduce complication rates to compete with modern GKS results by using complex multiisocenter planning. Aggressive advertising and marketing from some of these centers even paradoxically suggests biological superiority of hypofractionation approaches over single-dose radiosurgery for vestibular schwannomas. At the same time these centers continue to use the term radiosurgery to describe their hypofractionated radiotherapy approach in an apparent effort to benefit from a GKS "halo effect." It must be reemphasized that as neurosurgeons our primary duty is to achieve permanent tumor control for our patients and not to eliminate complications at the expense of potential late recurrence. The answer to minimizing complications while maintaining maximum tumor control is improved conformality of radiosurgery dose planning and not resorting to homeopathic radiosurgery doses or hypofractionation radiotherapy schemes.

Stereotactic radiosurgery versus stereotactic radiotherapy for patients with vestibular schwannoma: a Leksell Gamma Knife Society 2000 debate.

PubMed

Linskey, Mark E

2013-12-01

By definition, the term "radiosurgery" refers to the delivery of a therapeutic radiation dose in a single fraction, not simply the use of stereotaxy. Multiple-fraction delivery is better termed "stereotactic radiotherapy." There are compelling radiobiological principles supporting the biological superiority of single-fraction radiation for achieving an optimal therapeutic response for the slowly proliferating, late-responding, tissue of a schwannoma. It is axiomatic that complication avoidance requires precise three-dimensional conformality between treatment and tumor volumes. This degree of conformality can only be achieved through complex multiisocenter planning. Alternative radiosurgery devices are generally limited to delivering one to four isocenters in a single treatment session. Although they can reproduce dose plans similar in conformality to early gamma knife dose plans by using a similar number of isocenters, they cannot reproduce the conformality of modern gamma knife plans based on magnetic resonance image--targeted localization and five to 30 isocenters. A disturbing trend is developing in which institutions without nongamma knife radiosurgery (GKS) centers are championing and/or shifting to hypofractionated stereotactic radiotherapy for vestibular schwannomas. This trend appears to be driven by a desire to reduce complication rates to compete with modern GKS results by using complex multiisocenter planning. Aggressive advertising and marketing from some of these centers even paradoxically suggests biological superiority of hypofractionation approaches over single-dose radiosurgery for vestibular schwannomas. At the same time these centers continue to use the term radiosurgery to describe their hypofractionated radiotherapy approach in an apparent effort to benefit from a GKS "halo effect." It must be reemphasized that as neurosurgeons our primary duty is to achieve permanent tumor control for our patients and not to eliminate complications at the expense of potential late recurrence. The answer to minimizing complications while maintaining maximum tumor control is improved conformality of radiosurgery dose planning and not resorting to homeopathic radiosurgery doses or hypofractionation radiotherapy schemes.

Comparison of stochastic optimization methods for all-atom folding of the Trp-Cage protein.

PubMed

Schug, Alexander; Herges, Thomas; Verma, Abhinav; Lee, Kyu Hwan; Wenzel, Wolfgang

2005-12-09

The performances of three different stochastic optimization methods for all-atom protein structure prediction are investigated and compared. We use the recently developed all-atom free-energy force field (PFF01), which was demonstrated to correctly predict the native conformation of several proteins as the global optimum of the free energy surface. The trp-cage protein (PDB-code 1L2Y) is folded with the stochastic tunneling method, a modified parallel tempering method, and the basin-hopping technique. All the methods correctly identify the native conformation, and their relative efficiency is discussed.

Dual-Level Method for Estimating Multistructural Partition Functions with Torsional Anharmonicity.

PubMed

Bao, Junwei Lucas; Xing, Lili; Truhlar, Donald G

2017-06-13

For molecules with multiple torsions, an accurate evaluation of the molecular partition function requires consideration of multiple structures and their torsional-potential anharmonicity. We previously developed a method called MS-T for this problem, and it requires an exhaustive conformational search with frequency calculations for all the distinguishable conformers; this can become expensive for molecules with a large number of torsions (and hence a large number of structures) if it is carried out with high-level methods. In the present work, we propose a cost-effective method to approximate the MS-T partition function when there are a large number of structures, and we test it on a transition state that has eight torsions. This new method is a dual-level method that combines an exhaustive conformer search carried out by a low-level electronic structure method (for instance, AM1, which is very inexpensive) and selected calculations with a higher-level electronic structure method (for example, density functional theory with a functional that is suitable for conformational analysis and thermochemistry). To provide a severe test of the new method, we consider a transition state structure that has 8 torsional degrees of freedom; this transition state structure is formed along one of the reaction pathways of the hydrogen abstraction reaction (at carbon-1) of ketohydroperoxide (KHP; its IUPAC name is 4-hydroperoxy-2-pentanone) by OH radical. We find that our proposed dual-level method is able to significantly reduce the computational cost for computing MS-T partition functions for this test case with a large number of torsions and with a large number of conformers because we carry out high-level calculations for only a fraction of the distinguishable conformers found by the low-level method. In the example studied here, the dual-level method with 40 high-level optimizations (1.8% of the number of optimizations in a coarse-grained full search and 0.13% of the number of optimizations in a fine-grained full search) reproduces the full calculation of the high-level partition function within a factor of 1.0 to 2.0 from 200 to 1000 K. The error in the dual-level method can be further reduced to factors of 0.6 to 1.1 over the whole temperature interval from 200 to 2400 K by optimizing 128 structures (5.9% of the number of optimizations in a fine-grained full search and 0.41% of the number of optimizations in a fine-grained full search). These factor-of-two or better errors are small compared to errors up to a factor of 1.0 × 10 3 if one neglects multistructural effects for the case under study.

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.

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

NASA Astrophysics Data System (ADS)

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

2017-06-01

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

Comparative evaluation of two dose optimization methods for image-guided, highly-conformal, tandem and ovoids cervix brachytherapy planning

NASA Astrophysics Data System (ADS)

Ren, Jiyun; Menon, Geetha; Sloboda, Ron

2013-04-01

Although the Manchester system is still extensively used to prescribe dose in brachytherapy (BT) for locally advanced cervix cancer, many radiation oncology centers are transitioning to 3D image-guided BT, owing to the excellent anatomy definition offered by modern imaging modalities. As automatic dose optimization is highly desirable for 3D image-based BT, this study comparatively evaluates the performance of two optimization methods used in BT treatment planning—Nelder-Mead simplex (NMS) and simulated annealing (SA)—for a cervix BT computer simulation model incorporating a Manchester-style applicator. Eight model cases were constructed based on anatomical structure data (for high risk-clinical target volume (HR-CTV), bladder, rectum and sigmoid) obtained from measurements on fused MR-CT images for BT patients. D90 and V100 for HR-CTV, D2cc for organs at risk (OARs), dose to point A, conformation index and the sum of dwell times within the tandem and ovoids were calculated for optimized treatment plans designed to treat the HR-CTV in a highly conformal manner. Compared to the NMS algorithm, SA was found to be superior as it could perform optimization starting from a range of initial dwell times, while the performance of NMS was strongly dependent on their initial choice. SA-optimized plans also exhibited lower D2cc to OARs, especially the bladder and sigmoid, and reduced tandem dwell times. For cases with smaller HR-CTV having good separation from adjoining OARs, multiple SA-optimized solutions were found which differed markedly from each other and were associated with different choices for initial dwell times. Finally and importantly, the SA method yielded plans with lower dwell time variability compared with the NMS method.

The principle of sufficiency and the evolution of control: using control analysis to understand the design principles of biological systems.

PubMed

Brown, Guy C

2010-10-01

Control analysis can be used to try to understand why (quantitatively) systems are the way that they are, from rate constants within proteins to the relative amount of different tissues in organisms. Many biological parameters appear to be optimized to maximize rates under the constraint of minimizing space utilization. For any biological process with multiple steps that compete for control in series, evolution by natural selection will tend to even out the control exerted by each step. This is for two reasons: (i) shared control maximizes the flux for minimum protein concentration, and (ii) the selection pressure on any step is proportional to its control, and selection will, by increasing the rate of a step (relative to other steps), decrease its control over a pathway. The control coefficient of a parameter P over fitness can be defined as (∂N/N)/(∂P/P), where N is the number of individuals in the population, and ∂N is the change in that number as a result of the change in P. This control coefficient is equal to the selection pressure on P. I argue that biological systems optimized by natural selection will conform to a principle of sufficiency, such that the control coefficient of all parameters over fitness is 0. Thus in an optimized system small changes in parameters will have a negligible effect on fitness. This principle naturally leads to (and is supported by) the dominance of wild-type alleles over null mutants.

Bladder radiotherapy treatment: A retrospective comparison of 3-dimensional conformal radiotherapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy plans

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

Pasciuti, Katia, E-mail: k.pasciuti@virgilio.it; Kuthpady, Shrinivas; Anderson, Anne

To examine tumor's and organ's response when different radiotherapy plan techniques are used. Ten patients with confirmed bladder tumors were first treated using 3-dimensional conformal radiotherapy (3DCRT) and subsequently the original plans were re-optimized using the intensity-modulated radiation treatment (IMRT) and volumetric-modulated arc therapy (VMAT)-techniques. Targets coverage in terms of conformity and homogeneity index, TCP, and organs' dose limits, including integral dose analysis were evaluated. In addition, MUs and treatment delivery times were compared. Better minimum target coverage (1.3%) was observed in VMAT plans when compared to 3DCRT and IMRT ones confirmed by a statistically significant conformity index (CI) results.more » Large differences were observed among techniques in integral dose results of the femoral heads. Even if no statistically significant differences were reported in rectum and tissue, a large amount of energy deposition was observed in 3DCRT plans. In any case, VMAT plans provided better organs and tissue sparing confirmed also by the normal tissue complication probability (NTCP) analysis as well as a better tumor control probability (TCP) result. Our analysis showed better overall results in planning using VMAT techniques. Furthermore, a total time reduction in treatment observed among techniques including gantry and collimator rotation could encourage using the more recent one, reducing target movements and patient discomfort.« less

Generalized Tumor Dose for Treatment Planning Decision Support

NASA Astrophysics Data System (ADS)

Zuniga, Areli A.

Modern radiation therapy techniques allow for improved target conformity and normal tissue sparing. These highly conformal treatment plans have allowed dose escalation techniques increasing the probability of tumor control. At the same time this conformation has introduced inhomogeneous dose distributions, making delivered dose characterizations more difficult. The concept of equivalent uniform dose (EUD) characterizes a heterogeneous dose distribution within irradiated structures as a single value and has been used in biologically based treatment planning (BBTP); however, there are no substantial validation studies on clinical outcome data supporting EUD's use and therefore has not been widely adopted as decision-making support. These highly conformal treatment plans have also introduced the need for safety margins around the target volume. These margins are designed to minimize geometrical misses, and to compensate for dosimetric and treatment delivery uncertainties. The margin's purpose is to reduce the chance of tumor recurrence. This dissertation introduces a new EUD formulation designed especially for tumor volumes, called generalized Tumor Dose (gTD). It also investigates, as a second objective, margins extensions for potential improvements in local control while maintaining or minimizing toxicity. The suitability of gTD to rank LC was assessed by means of retrospective studies in a head and neck (HN) squamous cell carcinoma (SCC) and non-small cell lung cancer (NSCLC) cohorts. The formulation was optimized based on two datasets (one of each type) and then, model validation was assessed on independent cohorts. The second objective of this dissertation was investigated by ranking the probability of LC of the primary disease adding different margin sizes. In order to do so, an already published EUD formula was used retrospectively in a HN and a NSCLC datasets. Finally, recommendations for the viability to implement this new formulation into a routine treatment planning process as well as the revision of safety margins to improve local tumor control maximizing normal tissue sparing in SCC of the HN and NSCLC are discussed.

Conformational analysis, X-ray crystallographic, FT-IR, FT-Raman, DFT, MEP and molecular docking studies on 1-(1-(3-methoxyphenyl) ethylidene) thiosemicarbazide

NASA Astrophysics Data System (ADS)

Saravanan, R. R.; Seshadri, S.; Gunasekaran, S.; Mendoza-Meroño, R.; Garcia-Granda, S.

2015-03-01

Conformational analysis, X-ray crystallographic, FT-IR, FT-Raman, DFT, MEP and molecular docking studies on 1-(1-(3-methoxyphenyl) ethylidene) thiosemicarbazide (MPET) are investigated. From conformational analysis the examination of the positions of a molecule taken and the energy changes is observed. The docking studies of the ligand MPET with target protein showed that this is a good molecule which docks well with target related to HMG-CoA. Hence MPET can be considered for developing into a potent anti-cholesterol drug. MEP assists in optimization of electrostatic interactions between the protein and the ligand. The MEP surface displays the molecular shape, size and electrostatic potential values. The optimized geometry of the compound was calculated from the DFT-B3LYP gradient calculations employing 6-31G (d, p) basis set and calculated vibrational frequencies are evaluated via comparison with experimental values.

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

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

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

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

Qiao, Qin, E-mail: qqiao@ust.hk; Zhang, Hou-Dao; Huang, Xuhui, E-mail: xuhuihuang@ust.hk

2016-04-21

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

Differential role of molten globule and protein folding in distinguishing unique features of botulinum neurotoxin.

PubMed

Kumar, Raj; Kukreja, Roshan V; Cai, Shuowei; Singh, Bal R

2014-06-01

Botulinum neurotoxins (BoNTs) are proteins of great interest not only because of their extreme toxicity but also paradoxically for their therapeutic applications. All the known serotypes (A-G) have varying degrees of longevity and potency inside the neuronal cell. Differential chemical modifications such as phosphorylation and ubiquitination have been suggested as possible mechanisms for their longevity, but the molecular basis of the longevity remains unclear. Since the endopeptidase domain (light chain; LC) of toxin apparently survives inside the neuronal cells for months, it is important to examine the structural features of this domain to understand its resistance to intracellular degradation. Published crystal structures (both botulinum neurotoxins and endopeptidase domain) have not provided adequate explanation for the intracellular longevity of the domain. Structural features obtained from spectroscopic analysis of LCA and LCB were similar, and a PRIME (PReImminent Molten Globule Enzyme) conformation appears to be responsible for their optimal enzymatic activity at 37°C. LCE, on the other hand, was although optimally active at 37°C, but its active conformation differed from the PRIME conformation of LCA and LCB. This study establishes and confirms our earlier finding that an optimally active conformation of these proteins in the form of PRIME exists for the most poisonous poison, botulinum neurotoxin. There are substantial variations in the structural and functional characteristics of these active molten globule related structures among the three BoNT endopeptidases examined. These differential conformations of LCs are important in understanding the fundamental structural features of proteins, and their possible connection to intracellular longevity could provide significant clues for devising new countermeasures and effective therapeutics. Copyright © 2014 Elsevier B.V. All rights reserved.

A Maximum-Likelihood Approach to Force-Field Calibration.

PubMed

Zaborowski, Bartłomiej; Jagieła, Dawid; Czaplewski, Cezary; Hałabis, Anna; Lewandowska, Agnieszka; Żmudzińska, Wioletta; Ołdziej, Stanisław; Karczyńska, Agnieszka; Omieczynski, Christian; Wirecki, Tomasz; Liwo, Adam

2015-09-28

A new approach to the calibration of the force fields is proposed, in which the force-field parameters are obtained by maximum-likelihood fitting of the calculated conformational ensembles to the experimental ensembles of training system(s). The maximum-likelihood function is composed of logarithms of the Boltzmann probabilities of the experimental conformations, calculated with the current energy function. Because the theoretical distribution is given in the form of the simulated conformations only, the contributions from all of the simulated conformations, with Gaussian weights in the distances from a given experimental conformation, are added to give the contribution to the target function from this conformation. In contrast to earlier methods for force-field calibration, the approach does not suffer from the arbitrariness of dividing the decoy set into native-like and non-native structures; however, if such a division is made instead of using Gaussian weights, application of the maximum-likelihood method results in the well-known energy-gap maximization. The computational procedure consists of cycles of decoy generation and maximum-likelihood-function optimization, which are iterated until convergence is reached. The method was tested with Gaussian distributions and then applied to the physics-based coarse-grained UNRES force field for proteins. The NMR structures of the tryptophan cage, a small α-helical protein, determined at three temperatures (T = 280, 305, and 313 K) by Hałabis et al. ( J. Phys. Chem. B 2012 , 116 , 6898 - 6907 ), were used. Multiplexed replica-exchange molecular dynamics was used to generate the decoys. The iterative procedure exhibited steady convergence. Three variants of optimization were tried: optimization of the energy-term weights alone and use of the experimental ensemble of the folded protein only at T = 280 K (run 1); optimization of the energy-term weights and use of experimental ensembles at all three temperatures (run 2); and optimization of the energy-term weights and the coefficients of the torsional and multibody energy terms and use of experimental ensembles at all three temperatures (run 3). The force fields were subsequently tested with a set of 14 α-helical and two α + β proteins. Optimization run 1 resulted in better agreement with the experimental ensemble at T = 280 K compared with optimization run 2 and in comparable performance on the test set but poorer agreement of the calculated folding temperature with the experimental folding temperature. Optimization run 3 resulted in the best fit of the calculated ensembles to the experimental ones for the tryptophan cage but in much poorer performance on the training set, suggesting that use of a small α-helical protein for extensive force-field calibration resulted in overfitting of the data for this protein at the expense of transferability. The optimized force field resulting from run 2 was found to fold 13 of the 14 tested α-helical proteins and one small α + β protein with the correct topologies; the average structures of 10 of them were predicted with accuracies of about 5 Å C(α) root-mean-square deviation or better. Test simulations with an additional set of 12 α-helical proteins demonstrated that this force field performed better on α-helical proteins than the previous parametrizations of UNRES. The proposed approach is applicable to any problem of maximum-likelihood parameter estimation when the contributions to the maximum-likelihood function cannot be evaluated at the experimental points and the dimension of the configurational space is too high to construct histograms of the experimental distributions.

Stereochemical and conformational study on fenoterol by ECD spectroscopy and TD-DFT calculations.

PubMed

Tedesco, Daniele; Zanasi, Riccardo; Wainer, Irving W; Bertucci, Carlo

2014-03-01

Fenoterol and its derivatives are selective β2-adrenergic receptor (β2-AR) agonists whose stereoselective biological activities have been extensively investigated in the past decade; a complete stereochemical characterization of fenoterol derivatives is therefore crucial for a better understanding of the effects of stereochemistry on β2-AR binding. In the present project, the relationship between chiroptical properties and absolute stereochemistry of the stereoisomers of fenoterol (1) was investigated by experimental ECD spectroscopy and time-dependent density functional theory (TD-DFT). DFT geometry optimizations were carried out at the RI-B97D/TZVP/IEFPCM(MeOH) level and subsequent TD-DFT calculations were performed using the PBE0 hybrid functional. Despite the large pool of equilibrium conformers found for the investigated compounds and the known limitations of the level of theory employed, the computational protocol was able to reproduce the experimental ECD spectra of the stereoisomers of 1. The main contribution to the overall chiroptical properties was found to arise from the absolute configuration of the chiral center in α-position to the resorcinol moiety. Based on this evidence, a thorough conformational analysis was performed on the optimized DFT conformers, which revealed the occurrence of a different equilibrium between conformational patterns for the diastereomers of fenoterol: the (R,R')/(S,S') enantiomeric pair showed a higher population of folded conformations than the (R,S')/(S,R') pair. Copyright © 2013 Elsevier B.V. All rights reserved.

Optimization of the GBMV2 implicit solvent force field for accurate simulation of protein conformational equilibria.

PubMed

Lee, Kuo Hao; Chen, Jianhan

2017-06-15

Accurate treatment of solvent environment is critical for reliable simulations of protein conformational equilibria. Implicit treatment of solvation, such as using the generalized Born (GB) class of models arguably provides an optimal balance between computational efficiency and physical accuracy. Yet, GB models are frequently plagued by a tendency to generate overly compact structures. The physical origins of this drawback are relatively well understood, and the key to a balanced implicit solvent protein force field is careful optimization of physical parameters to achieve a sufficient level of cancellation of errors. The latter has been hampered by the difficulty of generating converged conformational ensembles of non-trivial model proteins using the popular replica exchange sampling technique. Here, we leverage improved sampling efficiency of a newly developed multi-scale enhanced sampling technique to re-optimize the generalized-Born with molecular volume (GBMV2) implicit solvent model with the CHARMM36 protein force field. Recursive optimization of key GBMV2 parameters (such as input radii) and protein torsion profiles (via the CMAP torsion cross terms) has led to a more balanced GBMV2 protein force field that recapitulates the structures and stabilities of both helical and β-hairpin model peptides. Importantly, this force field appears to be free of the over-compaction bias, and can generate structural ensembles of several intrinsically disordered proteins of various lengths that seem highly consistent with available experimental data. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Calcium-controlled conformational choreography in the N-terminal half of adseverin

NASA Astrophysics Data System (ADS)

Chumnarnsilpa, Sakesit; Robinson, Robert C.; Grimes, Jonathan M.; Leyrat, Cedric

2015-09-01

Adseverin is a member of the calcium-regulated gelsolin superfamily of actin-binding proteins. Here we report the crystal structure of the calcium-free N-terminal half of adseverin (iA1-A3) and the Ca2+-bound structure of A3, which reveal structural similarities and differences with gelsolin. Solution small-angle X-ray scattering combined with ensemble optimization revealed a dynamic Ca2+-dependent equilibrium between inactive, intermediate and active conformations. Increasing calcium concentrations progressively shift this equilibrium from a main population of inactive conformation to the active form. Molecular dynamics simulations of iA1-A3 provided insights into Ca2+-induced destabilization, implicating a critical role for the A2 type II calcium-binding site and the A2A3 linker in the activation process. Finally, mutations that disrupt the A1/A3 interface increase Ca2+-independent F-actin severing by A1-A3, albeit at a lower efficiency than observed for gelsolin domains G1-G3. Together, these data address the calcium dependency of A1-A3 activity in relation to the calcium-independent activity of G1-G3.

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.

SU-E-T-214: Intensity Modulated Proton Therapy (IMPT) Based On Passively Scattered Protons and Multi-Leaf Collimation: Prototype TPS and Dosimetry Study

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

Sanchez-Parcerisa, D; Carabe-Fernandez, A

2014-06-01

Purpose. Intensity-modulated proton therapy is usually implemented with multi-field optimization of pencil-beam scanning (PBS) proton fields. However, at the view of the experience with photon-IMRT, proton facilities equipped with double-scattering (DS) delivery and multi-leaf collimation (MLC) could produce highly conformal dose distributions (and possibly eliminate the need for patient-specific compensators) with a clever use of their MLC field shaping, provided that an optimal inverse TPS is developed. Methods. A prototype TPS was developed in MATLAB. The dose calculation process was based on a fluence-dose algorithm on an adaptive divergent grid. A database of dose kernels was precalculated in order tomore » allow for fast variations of the field range and modulation during optimization. The inverse planning process was based on the adaptive simulated annealing approach, with direct aperture optimization of the MLC leaves. A dosimetry study was performed on a phantom formed by three concentrical semicylinders separated by 5 mm, of which the inner-most and outer-most were regarded as organs at risk (OARs), and the middle one as the PTV. We chose a concave target (which is not treatable with conventional DS fields) to show the potential of our technique. The optimizer was configured to minimize the mean dose to the OARs while keeping a good coverage of the target. Results. The plan produced by the prototype TPS achieved a conformity index of 1.34, with the mean doses to the OARs below 78% of the prescribed dose. This Result is hardly achievable with traditional conformal DS technique with compensators, and it compares to what can be obtained with PBS. Conclusion. It is certainly feasible to produce IMPT fields with MLC passive scattering fields. With a fully developed treatment planning system, the produced plans can be superior to traditional DS plans in terms of plan conformity and dose to organs at risk.« less

Automated identification of functional dynamic networks from X-ray crystallography

PubMed Central

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

2013-01-01

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

DFT studies of the hydrated carbohydrate, glucose: optimization and DFTMD simulations of ten explicit waters superimposed with an implicit solvation method, COSMO

USDA-ARS?s Scientific Manuscript database

One of the most important and least understood properties of carbohydrates is their conformational profile in solution. The study of carbohydrates in solution is a most difficult computational problem, a result of the many soft conformational variables (hydroxyl groups) inherent in the structures of...

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.

4-Arylflavan-3-ols as Proanthocyanidin Models: Absolute Configuration via Density Functional Calculation of Electronic Circular Dichroism

USDA-ARS?s Scientific Manuscript database

Density functional theory/B3LYP has been employed to optimize the conformations of selected 4-arylflavan-3-ols and their phenolic methyl ether 3-O-acetates. The electronic circular dichroism spectra of the major conformers have been calculated using time-dependent density functional theory to valida...

DFT study of conformational and vibrational characteristics of 2-(2-hydroxyphenyl)benzothiazole molecule.

PubMed

Pandey, Urmila; Srivastava, Mayuri; Singh, R P; Yadav, R A

2014-08-14

The conformational and IR and Raman spectral studies of 2-(2-hydroxyphenyl)benzothiazole have been carried out by using the DFT method at the B3LYP/6-311++G(**) level. The detailed vibrational assignments have been done on the basis of calculated potential energy distributions. Comparative studies of molecular geometries, atomic charges and vibrational fundamentals of all the conformers have been made. There are four possible conformers for this molecule. The optimized geometrical parameters obtained by B3LYP/6-311++G(**) method showed good agreement with the experimental X-ray data. The atomic polar tensor (APT) charges, Mulliken atomic charges, natural bond orbital (NBO) analysis and HOMO-LUMO energy gap of HBT and its conformers were also computed. Copyright © 2014 Elsevier B.V. All rights reserved.

High-throughput screening and stability optimization of anti-streptavidin IgG1 and IgG2 formulations.

PubMed

Alekseychyk, Larysa; Su, Cheng; Becker, Gerald W; Treuheit, Michael J; Razinkov, Vladimir I

2014-10-01

Selection of a suitable formulation that provides adequate product stability is an important aspect of the development of biopharmaceutical products. Stability of proteins includes not only resistance to chemical modifications but also conformational and colloidal stabilities. While chemical degradation of antibodies is relatively easy to detect and control, propensity for conformational changes and/or aggregation during manufacturing or long-term storage is difficult to predict. In many cases, the formulation factors that increase one type of stability may significantly decrease another type under the same or different conditions. Often compromise is necessary to minimize the adverse effects of an antibody formulation by careful optimization of multiple factors responsible for overall stability. In this study, high-throughput stress and characterization techniques were applied to 96 formulations of anti-streptavidin antibodies (an IgG1 and an IgG2) to choose optimal formulations. Stress and analytical methods applied in this study were 96-well plate based using an automated liquid handling system to prepare the different formulations and sample plates. Aggregation and clipping propensity were evaluated by temperature and mechanical stresses. Multivariate regression analysis of high-throughput data was performed to find statistically significant formulation factors that alter measured parameters such as monomer percentage or unfolding temperature. The results of the regression models were used to maximize the stabilities of antibodies under different formulations and to find the optimal formulation space for each molecule. Comparison of the IgG1 and IgG2 data indicated an overall greater stability of the IgG1 molecule under the conditions studied. The described method can easily be applied to both initial preformulation screening and late-stage formulation development of biopharmaceutical products. © 2014 Society for Laboratory Automation and Screening.

Engine speed control apparatus

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

Ishii, M.; Miyazaki, M.; Nakamura, N.

1986-11-04

This patent describes an engine speed control apparatus. The system comprises an actuator for adjusting an engine speed, a first unit for computing a desired engine speed, a second unit for detecting the actual engine speed, and a third unit for detecting the difference between the outputs of the first and second units. The system also includes a fourth unit for computing a control pulse width for the actuator in accordance with the output of the third unit, a fifth unit for generating a control signal, a sixth unit for driving the actuator in response to the output of themore » fifth unit, and a seventh unit for computing an optimal halt time to interrupt the driving of the actuator. The actuator is driven intermittently in conformity in the control pulse width and the halt time.« less

PDB ligand conformational energies calculated quantum-mechanically.

PubMed

Sitzmann, Markus; Weidlich, Iwona E; Filippov, Igor V; Liao, Chenzhong; Peach, Megan L; Ihlenfeldt, Wolf-Dietrich; Karki, Rajeshri G; Borodina, Yulia V; Cachau, Raul E; Nicklaus, Marc C

2012-03-26

We present here a greatly updated version of an earlier study on the conformational energies of protein-ligand complexes in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med. Chem. 1995, 3, 411-428], with the goal of improving on all possible aspects such as number and selection of ligand instances, energy calculations performed, and additional analyses conducted. Starting from about 357,000 ligand instances deposited in the 2008 version of the Ligand Expo database of the experimental 3D coordinates of all small-molecule instances in the PDB, we created a "high-quality" subset of ligand instances by various filtering steps including application of crystallographic quality criteria and structural unambiguousness. Submission of 640 Gaussian 03 jobs yielded a set of about 415 successfully concluded runs. We used a stepwise optimization of internal degrees of freedom at the DFT level of theory with the B3LYP/6-31G(d) basis set and a single-point energy calculation at B3LYP/6-311++G(3df,2p) after each round of (partial) optimization to separate energy changes due to bond length stretches vs bond angle changes vs torsion changes. Even for the most "conservative" choice of all the possible conformational energies-the energy difference between the conformation in which all internal degrees of freedom except torsions have been optimized and the fully optimized conformer-significant energy values were found. The range of 0 to ~25 kcal/mol was populated quite evenly and independently of the crystallographic resolution. A smaller number of "outliers" of yet higher energies were seen only at resolutions above 1.3 Å. The energies showed some correlation with molecular size and flexibility but not with crystallographic quality metrics such as the Cruickshank diffraction-component precision index (DPI) and R(free)-R, or with the ligand instance-specific metrics such as occupancy-weighted B-factor (OWAB), real-space R factor (RSR), and real-space correlation coefficient (RSCC). We repeated these calculations with the solvent model IEFPCM, which yielded energy differences that were generally somewhat lower than the corresponding vacuum results but did not produce a qualitatively different picture. Torsional sampling around the crystal conformation at the molecular mechanics level using the MMFF94s force field typically led to an increase in energy. © 2012 American Chemical Society

Comparison of the progressive resolution optimizer and photon optimizer in VMAT optimization for stereotactic treatments.

PubMed

Liu, Han; Sintay, Benjamin; Pearman, Keith; Shang, Qingyang; Hayes, Lane; Maurer, Jacqueline; Vanderstraeten, Caroline; Wiant, David

2018-05-20

The photon optimization (PO) algorithm was recently released by Varian Medical Systems to improve volumetric modulated arc therapy (VMAT) optimization within Eclipse (Version 13.5). The purpose of this study is to compare the PO algorithm with its predecessor, progressive resolution optimizer (PRO) for lung SBRT and brain SRS treatments. A total of 30 patients were selected retrospectively. Previously, all the plans were generated with the PRO algorithm within Eclipse Version 13.6. In the new version of PO algorithm (Version 15), dynamic conformal arcs (DCA) were first conformed to the target, then VMAT inverse planning was performed to achieve the desired dose distributions. PTV coverages were forced to be identical for the same patient for a fair comparison. SBRT plan quality was assessed based on selected dose-volume parameters, including the conformity index, V 20 for lung, V 30 Gy for chest wall, and D 0.035 cc for other critical organs. SRS plan quality was evaluated based on the conformity index and normal tissue volumes encompassed by the 12 and 6 Gy isodose lines (V 12 and V 6 ). The modulation complexity score (MCS) was used to compare plan complexity of two algorithms. No statistically significant differences between the PRO and PO algorithms were found for any of the dosimetric parameters studied, which indicates both algorithms produce comparable plan quality. Significant improvements in the gamma passing rate (increased from 97.0% to 99.2% for SBRT and 96.1% to 98.4% for SRS), MCS (average increase of 0.15 for SBRT and 0.10 for SRS), and delivery efficiency (MU reduction of 29.8% for SBRT and 28.3% for SRS) were found for the PO algorithm. MCS showed a strong correlation with the gamma passing rate, and an inverse correlation with total MUs used. The PO algorithm offers comparable plan quality to the PRO, while minimizing MLC complexity, thereby improving the delivery efficiency and accuracy. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Sail Plan Configuration Optimization for a Modern Clipper Ship

NASA Astrophysics Data System (ADS)

Gerritsen, Margot; Doyle, Tyler; Iaccarino, Gianluca; Moin, Parviz

2002-11-01

We investigate the use of gradient-based and evolutionary algorithms for sail shape optimization. We present preliminary results for the optimization of sheeting angles for the rig of the future three-masted clipper yacht Maltese Falcon. This yacht will be equipped with square-rigged masts made up of yards of circular arc cross sections. This design is especially attractive for megayachts because it provides a large sail area while maintaining aerodynamic and structural efficiency. The rig remains almost rigid in a large range of wind conditions and therefore a simple geometrical model can be constructed without accounting for the true flying shape. The sheeting angle optimization studies are performed using both gradient-based cost function minimization and evolutionary algorithms. The fluid flow is modeled by the Reynolds-averaged Navier-Stokes equations with the Spallart-Allmaras turbulence model. Unstructured non-conforming grids are used to increase robustness and computational efficiency. The optimization process is automated by integrating the system components (geometry construction, grid generation, flow solver, force calculator, optimization). We compare the optimization results to those done previously by user-controlled parametric studies using simple cost functions and user intuition. We also investigate the effectiveness of various cost functions in the optimization (driving force maximization, ratio of driving force to heeling force maximization).

Comparative conformational studies of 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxyhex-1-enitols at the DFT level.

PubMed

Nowacki, Andrzej; Liberek, Beata

2018-06-15

B3LYP and M06-2X optimization and MP2 single point calculations are reported for the 4 H 5 and 5 H 4 conformations of 3,4,6-tri-O-acetyl-D-allal, 3,4,6-tri-O-acetyl-D-galactal, 3,4,6-tri-O-acetyl-D-glucal, and 3,4,6-tri-O-acetyl-D-gulal. Significant discrepancies in predictions of relative energies and conformers' population for B3LYP and M06-2X optimized geometries are observed. Generally, B3LYP overestimates the conformers' energies with respect to MP2, whereas M06-2X slightly underestimates the conformers' energies. B3LYP failed to estimate the 4 H 5 ⇄ 5 H 4 conformational equilibrium for 3,4,6-tri-O-acetyl-D-galactal and 3,4,6-tri-O-acetyl-D-glucal. The M06-2X functional showed good agreement with experimental results for all glycals studied. The 4 H 5 ⇄ 5 H 4 conformational equilibrium for 3,4,6-tri-O-acetyl-D-allal and 3,4,6-tri-O-acetyl-D-gulal is governed by the vinylogous anomeric effect (VAE), whereas competition between the VAE and quasi 1,3-diaxial interactions influence this equilibrium for 3,4,6-tri-O-acetyl-D-galactal and 3,4,6-tri-O-acetyl-D-glucal. The orientation of the 4-OAc group influences the strength of the quasi 1,3-diaxial interactions between the 3-OAc and 5-CH 2 OAc groups. AIM analysis shows weak bonding interaction between the 3-OAc and 5-CH 2 OAc groups. Copyright © 2018 Elsevier Ltd. All rights reserved.

Conformational exchange of aromatic side chains characterized by L-optimized TROSY-selected ¹³C CPMG relaxation dispersion.

PubMed

Weininger, Ulrich; Respondek, Michal; Akke, Mikael

2012-09-01

Protein dynamics on the millisecond time scale commonly reflect conformational transitions between distinct functional states. NMR relaxation dispersion experiments have provided important insights into biologically relevant dynamics with site-specific resolution, primarily targeting the protein backbone and methyl-bearing side chains. Aromatic side chains represent attractive probes of protein dynamics because they are over-represented in protein binding interfaces, play critical roles in enzyme catalysis, and form an important part of the core. Here we introduce a method to characterize millisecond conformational exchange of aromatic side chains in selectively (13)C labeled proteins by means of longitudinal- and transverse-relaxation optimized CPMG relaxation dispersion. By monitoring (13)C relaxation in a spin-state selective manner, significant sensitivity enhancement can be achieved in terms of both signal intensity and the relative exchange contribution to transverse relaxation. Further signal enhancement results from optimizing the longitudinal relaxation recovery of the covalently attached (1)H spins. We validated the L-TROSY-CPMG experiment by measuring fast folding-unfolding kinetics of the small protein CspB under native conditions. The determined unfolding rate matches perfectly with previous results from stopped-flow kinetics. The CPMG-derived chemical shift differences between the folded and unfolded states are in excellent agreement with those obtained by urea-dependent chemical shift analysis. The present method enables characterization of conformational exchange involving aromatic side chains and should serve as a valuable complement to methods developed for other types of protein side chains.

BetaSCPWeb: side-chain prediction for protein structures using Voronoi diagrams and geometry prioritization

PubMed Central

Ryu, Joonghyun; Lee, Mokwon; Cha, Jehyun; Laskowski, Roman A.; Ryu, Seong Eon; Kim, Deok-Soo

2016-01-01

Many applications, such as protein design, homology modeling, flexible docking, etc. require the prediction of a protein's optimal side-chain conformations from just its amino acid sequence and backbone structure. Side-chain prediction (SCP) is an NP-hard energy minimization problem. Here, we present BetaSCPWeb which efficiently computes a conformation close to optimal using a geometry-prioritization method based on the Voronoi diagram of spherical atoms. Its outputs are visual, textual and PDB file format. The web server is free and open to all users at http://voronoi.hanyang.ac.kr/betascpweb with no login requirement. PMID:27151195

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

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

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

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

Transformational Optics

DTIC Science & Technology

2016-12-19

32λ (angular divergence of 1.8°) which is quasi -monochromatic with a full width at half maximum of 70 nm. These experimental results show good...devices; plasmonic TO structures; and tapered waveguide analog TO devices. Of particular relevance is the development of quasi - conformal (QC...the development of quasi -conformal (QC) optimization techniques that lead to more realizable TO designs, appropriate for the shorter wavelengths of

Impaired protein conformational landscapes as revealed in anomalous Arrhenius prefactors.

PubMed

Nagel, Zachary D; Dong, Ming; Bahnson, Brian J; Klinman, Judith P

2011-06-28

A growing body of data supports a role for protein motion in enzyme catalysis. In particular, the ability of enzymes to sample catalytically relevant conformational substates has been invoked to model kinetic and spectroscopic data. However, direct experimental links between rapidly interconverting conformations and the chemical steps of catalysis remain rare. We report here on the kinetic analysis and characterization of the hydride transfer step catalyzed by a series of mutant thermophilic alcohol dehydrogenases (ht-ADH), presenting evidence for Arrhenius prefactor values that become enormously elevated above an expected value of approximately 10(13) s(-1) when the enzyme operates below its optimal temperature range. Restoration of normal Arrhenius behavior in the ht-ADH reaction occurs at elevated temperatures. A simple model, in which reduced temperature alters the ability of the ht-ADH variants to sample the catalytically relevant region of conformational space, can reproduce the available data. These findings indicate an impaired landscape that has been generated by the combined condition of reduced temperature and mutation at a single, active-site hydrophobic side chain. The broader implication is that optimal enzyme function requires the maintenance of a relatively smooth landscape that minimizes low energy traps.

Impaired protein conformational landscapes as revealed in anomalous Arrhenius prefactors

PubMed Central

Nagel, Zachary D.; Dong, Ming; Bahnson, Brian J.; Klinman, Judith P.

2011-01-01

A growing body of data supports a role for protein motion in enzyme catalysis. In particular, the ability of enzymes to sample catalytically relevant conformational substates has been invoked to model kinetic and spectroscopic data. However, direct experimental links between rapidly interconverting conformations and the chemical steps of catalysis remain rare. We report here on the kinetic analysis and characterization of the hydride transfer step catalyzed by a series of mutant thermophilic alcohol dehydrogenases (ht-ADH), presenting evidence for Arrhenius prefactor values that become enormously elevated above an expected value of approximately 1013 s-1 when the enzyme operates below its optimal temperature range. Restoration of normal Arrhenius behavior in the ht-ADH reaction occurs at elevated temperatures. A simple model, in which reduced temperature alters the ability of the ht-ADH variants to sample the catalytically relevant region of conformational space, can reproduce the available data. These findings indicate an impaired landscape that has been generated by the combined condition of reduced temperature and mutation at a single, active-site hydrophobic side chain. The broader implication is that optimal enzyme function requires the maintenance of a relatively smooth landscape that minimizes low energy traps. PMID:21670258

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.

Progress on thermobrachytherapy surface applicator for superficial tissue disease

NASA Astrophysics Data System (ADS)

Arunachalam, Kavitha; Craciunescu, Oana I.; Maccarini, Paolo F.; Schlorff, Jaime L.; Markowitz, Edward; Stauffer, Paul R.

2009-02-01

This work reports the ongoing development of a combination applicator for simultaneous heating of superficial tissue disease using a 915 MHz DCC (dual concentric conductor) array and High Dose Rate (HDR) brachytherapy delivered via an integrated conformal catheter array. The progress includes engineering design changes in the waterbolus, DCC configurations and fabrication techniques of the conformal multilayer applicator. The dosimetric impact of the thin copper DCC array is also assessed. Steady state fluid dynamics of the new waterbolus bag indicates nearly uniform flow with less than 1°C variation across a large (19×32cm) bolus. Thermometry data of the torso phantom acquired with computer controlled movement of fiberoptic temperature probes inside thermal mapping catheters indicate feasibility of real time feedback control for the DCC array. MR (magnetic resonance) scans of a torso phantom indicate that the waterbolus thickness across the treatment area is controlled by the pressure applied by the surrounding inflatable airbladder and applicator securing straps. The attenuation coefficient of the DCC array was measured as 3+/- 0.001% and 2.95+/-0.03 % using an ion chamber and OneDose dosimeters respectively. The performance of the combination applicator on patient phantoms provides valuable feedback to optimize the applicator prior use in the patient clinic.

Quantifying side-chain conformational variations in protein structure

PubMed Central

Miao, Zhichao; Cao, Yang

2016-01-01

Protein side-chain conformation is closely related to their biological functions. The side-chain prediction is a key step in protein design, protein docking and structure optimization. However, side-chain polymorphism comprehensively exists in protein as various types and has been long overlooked by side-chain prediction. But such conformational variations have not been quantitatively studied and the correlations between these variations and residue features are vague. Here, we performed statistical analyses on large scale data sets and found that the side-chain conformational flexibility is closely related to the exposure to solvent, degree of freedom and hydrophilicity. These analyses allowed us to quantify different types of side-chain variabilities in PDB. The results underscore that protein side-chain conformation prediction is not a single-answer problem, leading us to reconsider the assessment approaches of side-chain prediction programs. PMID:27845406

Quantifying side-chain conformational variations in protein structure

NASA Astrophysics Data System (ADS)

Miao, Zhichao; Cao, Yang

2016-11-01

Protein side-chain conformation is closely related to their biological functions. The side-chain prediction is a key step in protein design, protein docking and structure optimization. However, side-chain polymorphism comprehensively exists in protein as various types and has been long overlooked by side-chain prediction. But such conformational variations have not been quantitatively studied and the correlations between these variations and residue features are vague. Here, we performed statistical analyses on large scale data sets and found that the side-chain conformational flexibility is closely related to the exposure to solvent, degree of freedom and hydrophilicity. These analyses allowed us to quantify different types of side-chain variabilities in PDB. The results underscore that protein side-chain conformation prediction is not a single-answer problem, leading us to reconsider the assessment approaches of side-chain prediction programs.

Quantifying side-chain conformational variations in protein structure.

PubMed

Miao, Zhichao; Cao, Yang

2016-11-15

Protein side-chain conformation is closely related to their biological functions. The side-chain prediction is a key step in protein design, protein docking and structure optimization. However, side-chain polymorphism comprehensively exists in protein as various types and has been long overlooked by side-chain prediction. But such conformational variations have not been quantitatively studied and the correlations between these variations and residue features are vague. Here, we performed statistical analyses on large scale data sets and found that the side-chain conformational flexibility is closely related to the exposure to solvent, degree of freedom and hydrophilicity. These analyses allowed us to quantify different types of side-chain variabilities in PDB. The results underscore that protein side-chain conformation prediction is not a single-answer problem, leading us to reconsider the assessment approaches of side-chain prediction programs.

The ribosome as an optimal decoder: a lesson in molecular recognition.

PubMed

Savir, Yonatan; Tlusty, Tsvi

2013-04-11

The ribosome is a complex molecular machine that, in order to synthesize proteins, has to decode mRNAs by pairing their codons with matching tRNAs. Decoding is a major determinant of fitness and requires accurate and fast selection of correct tRNAs among many similar competitors. However, it is unclear whether the modern ribosome, and in particular its large conformational changes during decoding, are the outcome of adaptation to its task as a decoder or the result of other constraints. Here, we derive the energy landscape that provides optimal discrimination between competing substrates and thereby optimal tRNA decoding. We show that the measured landscape of the prokaryotic ribosome is sculpted in this way. This model suggests that conformational changes of the ribosome and tRNA during decoding are means to obtain an optimal decoder. Our analysis puts forward a generic mechanism that may be utilized broadly by molecular recognition systems. Copyright © 2013 Elsevier Inc. All rights reserved.

Choosing the appropriate forecasting model for predictive parameter control.

PubMed

Aleti, Aldeida; Moser, Irene; Meedeniya, Indika; Grunske, Lars

2014-01-01

All commonly used stochastic optimisation algorithms have to be parameterised to perform effectively. Adaptive parameter control (APC) is an effective method used for this purpose. APC repeatedly adjusts parameter values during the optimisation process for optimal algorithm performance. The assignment of parameter values for a given iteration is based on previously measured performance. In recent research, time series prediction has been proposed as a method of projecting the probabilities to use for parameter value selection. In this work, we examine the suitability of a variety of prediction methods for the projection of future parameter performance based on previous data. All considered prediction methods have assumptions the time series data has to conform to for the prediction method to provide accurate projections. Looking specifically at parameters of evolutionary algorithms (EAs), we find that all standard EA parameters with the exception of population size conform largely to the assumptions made by the considered prediction methods. Evaluating the performance of these prediction methods, we find that linear regression provides the best results by a very small and statistically insignificant margin. Regardless of the prediction method, predictive parameter control outperforms state of the art parameter control methods when the performance data adheres to the assumptions made by the prediction method. When a parameter's performance data does not adhere to the assumptions made by the forecasting method, the use of prediction does not have a notable adverse impact on the algorithm's performance.

Intensity modulated neutron radiotherapy optimization by photon proxy

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

Snyder, Michael; Hammoud, Ahmad; Bossenberger, Todd

2012-08-15

Purpose: Introducing intensity modulation into neutron radiotherapy (IMNRT) planning has the potential to mitigate some normal tissue complications seen in past neutron trials. While the hardware to deliver IMNRT plans has been in use for several years, until recently the IMNRT planning process has been cumbersome and of lower fidelity than conventional photon plans. Our in-house planning system used to calculate neutron therapy plans allows beam weight optimization of forward planned segments, but does not provide inverse optimization capabilities. Commercial treatment planning systems provide inverse optimization capabilities, but currently cannot model our neutron beam. Methods: We have developed a methodologymore » and software suite to make use of the robust optimization in our commercial planning system while still using our in-house planning system to calculate final neutron dose distributions. Optimized multileaf collimator (MLC) leaf positions for segments designed in the commercial system using a 4 MV photon proxy beam are translated into static neutron ports that can be represented within our in-house treatment planning system. The true neutron dose distribution is calculated in the in-house system and then exported back through the MATLAB software into the commercial treatment planning system for evaluation. Results: The planning process produces optimized IMNRT plans that reduce dose to normal tissue structures as compared to 3D conformal plans using static MLC apertures. The process involves standard planning techniques using a commercially available treatment planning system, and is not significantly more complex than conventional IMRT planning. Using a photon proxy in a commercial optimization algorithm produces IMNRT plans that are more conformal than those previously designed at our center and take much less time to create. Conclusions: The planning process presented here allows for the optimization of IMNRT plans by a commercial treatment planning optimization algorithm, potentially allowing IMNRT to achieve similar conformality in treatment as photon IMRT. The only remaining requirements for the delivery of very highly modulated neutron treatments are incremental improvements upon already implemented hardware systems that should be readily achievable.« less

Investigating energy-based pool structure selection in the structure ensemble modeling with experimental distance constraints: The example from a multidomain protein Pub1.

PubMed

Zhu, Guanhua; Liu, Wei; Bao, Chenglong; Tong, Dudu; Ji, Hui; Shen, Zuowei; Yang, Daiwen; Lu, Lanyuan

2018-05-01

The structural variations of multidomain proteins with flexible parts mediate many biological processes, and a structure ensemble can be determined by selecting a weighted combination of representative structures from a simulated structure pool, producing the best fit to experimental constraints such as interatomic distance. In this study, a hybrid structure-based and physics-based atomistic force field with an efficient sampling strategy is adopted to simulate a model di-domain protein against experimental paramagnetic relaxation enhancement (PRE) data that correspond to distance constraints. The molecular dynamics simulations produce a wide range of conformations depicted on a protein energy landscape. Subsequently, a conformational ensemble recovered with low-energy structures and the minimum-size restraint is identified in good agreement with experimental PRE rates, and the result is also supported by chemical shift perturbations and small-angle X-ray scattering data. It is illustrated that the regularizations of energy and ensemble-size prevent an arbitrary interpretation of protein conformations. Moreover, energy is found to serve as a critical control to refine the structure pool and prevent data overfitting, because the absence of energy regularization exposes ensemble construction to the noise from high-energy structures and causes a more ambiguous representation of protein conformations. Finally, we perform structure-ensemble optimizations with a topology-based structure pool, to enhance the understanding on the ensemble results from different sources of pool candidates. © 2018 Wiley Periodicals, Inc.

Predicting bioactive conformations and binding modes of macrocycles

NASA Astrophysics Data System (ADS)

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

2016-10-01

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

Structural rearrangement of β-lactoglobulin at different oil-water interfaces and its effect on emulsion stability.

PubMed

Zhai, Jiali; Wooster, Tim J; Hoffmann, Søren V; Lee, Tzong-Hsien; Augustin, Mary Ann; Aguilar, Marie-Isabel

2011-08-02

Understanding the factors that control protein structure and stability at the oil-water interface continues to be a major focus to optimize the formulation of protein-stabilized emulsions. In this study, a combination of synchrotron radiation circular dichroism spectroscopy, front-face fluorescence spectroscopy, and dual polarization interferometry (DPI) was used to characterize the conformation and geometric structure of β-lactoglobulin (β-Lg) upon adsorption to two oil-water interfaces: a hexadecane-water interface and a tricaprylin-water interface. The results show that, upon adsorption to both oil-water interfaces, β-Lg went through a β-sheet to α-helix transition with a corresponding loss of its globular tertiary structure. The degree of conformational change was also a function of the oil phase polarity. The hexadecane oil induced a much higher degree of non-native α-helix compared to the tricaprylin oil. In contrast to the β-Lg conformation in solution, the non-native α-helical-rich conformation of β-Lg at the interface was resistant to further conformational change upon heating. DPI measurements suggest that β-Lg formed a thin dense layer at emulsion droplet surfaces. The effects of high temperature and the presence of salt on these β-Lg emulsions were then investigated by monitoring changes in the ζ-potential and particle size. In the absence of salt, high electrostatic repulsion meant β-Lg-stabilized emulsions were resistant to heating to 90 °C. Adding salt (120 mM NaCl) before or after heating led to emulsion flocculation due to the screening of the electrostatic repulsion between colloidal particles. This study has provided insight into the structural properties of proteins adsorbed at the oil-water interface and has implications in the formulation and production of emulsions stabilized by globular proteins.

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

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

Yu, Yuqi; Wang, Jinan; Shao, Qiang, E-mail: qshao@mail.shcnc.ac.cn, E-mail: Jiye.Shi@ucb.com, E-mail: wlzhu@mail.shcnc.ac.cn

2015-03-28

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

Structure, Intent and Conformance Monitoring in ATC

NASA Technical Reports Server (NTRS)

Reynolds, Tom G.; Histon, Jonathan M.; Davison, Hayley J.; Hansman, R. John

2004-01-01

Infield studies of current Air Traffic Control operations it is found that controllers rely on underlying airspace structure to reduce the complexity of the planning and conformance monitoring tasks. The structure appears to influence the controller's working mental model through abstractions that reduce the apparent cognitive complexity. These structure-based abstractions are useful for the controller's key tasks of planning, implementing, monitoring, and evaluating tactical situations. In addition, the structure-based abstractions appear to be important in the maintenance of Situation Awareness. The process of conformance monitoring is analyzed in more detail and an approach to conformance monitoring which utilizes both the structure-based abstractions and intent is presented.

Residues with similar hexagon neighborhoods share similar side-chain conformations.

PubMed

Li, Shuai Cheng; Bu, Dongbo; Li, Ming

2012-01-01

We present in this study a new approach to code protein side-chain conformations into hexagon substructures. Classical side-chain packing methods consist of two steps: first, side-chain conformations, known as rotamers, are extracted from known protein structures as candidates for each residue; second, a searching method along with an energy function is used to resolve conflicts among residues and to optimize the combinations of side chain conformations for all residues. These methods benefit from the fact that the number of possible side-chain conformations is limited, and the rotamer candidates are readily extracted; however, these methods also suffer from the inaccuracy of energy functions. Inspired by threading and Ab Initio approaches to protein structure prediction, we propose to use hexagon substructures to implicitly capture subtle issues of energy functions. Our initial results indicate that even without guidance from an energy function, hexagon structures alone can capture side-chain conformations at an accuracy of 83.8 percent, higher than 82.6 percent by the state-of-art side-chain packing methods.

BetaSCPWeb: side-chain prediction for protein structures using Voronoi diagrams and geometry prioritization.

PubMed

Ryu, Joonghyun; Lee, Mokwon; Cha, Jehyun; Laskowski, Roman A; Ryu, Seong Eon; Kim, Deok-Soo

2016-07-08

Many applications, such as protein design, homology modeling, flexible docking, etc. require the prediction of a protein's optimal side-chain conformations from just its amino acid sequence and backbone structure. Side-chain prediction (SCP) is an NP-hard energy minimization problem. Here, we present BetaSCPWeb which efficiently computes a conformation close to optimal using a geometry-prioritization method based on the Voronoi diagram of spherical atoms. Its outputs are visual, textual and PDB file format. The web server is free and open to all users at http://voronoi.hanyang.ac.kr/betascpweb with no login requirement. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

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

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

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

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.

Ant groups optimally amplify the effect of transiently informed individuals

NASA Astrophysics Data System (ADS)

Gelblum, Aviram; Pinkoviezky, Itai; Fonio, Ehud; Ghosh, Abhijit; Gov, Nir; Feinerman, Ofer

2015-07-01

To cooperatively transport a large load, it is important that carriers conform in their efforts and align their forces. A downside of behavioural conformism is that it may decrease the group's responsiveness to external information. Combining experiment and theory, we show how ants optimize collective transport. On the single-ant scale, optimization stems from decision rules that balance individuality and compliance. Macroscopically, these rules poise the system at the transition between random walk and ballistic motion where the collective response to the steering of a single informed ant is maximized. We relate this peak in response to the divergence of susceptibility at a phase transition. Our theoretical models predict that the ant-load system can be transitioned through the critical point of this mesoscopic system by varying its size; we present experiments supporting these predictions. Our findings show that efficient group-level processes can arise from transient amplification of individual-based knowledge.

Ant groups optimally amplify the effect of transiently informed individuals

PubMed Central

Gelblum, Aviram; Pinkoviezky, Itai; Fonio, Ehud; Ghosh, Abhijit; Gov, Nir; Feinerman, Ofer

2015-01-01

To cooperatively transport a large load, it is important that carriers conform in their efforts and align their forces. A downside of behavioural conformism is that it may decrease the group's responsiveness to external information. Combining experiment and theory, we show how ants optimize collective transport. On the single-ant scale, optimization stems from decision rules that balance individuality and compliance. Macroscopically, these rules poise the system at the transition between random walk and ballistic motion where the collective response to the steering of a single informed ant is maximized. We relate this peak in response to the divergence of susceptibility at a phase transition. Our theoretical models predict that the ant-load system can be transitioned through the critical point of this mesoscopic system by varying its size; we present experiments supporting these predictions. Our findings show that efficient group-level processes can arise from transient amplification of individual-based knowledge. PMID:26218613

Precise structural analysis of α-helical polypeptide by quantum-chemical calculation related to reciprocal side-chain combination of two L-phenylalanine residues

NASA Astrophysics Data System (ADS)

Niimura, Subaru; Kurosu, Hiromichi; Shoji, Akira

2010-04-01

To clarify the positive role of side-chain conformation in the stability of protein secondary structure (main-chain conformation), we successfully calculated the optimization structure of a series of well-defined α-helical octadecapeptides composed of two L-phenylalanine (Phe) and 16 L-alanine (Ala) residues, based on the molecular orbital calculation with density functional theory (DFT/B3LYP/6-31G(d)). From the total energy calculation and the precise secondary structural analysis, we found that the conformational stability of the α-helix is closely related to the reciprocal side-chain combinations (such as positional relation and side-chain conformation) of two Phe residues in this system. Furthermore, we demonstrated that the 1H, 13C, 15N and 17O isotropic chemical shifts of each Phe residue depend on the respective side-chain conformations of the Phe residue.

Optimal Predictions in Everyday Cognition: The Wisdom of Individuals or Crowds?

ERIC Educational Resources Information Center

Mozer, Michael C.; Pashler, Harold; Homaei, Hadjar

2008-01-01

Griffiths and Tenenbaum (2006) asked individuals to make predictions about the duration or extent of everyday events (e.g., cake baking times), and reported that predictions were optimal, employing Bayesian inference based on veridical prior distributions. Although the predictions conformed strikingly to statistics of the world, they reflect…

Determination of conformation and orientation of immobilized peptides and proteins at buried interfaces

NASA Astrophysics Data System (ADS)

Shen, Lei; Ulrich, Nathan W.; Mello, Charlene M.; Chen, Zhan

2015-01-01

Surface immobilized peptides/proteins have important applications such as antimicrobial coating and biosensing. We report a study of such peptides/proteins using sum frequency generation vibrational spectroscopy and ATR-FTIR. Immobilization on surfaces via physical adsorption and chemical coupling revealed that structures of chemically immobilized peptides are determined by immobilization sites, chemical environments, and substrate surfaces. In addition, controlling enzyme orientation by engineering the surface immobilization site demonstrated that structures can be well-correlated to measured chemical activity. This research facilitates the development of immobilized peptides/proteins with improved activities by optimizing their surface orientation and structure.

TH-AB-BRB-01: Trajectory Modulated Arc Therapy: Application to Partial Breast Irradiation

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

Hristov, D.

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

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

Guida, K; Qamar, K; Thompson, M

Purpose: The RTOG 1005 trial offered a hypofractionated arm in delivering WBRT+SIB. Traditionally, treatments were planned at our institution using field-in-field (FiF) tangents with a concurrent 3D conformal boost. With the availability of VMAT, it is possible that a hybrid VMAT-3D planning technique could provide another avenue in treating WBRT+SIB. Methods: A retrospective study of nine patients previously treated using RTOG 1005 guidelines was performed to compare FiF+3D plans with the hybrid technique. A combination of static tangents and partial VMAT arcs were used in base-dose optimization. The hybrid plans were optimized to deliver 4005cGy to the breast PTVeval andmore » 4800cGy to the lumpectomy PTVeval over 15 fractions. Plans were optimized to meet the planning goals dictated by RTOG 1005. Results: Hybrid plans yielded similar coverage of breast and lumpectomy PTVs (average D95 of 4013cGy compared to 3990cGy for conventional), while reducing the volume of high dose within the breast; the average D30 and D50 for the hybrid technique were 4517cGy and 4288cGy, compared to 4704cGy and 4377cGy for conventional planning. Hybrid plans increased conformity as well, yielding CI95% values of 1.22 and 1.54 for breast and lumpectomy PTVeval volumes; in contrast, conventional plans averaged 1.49 and 2.27, respectively. The nearby organs at risk (OARs) received more low dose with the hybrid plans due to low dose spray from the partial arcs, but all hybrid plans did meet the acceptable constraints, at a minimum, from the protocol. Treatment planning time was also reduced, as plans were inversely optimized (VMAT) rather than forward optimized. Conclusion: Hybrid-VMAT could be a solution in delivering WB+SIB, as plans yield very conformal treatment plans and maintain clinical standards in OAR sparing. For treating breast cancer patients with a simultaneously-integrated boost, Hybrid-VMAT offers superiority in dosimetric conformity and planning time as compared to FIF techniques.« less

A New Method for Determining Structure Ensemble: Application to a RNA Binding Di-Domain Protein.

PubMed

Liu, Wei; Zhang, Jingfeng; Fan, Jing-Song; Tria, Giancarlo; Grüber, Gerhard; Yang, Daiwen

2016-05-10

Structure ensemble determination is the basis of understanding the structure-function relationship of a multidomain protein with weak domain-domain interactions. Paramagnetic relaxation enhancement has been proven a powerful tool in the study of structure ensembles, but there exist a number of challenges such as spin-label flexibility, domain dynamics, and overfitting. Here we propose a new (to our knowledge) method to describe structure ensembles using a minimal number of conformers. In this method, individual domains are considered rigid; the position of each spin-label conformer and the structure of each protein conformer are defined by three and six orthogonal parameters, respectively. First, the spin-label ensemble is determined by optimizing the positions and populations of spin-label conformers against intradomain paramagnetic relaxation enhancements with a genetic algorithm. Subsequently, the protein structure ensemble is optimized using a more efficient genetic algorithm-based approach and an overfitting indicator, both of which were established in this work. The method was validated using a reference ensemble with a set of conformers whose populations and structures are known. This method was also applied to study the structure ensemble of the tandem di-domain of a poly (U) binding protein. The determined ensemble was supported by small-angle x-ray scattering and nuclear magnetic resonance relaxation data. The ensemble obtained suggests an induced fit mechanism for recognition of target RNA by the protein. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Real-time inverse planning for Gamma Knife radiosurgery.

PubMed

Wu, Q Jackie; Chankong, Vira; Jitprapaikulsarn, Suradet; Wessels, Barry W; Einstein, Douglas B; Mathayomchan, Boonyanit; Kinsella, Timothy J

2003-11-01

The challenges of real-time Gamma Knife inverse planning are the large number of variables involved and the unknown search space a priori. With limited collimator sizes, shots have to be heavily overlapped to form a smooth prescription isodose line that conforms to the irregular target shape. Such overlaps greatly influence the total number of shots per plan, making pre-determination of the total number of shots impractical. However, this total number of shots usually defines the search space, a pre-requisite for most of the optimization methods. Since each shot only covers part of the target, a collection of shots in different locations and various collimator sizes selected makes up the global dose distribution that conforms to the target. Hence, planning or placing these shots is a combinatorial optimization process that is computationally expensive by nature. We have previously developed a theory of shot placement and optimization based on skeletonization. The real-time inverse planning process, reported in this paper, is an expansion and the clinical implementation of this theory. The complete planning process consists of two steps. The first step is to determine an optimal number of shots including locations and sizes and to assign initial collimator size to each of the shots. The second step is to fine-tune the weights using a linear-programming technique. The objective function is to minimize the total dose to the target boundary (i.e., maximize the dose conformity). Results of an ellipsoid test target and ten clinical cases are presented. The clinical cases are also compared with physician's manual plans. The target coverage is more than 99% for manual plans and 97% for all the inverse plans. The RTOG PITV conformity indices for the manual plans are between 1.16 and 3.46, compared to 1.36 to 2.4 for the inverse plans. All the inverse plans are generated in less than 2 min, making real-time inverse planning a reality.

Inverse planning in the age of digital LINACs: station parameter optimized radiation therapy (SPORT)

NASA Astrophysics Data System (ADS)

Xing, Lei; Li, Ruijiang

2014-03-01

The last few years have seen a number of technical and clinical advances which give rise to a need for innovations in dose optimization and delivery strategies. Technically, a new generation of digital linac has become available which offers features such as programmable motion between station parameters and high dose-rate Flattening Filter Free (FFF) beams. Current inverse planning methods are designed for traditional machines and cannot accommodate these features of new generation linacs without compromising either dose conformality and/or delivery efficiency. Furthermore, SBRT is becoming increasingly important, which elevates the need for more efficient delivery, improved dose distribution. Here we will give an overview of our recent work in SPORT designed to harness the digital linacs and highlight the essential components of SPORT. We will summarize the pros and cons of traditional beamlet-based optimization (BBO) and direct aperture optimization (DAO) and introduce a new type of algorithm, compressed sensing (CS)-based inverse planning, that is capable of automatically removing the redundant segments during optimization and providing a plan with high deliverability in the presence of a large number of station control points (potentially non-coplanar, non-isocentric, and even multi-isocenters). We show that CS-approach takes the interplay between planning and delivery into account and allows us to balance the dose optimality and delivery efficiency in a controlled way and, providing a viable framework to address various unmet demands of the new generation linacs. A few specific implementation strategies of SPORT in the forms of fixed-gantry and rotational arc delivery are also presented.

Quantum chemical calculation (electronic and topologic) and experimental (FT-IR, FT-Raman and UV) analysis of isonicotinic acid N-oxide

NASA Astrophysics Data System (ADS)

Karaca, Caglar; Atac, Ahmet; Karabacak, Mehmet

2015-04-01

In this work, the molecular conformation, vibrational and electronic analysis of isonicotinic acid N-oxide (iso-NANO) were presented in the ground state using experimental techniques (FT-IR, FT-Raman and UV) and density functional theory (DFT) employing B3LYP exchange correlation with the 6-311++G(d,p) basis set. The geometry optimization and energies associated possible two conformers (Rot-I and Rot-II) were computed. The vibrational spectra were calculated and fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. The obtained structures were analyzed with the Atoms in Molecules (AIMs) methodology. The computational results diagnose the most stable conformer of iso-NANO as the Rot-I form. Total density of state (TDOS) and partial density of state (PDOS) and also overlap population density of state (OPDOS) diagrams analysis for the most stable conformer (Rot-I) were calculated using the same method. Thermodynamic properties (heat capacity, entropy and enthalpy) of the title compound at different temperatures were calculated. As a result, the optimized geometry and calculated spectroscopic data show a good agreement with the experimental results.

Conformational studies of bacterial peptidoglycan: structure and stereochemistry of N-acetyl-β- D-glucosamine and N-acetyl-β- D-muramic acid

NASA Astrophysics Data System (ADS)

Yadav, P. N. S.; Rai, D. K.; Yadav, J. S.

1989-03-01

The energies of various conformations of N-acetyl-β- D-glucosamine (NAG) and its 3-O- D-lactic acid derivative N-acetyl-β- D-muramic acid (NAM) have been calculated by geometry optimization using the molecular mechanics program MM2. The geometries of these systems have been analyzed in the light of ring torsion, bond lengths, bond angles and conformational states of side groups of the pyranosyl ring and compared with available experimental data of similar pyranose derivatives. The present study indicates the presence of hydrogen bonds to stabilize the side group conformations. Discrepancies with experimental data that are seen in a few cases are ascribed to the nature of the side groups and their geometry.

Nondimensional parameter for conformal grinding: combining machine and process parameters

NASA Astrophysics Data System (ADS)

Funkenbusch, Paul D.; Takahashi, Toshio; Gracewski, Sheryl M.; Ruckman, Jeffrey L.

1999-11-01

Conformal grinding of optical materials with CNC (Computer Numerical Control) machining equipment can be used to achieve precise control over complex part configurations. However complications can arise due to the need to fabricate complex geometrical shapes at reasonable production rates. For example high machine stiffness is essential, but the need to grind 'inside' small or highly concave surfaces may require use of tooling with less than ideal stiffness characteristics. If grinding generates loads sufficient for significant tool deflection, the programmed removal depth will not be achieved. Moreover since grinding load is a function of the volumetric removal rate the amount of load deflection can vary with location on the part, potentially producing complex figure errors. In addition to machine/tool stiffness and removal rate, load generation is a function of the process parameters. For example by reducing the feed rate of the tool into the part, both the load and resultant deflection/removal error can be decreased. However this must be balanced against the need for part through put. In this paper a simple model which permits combination of machine stiffness and process parameters into a single non-dimensional parameter is adapted for a conformal grinding geometry. Errors in removal can be minimized by maintaining this parameter above a critical value. Moreover, since the value of this parameter depends on the local part geometry, it can be used to optimize process settings during grinding. For example it may be used to guide adjustment of the feed rate as a function of location on the part to eliminate figure errors while minimizing the total grinding time required.

Design and analysis of a conformal patch antenna for a wearable breast hyperthermia treatment system

NASA Astrophysics Data System (ADS)

Curto, Sergio; Ramasamy, Manoshika; Suh, Minyoung; Prakash, Punit

2015-03-01

To overcome the limitations of currently available clinical hyperthermia systems which are based on rigid waveguide antennas, a wearable microwave hyperthermia system is presented. A light wearable system can improve patient comfort and be located in close proximity to the breast, thereby enhancing energy deposition and reducing power requirements. The objective of this work was to design and assess the feasibility of a conformal patch antenna element of an array system to be integrated into a wearable hyperthermia bra. The feasibility of implementing antennas with silver printed ink technology on flexible substrates was evaluated. A coupled electromagnetic-bioheat transfer solver and a hemispheric heterogeneous numerical breast phantom were used to design and optimize a 915 MHz patch antenna. The optimization goals were device miniaturization, operating bandwidth, enhanced energy deposition pattern in targets, and reduced Efield back radiation. The antenna performance was evaluated for devices incorporating a hemispheric conformal groundplane and a rectangular groundplane configuration. Simulated results indicated a stable -10 dB return loss bandwidth of 88 MHz for both the conformal and rectangular groundplane configurations. Considering applied power levels restricted to 15 W, treatment volumes (T>410C) and depth from the skin surface were 11.32 cm3 and 27.94 mm, respectively, for the conformal groundplane configuration, and 2.79 cm3 and 19.72 mm, respectively, for the rectangular groundplane configuration. E-field back-radiation reduced by 85.06% for the conformal groundplane compared to the rectangular groundplane configuration. A prototype antenna with rectangular groundplane was fabricatd and experimentally evaluated. The groundplane was created by printing silver ink (Metalon JS-B25P) on polyethylene terephthalate (PET) film surface. Experiments revealed stable antenna performance for power levels up to 15.3 W. In conclusion, the proposed patch antenna with conformal groundplane and prined ink technology shows promising performance to be integrated in a clinical array system.

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.

Direct aperture optimization: a turnkey solution for step-and-shoot IMRT.

PubMed

Shepard, D M; Earl, M A; Li, X A; Naqvi, S; Yu, C

2002-06-01

IMRT treatment plans for step-and-shoot delivery have traditionally been produced through the optimization of intensity distributions (or maps) for each beam angle. The optimization step is followed by the application of a leaf-sequencing algorithm that translates each intensity map into a set of deliverable aperture shapes. In this article, we introduce an automated planning system in which we bypass the traditional intensity optimization, and instead directly optimize the shapes and the weights of the apertures. We call this approach "direct aperture optimization." This technique allows the user to specify the maximum number of apertures per beam direction, and hence provides significant control over the complexity of the treatment delivery. This is possible because the machine dependent delivery constraints imposed by the MLC are enforced within the aperture optimization algorithm rather than in a separate leaf-sequencing step. The leaf settings and the aperture intensities are optimized simultaneously using a simulated annealing algorithm. We have tested direct aperture optimization on a variety of patient cases using the EGS4/BEAM Monte Carlo package for our dose calculation engine. The results demonstrate that direct aperture optimization can produce highly conformal step-and-shoot treatment plans using only three to five apertures per beam direction. As compared with traditional optimization strategies, our studies demonstrate that direct aperture optimization can result in a significant reduction in both the number of beam segments and the number of monitor units. Direct aperture optimization therefore produces highly efficient treatment deliveries that maintain the full dosimetric benefits of IMRT.

A distributed predictive control approach for periodic flow-based networks: application to drinking water systems

NASA Astrophysics Data System (ADS)

Grosso, Juan M.; Ocampo-Martinez, Carlos; Puig, Vicenç

2017-10-01

This paper proposes a distributed model predictive control approach designed to work in a cooperative manner for controlling flow-based networks showing periodic behaviours. Under this distributed approach, local controllers cooperate in order to enhance the performance of the whole flow network avoiding the use of a coordination layer. Alternatively, controllers use both the monolithic model of the network and the given global cost function to optimise the control inputs of the local controllers but taking into account the effect of their decisions over the remainder subsystems conforming the entire network. In this sense, a global (all-to-all) communication strategy is considered. Although the Pareto optimality cannot be reached due to the existence of non-sparse coupling constraints, the asymptotic convergence to a Nash equilibrium is guaranteed. The resultant strategy is tested and its effectiveness is shown when applied to a large-scale complex flow-based network: the Barcelona drinking water supply system.

Conformational Phase Diagram for Polymers Adsorbed on Ultrathin Nanowires

NASA Astrophysics Data System (ADS)

Vogel, Thomas; Bachmann, Michael

2010-05-01

We study the conformational behavior of a polymer adsorbed at an attractive stringlike nanowire and construct the complete structural phase diagram in dependence of the binding strength and effective thickness of the nanowire. For this purpose, Monte Carlo optimization techniques are employed to identify lowest-energy structures for a coarse-grained model of a polymer in contact with the nanowire. Among the representative conformations in the different phases are, for example, compact droplets attached to the wire and also nanotubelike monolayer films wrapping it in a very ordered way. We here systematically analyze low-energy shapes and structural order parameters to elucidate the transitions between the structural phases.

Conformational phase diagram for polymers adsorbed on ultrathin nanowires.

PubMed

Vogel, Thomas; Bachmann, Michael

2010-05-14

We study the conformational behavior of a polymer adsorbed at an attractive stringlike nanowire and construct the complete structural phase diagram in dependence of the binding strength and effective thickness of the nanowire. For this purpose, Monte Carlo optimization techniques are employed to identify lowest-energy structures for a coarse-grained model of a polymer in contact with the nanowire. Among the representative conformations in the different phases are, for example, compact droplets attached to the wire and also nanotubelike monolayer films wrapping it in a very ordered way. We here systematically analyze low-energy shapes and structural order parameters to elucidate the transitions between the structural phases.

CLASSICAL AREAS OF PHENOMENOLOGY: Correcting dynamic residual aberrations of conformal optical systems using AO technology

NASA Astrophysics Data System (ADS)

Li, Yan; Li, Lin; Huang, Yi-Fan; Du, Bao-Lin

2009-07-01

This paper analyses the dynamic residual aberrations of a conformal optical system and introduces adaptive optics (AO) correction technology to this system. The image sharpening AO system is chosen as the correction scheme. Communication between MATLAB and Code V is established via ActiveX technique in computer simulation. The SPGD algorithm is operated at seven zoom positions to calculate the optimized surface shape of the deformable mirror. After comparison of performance of the corrected system with the baseline system, AO technology is proved to be a good way of correcting the dynamic residual aberration in conformal optical design.

Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement.

PubMed

Goi, Pedro Domingues; Goi, Julia Domingues; Cordini, Kariny Larissa; Ceresér, Keila Mendes; Rocha, Neusa Sica da

2014-01-01

Case-control studies are important in developing clinical and public health knowledge. The STROBE statement (STrengthening the Reporting of OBservational Studies in Epidemiology) was developed to establish a checklist of items that should be included in articles reporting observational studies. Our aim was to analyze whether the psychiatric case-control articles published in Brazilian journals with CAPES Qualis rating B1/B2 in 2009 conformed with the STROBE statement. Descriptive study on psychiatric papers published in Brazilian journals, within the Postgraduate Medical Program on Psychiatry, at Universidade Federal do Rio Grande do Sul. All psychiatric case-control studies from Brazilian Qualis B1/B2 journals of psychiatry, neurology and public health in 2009 were analyzed. The four most specific items of the STROBE statement were used to evaluate whether these studies fitted within the case-control parameters: 1) selection of cases and controls; 2) controlling for bias; 3) statistical analysis; and 4) presentation of results. Sixteen case-control studies were identified, of which eleven (68.75%) were in psychiatry-focused journals. From analysis using the STROBE statement, all of the articles conformed with item 1; two (12.5%) completely conformed with item 2; none completely conformed with item 3; and only three (18.8%) conformed with item 4. The case-control studies analyzed here did not completely conform with the four STROBE statement items for case-control design. In view of the inadequate methodology of the published studies, these findings justify focusing on research and methodology and expanding the investigations on adherence of studies to their designs.

Solvent-induced conformational flexibility of a bicyclic proline analogue: Octahydroindole-2-carboxylic acid.

PubMed

Torras, Juan; Warren, Javier G; Revilla-López, Guillem; Jiménez, Ana I; Cativiela, Carlos; Alemán, Carlos

2014-03-01

The conformational preferences of the N-acetyl-N'-methylamide derivatives of the four octahydroindole-2-carboxylic acid (Oic) stereoisomers have been investigated in the gas-phase and in aqueous solution using quantum mechanical calculations. In addition to the conformational effects provoked by the stereochemical diversity of Oic, which presents three chiral centers, results provide evidence of interesting and rather unusual features. The conformational preferences of the Oic stereoisomers in solution are only well described by applying a complete and systematic search process, results achieved by simple re-optimization of the gas-phase minima being very imprecise. This is because the conformational rigidity detected in the gas-phase, which is imposed by the chemical restrictions of the fused bicyclic skeleton, disappears in aqueous solution, the four stereoisomers behaving as flexible molecules in this environment. Thus, in general, the γ-turn is the only minimum energy conformation in the gas-phase while in aqueous solution the helical, polyproline-II and γ-turn motifs are energetically favored. Molecular dynamics simulations indicate that the conformational flexibility predicted by quantum mechanical calculations for the four Oic stereoisomers in solution is satisfactorily reproduced by classical force-fields. Copyright © 2014 Wiley Periodicals, Inc.

Control effects of stimulus paradigms on characteristic firings of parkinsonism

NASA Astrophysics Data System (ADS)

Zhang, Honghui; Wang, Qingyun; Chen, Guanrong

2014-09-01

Experimental studies have shown that neuron population located in the basal ganglia of parkinsonian primates can exhibit characteristic firings with certain firing rates differing from normal brain activities. Motivated by recent experimental findings, we investigate the effects of various stimulation paradigms on the firing rates of parkinsonism based on the proposed dynamical models. Our results show that the closed-loop deep brain stimulation is superior in ameliorating the firing behaviors of the parkinsonism, and other control strategies have similar effects according to the observation of electrophysiological experiments. In addition, in conformity to physiological experiments, we found that there exists optimal delay of input in the closed-loop GPtrain|M1 paradigm, where more normal behaviors can be obtained. More interestingly, we observed that W-shaped curves of the firing rates always appear as stimulus delay varies. We furthermore verify the robustness of the obtained results by studying three pallidal discharge rates of the parkinsonism based on the conductance-based model, as well as the integrate-and-fire-or-burst model. Finally, we show that short-term plasticity can improve the firing rates and optimize the control effects on parkinsonism. Our conclusions may give more theoretical insight into Parkinson's disease studies.

Conformal fabrication of colloidal quantum dot solids for optically enhanced photovoltaics.

PubMed

Labelle, André J; Thon, Susanna M; Kim, Jin Young; Lan, Xinzheng; Zhitomirsky, David; Kemp, Kyle W; Sargent, Edward H

2015-05-26

Colloidal quantum dots (CQD) are an attractive thin-film material for photovoltaic applications due to low material costs, ease of fabrication, and size-tunable band gap. Unfortunately, today they suffer from a compromise between light absorption and photocarrier extraction, a fact that currently prevents the complete harvest of incoming above-band-gap solar photons. We have investigated the use of structured substrates and/or electrodes to increase the effective light path through the active material and found that these designs require highly conformal application of the light-absorbing films to achieve the greatest enhancement. This conformality requirement derives from the need for maximal absorption enhancement combined with shortest-distance charge transport. Here we report on a means of processing highly conformal layer-by-layer deposited CQD absorber films onto microstructured, light-recycling electrodes. Specifically, we engineer surface hydrophilicity to achieve conformal deposition of upper layers atop underlying ones. We show that only with the application of conformal coating can we achieve optimal quantum efficiency and enhanced power conversion efficiency in structured-electrode CQD cells.

Adjustment of Conformational Flexibility is a Key Event in the Thermal Adaptation of Proteins

NASA Astrophysics Data System (ADS)

Zavodszky, Peter; Kardos, Jozsef; Svingor, Adam; Petsko, Gregory A.

1998-06-01

3-Isopropylmalate dehydrogenase (IPMDH, E.C. 1.1.1.85) from the thermophilic bacterium Thermus thermophilus HB8 is homologous to IPMDH from the mesophilic Escherichia coli, but has an approximately 17 degrees C higher melting temperature. Its temperature optimum is 22-25 degrees C higher than that of the E. coli enzyme; however, it is hardly active at room temperature. The increased conformational rigidity required to stabilize the thermophilic enzyme against heat denaturation might explain its different temperature-activity profile. Hydrogen/deuterium exchange studies were performed on this thermophilic-mesophilic enzyme pair to compare their conformational flexibilities. It was found that Th. thermophilus IPMDH is significantly more rigid at room temperature than E. coli IPMDH, whereas the enzymes have nearly identical flexibilities under their respective optimal working conditions, suggesting that evolutionary adaptation tends to maintain a ``corresponding state'' regarding conformational flexibility. These observations confirm that conformational fluctuations necessary for catalytic function are restricted at room temperature in the thermophilic enzyme, suggesting a close relationship between conformational flexibility and enzyme function.

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.

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

NASA Astrophysics Data System (ADS)

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

2017-11-01

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

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

NASA Astrophysics Data System (ADS)

LaPlante, Arthur J.; Stidham, Howard D.

2009-10-01

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

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

PubMed

LaPlante, Arthur J; Stidham, Howard D

2009-10-15

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

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

NASA Astrophysics Data System (ADS)

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

1997-08-01

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

The structural, electronic and spectroscopic properties of 4FPBAPE molecule: Experimental and theoretical study

NASA Astrophysics Data System (ADS)

Tanış, Emine; Babur Sas, Emine; Kurban, Mustafa; Kurt, Mustafa

2018-02-01

The experimental and theoretical study of 4-Formyl Phenyl Boronic Acid Pinacol Ester (4FPBAPE) molecule were performed in this work. 1H, 13C NMR and UV-Vis spectra were tested in dimethyl sulfoxide (DMSO). The structural, spectroscopic properties and energies of 4FPBAPE were obtained for two potential conformers from density functional theory (DFT) with B3LYP/6-311G (d, p) and CAM-B3LYP/6-311G (d, p) basis sets. The optimal geometry of those structures was obtained according to the position of oxygen atom upon determining the scan coordinates for each conformation. The most stable conformer was found as the A2 form. The fundamental vibrations were determined based on optimized structure in terms of total energy distribution. Electronic properties such as oscillator strength, wavelength, excitation energy, HOMO, LUMO and molecular electrostatic potential and structural properties such as radial distribution functions (RDF) and probability density depending on coordination number are presented. Theoretical results of 4-FPBAPE spectra were found to be compatible with observed spectra.

A geometrically based method for automated radiosurgery planning.

PubMed

Wagner, T H; Yi, T; Meeks, S L; Bova, F J; Brechner, B L; Chen, Y; Buatti, J M; Friedman, W A; Foote, K D; Bouchet, L G

2000-12-01

A geometrically based method of multiple isocenter linear accelerator radiosurgery treatment planning optimization was developed, based on a target's solid shape. Our method uses an edge detection process to determine the optimal sphere packing arrangement with which to cover the planning target. The sphere packing arrangement is converted into a radiosurgery treatment plan by substituting the isocenter locations and collimator sizes for the spheres. This method is demonstrated on a set of 5 irregularly shaped phantom targets, as well as a set of 10 clinical example cases ranging from simple to very complex in planning difficulty. Using a prototype implementation of the method and standard dosimetric radiosurgery treatment planning tools, feasible treatment plans were developed for each target. The treatment plans generated for the phantom targets showed excellent dose conformity and acceptable dose homogeneity within the target volume. The algorithm was able to generate a radiosurgery plan conforming to the Radiation Therapy Oncology Group (RTOG) guidelines on radiosurgery for every clinical and phantom target examined. This automated planning method can serve as a valuable tool to assist treatment planners in rapidly and consistently designing conformal multiple isocenter radiosurgery treatment plans.

Conformational, vibrational spectroscopic and nonlinear optical activity studies on N,N-Di-Boc-2-amino pyridine : A DFT approach

NASA Astrophysics Data System (ADS)

Asath, R. Mohamed; Premkumar, R.; Mathavan, T.; Benial, A. Milton Franklin

2017-05-01

The conformational analysis was carried out for N,N-Di-Boc-2-amino pyridine using potential energy surface (PES) scan and the most stable optimized conformer was predicted. The theoretical vibrational frequencies were calculated for the optimized geometry using DFT/B3LYP cc-pVTZ basis set by Gaussian 09 Program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using VEDA 4.0 program package. The Mulliken atomic charge values were calculated. In the Frontier molecular orbitals analysis, the molecular reactivity, kinetic stability, intermolecular charge transfer studies and the calculation of ionization energy, electron affinity, global hardness, chemical potential, electrophilicity index and softness of the molecule were carried out. The nonlinear optical (NLO) activity was examined and the first order hyperpolarizability value was computed, which was 2.27 times greater than the urea. The natural bond orbital analysis was also performed to confirm the NLO activity of the molecule. Hence, the DBAP molecule is a promising candidate for NLO materials.

Vibrational spectra, DFT quantum chemical calculations and conformational analysis of P-iodoanisole.

PubMed

Arivazhagan, M; Anitha Rexalin, D; Geethapriya, J

2013-09-01

The solid phase FT-IR and FT-Raman spectra of P-iodoanisole (P-IA) have been recorded in the regions 400-4000 and 50-4000 cm(-1), respectively. The spectra were interpreted in terms of fundamentals modes, combination and overtone bands. The structure of the molecule was optimized and the structural characteristics were determined by ab initio (HF) and density functional theory (B3LYP) methods with LanL2DZ as basis set. The potential energy surface scan for the selected dihedral angle of P-IA has been performed to identify stable conformer. The optimized structure parameters and vibrational wavenumbers of stable conformer have been predicted by density functional B3LYP method with LanL2DZ (with effective core potential representations of electrons near the nuclei for post-third row atoms) basis set. The nucleophilic and electrophilic sites obtained from the molecular electrostatic potential (MEP) surface were calculated. The temperature dependence of thermodynamic properties has been analyzed. Several thermodynamic parameters have been calculated using B3LYP with LanL2DZ basis set. Copyright © 2013 Elsevier B.V. All rights reserved.

Optimization and quality control of genome-wide Hi-C library preparation.

PubMed

Zhang, Xiang-Yuan; He, Chao; Ye, Bing-Yu; Xie, De-Jian; Shi, Ming-Lei; Zhang, Yan; Shen, Wen-Long; Li, Ping; Zhao, Zhi-Hu

2017-09-20

Highest-throughput chromosome conformation capture (Hi-C) is one of the key assays for genome- wide chromatin interaction studies. It is a time-consuming process that involves many steps and many different kinds of reagents, consumables, and equipments. At present, the reproducibility is unsatisfactory. By optimizing the key steps of the Hi-C experiment, such as crosslinking, pretreatment of digestion, inactivation of restriction enzyme, and in situ ligation etc., we established a robust Hi-C procedure and prepared two biological replicates of Hi-C libraries from the GM12878 cells. After preliminary quality control by Sanger sequencing, the two replicates were high-throughput sequenced. The bioinformatics analysis of the raw sequencing data revealed the mapping-ability and pair-mate rate of the raw data were around 90% and 72%, respectively. Additionally, after removal of self-circular ligations and dangling-end products, more than 96% of the valid pairs were reached. Genome-wide interactome profiling shows clear topological associated domains (TADs), which is consistent with previous reports. Further correlation analysis showed that the two biological replicates strongly correlate with each other in terms of both bin coverage and all bin pairs. All these results indicated that the optimized Hi-C procedure is robust and stable, which will be very helpful for the wide applications of the Hi-C assay.

Control of retinal isomerization in bacteriorhodopsin in the high-intensity regime

PubMed Central

Florean, Andrei C.; Cardoza, David; White, James L.; Lanyi, J. K.; Sension, Roseanne J.; Bucksbaum, Philip H.

2009-01-01

A learning algorithm was used to manipulate optical pulse shapes and optimize retinal isomerization in bacteriorhodopsin, for excitation levels up to 1.8 × 1016 photons per square centimeter. Below 1/3 the maximum excitation level, the yield was not sensitive to pulse shape. Above this level the learning algorithm found that a Fourier-transform-limited (TL) pulse maximized the 13-cis population. For this optimal pulse the yield increases linearly with intensity well beyond the saturation of the first excited state. To understand these results we performed systematic searches varying the chirp and energy of the pump pulses while monitoring the isomerization yield. The results are interpreted including the influence of 1-photon and multiphoton transitions. The population dynamics in each intermediate conformation and the final branching ratio between the all-trans and 13-cis isomers are modified by changes in the pulse energy and duration. PMID:19564608

Solution-Phase Conformation and Dynamics of Conjugated Isoindigo-Based Donor–Acceptor Polymer Single Chains

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

Lee, Franklin L.; Farimani, Amir Barati; Gu, Kevin L.

Conjugated polymers are the key material in thin-film organic optoelectronic devices due to the versatility of these molecules combined with their semiconducting properties. A molecular-scale understanding of conjugated polymers is important to the optimization of the thin-film morphology. We examine the solution-phase behavior of conjugated isoindigo-based donor–acceptor polymer single chains of various chain lengths using atomistic molecular dynamics simulations. Our simulations elucidate the transition from a rod-like to a coil-like conformation from an analysis of normal modes and persistence length. In addition, we find another transition based on the solvent environment, contrasting the coil-like conformation in a good solvent withmore » a globule-like conformation in a poor solvent. Altogether, our results provide valuable insights into the transition between conformational regimes for conjugated polymers as a function of both the chain length and the solvent environment, which will help to accurately parametrize higher level models.« less

Solution-Phase Conformation and Dynamics of Conjugated Isoindigo-Based Donor–Acceptor Polymer Single Chains

DOE PAGES

Lee, Franklin L.; Farimani, Amir Barati; Gu, Kevin L.; ...

2017-10-25

Conjugated polymers are the key material in thin-film organic optoelectronic devices due to the versatility of these molecules combined with their semiconducting properties. A molecular-scale understanding of conjugated polymers is important to the optimization of the thin-film morphology. We examine the solution-phase behavior of conjugated isoindigo-based donor–acceptor polymer single chains of various chain lengths using atomistic molecular dynamics simulations. Our simulations elucidate the transition from a rod-like to a coil-like conformation from an analysis of normal modes and persistence length. In addition, we find another transition based on the solvent environment, contrasting the coil-like conformation in a good solvent withmore » a globule-like conformation in a poor solvent. Altogether, our results provide valuable insights into the transition between conformational regimes for conjugated polymers as a function of both the chain length and the solvent environment, which will help to accurately parametrize higher level models.« less

Dosimetric comparison between VMAT and RC3D techniques: case of prostate treatment

NASA Astrophysics Data System (ADS)

Chemingui, Fatima Zohra; Benrachi, Fatima; Bali, Mohamed Saleh; Ladjal, Hamid

2017-09-01

Considered as the second men cancer in Algeria, prostate cancer is treated in 70% by radiation. That's why radiation therapy is therapeutic weapon for prostate cancer. Conformational Radiotherapy in 3D is the most common technique [1-5]. The use of conventionally optimized treatment plans was compared at case scenario of optimized treatment plans VMAT for prostate cancer. The evaluation of the two optimizations strategies focused on the resulting plans ability to retain dose objectives under the influence of patient set up. Dose Volume Histogram in the Planning Target Volume and dose in the Organs At Risks were used to calculate the conformity index, and evaluation ratio of irradiated volume which represent the main tool of comparison [6,7]. The situation was analysed systematically. The 14% dose increase in the target leads to a decrease in the dose in adjacent organs with 39% in the bladder. Therefore, the criterion for better efficacy and less toxicity reveal that VMAT is the best choice.

46 CFR 160.170-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

46 CFR 160.170-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

46 CFR 160.133-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

46 CFR 160.170-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

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.

Optimization of leaf margins for lung stereotactic body radiotherapy using a flattening filter-free beam

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

Wakai, Nobuhide, E-mail: wakai@naramed-u.ac.jp; Sumida, Iori; Otani, Yuki

Purpose: The authors sought to determine the optimal collimator leaf margins which minimize normal tissue dose while achieving high conformity and to evaluate differences between the use of a flattening filter-free (FFF) beam and a flattening-filtered (FF) beam. Methods: Sixteen lung cancer patients scheduled for stereotactic body radiotherapy underwent treatment planning for a 7 MV FFF and a 6 MV FF beams to the planning target volume (PTV) with a range of leaf margins (−3 to 3 mm). Forty grays per four fractions were prescribed as a PTV D95. For PTV, the heterogeneity index (HI), conformity index, modified gradient indexmore » (GI), defined as the 50% isodose volume divided by target volume, maximum dose (Dmax), and mean dose (Dmean) were calculated. Mean lung dose (MLD), V20 Gy, and V5 Gy for the lung (defined as the volumes of lung receiving at least 20 and 5 Gy), mean heart dose, and Dmax to the spinal cord were measured as doses to organs at risk (OARs). Paired t-tests were used for statistical analysis. Results: HI was inversely related to changes in leaf margin. Conformity index and modified GI initially decreased as leaf margin width increased. After reaching a minimum, the two values then increased as leaf margin increased (“V” shape). The optimal leaf margins for conformity index and modified GI were −1.1 ± 0.3 mm (mean ± 1 SD) and −0.2 ± 0.9 mm, respectively, for 7 MV FFF compared to −1.0 ± 0.4 and −0.3 ± 0.9 mm, respectively, for 6 MV FF. Dmax and Dmean for 7 MV FFF were higher than those for 6 MV FF by 3.6% and 1.7%, respectively. There was a positive correlation between the ratios of HI, Dmax, and Dmean for 7 MV FFF to those for 6 MV FF and PTV size (R = 0.767, 0.809, and 0.643, respectively). The differences in MLD, V20 Gy, and V5 Gy for lung between FFF and FF beams were negligible. The optimal leaf margins for MLD, V20 Gy, and V5 Gy for lung were −0.9 ± 0.6, −1.1 ± 0.8, and −2.1 ± 1.2 mm, respectively, for 7 MV FFF compared to −0.9 ± 0.6, −1.1 ± 0.8, and −2.2 ± 1.3 mm, respectively, for 6 MV FF. With the heart inside the radiation field, the mean heart dose showed a V-shaped relationship with leaf margins. The optimal leaf margins were −1.0 ± 0.6 mm for both beams. Dmax to the spinal cord showed no clear trend for changes in leaf margin. Conclusions: The differences in doses to OARs between FFF and FF beams were negligible. Conformity index, modified GI, MLD, lung V20 Gy, lung V5 Gy, and mean heart dose showed a V-shaped relationship with leaf margins. There were no significant differences in optimal leaf margins to minimize these parameters between both FFF and FF beams. The authors’ results suggest that a leaf margin of −1 mm achieves high conformity and minimizes doses to OARs for both FFF and FF beams.« less

Multiple response optimization of processing and formulation parameters of Eudragit RL/RS-based matrix tablets for sustained delivery of diclofenac.

PubMed

Elzayat, Ehab M; Abdel-Rahman, Ali A; Ahmed, Sayed M; Alanazi, Fars K; Habib, Walid A; Sakr, Adel

2017-11-01

Multiple response optimization is an efficient technique to develop sustained release formulation while decreasing the number of experiments based on trial and error approach. Diclofenac matrix tablets were optimized to achieve a release profile conforming to USP monograph, matching Voltaren ® SR and withstand formulation variables. The percent of drug released at predetermined multiple time points were the response variables in the design. Statistical models were obtained with relative contour diagrams being overlaid to predict process and formulation parameters expected to produce the target release profile. Tablets were prepared by wet granulation using mixture of equivalent quantities of Eudragit RL/RS at overall polymer concentration of 10-30%w/w and compressed at 5-15KN. Drug release from the optimized formulation E4 (15%w/w, 15KN) was similar to Voltaren, conformed to USP monograph and found to be stable. Substituting lactose with mannitol, reversing the ratio between lactose and microcrystalline cellulose or increasing drug load showed no significant difference in drug release. Using dextromethorphan hydrobromide as a model soluble drug showed burst release due to higher solubility and formation of micro cavities. A numerical optimization technique was employed to develop a stable consistent promising formulation for sustained delivery of diclofenac.

Transferability of different classical force fields for right and left handed α-helices constructed from enantiomeric amino acids.

PubMed

Biswas, Santu; Sarkar, Sujit; Pandey, Prithvi Raj; Roy, Sudip

2016-02-21

Amino acids can form d and l enantiomers, of which the l enantiomer is abundant in nature. The naturally occurring l enantiomer has a greater preference for a right handed helical conformation, and the d enantiomer for a left handed helical conformation. The other conformations, that is, left handed helical conformations of the l enantiomers and right handed helical conformations of the d enantiomers, are not common. The energetic differences between left and right handed alpha helical peptide chains constructed from enantiomeric amino acids are investigated using quantum chemical calculations (using the M06/6-311g(d,p) level of theory). Further, the performances of commonly used biomolecular force fields (OPLS/AA, CHARMM27/CMAP and AMBER) to represent the different helical conformations (left and right handed) constructed from enantiomeric (D and L) amino acids are evaluated. 5- and 10-mer chains from d and l enantiomers of alanine, leucine, lysine, and glutamic acid, in right and left handed helical conformations, are considered in the study. Thus, in total, 32 α-helical polypeptides (4 amino acids × 4 conformations of 5-mer and 10-mer) are studied. Conclusions, with regards to the performance of the force fields, are derived keeping the quantum optimized geometry as the benchmark, and on the basis of phi and psi angle calculations, hydrogen bond analysis, and different long range helical order parameters.

Demonstrating the importance of polymer-conjugate conformation in solution on its therapeutic output: Diethylstilbestrol (DES)-polyacetals as prostate cancer treatment.

PubMed

Giménez, Vanessa; James, Craig; Armiñán, Ana; Schweins, Ralf; Paul, Alison; Vicent, María J

2012-04-30

The design of improved polymeric carriers to be used in the next generation of polymer therapeutics is an ongoing challenge. Biodegradable systems present potential advantages regarding safety benefit apart from the possibility to use higher molecular weight (Mw) carriers allowing PK optimization, by exploiting the enhanced permeability and retention (EPR)-mediated tumor targeting. Within this context, we previously designed pH-responsive polyacetalic systems, tert-polymers, where a drug with the adequate diol-functionality was incorporated within the polymer mainchain. The synthetic, non-steroidal estrogen, diethylstilboestrol (DES) clinically used for the treatment of advanced prostate cancer was chosen as drug. In order to improve the properties of this tert-polymer, novel polyacetalic systems as block-co-polymers, with more defined structure have been obtained. This second generation polyacetals allowed higher drug capacity than the tert-polymer, a biphasic DES release profile at acidic pH and due to its controlled amphiphilic character readily formed micelle-like structures in solution. These features result in an enhancement of conjugate therapeutic value in selected prostate cancer cell models. Exhaustive physico-chemical characterization focusing on nanoconjugate solution behavior and using advanced techniques, such as, pulsed-gradient spin-echo NMR (PGSE-NMR) and small-angle neutron scattering (SANS), has been carried out in order to demonstrate this hypothesis. Clear evidence of significantly different conformation in solution has been obtained for both polyacetals. These results demonstrate that an adequate control on molecular or supramolecular conformation in solution with polymer therapeutics is crucial in order to achieve the desired therapeutic output. Copyright © 2012 Elsevier B.V. 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

Hartree-Fock and density functional theory study of alpha-cyclodextrin conformers.

PubMed

Jiménez, Verónica; Alderete, Joel B

2008-01-31

Herein, we report the geometry optimization of four conformers of alpha-cyclodextrin (alpha-CD) by means of PM3, HF/STO-3G, HF/3-21G, HF/6-31G(d), B3LYP/6-31G(d), and X3LYP/6-31G(d) calculations. The analysis of several geometrical parameters indicates that all conformers possess bond lengths, angles, and dihedrals that agree fairly well with the crystalline structure of alpha-CD. However, only three of them (1-3) resemble the polar character of CDs and show intramolecular hydrogen-bonding patterns that agree with experimental NMR data. Among them, conformer 3 appears to be the most stable species both in the gas phase and in solution; therefore, it is expected to be the most suitable representative structure for alpha-CD conformation. The purpose of selecting such a species is to identify an appropriate structure to be employed as a starting point for reliable computational studies on complexation phenomena. Our results indicate that the choice of a particular alpha-CD conformer should affect the results of ab initio computational studies on the inclusion complexation with this cyclodextrin since both the direction and the magnitude of the dipole moment depend strongly on the conformation of alpha-CD.

Conformational Space Annealing explained: A general optimization algorithm, with diverse applications

NASA Astrophysics Data System (ADS)

Joung, InSuk; Kim, Jong Yun; Gross, Steven P.; Joo, Keehyoung; Lee, Jooyoung

2018-02-01

Many problems in science and engineering can be formulated as optimization problems. One way to solve these problems is to develop tailored problem-specific approaches. As such development is challenging, an alternative is to develop good generally-applicable algorithms. Such algorithms are easy to apply, typically function robustly, and reduce development time. Here we provide a description for one such algorithm called Conformational Space Annealing (CSA) along with its python version, PyCSA. We previously applied it to many optimization problems including protein structure prediction and graph community detection. To demonstrate its utility, we have applied PyCSA to two continuous test functions, namely Ackley and Eggholder functions. In addition, in order to provide complete generality of PyCSA to any types of an objective function, we demonstrate the way PyCSA can be applied to a discrete objective function, namely a parameter optimization problem. Based on the benchmarking results of the three problems, the performance of CSA is shown to be better than or similar to the most popular optimization method, simulated annealing. For continuous objective functions, we found that, L-BFGS-B was the best performing local optimization method, while for a discrete objective function Nelder-Mead was the best. The current version of PyCSA can be run in parallel at the coarse grained level by calculating multiple independent local optimizations separately. The source code of PyCSA is available from http://lee.kias.re.kr.

46 CFR 160.115-15 - Production inspections, tests, quality control, and conformance of winches.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and... Launching Appliances-Winches § 160.115-15 Production inspections, tests, quality control, and conformance of... necessary to maintain quality control and to monitor compliance with the requirements of this subpart. (b...

46 CFR 160.115-15 - Production inspections, tests, quality control, and conformance of winches.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Production inspections, tests, quality control, and... Launching Appliances-Winches § 160.115-15 Production inspections, tests, quality control, and conformance of... necessary to maintain quality control and to monitor compliance with the requirements of this subpart. (b...

46 CFR 160.132-15 - Production inspections, tests, quality control, and conformance of davits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and... Launching Appliances-Davits § 160.132-15 Production inspections, tests, quality control, and conformance of... necessary to maintain quality control and to monitor compliance with the requirements of this subpart. (b...

46 CFR 160.115-15 - Production inspections, tests, quality control, and conformance of winches.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and... Launching Appliances-Winches § 160.115-15 Production inspections, tests, quality control, and conformance of... necessary to maintain quality control and to monitor compliance with the requirements of this subpart. (b...

46 CFR 160.132-15 - Production inspections, tests, quality control, and conformance of davits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Production inspections, tests, quality control, and... Launching Appliances-Davits § 160.132-15 Production inspections, tests, quality control, and conformance of... necessary to maintain quality control and to monitor compliance with the requirements of this subpart. (b...

46 CFR 160.132-15 - Production inspections, tests, quality control, and conformance of davits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and... Launching Appliances-Davits § 160.132-15 Production inspections, tests, quality control, and conformance of... necessary to maintain quality control and to monitor compliance with the requirements of this subpart. (b...

N-propyl nitrate vibrational spectrum analysis using DFT B3LYP quantum-chemical method

NASA Astrophysics Data System (ADS)

Shaikhullina, R. M.; Hrapkovsky, G. M.; Shaikhullina, M. M.

2018-05-01

Calculation of a molecular structure, conformation and related vibrational spectra of the n- propyl nitrate C3H7NO3 was carried out by means of density functional theory (DFT) by employing the Gaussian 03 package. The molecular geometries were fully optimized by using the Becker's three-parameter hybrid exchange functional combined with the Lee–Yang–Parr correlation functional (B3LYP) and using the 6-31G(d) basis set. By scanning the dihedral angles around C-O and C-C bonds, five energetically most favorable conformers of n-propyl nitrate - TG, TT, GT, GG and G´G forms were found. Vibrational spectra of the most energetically favorable conformers were calculated. The comparative analysis of calculated and experimental spectra is carried out, the spectral features of the conformational state of n-propyl nitrate and the spectral effects of formation of intramolecular hydrogen bonds are established.

Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation.

PubMed

Belaghzal, Houda; Dekker, Job; Gibcus, Johan H

2017-07-01

Chromosome conformation capture-based methods such as Hi-C have become mainstream techniques for the study of the 3D organization of genomes. These methods convert chromatin interactions reflecting topological chromatin structures into digital information (counts of pair-wise interactions). Here, we describe an updated protocol for Hi-C (Hi-C 2.0) that integrates recent improvements into a single protocol for efficient and high-resolution capture of chromatin interactions. This protocol combines chromatin digestion and frequently cutting enzymes to obtain kilobase (kb) resolution. It also includes steps to reduce random ligation and the generation of uninformative molecules, such as unligated ends, to improve the amount of valid intra-chromosomal read pairs. This protocol allows for obtaining information on conformational structures such as compartment and topologically associating domains, as well as high-resolution conformational features such as DNA loops. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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

NASA Astrophysics Data System (ADS)

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

2010-08-01

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

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.

Structure change of β-hairpin induced by turn optimization: an enhanced sampling molecular dynamics simulation study.

PubMed

Shao, Qiang; Yang, Lijiang; Gao, Yi Qin

2011-12-21

Our previous study showed that for the tested polypeptides which have similar β-hairpin structures but different sequences, their folding free energy pathways are dominantly determined by the turn conformational propensity. In this study, we study how the turn conformational propensity affects the structure of hairpins. The folding of two mutants of GB1p peptide (GB1m2 and GB1m3), which have the optimized turn sequence ((6)DDATK(11)T → (6)NPATG(11)K) with native structures unsolved, were simulated using integrated tempering sampling molecular dynamics simulations and the predicted stable structures were compared to wild-type GB1p. It was observed that the turn optimization of GB1p generates a more favored 5-residue type I(') turn in addition to the 6-residue type I turn in wild-type GB1p. As a result two distinctly different hairpin structures are formed corresponding to the "misfolded" (M) and the "folded" (F) states. M state is a one-residue-shifted asymmetric β-hairpin structure whereas F state has the similar symmetric hairpin structure as wild-type GB1p. The formation of the favored type I(') turn has a small free energy barrier and leads to the shifted β-hairpin structure, following the modified "zipping" model. The presence of disfavored type I turn structure makes the folding of a β-hairpin consistent with the "hydrophobic-core-centric" model. On the other hand, the folding simulations on other two GB1p mutants (GB1r1 and GBr2), which have the position of the hydrophobic core cluster further away from the turn compared to wild-type GB1p, showed that moving the hydrophobic core cluster away from the turn region destabilizes but does not change the hairpin structure. Therefore, the present study showed that the turn conformational propensity is a key factor in affecting not only the folding pathways but also the stable structure of β-hairpins, and the turn conformational change induced by the turn optimization leads to significant changes of β-hairpin structure.

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

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

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

Traveling salesman problem, conformal invariance, and dense polymers.

PubMed

Jacobsen, J L; Read, N; Saleur, H

2004-07-16

We propose that the statistics of the optimal tour in the planar random Euclidean traveling salesman problem is conformally invariant on large scales. This is exhibited in the power-law behavior of the probabilities for the tour to zigzag repeatedly between two regions, and in subleading corrections to the length of the tour. The universality class should be the same as for dense polymers and minimal spanning trees. The conjectures for the length of the tour on a cylinder are tested numerically.

Conformational analysis of capsaicin using 13C, 15N MAS NMR, GIAO DFT and GA calculations

NASA Astrophysics Data System (ADS)

Siudem, Paweł; Paradowska, Katarzyna; Bukowicki, Jarosław

2017-10-01

Capsaicin produced by plants from genus Capsicum exerts multiple pharmacological effects and has found applications in food and pharmaceutical industry. The alkaloid was studied by a combined approach: solid-state NMR, GA conformational search and GIAO DFT methods. The 13C CPMAS NMR spectra were recorded using variable contact time and dipolar dephasing experiments. The results of cross-polarization (CP) kinetics, such as TCP values and long T1ρH (100-200 ms), indicated that the capsaicin molecule is fairly mobile, especially at the end of the aliphatic chain. The15N MAS NMR spectrum showed one narrow signal at -255 ppm. Genetic algorithm (GA) search with multi modal optimization was used to find low-energy conformations of capsaicin. Theoretical GIAO DFT calculations were performed using different basis sets to characterize five selected conformations. 13C CPMAS NMR was used as a validation method and the experimental chemical shifts were compared with those calculated for selected stable conformers. Conformational analysis suggests that the side chain can be bent or extended. A comparison of the experimental and the calculated chemical shifts indicates that solid capsaicin does not have the same structure as those established by PWXRD.

Solvent, Temperature And Concentration Effects on the Optical Activity of Chiral FIVE-And-SIX Membered Ring Ketones Conformers

NASA Astrophysics Data System (ADS)

Al-Basheer, Watheq

2017-06-01

Chiral five-and-six membered ring ketones are important molecules that are found in many biological systems and can exist in many possible conformers. In this talk, experimental and computational investigation of solvent, temperature and concentration effects on the circular dichroism (CD) and optical rotation (OR) of (R)-3 -methylcyclohexanone (R3MCH), (R)-3-methylcyclopentanone (R3MCP) and carvone conformers will be discussed. CD and OR measurements of these ketones gaseous samples and in ten common solvents of wide polarity range for different concentrations and sample temperatures were recorded and related to molecular conformation. Density functional theoretical calculations were performed using Gaussian09 at B3LYP functions with aug-cc-pVDZ level of theory. Also, CD and OR spectra for the optimized geometries of the ketones dominant conformers were computed over the ultraviolet and visible region in the gas phase as well as in ten solvents of varying polarity range, and under the umbrella of the polarizable continuum model (PCM). By comparing theoretical and experimental results, few thermodynamic parameters were deduced for the individual equatorial and axial conformers of each molecule in gas phase and in solvation.

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

PubMed

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

2014-10-01

The catalytic domain of the adenyl cyclase (AC) toxin from Bordetella pertussis is activated by interaction with calmodulin (CaM), resulting in cAMP overproduction in the infected cell. In the X-ray crystallographic structure of the complex between AC and the C terminal lobe of CaM, the toxin displays a markedly elongated shape. As for the structure of the isolated protein, experimental results support the hypothesis that more globular conformations are sampled, but information at atomic resolution is still lacking. Here, we use temperature-accelerated molecular dynamics (TAMD) simulations to generate putative all-atom models of globular conformations sampled by CaM-free AC. As collective variables, we use centers of mass coordinates of groups of residues selected from the analysis of standard molecular dynamics (MD) simulations. Results show that TAMD allows extended conformational sampling and generates AC conformations that are more globular than in the complexed state. These structures are then refined via energy minimization and further unrestrained MD simulations to optimize inter-domain packing interactions, thus resulting in the identification of a set of hydrogen bonds present in the globular conformations. © 2014 Wiley Periodicals, Inc.

A latent class regression analysis of men's conformity to masculine norms and psychological distress.

PubMed

Wong, Y Joel; Owen, Jesse; Shea, Munyi

2012-01-01

How are specific dimensions of masculinity related to psychological distress in specific groups of men? To address this question, the authors used latent class regression to assess the optimal number of latent classes that explained differential relationships between conformity to masculine norms and psychological distress in a racially diverse sample of 223 men. The authors identified a 2-class solution. Both latent classes demonstrated very different associations between conformity to masculine norms and psychological distress. In Class 1 (labeled risk avoiders; n = 133), conformity to the masculine norm of risk-taking was negatively related to psychological distress. In Class 2 (labeled detached risk-takers; n = 90), conformity to the masculine norms of playboy, self-reliance, and risk-taking was positively related to psychological distress, whereas conformity to the masculine norm of violence was negatively related to psychological distress. A post hoc analysis revealed that younger men and Asian American men (compared with Latino and White American men) had significantly greater odds of being in Class 2 versus Class 1. The implications of these findings for future research and clinical practice are examined. (c) 2012 APA, all rights reserved.

Trajectory modulated prone breast irradiation: a LINAC-based technique combining intensity modulated delivery and motion of the couch.

PubMed

Fahimian, Benjamin; Yu, Victoria; Horst, Kathleen; Xing, Lei; Hristov, Dimitre

2013-12-01

External beam radiation therapy (EBRT) provides a non-invasive treatment alternative for accelerated partial breast irradiation (APBI), however, limitations in achievable dose conformity of current EBRT techniques have been correlated to reported toxicity. To enhance the conformity of EBRT APBI, a technique for conventional LINACs is developed, which through combined motion of the couch, intensity modulated delivery, and a prone breast setup, enables wide-angular coronal arc irradiation of the ipsilateral breast without irradiating through the thorax and contralateral breast. A couch trajectory optimization technique was developed to determine the trajectories that concurrently avoid collision with the LINAC and maintain the target within the MLC apertures. Inverse treatment planning was performed along the derived trajectory. The technique was experimentally implemented by programming the Varian TrueBeam™ STx in Developer Mode. The dosimetric accuracy of the delivery was evaluated by ion chamber and film measurements in phantom. The resulting optimized trajectory was shown to be necessarily non-isocentric, and contain both translation and rotations of the couch. Film measurements resulted in 93% of the points in the measured two-dimensional dose maps passing the 3%/3mm Gamma criterion. Preliminary treatment plan comparison to 5-field 3D-conformal, IMRT, and VMAT demonstrated enhancement in conformity, and reduction of the normal tissue V50% and V100% parameters that have been correlated with EBRT toxicity. The feasibility of wide-angular intensity modulated partial breast irradiation using motion of the couch has been demonstrated experimentally on a standard LINAC for the first time. For patients eligible for a prone setup, the technique may enable improvement of dose conformity and associated dose-volume parameters correlated with toxicity. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Fitmunk: improving protein structures by accurate, automatic modeling of side-chain conformations.

PubMed

Porebski, Przemyslaw Jerzy; Cymborowski, Marcin; Pasenkiewicz-Gierula, Marta; Minor, Wladek

2016-02-01

Improvements in crystallographic hardware and software have allowed automated structure-solution pipelines to approach a near-`one-click' experience for the initial determination of macromolecular structures. However, in many cases the resulting initial model requires a laborious, iterative process of refinement and validation. A new method has been developed for the automatic modeling of side-chain conformations that takes advantage of rotamer-prediction methods in a crystallographic context. The algorithm, which is based on deterministic dead-end elimination (DEE) theory, uses new dense conformer libraries and a hybrid energy function derived from experimental data and prior information about rotamer frequencies to find the optimal conformation of each side chain. In contrast to existing methods, which incorporate the electron-density term into protein-modeling frameworks, the proposed algorithm is designed to take advantage of the highly discriminatory nature of electron-density maps. This method has been implemented in the program Fitmunk, which uses extensive conformational sampling. This improves the accuracy of the modeling and makes it a versatile tool for crystallographic model building, refinement and validation. Fitmunk was extensively tested on over 115 new structures, as well as a subset of 1100 structures from the PDB. It is demonstrated that the ability of Fitmunk to model more than 95% of side chains accurately is beneficial for improving the quality of crystallographic protein models, especially at medium and low resolutions. Fitmunk can be used for model validation of existing structures and as a tool to assess whether side chains are modeled optimally or could be better fitted into electron density. Fitmunk is available as a web service at http://kniahini.med.virginia.edu/fitmunk/server/ or at http://fitmunk.bitbucket.org/.

DNA and Protein Requirements for Substrate Conformational Changes Necessary for Human Flap Endonuclease-1-catalyzed Reaction*

PubMed Central

Algasaier, Sana I.; Exell, Jack C.; Bennet, Ian A.; Thompson, Mark J.; Gotham, Victoria J. B.; Shaw, Steven J.; Craggs, Timothy D.; Finger, L. David; Grasby, Jane A.

2016-01-01

Human flap endonuclease-1 (hFEN1) catalyzes the essential removal of single-stranded flaps arising at DNA junctions during replication and repair processes. hFEN1 biological function must be precisely controlled, and consequently, the protein relies on a combination of protein and substrate conformational changes as a prerequisite for reaction. These include substrate bending at the duplex-duplex junction and transfer of unpaired reacting duplex end into the active site. When present, 5′-flaps are thought to thread under the helical cap, limiting reaction to flaps with free 5′-termini in vivo. Here we monitored DNA bending by FRET and DNA unpairing using 2-aminopurine exciton pair CD to determine the DNA and protein requirements for these substrate conformational changes. Binding of DNA to hFEN1 in a bent conformation occurred independently of 5′-flap accommodation and did not require active site metal ions or the presence of conserved active site residues. More stringent requirements exist for transfer of the substrate to the active site. Placement of the scissile phosphate diester in the active site required the presence of divalent metal ions, a free 5′-flap (if present), a Watson-Crick base pair at the terminus of the reacting duplex, and the intact secondary structure of the enzyme helical cap. Optimal positioning of the scissile phosphate additionally required active site conserved residues Tyr40, Asp181, and Arg100 and a reacting duplex 5′-phosphate. These studies suggest a FEN1 reaction mechanism where junctions are bound and 5′-flaps are threaded (when present), and finally the substrate is transferred onto active site metals initiating cleavage. PMID:26884332

46 CFR 160.133-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and..., tests, quality control, and conformance of release mechanisms. (a) Unless the Commandant directs.... The Commandant may prescribe additional production tests and inspections necessary to maintain quality...

46 CFR 160.133-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and..., tests, quality control, and conformance of release mechanisms. (a) Unless the Commandant directs.... The Commandant may prescribe additional production tests and inspections necessary to maintain quality...

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

PubMed

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

2016-01-01

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

Conformation analysis of 1″,4″-Dispirocyclohexane-6,6'-bis(benzothiazoline): Combined IR, Raman, XRD and DFT approach.

PubMed

P J, Arathi; Gupta, Parth; Babu N, Jagadeesh; C N, Sundaresan; Venkatnarayan, Ramanathan

2016-03-15

The subject of the study is the structure and conformation of 1″,4″-Dispiro-cyclohexane-6,6'-bis(benzothiazoline), a dispiro compound that has a cyclohexyl ring flanked by two benzothiazoline rings on either side. Using single crystal X-ray diffraction measurements, Infra-red absorption, and Raman spectroscopy techniques, it is found that the central cyclohexyl ring assumes the chair conformation and the sulfur, nitrogen atoms in both the benzothiazole rings are in the trans configurations. The experimental findings are further corroborated by geometry optimization and frequency calculations at B3LYP/6-311++G** level of theory using Gaussian 09 suite of program. Copyright © 2015 Elsevier B.V. All rights reserved.

Theoretical calculations of Electron Paramagnetic Resonance parameters of liquid phase Orotic acid radical

NASA Astrophysics Data System (ADS)

Sarikaya, Ebru Karakaş; Dereli, Ömer

2017-02-01

To obtain liquid phase molecular structure, conformational analysis of Orotic acid was performed and six conformers were determined. For these conformations, eight possible radicals were modelled by using Density Functional Theory computations with respect to molecular structure. Electron Paramagnetic Resonance parameters of these model radicals were calculated and then they were compared with the experimental ones. Geometry optimizations of the molecule and modeled radicals were performed using Becke's three-parameter hybrid-exchange functional combined with the Lee-Yang-Parr correlation functional of Density Functional Theory and 6-311++G(d,p) basis sets in p-dioxane solution. Because Orotic acid can be mutagenic in mammalian somatic cells and it is also mutagenic for bacteria and yeast, it has been studied.

Protein Loop Structure Prediction Using Conformational Space Annealing.

PubMed

Heo, Seungryong; Lee, Juyong; Joo, Keehyoung; Shin, Hang-Cheol; Lee, Jooyoung

2017-05-22

We have developed a protein loop structure prediction method by combining a new energy function, which we call E PLM (energy for protein loop modeling), with the conformational space annealing (CSA) global optimization algorithm. The energy function includes stereochemistry, dynamic fragment assembly, distance-scaled finite ideal gas reference (DFIRE), and generalized orientation- and distance-dependent terms. For the conformational search of loop structures, we used the CSA algorithm, which has been quite successful in dealing with various hard global optimization problems. We assessed the performance of E PLM with two widely used loop-decoy sets, Jacobson and RAPPER, and compared the results against the DFIRE potential. The accuracy of model selection from a pool of loop decoys as well as de novo loop modeling starting from randomly generated structures was examined separately. For the selection of a nativelike structure from a decoy set, E PLM was more accurate than DFIRE in the case of the Jacobson set and had similar accuracy in the case of the RAPPER set. In terms of sampling more nativelike loop structures, E PLM outperformed E DFIRE for both decoy sets. This new approach equipped with E PLM and CSA can serve as the state-of-the-art de novo loop modeling method.

Chiral pathways in DNA dinucleotides using gradient optimized refinement along metastable borders

NASA Astrophysics Data System (ADS)

Romano, Pablo; Guenza, Marina

We present a study of DNA breathing fluctuations using Markov state models (MSM) with our novel refinement procedure. MSM have become a favored method of building kinetic models, however their accuracy has always depended on using a significant number of microstates, making the method costly. We present a method which optimizes macrostates by refining borders with respect to the gradient along the free energy surface. As the separation between macrostates contains highest discretization errors, this method corrects for any errors produced by limited microstate sampling. Using our refined MSM methods, we investigate DNA breathing fluctuations, thermally induced conformational changes in native B-form DNA. Running several microsecond MD simulations of DNA dinucleotides of varying sequences, to include sequence and polarity effects, we've analyzed using our refined MSM to investigate conformational pathways inherent in the unstacking of DNA bases. Our kinetic analysis has shown preferential chirality in unstacking pathways that may be critical in how proteins interact with single stranded regions of DNA. These breathing dynamics can help elucidate the connection between conformational changes and key mechanisms within protein-DNA recognition. NSF Chemistry Division (Theoretical Chemistry), the Division of Physics (Condensed Matter: Material Theory), XSEDE.

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

PubMed

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

2016-01-01

It is generally accepted that the important characteristic features of the Watson-Crick duplex originate from the molecular structure of its subunits. However, it still remains to elucidate what properties of each subunit are responsible for the significant characteristic features of the DNA structure. The computations of desoxydinucleoside monophosphates complexes with Na-ions using density functional theory revealed a pivotal role of DNA conformational properties of single-chain minimal fragments in the development of unique features of the Watson-Crick duplex. We found that directionality of the sugar-phosphate backbone and the preferable ranges of its torsion angles, combined with the difference between purines and pyrimidines. in ring bases, define the dependence of three-dimensional structure of the Watson-Crick duplex on nucleotide base sequence. In this work, we extended these density functional theory computations to the minimal' fragments of DNA duplex, complementary desoxydinucleoside monophosphates complexes with Na-ions. Using several computational methods and various functionals, we performed a search for energy minima of BI-conformation for complementary desoxydinucleoside monophosphates complexes with different nucleoside sequences. Two sequences are optimized using ab initio method at the MP2/6-31++G** level of theory. The analysis of torsion angles, sugar ring puckering and mutual base positions of optimized structures demonstrates that the conformational characteristic features of complementary desoxydinucleoside monophosphates complexes with Na-ions remain within BI ranges and become closer to the corresponding characteristic features of the Watson-Crick duplex crystals. Qualitatively, the main characteristic features of each studied complementary desoxydinucleoside monophosphates complex remain invariant when different computational methods are used, although the quantitative values of some conformational parameters could vary lying within the limits typical for the corresponding family. We observe that popular functionals in density functional theory calculations lead to the overestimated distances between base pairs, while MP2 computations and the newer complex functionals produce the structures that have too close atom-atom contacts. A detailed study of some complementary desoxydinucleoside monophosphate complexes with Na-ions highlights the existence of several energy minima corresponding to BI-conformations, in other words, the complexity of the relief pattern of the potential energy surface of complementary desoxydinucleoside monophosphate complexes. This accounts for variability of conformational parameters of duplex fragments with the same base sequence. Popular molecular mechanics force fields AMBER and CHARMM reproduce most of the conformational characteristics of desoxydinucleoside monophosphates and their complementary complexes with Na-ions but fail to reproduce some details of the dependence of the Watson-Crick duplex conformation on the nucleotide sequence.

Controlling Molecular Ordering in Solution-State Conjugated Polymers

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

Zhu, Jiahua; Han, Youngkyu; Kumar, Rajeev

Rationally encoding molecular interactions that can control the assembly structure and functional expression in solution of conjugated polymers holds great potential for enabling optimal organic optoelectronic and sensory materials. In this work, we show that thermally-controlled and surfactant-guided assembly of water-soluble conjugated polymers in aqueous solution is a simple and effective strategy to generate optoelectronic materials with desired molecular ordering. We have studied a conjugated polymer consisting of a hydrophobic thiophene backbone and hydrophilic, thermo-responsive ethylene oxide side groups, which shows a step-wise, multi-dimensional assembly in water. By incorporating the polymer into phase-segregated domains of an amphiphilic surfactant in solution,more » we demonstrate that both chain conformation and degree of molecular ordering of the conjugated polymer can be tuned in hexagonal, micellar and lamellar phases of the surfactant solution. The controlled molecular ordering in conjugated polymer assembly is demonstrated as a key factor determining the electronic interaction and optical function.« less

Controlling Molecular Ordering in Solution-State Conjugated Polymers

DOE PAGES

Zhu, Jiahua; Han, Youngkyu; Kumar, Rajeev; ...

2015-07-17

Rationally encoding molecular interactions that can control the assembly structure and functional expression in solution of conjugated polymers holds great potential for enabling optimal organic optoelectronic and sensory materials. In this work, we show that thermally-controlled and surfactant-guided assembly of water-soluble conjugated polymers in aqueous solution is a simple and effective strategy to generate optoelectronic materials with desired molecular ordering. We have studied a conjugated polymer consisting of a hydrophobic thiophene backbone and hydrophilic, thermo-responsive ethylene oxide side groups, which shows a step-wise, multi-dimensional assembly in water. By incorporating the polymer into phase-segregated domains of an amphiphilic surfactant in solution,more » we demonstrate that both chain conformation and degree of molecular ordering of the conjugated polymer can be tuned in hexagonal, micellar and lamellar phases of the surfactant solution. The controlled molecular ordering in conjugated polymer assembly is demonstrated as a key factor determining the electronic interaction and optical function.« less

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

The role of molecular structure of sugar-phosphate backbone and nucleic acid bases in the formation of single-stranded and double-stranded DNA structures.

PubMed

Poltev, Valeri; Anisimov, Victor M; Danilov, Victor I; Garcia, Dolores; Sanchez, Carolina; Deriabina, Alexandra; Gonzalez, Eduardo; Rivas, Francisco; Polteva, Nina

2014-06-01

Our previous DFT computations of deoxydinucleoside monophosphate complexes with Na(+)-ions (dDMPs) have demonstrated that the main characteristics of Watson-Crick (WC) right-handed duplex families are predefined in the local energy minima of dDMPs. In this work, we study the mechanisms of contribution of chemically monotonous sugar-phosphate backbone and the bases into the double helix irregularity. Geometry optimization of sugar-phosphate backbone produces energy minima matching the WC DNA conformations. Studying the conformational variability of dDMPs in response to sequence permutation, we found that simple replacement of bases in the previously fully optimized dDMPs, e.g. by constructing Pyr-Pur from Pur-Pyr, and Pur-Pyr from Pyr-Pur sequences, while retaining the backbone geometry, automatically produces the mutual base position characteristic of the target sequence. Based on that, we infer that the directionality and the preferable regions of the sugar-phosphate torsions, combined with the difference of purines from pyrimidines in ring shape, determines the sequence dependence of the structure of WC DNA. No such sequence dependence exists in dDMPs corresponding to other DNA conformations (e.g., Z-family and Hoogsteen duplexes). Unlike other duplexes, WC helix is unique by its ability to match the local energy minima of the free single strand to the preferable conformations of the duplex. Copyright © 2013 Wiley Periodicals, Inc.

Optimization of Tape Winding Process Parameters to Enhance the Performance of Solid Rocket Nozzle Throat Back Up Liners using Taguchi's Robust Design Methodology

NASA Astrophysics Data System (ADS)

Nath, Nayani Kishore

2017-08-01

The throat back up liners is used to protect the nozzle structural members from the severe thermal environment in solid rocket nozzles. The throat back up liners is made with E-glass phenolic prepregs by tape winding process. The objective of this work is to demonstrate the optimization of process parameters of tape winding process to achieve better insulative resistance using Taguchi's robust design methodology. In this method four control factors machine speed, roller pressure, tape tension, tape temperature that were investigated for the tape winding process. The presented work was to study the cogency and acceptability of Taguchi's methodology in manufacturing of throat back up liners. The quality characteristic identified was Back wall temperature. Experiments carried out using L 9 ' (34) orthogonal array with three levels of four different control factors. The test results were analyzed using smaller the better criteria for Signal to Noise ratio in order to optimize the process. The experimental results were analyzed conformed and successfully used to achieve the minimum back wall temperature of the throat back up liners. The enhancement in performance of the throat back up liners was observed by carrying out the oxy-acetylene tests. The influence of back wall temperature on the performance of throat back up liners was verified by ground firing test.

Discrepancies between conformational distributions of a polyalanine peptide in solution obtained from molecular dynamics force fields and amide I' band profiles.

PubMed

Verbaro, Daniel; Ghosh, Indrajit; Nau, Werner M; Schweitzer-Stenner, Reinhard

2010-12-30

Structural preferences in the unfolded state of peptides determined by molecular dynamics still contradict experimental data. A remedy in this regard has been suggested by MD simulations with an optimized Amber force field ff03* ( Best, R. Hummer, G. J. Phys. Chem. B 2009 , 113 , 9004 - 9015 ). The simulations yielded a statistical coil distribution for alanine which is at variance with recent experimental results. To check the validity of this distribution, we investigated the peptide H-A(5)W-OH, which with the exception of the additional terminal tryptophan is analogous to the peptide used to optimize the force fields ff03*. Electronic circular dichroism, vibrational circular dichroism, and infrared spectroscopy as well as J-coupling constants obtained from NMR experiments were used to derive the peptide's conformational ensemble. Additionally, Förster resonance energy transfer between the terminal chromophores of the fluorescently labeled peptide analogue H-Dbo-A(5)W-OH was used to determine its average length, from which the end-to-end distance of the unlabeled peptide was estimated. Qualitatively, the experimental (3)J(H(N),C(α)), VCD, and ECD indicated a preference of alanine for polyproline II-like conformations. The experimental (3)J(H(N),C(α)) for A(5)W closely resembles the constants obtained for A(5). In order to quantitatively relate the conformational distribution of A(5) obtained with the optimized AMBER ff03* force field to experimental data, the former was used to derive a distribution function which expressed the conformational ensemble as a mixture of polyproline II, β-strand, helical, and turn conformations. This model was found to satisfactorily reproduce all experimental J-coupling constants. We employed the model to calculate the amide I' profiles of the IR and vibrational circular dichroism spectrum of A(5)W, as well as the distance between the two terminal peptide carbonyls. This led to an underestimated negative VCD couplet and an overestimated distance between terminal carbonyl groups. In order to more accurately account for the experimental data, we changed the distribution parameters based on results recently obtained for the alanine-based tripeptides. The final model, which satisfactorily reproduced amide I' profiles, J-coupling constant, and the end-to-end distance of A(5)W, reinforces alanine's high structural preference for polyproline II. Our results suggest that distributions obtained from MD simulations suggesting a statistical coil-like distribution for alanine are still based on insufficiently accurate force fields.

A Theoretical Study of the Conformational Landscape of Serotonin

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

Mourik, Van Tonja; Emson, Laura E.

2002-10-25

The conformational landscape of neutral serotonin has been investigated by several theoretical methods. The potential energy surface was scanned by systematically varying the three dihedral angles that determine the conformation of the alkyl side chain. In addition, the two possible conformations of the phenol hydroxyl group (anti and syn with respect to the indole NH) were considered. The OH-anti stationary points located with SCF/6-31G* have been re-optimized with B3LYP/6-31+G*, which resulted in twelve true minima. Eleven of these have a corresponding OH-syn conformer that is 1-4 kJ/mol higher in energy. IR vibrational spectra of all twenty-three serotonin conformers, computed atmore » the B3LYP/6-31+G* level f theory, are presented. The initial scan of the serotonin potential energy surface has been repeated with several computationally cheaper methods, to assess their reliability for locating the correct serotonin conformers. It is found that the semi-empirical methods AM1 and PM3 do no t yield sufficiently accurate results, due to their inability to account for subtle intramolecular interactions within the serotonin molecule. On the other hand, SCF in combination with the 3-21G* basis set is ascertained to be a good alternative to SCF/6-31G* for performing the initial scan of the potential energy surface of flexible molecules.« less

Atomic Charge Parameters for the Finite Difference Poisson-Boltzmann Method Using Electronegativity Neutralization.

PubMed

Yang, Qingyi; Sharp, Kim A

2006-07-01

An optimization of Rappe and Goddard's charge equilibration (QEq) method of assigning atomic partial charges is described. This optimization is designed for fast and accurate calculation of solvation free energies using the finite difference Poisson-Boltzmann (FDPB) method. The optimization is performed against experimental small molecule solvation free energies using the FDPB method and adjusting Rappe and Goddard's atomic electronegativity values. Using a test set of compounds for which experimental solvation energies are available and a rather small number of parameters, very good agreement was obtained with experiment, with a mean unsigned error of about 0.5 kcal/mol. The QEq atomic partial charge assignment method can reflect the effects of the conformational changes and solvent induction on charge distribution in molecules. In the second section of the paper we examined this feature with a study of the alanine dipeptide conformations in water solvent. The different contributions to the energy surface of the dipeptide were examined and compared with the results from fixed CHARMm charge potential, which is widely used for molecular dynamics studies.

Exploratory factor analysis of signalment and conformational measurements in Thoroughbred horses with and without recurrent laryngeal neuropathy.

PubMed

McGivney, C L; Gough, K F; McGivney, B A; Farries, G; Hill, E W; Katz, L M

2018-06-23

Conflicting results have been reported for risk factors for recurrent laryngeal neuropathy (RLN) based on resting endoscopic evaluation and comparison of single conformation traits, with many traits correlated to one another. To simplify identification of signalment and conformation traits (i.e. variables) associated with RLN cases and controls diagnosed with exercising overground endoscopy (OGE) using exploratory factor analysis (EFA). Prospective cohort. Pearson's rank correlation was used to establish significance and association between variables collected from n = 188 Thoroughbreds from one stable by observers blinded to OGE results. Exploratory factor analysis was conducted on 9 variables for cases and controls; common elements between variables developed a factor, with variables grouped into 3 factors for cases and controls, respectively. Correlation (loading) between each variable and factor was calculated to rank relationships between variables and cases/controls, with factors retrospectively named based on their underlying correlations with variables. Numerous inter-correlations were present between variables. Most strongly correlated in cases were wither height with body weight (r = 0.70) and ventral neck length (r = 0.68) and in controls body weight with rostral neck circumference (r = 0.58). Wither height (r = 0.61) significantly loaded the top-ranked factor for cases ('height RLN '), explaining 25% of conformational variance. Ventral neck length (r = 0.69) and age (r = 0.57) significantly loaded the second-ranked factor for cases ('neck length RLN '), explaining 16% of conformational variance. Rostral neck circumference (r = 0.86) and body weight (r = 0.6) significantly loaded the top-ranked factor for controls ('body size CON '), explaining 19% of the variance. Wither height (r = 0.84) significantly loaded the second-ranked factor for controls ('height CON '), explaining 13% of the variance. Horses had not reached skeletal maturity. Exploratory factor analysis allowed weightings to be determined for each variable. Wither height was the predominant conformational feature associated with RLN. Exploratory factor analysis confirms aggregated conformational differences exist between RLN cases and controls, suitable for future evaluations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Spatial frequency performance limitations of radiation dose optimization and beam positioning

NASA Astrophysics Data System (ADS)

Stewart, James M. P.; Stapleton, Shawn; Chaudary, Naz; Lindsay, Patricia E.; Jaffray, David A.

2018-06-01

The flexibility and sophistication of modern radiotherapy treatment planning and delivery methods have advanced techniques to improve the therapeutic ratio. Contemporary dose optimization and calculation algorithms facilitate radiotherapy plans which closely conform the three-dimensional dose distribution to the target, with beam shaping devices and image guided field targeting ensuring the fidelity and accuracy of treatment delivery. Ultimately, dose distribution conformity is limited by the maximum deliverable dose gradient; shallow dose gradients challenge techniques to deliver a tumoricidal radiation dose while minimizing dose to surrounding tissue. In this work, this ‘dose delivery resolution’ observation is rigorously formalized for a general dose delivery model based on the superposition of dose kernel primitives. It is proven that the spatial resolution of a delivered dose is bounded by the spatial frequency content of the underlying dose kernel, which in turn defines a lower bound in the minimization of a dose optimization objective function. In addition, it is shown that this optimization is penalized by a dose deposition strategy which enforces a constant relative phase (or constant spacing) between individual radiation beams. These results are further refined to provide a direct, analytic method to estimate the dose distribution arising from the minimization of such an optimization function. The efficacy of the overall framework is demonstrated on an image guided small animal microirradiator for a set of two-dimensional hypoxia guided dose prescriptions.

Conformer-specific hydrogen atom tunnelling in trifluoromethylhydroxycarbene

NASA Astrophysics Data System (ADS)

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

2017-01-01

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

Linoleic acid and its potassium and sodium salts: A combined experimental and theoretical study

NASA Astrophysics Data System (ADS)

Gocen, Tuğba; Haman Bayarı, Sevgi; Haluk Guven, Mehmet

2017-12-01

Linoleic acid (cis, cis-9,12-octodecadienoic acid) is the main polyunsaturated -omega 6- essential fatty acid. The conformational behaviour of linoleic acid (LA) in the gas phase was investigated by means of density functional theory (DFT). The structures of conformers of LA were fully optimized by using the B3LYP/6-311++G(d,p) method. The theory showed that the tttttts‧CssCs‧tt conformation of LA (conformer I) is the more stable than the other conformations. Fourier Transform Infrared (FTIR) and micro-Raman spectra of pure LA in liquid form were recorded in the region 4000-450 and 3500-100 cm-1, respectively. The DFT calculations on the molecular structure and vibrational spectra of the dimer form of most stable conformer of LA were also performed using the same method. The assignment of the vibrational modes was made based on calculated potential energy distributions (PEDs). The simulated spectra of dimer form of LA are in reasonably good agreement with the experimental spectra. The sodium and potassium salts of LA were synthesized and characterized by FTIR and Raman spectroscopy, X-ray diffraction and DFT calculations. Several molecular and electronic properties of LA and its salts such as HOMO-LUMO energies, chemical hardness and electronegativity were also calculated and interpreted.

Conformational Studies of 1-OCTYNE from Rotational Spectroscopy

NASA Astrophysics Data System (ADS)

Maturo, Mark P.; Obenchain, Daniel A.; Melchreit, Robert; Cooke, S. A.; Novick, Stewart E.

2017-06-01

Alkanes of the form CH_3(CH_2)_nCH_3 generally favor ground state geometries that have co-planar carbon atoms. In this study, we have looked at a long chain hydrocarbon with a terminal carbon-carbon triple bond, viz., 1-octyne. Guided by the results of the 1-hexyne studies, three possible low energy conformers were studied which we reference as anti-anti (AA, straight chain), anti-gauche (AG, terminal methyl group is gauche), and gauche-anti (GA, ethyl group is gauche). An initial broadband chirp-pulse was performed between 7-13 GHz and a total of sixty-eight transitions were fit. Additional measurements on a Balle Flygare cavity instrument yielded an additional seventy-three lines belonging to three of the conformers. Transitions for all 8 of the singly substituted ^{13}C isotopologues, in natural abundance, have also been observed for the AA conformer. Ab-initio optimizations at the MP2/6-311++g(2d,2p) level of theory and basis set for these three conformers will be compared to experimental rotational constants. Structure determinations of the AA conformer will also be discussed. Atticks, K.; Bohn, R. K.; Michaels H. H. Int'l J. of Quantum Chem. 2001, 85, 514-519; Utzat, K.; Bohn, R. K.; Michaels H. H. J. Mol. Struct. 2007, 841, 22-27

Conforming and nonconforming virtual element methods for elliptic problems

DOE PAGES

Cangiani, Andrea; Manzini, Gianmarco; Sutton, Oliver J.

2016-08-03

Here we present, in a unified framework, new conforming and nonconforming virtual element methods for general second-order elliptic problems in two and three dimensions. The differential operator is split into its symmetric and nonsymmetric parts and conditions for stability and accuracy on their discrete counterparts are established. These conditions are shown to lead to optimal H 1- and L 2-error estimates, confirmed by numerical experiments on a set of polygonal meshes. The accuracy of the numerical approximation provided by the two methods is shown to be comparable.

Conforming and nonconforming virtual element methods for elliptic problems

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

Cangiani, Andrea; Manzini, Gianmarco; Sutton, Oliver J.

Here we present, in a unified framework, new conforming and nonconforming virtual element methods for general second-order elliptic problems in two and three dimensions. The differential operator is split into its symmetric and nonsymmetric parts and conditions for stability and accuracy on their discrete counterparts are established. These conditions are shown to lead to optimal H 1- and L 2-error estimates, confirmed by numerical experiments on a set of polygonal meshes. The accuracy of the numerical approximation provided by the two methods is shown to be comparable.

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

PubMed Central

Yongye, Austin B.; Bender, Andreas

2010-01-01

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

46 CFR 160.135-15 - Production inspections, tests, quality control, and conformance of lifeboats.

Code of Federal Regulations, 2013 CFR

2013-10-01

... materials are as per the plans approved under § 160.135-13(h) of this subpart. (2) Post assembly tests and... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and... Lifeboats (SOLAS) § 160.135-15 Production inspections, tests, quality control, and conformance of lifeboats...

46 CFR 160.135-15 - Production inspections, tests, quality control, and conformance of lifeboats.

Code of Federal Regulations, 2012 CFR

2012-10-01

... materials are as per the plans approved under § 160.135-13(h) of this subpart. (2) Post assembly tests and... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and... Lifeboats (SOLAS) § 160.135-15 Production inspections, tests, quality control, and conformance of lifeboats...

Optimizing the compatibility between rating scales and measures of productive second language competence.

PubMed

Weaver, Christopher

2011-01-01

This study presents a systematic investigation concerning the performance of different rating scales used in the English section of a university entrance examination to assess 1,287 Japanese test takers' ability to write a third-person introduction speech. Although the rating scales did not conform to all of the expectations of the Rasch model, they successfully defined a meaningful continuum of English communicative competence. In some cases, the expectations of the Rasch model needed to be weighed against the specific assessment needs of the university entrance examination. This investigation also found that the degree of compatibility between the number of points allotted to the different rating scales and the various requirements of an introduction speech played a considerable role in determining the extent to which the different rating scales conformed to the expectations of the Rasch model. Compatibility thus becomes an important factor to consider for optimal rating scale performance.

Synthesis and spectral characterization of hydrazone derivative of furfural using experimental and DFT methods.

PubMed

Babu, N Ramesh; Subashchandrabose, S; Ali Padusha, M Syed; Saleem, H; Erdoğdu, Y

2014-01-01

The Spectral Characterization of (E)-1-(Furan-2-yl) methylene)-2-(1-phenylvinyl) hydrazine (FMPVH) were carried out by using FT-IR, FT-Raman and UV-Vis., Spectrometry. The B3LYP/6-311++G(d,p) level of optimization has been performed on the title compound. The conformational analysis was performed for this molecule, in which the cis and trans conformers were studied for spectral characterization. The recorded spectral results were compared with calculated results. The optimized bond parameters of FMPVH molecule was compared with X-ray diffraction data of related molecule. To study the intra-molecular charge transfers within the molecule the Lewis (bonding) and Non-Lewis (anti-bonding) structural calculation was performed. The Non-linear optical behavior of the title compound was measured using first order hyperpolarizability calculation. The atomic charges were calculated and analyzed. Copyright © 2013 Elsevier B.V. All rights reserved.

SDU: A Semidefinite Programming-Based Underestimation Method for Stochastic Global Optimization in Protein Docking

DTIC Science & Technology

2007-04-01

optimization methodology we introduce. State-of-the-art protein - protein docking approaches start by identifying conformations with good surface /chemical com...side-chains on the interface ). The protein - protein docking literature (e.g., [8] and the references therein) is predominantly treating the docking...mations by various measures of surface complementarity which can be efficiently computed using fast Fourier correlation tech- niques (FFTs). However, when

A detailed dosimetric comparison between manual and inverse plans in HDR intracavitary/interstitial cervical cancer brachytherapy.

PubMed

Trnková, Petra; Baltas, Dimos; Karabis, Andreas; Stock, Markus; Dimopoulos, Johannes; Georg, Dietmar; Pötter, Richard; Kirisits, Christian

2010-12-01

The purpose of this study was to compare two inverse planning algorithms for cervical cancer brachytherapy and a conventional manual treatment planning according to the MUW (Medical University of Vienna) protocol. For 20 patients, manually optimized, and, inversely optimized treatment plans with Hybrid Inverse treatment Planning and Optimization (HIPO) and with Inverse Planning Simulated Annealing (IPSA) were created. Dosimetric parameters, absolute volumes of normal tissue receiving reference doses, absolute loading times of tandem, ring and interstitial needles, Paddick and COIN conformity indices were evaluated. HIPO was able to achieve a similar dose distribution to manual planning with the restriction of high dose regions. It reduced the loading time of needles and the overall treatment time. The values of both conformity indices were the lowest. IPSA was able to achieve acceptable dosimetric results. However, it overloaded the needles. This resulted in high dose regions located in the normal tissue. The Paddick index for the volume of two times prescribed dose was outstandingly low. HIPO can produce clinically acceptable treatment plans with the elimination of high dose regions in normal tissue. Compared to IPSA, it is an inverse optimization method which takes into account current clinical experience gained from manual treatment planning.

A detailed dosimetric comparison between manual and inverse plans in HDR intracavitary/interstitial cervical cancer brachytherapy

PubMed Central

Baltas, Dimos; Karabis, Andreas; Stock, Markus; Dimopoulos, Johannes; Georg, Dietmar; Pötter, Richard; Kirisits, Christian

2011-01-01

Purpose The purpose of this study was to compare two inverse planning algorithms for cervical cancer brachytherapy and a conventional manual treatment planning according to the MUW (Medical University of Vienna) protocol. Material and methods For 20 patients, manually optimized, and, inversely optimized treatment plans with Hybrid Inverse treatment Planning and Optimization (HIPO) and with Inverse Planning Simulated Annealing (IPSA) were created. Dosimetric parameters, absolute volumes of normal tissue receiving reference doses, absolute loading times of tandem, ring and interstitial needles, Paddick and COIN conformity indices were evaluated. Results HIPO was able to achieve a similar dose distribution to manual planning with the restriction of high dose regions. It reduced the loading time of needles and the overall treatment time. The values of both conformity indices were the lowest. IPSA was able to achieve acceptable dosimetric results. However, it overloaded the needles. This resulted in high dose regions located in the normal tissue. The Paddick index for the volume of two times prescribed dose was outstandingly low. Conclusions HIPO can produce clinically acceptable treatment plans with the elimination of high dose regions in normal tissue. Compared to IPSA, it is an inverse optimization method which takes into account current clinical experience gained from manual treatment planning. PMID:27853479

Metric Optimization for Surface Analysis in the Laplace-Beltrami Embedding Space

PubMed Central

Lai, Rongjie; Wang, Danny J.J.; Pelletier, Daniel; Mohr, David; Sicotte, Nancy; Toga, Arthur W.

2014-01-01

In this paper we present a novel approach for the intrinsic mapping of anatomical surfaces and its application in brain mapping research. Using the Laplace-Beltrami eigen-system, we represent each surface with an isometry invariant embedding in a high dimensional space. The key idea in our system is that we realize surface deformation in the embedding space via the iterative optimization of a conformal metric without explicitly perturbing the surface or its embedding. By minimizing a distance measure in the embedding space with metric optimization, our method generates a conformal map directly between surfaces with highly uniform metric distortion and the ability of aligning salient geometric features. Besides pairwise surface maps, we also extend the metric optimization approach for group-wise atlas construction and multi-atlas cortical label fusion. In experimental results, we demonstrate the robustness and generality of our method by applying it to map both cortical and hippocampal surfaces in population studies. For cortical labeling, our method achieves excellent performance in a cross-validation experiment with 40 manually labeled surfaces, and successfully models localized brain development in a pediatric study of 80 subjects. For hippocampal mapping, our method produces much more significant results than two popular tools on a multiple sclerosis study of 109 subjects. PMID:24686245

On the effects of basis set truncation and electron correlation in conformers of 2-hydroxy-acetamide

NASA Astrophysics Data System (ADS)

Szarecka, A.; Day, G.; Grout, P. J.; Wilson, S.

Ab initio quantum chemical calculations have been used to study the differences in energy between two gas phase conformers of the 2-hydroxy-acetamide molecule that possess intramolecular hydrogen bonding. In particular, rotation around the central C-C bond has been considered as a factor determining the structure of the hydrogen bond and stabilization of the conformer. Energy calculations include full geometiy optimization using both the restricted matrix Hartree-Fock model and second-order many-body perturbation theory with a number of commonly used basis sets. The basis sets employed ranged from the minimal STO-3G set to [`]split-valence' sets up to 6-31 G. The effects of polarization functions were also studied. The results display a strong basis set dependence.

Theoretical study on the reaction mechanisms of Michael chirality addition between propionaldehyde and nitroalkene catalyzed by an enantioselective catalyst.

PubMed

Zhou, Xinming; Li, Ling; Sun, Xuejun; Wang, Yajun; Du, Dongmei; Fu, Hui

2018-06-01

The asymmetric Michael addition between propionaldehyde and nitroalkene catalyzed by 8-(ethoxycarbonyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid has obtained relatively high yields and excellent enantioselectivities at room temperature. In this study, the molecular structures and optical activity of the most stable conformation I are optimized at B3LYP/6-311++ G(d,p) level. We find that levorotatory conformation I catalyzing the same Michael addition can produce laevo-product A and dextrorotatory conformation I' can obtain the dextral-product A'. These results have guiding significance for further studying on the new chemzymes and the mechanism of the obtained different chiral products. © 2018 Wiley Periodicals, Inc.

Electrostatic mechanism of nucleosomal array folding revealed by computer simulation

PubMed Central

Sun, Jian; Zhang, Qing; Schlick, Tamar

2005-01-01

Although numerous experiments indicate that the chromatin fiber displays salt-dependent conformations, the associated molecular mechanism remains unclear. Here, we apply an irregular Discrete Surface Charge Optimization (DiSCO) model of the nucleosome with all histone tails incorporated to describe by Monte Carlo simulations salt-dependent rearrangements of a nucleosomal array with 12 nucleosomes. The ensemble of nucleosomal array conformations display salt-dependent condensation in good agreement with hydrodynamic measurements and suggest that the array adopts highly irregular 3D zig-zag conformations at high (physiological) salt concentrations and transitions into the extended “beads-on-a-string” conformation at low salt. Energy analyses indicate that the repulsion among linker DNA leads to this extended form, whereas internucleosome attraction drives the folding at high salt. The balance between these two contributions determines the salt-dependent condensation. Importantly, the internucleosome and linker DNA–nucleosome attractions require histone tails; we find that the H3 tails, in particular, are crucial for stabilizing the moderately folded fiber at physiological monovalent salt. PMID:15919827

Novel fused pyrimidine and isoquinoline derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2016105532A1, WO2016105534A1 and WO2016105564A1.

PubMed

Kang, Dongwei; Huo, Zhipeng; Wu, Gaochan; Xu, Jiabao; Zhan, Peng; Liu, Xinyong

2017-04-01

In the three patent applications, the impact of changing the pyrimidine core of the rilpivirine (RPV) to a variety of alternative fused cores was explored, culminating in the identification of a series of conformationally restricted compounds with comparable potencies against WT and mutant HIV-1 strains with those of efavirenz (EFV) and RPV, and higher security in the Human Ether-a-go-go-Related Gene (hERG) assay. Areas covered: The present review provides a fused pyrimidine and isoquinoline derivatives as potent HIV-1 NNRTIs, and highlights the conformational restriction strategies in the development of NNRTIs. Expert opinion: The molecular docking analysis of the newly synthesized compounds maintain the classical horseshoe conformation and shares similar binding mode with RPV. The conformational restriction strategies have greatly accelerated the optimization of the DAPY NNRTIs and contribute to finding new chemical entities (NCEs) with favorable druggability.

Electrostatic mechanism of nucleosomal array folding revealed by computer simulation.

PubMed

Sun, Jian; Zhang, Qing; Schlick, Tamar

2005-06-07

Although numerous experiments indicate that the chromatin fiber displays salt-dependent conformations, the associated molecular mechanism remains unclear. Here, we apply an irregular Discrete Surface Charge Optimization (DiSCO) model of the nucleosome with all histone tails incorporated to describe by Monte Carlo simulations salt-dependent rearrangements of a nucleosomal array with 12 nucleosomes. The ensemble of nucleosomal array conformations display salt-dependent condensation in good agreement with hydrodynamic measurements and suggest that the array adopts highly irregular 3D zig-zag conformations at high (physiological) salt concentrations and transitions into the extended "beads-on-a-string" conformation at low salt. Energy analyses indicate that the repulsion among linker DNA leads to this extended form, whereas internucleosome attraction drives the folding at high salt. The balance between these two contributions determines the salt-dependent condensation. Importantly, the internucleosome and linker DNA-nucleosome attractions require histone tails; we find that the H3 tails, in particular, are crucial for stabilizing the moderately folded fiber at physiological monovalent salt.

Application of exopolysaccharides to improve the performance of ceramic bodies in the unidirectional dry pressing process

NASA Astrophysics Data System (ADS)

Caneira, Inês; Machado-Moreira, Bernardino; Dionísio, Amélia; Godinho, Vasco; Neves, Orquídia; Dias, Diamantino; Saiz-Jimenez, Cesareo; Miller, Ana Z.

2015-04-01

Ceramic industry represents an important sector of economic activity in the European countries and involves complex and numerous manufacturing processes. The unidirectional dry pressing process includes milling and stirring of raw materials (mainly clay and talc minerals) in aqueous suspensions, followed by spray drying to remove excess water obtaining spray-dried powders further subjected to dry pressing process (conformation). However, spray-dried ceramic powders exhibit an important variability in their performance when subjected to the dry pressing process, particularly in the adhesion to the mold and mechanical strength, affecting the quality of the final conformed ceramic products. Therefore, several synthetic additives (deflocculants, antifoams, binders, lubricants and plasticizers) are introduced in the ceramic slips to achieve uniform and homogeneous pastes, conditioning their rheological properties. However, an important variability associated with the performance of the conformed products is still reported. Exopolysaccharides or Extracellular Polymeric Substances (EPS) are polymers excreted by living organisms, such as bacteria, fungi and algae, which may confer unique and potentially interesting properties with potential industrial uses, such as viscosity control, gelation, and flocculation. Polysaccharides, such as pullulan, gellan, carrageenan and xanthan have found a wide range of applications in food, pharmaceutical, petroleum, and in other industries. The aim of this study was the assessment of exopolysaccharides as natural additives to optimize the performance of spray-dried ceramic powders during the unidirectional dry pressing process, replacing the synthetic additives used in the ceramic production process. Six exopolysaccharides, namely pullulan, gellan, xanthan gum, κappa- and iota-carrageenan, and guar gum were tested in steatite-based spray-dried ceramic powders at different concentrations. Subsequently, these ceramic powders were submitted to unidirectional dry pressing process (conformation) and the green conformed bodies were tested on the following properties: mechanical flexural strength and adhesion/disaggregation of the conformed material. The binding state of polysaccharides and mineral grains was evaluated by field emission scanning electron microscopy (FESEM). Our data showed that xanthan gum and pullulan were the most effective polysaccharides in improving the performance of spray-dried ceramic powders during unidirectional dry pressing process, in comparison to the control steatite-based ceramic bodies containing synthetic additives. In addition, these polysaccharides yielded the best cost-benefit relationship, representing an eco-friendly and cost-effective alternative to synthetic additives used in technical ceramics industry. Hence, this study has contributed to define a new and sustainable strategy to improve the performance of ceramic materials during unidirectional dry pressing process, reduce production costs and minimize environmental impact. Acknowledgments: This study was financed by Portuguese funds through FCT- Fundação para a Ciência e a Tecnologia (project EXPL/CTM-CER/0637/2012) and supported by Rauschert Portuguesa, SA.

Intelligent QoS routing algorithm based on improved AODV protocol for Ad Hoc networks

NASA Astrophysics Data System (ADS)

Huibin, Liu; Jun, Zhang

2016-04-01

Mobile Ad Hoc Networks were playing an increasingly important part in disaster reliefs, military battlefields and scientific explorations. However, networks routing difficulties are more and more outstanding due to inherent structures. This paper proposed an improved cuckoo searching-based Ad hoc On-Demand Distance Vector Routing protocol (CSAODV). It elaborately designs the calculation methods of optimal routing algorithm used by protocol and transmission mechanism of communication-package. In calculation of optimal routing algorithm by CS Algorithm, by increasing QoS constraint, the found optimal routing algorithm can conform to the requirements of specified bandwidth and time delay, and a certain balance can be obtained among computation spending, bandwidth and time delay. Take advantage of NS2 simulation software to take performance test on protocol in three circumstances and validate the feasibility and validity of CSAODV protocol. In results, CSAODV routing protocol is more adapt to the change of network topological structure than AODV protocol, which improves package delivery fraction of protocol effectively, reduce the transmission time delay of network, reduce the extra burden to network brought by controlling information, and improve the routing efficiency of network.

The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade.

PubMed

Kupzig, Sabine; Walker, Simon A; Cullen, Peter J

2005-05-24

Ras proteins are binary switches that, by cycling through inactive GDP- and active GTP-bound conformations, regulate multiple cellular signaling pathways, including those that control growth and differentiation. For some time, it has been known that receptor-mediated increases in the concentration of intracellular free calcium ([Ca(2+)](i)) can modulate Ras activation. Increases in [Ca(2+)](i) often occur as repetitive Ca(2+) spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca(2+) oscillations increase in frequency with the amplitude of receptor stimuli, a phenomenon critical for the induction of selective cellular functions. Here, we show that Ca(2+) oscillations are optimized for Ca(2+)-mediated activation of Ras and signaling through the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade. We present additional evidence that Ca(2+) oscillations reduce the effective Ca(2+) threshold for the activation of Ras and that the oscillatory frequency is optimized for activation of Ras and the ERK/MAPK pathway. Our results describe a hitherto unrecognized link between complex Ca(2+) signals and the modulation of the Ras/ERK/MAPK signaling cascade.

Analysis of rotary balance data for the F-15 airplane including the effect of conformal fuel tanks

NASA Technical Reports Server (NTRS)

Barnhart, B.

1982-01-01

F-15 rotary balance data was analyzed, and the influence of control deflections, Reynolds number and airplane components, i.e., body, wing, horizontal and vertical tails, as well as conformal tanks, on the aerodynamics up to 90 degrees angle of attack are discussed. Steady state spin mode predictions using these data are presented, which show excellent correlation with spin tunnel and flight test results. Generally, the data shows damped yawing moment slopes with rotation at all angles of attack, and good control effectiveness. Differences in the rotary aerodynamics due to the addition of conformal tanks are minimal. The small differences in the region of the flat spin do, however, indicate that the resulting spin mode would be slightly flatter and faster for a conformal tank equipped airplane. The addition of conformal tanks make the airplane more departure susceptible.

46 CFR 160.156-15 - Production inspections, tests, quality control, and conformance of rescue boats and fast rescue...

Code of Federal Regulations, 2012 CFR

2012-10-01

... materials are as per the plans approved under § 160.156-13(h) of this subpart. (2) Post assembly tests and... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and... inspections, tests, quality control, and conformance of rescue boats and fast rescue boats. (a) Unless the...

46 CFR 160.156-15 - Production inspections, tests, quality control, and conformance of rescue boats and fast rescue...

Code of Federal Regulations, 2013 CFR

2013-10-01

... materials are as per the plans approved under § 160.156-13(h) of this subpart. (2) Post assembly tests and... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and... inspections, tests, quality control, and conformance of rescue boats and fast rescue boats. (a) Unless the...

A computational study of vicinal fluorination in 2,3-difluorobutane: implications for conformational control in alkane chains.

PubMed

Fox, Stephen J; Gourdain, Stephanie; Coulthurst, Anton; Fox, Clare; Kuprov, Ilya; Essex, Jonathan W; Skylaris, Chris-Kriton; Linclau, Bruno

2015-01-19

A comprehensive conformational analysis of both 2,3-difluorobutane diastereomers is presented based on density functional theory calculations in vacuum and in solution, as well as NMR experiments in solution. While for 1,2-difluoroethane the fluorine gauche effect is clearly the dominant effect determining its conformation, it was found that for 2,3-difluorobutane there is a complex interplay of several effects, which are of similar magnitude but often of opposite sign. As a result, unexpected deviations in dihedral angles, relative conformational energies and populations are observed which cannot be rationalised only by chemical intuition. Furthermore, it was found that it is important to consider the free energies of the various conformers, as these lead to qualitatively different results both in vacuum and in solvent, when compared to calculations based only on the electronic energies. In contrast to expectations, it was found that vicinal syn-difluoride introduction in the butane and by extension, longer hydrocarbon chains, is not expected to lead to an effective stabilisation of the linear conformation. Our findings have implications for the use of the vicinal difluoride motif for conformational control. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enhanced Conformational Sampling in Molecular Dynamics Simulations of Solvated Peptides: Fragment-Based Local Elevation Umbrella Sampling.

PubMed

Hansen, Halvor S; Daura, Xavier; Hünenberger, Philippe H

2010-09-14

A new method, fragment-based local elevation umbrella sampling (FB-LEUS), is proposed to enhance the conformational sampling in explicit-solvent molecular dynamics (MD) simulations of solvated polymers. The method is derived from the local elevation umbrella sampling (LEUS) method [ Hansen and Hünenberger , J. Comput. Chem. 2010 , 31 , 1 - 23 ], which combines the local elevation (LE) conformational searching and the umbrella sampling (US) conformational sampling approaches into a single scheme. In LEUS, an initial (relatively short) LE build-up (searching) phase is used to construct an optimized (grid-based) biasing potential within a subspace of conformationally relevant degrees of freedom, which is then frozen and used in a (comparatively longer) US sampling phase. This combination dramatically enhances the sampling power of MD simulations but, due to computational and memory costs, is only applicable to relevant subspaces of low dimensionalities. As an attempt to expand the scope of the LEUS approach to solvated polymers with more than a few relevant degrees of freedom, the FB-LEUS scheme involves an US sampling phase that relies on a superposition of low-dimensionality biasing potentials optimized using LEUS at the fragment level. The feasibility of this approach is tested using polyalanine (poly-Ala) and polyvaline (poly-Val) oligopeptides. Two-dimensional biasing potentials are preoptimized at the monopeptide level, and subsequently applied to all dihedral-angle pairs within oligopeptides of 4,  6,  8, or 10 residues. Two types of fragment-based biasing potentials are distinguished: (i) the basin-filling (BF) potentials act so as to "fill" free-energy basins up to a prescribed free-energy level above the global minimum; (ii) the valley-digging (VD) potentials act so as to "dig" valleys between the (four) free-energy minima of the two-dimensional maps, preserving barriers (relative to linearly interpolated free-energy changes) of a prescribed magnitude. The application of these biasing potentials may lead to an impressive enhancement of the searching power (volume of conformational space visited in a given amount of simulation time). However, this increase is largely offset by a deterioration of the statistical efficiency (representativeness of the biased ensemble in terms of the conformational distribution appropriate for the physical ensemble). As a result, it appears difficult to engineer FB-LEUS schemes representing a significant improvement over plain MD, at least for the systems considered here.

Aluminum and its effect in the equilibrium between folded/unfolded conformation of NADH.

PubMed

Formoso, Elena; Mujika, Jon I; Grabowski, Slawomir J; Lopez, Xabier

2015-11-01

Nicotinamide adenine dinucleotide (NADH) is one of the most abundant cofactor employed by proteins and enzymes. The molecule is formed by two nucleotides that can lead to two main conformations: folded/closed and unfolded/open. Experimentally, it has been determined that the closed form is about 2 kcal/mol more stable than the open formed. Computationally, a correct description of the NADH unfolding process is challenging due to different reasons: 1) The unfolding process shows a very low energy difference between the two conformations 2) The molecule can form a high number of internal hydrogen bond interactions 3) Subtle effects such as dispersion may be important. In order to tackle all these effects, we have employed a number of different state of the art computational techniques, including: a) well-tempered metadynamics, b) geometry optimizations, and c) Quantum Theory of Atoms in Molecules (QTAIM) calculations, to investigate the conformational change of NADH in solution and interacting with aluminum. All the results indicate that aluminum indeed favors the closed conformation of NADH, due mainly to the formation of a more rigid structure through key hydrogen bond interactions. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Physics-based method to validate and repair flaws in protein structures

PubMed Central

Martin, Osvaldo A.; Arnautova, Yelena A.; Icazatti, Alejandro A.; Scheraga, Harold A.; Vila, Jorge A.

2013-01-01

A method that makes use of information provided by the combination of 13Cα and 13Cβ chemical shifts, computed at the density functional level of theory, enables one to (i) validate, at the residue level, conformations of proteins and detect backbone or side-chain flaws by taking into account an ensemble average of chemical shifts over all of the conformations used to represent a protein, with a sensitivity of ∼90%; and (ii) provide a set of (χ1/χ2) torsional angles that leads to optimal agreement between the observed and computed 13Cα and 13Cβ chemical shifts. The method has been incorporated into the CheShift-2 protein validation Web server. To test the reliability of the provided set of (χ1/χ2) torsional angles, the side chains of all reported conformations of five NMR-determined protein models were refined by a simple routine, without using NOE-based distance restraints. The refinement of each of these five proteins leads to optimal agreement between the observed and computed 13Cα and 13Cβ chemical shifts for ∼94% of the flaws, on average, without introducing a significantly large number of violations of the NOE-based distance restraints for a distance range ≤ 0.5 Ǻ, in which the largest number of distance violations occurs. The results of this work suggest that use of the provided set of (χ1/χ2) torsional angles together with other observables, such as NOEs, should lead to a fast and accurate refinement of the side-chain conformations of protein models. PMID:24082119

Physics-based method to validate and repair flaws in protein structures.

PubMed

Martin, Osvaldo A; Arnautova, Yelena A; Icazatti, Alejandro A; Scheraga, Harold A; Vila, Jorge A

2013-10-15

A method that makes use of information provided by the combination of (13)C(α) and (13)C(β) chemical shifts, computed at the density functional level of theory, enables one to (i) validate, at the residue level, conformations of proteins and detect backbone or side-chain flaws by taking into account an ensemble average of chemical shifts over all of the conformations used to represent a protein, with a sensitivity of ∼90%; and (ii) provide a set of (χ1/χ2) torsional angles that leads to optimal agreement between the observed and computed (13)C(α) and (13)C(β) chemical shifts. The method has been incorporated into the CheShift-2 protein validation Web server. To test the reliability of the provided set of (χ1/χ2) torsional angles, the side chains of all reported conformations of five NMR-determined protein models were refined by a simple routine, without using NOE-based distance restraints. The refinement of each of these five proteins leads to optimal agreement between the observed and computed (13)C(α) and (13)C(β) chemical shifts for ∼94% of the flaws, on average, without introducing a significantly large number of violations of the NOE-based distance restraints for a distance range ≤ 0.5 , in which the largest number of distance violations occurs. The results of this work suggest that use of the provided set of (χ1/χ2) torsional angles together with other observables, such as NOEs, should lead to a fast and accurate refinement of the side-chain conformations of protein models.

Gas-phase Conformational Analysis of (R,R)-Tartaric Acid, its Diamide, N,N,N',N'- Tetramethyldiamide and Model Compounds

NASA Astrophysics Data System (ADS)

Hoffmann, Marcin; Szarecka, Agnieszka; Rychlewski, Jacek

A review over most recent ab initio studies carried out at both RHF and MP2 levels on (R,R)-tartaric acid (TA), its diamide (DA), tetramethyldiamide (TMDA) and on three prototypic model systems (each of them constitutes a half of the respective parental molecule), i.e. 2-hydroxyacetic acid (HA), 2-hydroxyacetamide (HD) and 2-hydroxy-N,N-dimethylacetamide (HMD) is presented. (R,R)-tartaric acid and the derivatives have been completely optimized at RHF/6-31G* level and subsequently single-point energies of all conformers have been calculated with the use of second order perturbation theory according to the scheme: MP2/6-31G*//RHF/6-31G*. In the complete optimization of the model molecules at RHF level we have employed relatively large basis sets, augmented with polarisation and diffuse functions, namely 3-21G, 6-31G*, 6-31++G** and 6-311++G**. Electronic correlation has been included with the largest basis set used in this study, i.e. MP2/6-311++G**//RHF/6-311++G** single-point energy calculations have been performed. General confomational preferences of tartaric acid derivatives have been analysed as well as an attempt has been made to define main factors affecting the conformational behaviour of these molecules in the isolated state, in particular, the role and stability of intramolecular hydrogen bonding. In the case of the model compounds, our study principally concerned the conformational preferences and hydrogen bonding structure within the [alpha]-hydroxy-X moiety, where X=COOH, CONH2, CON(CH3)2.

Tautomeric properties, conformations and structure of N-(2-hydroxy-5-chlorophenyl) salicylaldimine

NASA Astrophysics Data System (ADS)

Elmali, A.; Kabak, M.; Kavlakoglu, E.; Elerman, Y.; Durlu, T. N.

1999-11-01

The crystal structure of N-(2-hydroxy-5-chlorophenyl) salicylaldimine (C 13H 10NO 2Cl) was determined by X-ray analysis. It crystallizes orthorhombic space group P2 12 12 1 with a=12.967(2) Å, b=14.438(3) Å, c=6.231(3) Å, V=1166.5(6) Å 3, Z=4, Dc=1.41 g cm -3 and μ(MoK α)=0.315 mm -1. The title compound is thermochromic and the molecule is nearly planar. Both tautomeric forms (keto and enol forms in 68(3) and 32(3)%, respectively) are present in the solid state. The molecules contain strong intramolecular hydrogen bonds, N1-H1⋯O1/O2 (2.515(1) and 2.581(2) Å) for the keto form and O1-H01⋯N1 for the enol one. There is also strong intermolecular O2-H⋯O1 hydrogen bonding (2.599(2) Å) between neighbouring molecules. Minimum energy conformations AM1 were calculated as a function of the three torsion angles, θ1(N1-C7-C6-C5), θ2(C8-N1-C7-C6) and θ3(C9-C8-N1-C7), varied every 10°. Although the molecule is nearly planar, the AM1 optimized geometry of the title compound is not planar. The non-planar conformation of the title compound corresponding to the optimized X-ray structure is the most stable conformation in all calculations.

Study of conformational stability, structural, electronic and charge transfer properties of cladrin using vibrational spectroscopy and DFT calculations.

PubMed

Singh, Swapnil; Singh, Harshita; Srivastava, Anubha; Tandon, Poonam; Sinha, Kirti; Bharti, Purnima; Kumar, Sudhir; Kumar, Padam; Maurya, Rakesh

2014-11-11

In the present work, a detailed conformational study of cladrin (3-(3,4-dimethoxy phenyl)-7-hydroxychromen-4-one) has been done by using spectroscopic techniques (FT-IR/FT-Raman/UV-Vis/NMR) and quantum chemical calculations. The optimized geometry, wavenumber and intensity of the vibrational bands of the cladrin in ground state were calculated by density functional theory (DFT) employing 6-311++G(d,p) basis sets. The study has been focused on the two most stable conformers that are selected after the full geometry optimization of the molecule. A detailed assignment of the FT-IR and FT-Raman spectra has been done for both the conformers along with potential energy distribution for each vibrational mode. The observed and scaled wavenumber of most of the bands has been found to be in good agreement. The UV-Vis spectrum has been recorded and compared with calculated spectrum. In addition, 1H and 13C nuclear magnetic resonance spectra have been also recorded and compared with the calculated data that shows the inter or intramolecular hydrogen bonding. The electronic properties such as HOMO-LUMO energies were calculated by using time-dependent density functional theory. Molecular electrostatic potential has been plotted to elucidate the reactive part of the molecule. Natural bond orbital analysis was performed to investigate the molecular stability. Non linear optical property of the molecule have been studied by calculating the electric dipole moment (μ) and the first hyperpolarizability (β) that results in the nonlinearity of the molecule. Copyright © 2014 Elsevier B.V. All rights reserved.

Beam’s-eye-view dosimetrics (BEVD) guided rotational station parameter optimized radiation therapy (SPORT) planning based on reweighted total-variation minimization

NASA Astrophysics Data System (ADS)

Kim, Hojin; Li, Ruijiang; Lee, Rena; Xing, Lei

2015-03-01

Conventional VMAT optimizes aperture shapes and weights at uniformly sampled stations, which is a generalization of the concept of a control point. Recently, rotational station parameter optimized radiation therapy (SPORT) has been proposed to improve the plan quality by inserting beams to the regions that demand additional intensity modulations, thus formulating non-uniform beam sampling. This work presents a new rotational SPORT planning strategy based on reweighted total-variation (TV) minimization (min.), using beam’s-eye-view dosimetrics (BEVD) guided beam selection. The convex programming based reweighted TV min. assures the simplified fluence-map, which facilitates single-aperture selection at each station for single-arc delivery. For the rotational arc treatment planning and non-uniform beam angle setting, the mathematical model needs to be modified by additional penalty term describing the fluence-map similarity and by determination of appropriate angular weighting factors. The proposed algorithm with additional penalty term is capable of achieving more efficient and deliverable plans adaptive to the conventional VMAT and SPORT planning schemes by reducing the dose delivery time about 5 to 10 s in three clinical cases (one prostate and two head-and-neck (HN) cases with a single and multiple targets). The BEVD guided beam selection provides effective and yet easy calculating methodology to select angles for denser, non-uniform angular sampling in SPORT planning. Our BEVD guided SPORT treatment schemes improve the dose sparing to femoral heads in the prostate and brainstem, parotid glands and oral cavity in the two HN cases, where the mean dose reduction of those organs ranges from 0.5 to 2.5 Gy. Also, it increases the conformation number assessing the dose conformity to the target from 0.84, 0.75 and 0.74 to 0.86, 0.79 and 0.80 in the prostate and two HN cases, while preserving the delivery efficiency, relative to conventional single-arc VMAT plans.

3D QSAR studies on protein tyrosine phosphatase 1B inhibitors: comparison of the quality and predictivity among 3D QSAR models obtained from different conformer-based alignments.

PubMed

Pandey, Gyanendra; Saxena, Anil K

2006-01-01

A set of 65 flexible peptidomimetic competitive inhibitors (52 in the training set and 13 in the test set) of protein tyrosine phosphatase 1B (PTP1B) has been used to compare the quality and predictive power of 3D quantitative structure-activity relationship (QSAR) comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for the three most commonly used conformer-based alignments, namely, cocrystallized conformer-based alignment (CCBA), docked conformer-based alignment (DCBA), and global minima energy conformer-based alignment (GMCBA). These three conformers of 5-[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)3-oxo-3-pentylamino)propyl]-2-(carboxymethoxy)benzoic acid (compound number 66) were obtained from the X-ray structure of its cocrystallized complex with PTP1B (PDB ID: 1JF7), its docking studies, and its global minima by simulated annealing. Among the 3D QSAR models developed using the above three alignments, the CCBA provided the optimal predictive CoMFA model for the training set with cross-validated r2 (q2)=0.708, non-cross-validated r2=0.902, standard error of estimate (s)=0.165, and F=202.553 and the optimal CoMSIA model with q2=0.440, r2=0.799, s=0.192, and F=117.782. These models also showed the best test set prediction for the 13 compounds with predictive r2 values of 0.706 and 0.683, respectively. Though the QSAR models derived using the other two alignments also produced statistically acceptable models in the order DCBA>GMCBA in terms of the values of q2, r2, and predictive r2, they were inferior to the corresponding models derived using CCBA. Thus, the order of preference for the alignment selection for 3D QSAR model development may be CCBA>DCBA>GMCBA, and the information obtained from the CoMFA and CoMSIA contour maps may be useful in designing specific PTP1B inhibitors.

Reirradiation of head and neck cancer using modern highly conformal techniques.

PubMed

Ho, Jennifer C; Phan, Jack

2018-04-23

Locoregional disease recurrence or development of a second primary cancer after definitive radiotherapy for head and neck cancers remains a treatment challenge. Reirradiation utilizing traditional techniques has been limited by concern for serious toxicity. With the advent of newer, more precise radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT), proton radiotherapy, and stereotactic body radiotherapy (SBRT), there has been renewed interest in curative-intent head and neck reirradiation. However, as most studies were retrospective, single-institutional experiences, the optimal modality is not clear. We provide a comprehensive review of the outcomes of relevant studies using these 3 head and neck reirradiation techniques, followed by an analysis and comparison of the toxicity, tumor control, concurrent systemic therapy, and prognostic factors. Overall, there is evidence that IMRT, proton therapy, and SBRT reirradiation are feasible treatment options that offer a chance for durable local control and survival. Prospective studies, particularly randomized trials, are needed. © 2018 Wiley Periodicals, Inc.

Placing and shaping liposomes with reconfigurable DNA nanocages

NASA Astrophysics Data System (ADS)

Zhang, Zhao; Yang, Yang; Pincet, Frederic; C. Llaguno, Marc; Lin, Chenxiang

2017-07-01

The diverse structure and regulated deformation of lipid bilayer membranes are among a cell's most fascinating features. Artificial membrane-bound vesicles, known as liposomes, are versatile tools for modelling biological membranes and delivering foreign objects to cells. To fully mimic the complexity of cell membranes and optimize the efficiency of delivery vesicles, controlling liposome shape (both statically and dynamically) is of utmost importance. Here we report the assembly, arrangement and remodelling of liposomes with designer geometry: all of which are exquisitely controlled by a set of modular, reconfigurable DNA nanocages. Tubular and toroid shapes, among others, are transcribed from DNA cages to liposomes with high fidelity, giving rise to membrane curvatures present in cells yet previously difficult to construct in vitro. Moreover, the conformational changes of DNA cages drive membrane fusion and bending with predictable outcomes, opening up opportunities for the systematic study of membrane mechanics.

Placing and shaping liposomes with reconfigurable DNA nanocages.

PubMed

Zhang, Zhao; Yang, Yang; Pincet, Frederic; Llaguno, Marc C; Lin, Chenxiang

2017-06-23

The diverse structure and regulated deformation of lipid bilayer membranes are among a cell's most fascinating features. Artificial membrane-bound vesicles, known as liposomes, are versatile tools for modelling biological membranes and delivering foreign objects to cells. To fully mimic the complexity of cell membranes and optimize the efficiency of delivery vesicles, controlling liposome shape (both statically and dynamically) is of utmost importance. Here we report the assembly, arrangement and remodelling of liposomes with designer geometry: all of which are exquisitely controlled by a set of modular, reconfigurable DNA nanocages. Tubular and toroid shapes, among others, are transcribed from DNA cages to liposomes with high fidelity, giving rise to membrane curvatures present in cells yet previously difficult to construct in vitro. Moreover, the conformational changes of DNA cages drive membrane fusion and bending with predictable outcomes, opening up opportunities for the systematic study of membrane mechanics.

40 CFR 1045.255 - What decisions may EPA make regarding my certificate of conformity?

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 34 2013-07-01 2013-07-01 false What decisions may EPA make regarding my certificate of conformity? 1045.255 Section 1045.255 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF EMISSIONS FROM SPARK-IGNITION PROPULSION...

40 CFR 1045.255 - What decisions may EPA make regarding my certificate of conformity?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 32 2010-07-01 2010-07-01 false What decisions may EPA make regarding my certificate of conformity? 1045.255 Section 1045.255 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF EMISSIONS FROM SPARK-IGNITION PROPULSION...

40 CFR 1045.255 - What decisions may EPA make regarding my certificate of conformity?

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 33 2014-07-01 2014-07-01 false What decisions may EPA make regarding my certificate of conformity? 1045.255 Section 1045.255 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF EMISSIONS FROM SPARK-IGNITION PROPULSION...

40 CFR 1045.255 - What decisions may EPA make regarding my certificate of conformity?

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 33 2011-07-01 2011-07-01 false What decisions may EPA make regarding my certificate of conformity? 1045.255 Section 1045.255 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF EMISSIONS FROM SPARK-IGNITION PROPULSION...

40 CFR 1045.255 - What decisions may EPA make regarding my certificate of conformity?

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 34 2012-07-01 2012-07-01 false What decisions may EPA make regarding my certificate of conformity? 1045.255 Section 1045.255 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF EMISSIONS FROM SPARK-IGNITION PROPULSION...

Unbiased, scalable sampling of protein loop conformations from probabilistic priors.

PubMed

Zhang, Yajia; Hauser, Kris

2013-01-01

Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences. Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (>10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints. Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion.

Unbiased, scalable sampling of protein loop conformations from probabilistic priors

PubMed Central

2013-01-01

Background Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences. Results Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (>10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints. Conclusion Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion. PMID:24565175

Non-Fullerene Electron Acceptors for Use in Organic Solar Cells

PubMed Central

2015-01-01

Conspectus The active layer in a solution processed organic photovoltaic device comprises a light absorbing electron donor semiconductor, typically a polymer, and an electron accepting fullerene acceptor. Although there has been huge effort targeted to optimize the absorbing, energetic, and transport properties of the donor material, fullerenes remain as the exclusive electron acceptor in all high performance devices. Very recently, some new non-fullerene acceptors have been demonstrated to outperform fullerenes in comparative devices. This Account describes this progress, discussing molecular design considerations and the structure–property relationships that are emerging. The motivation to replace fullerene acceptors stems from their synthetic inflexibility, leading to constraints in manipulating frontier energy levels, as well as poor absorption in the solar spectrum range, and an inherent tendency to undergo postfabrication crystallization, resulting in device instability. New acceptors have to address these limitations, providing tunable absorption with high extinction coefficients, thus contributing to device photocurrent. The ability to vary and optimize the lowest unoccupied molecular orbital (LUMO) energy level for a specific donor polymer is also an important requirement, ensuring minimal energy loss on electron transfer and as high an internal voltage as possible. Initially perylene diimide acceptors were evaluated as promising acceptor materials. These electron deficient aromatic molecules can exhibit good electron transport, facilitated by close packed herringbone crystal motifs, and their energy levels can be synthetically tuned. The principal drawback of this class of materials, their tendency to crystallize on too large a length scale for an optimal heterojunction nanostructure, has been shown to be overcome through introduction of conformation twisting through steric effects. This has been primarily achieved by coupling two units together, forming dimers with a large intramolecular twist, which suppresses both nucleation and crystal growth. The generic design concept of rotationally symmetrical aromatic small molecules with extended π orbital delocalization, including polyaromatic hydrocarbons, phthalocyanines, etc., has also provided some excellent small molecule acceptors. In most cases, additional electron withdrawing functionality, such as imide or ester groups, can be incorporated to stabilize the LUMO and improve properties. New calamitic acceptors have been developed, where molecular orbital hybridization of electron rich and poor segments can be judiciously employed to precisely control energy levels. Conformation and intermolecular associations can be controlled by peripheral functionalization leading to optimization of crystallization length scales. In particular, the use of rhodanine end groups, coupled electronically through short bridged aromatic chains, has been a successful strategy, with promising device efficiencies attributed to high lying LUMO energy levels and subsequently large open circuit voltages. PMID:26505279

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.

Materials and optimized designs for human-machine interfaces via epidermal electronics.

PubMed

Jeong, Jae-Woong; Yeo, Woon-Hong; Akhtar, Aadeel; Norton, James J S; Kwack, Young-Jin; Li, Shuo; Jung, Sung-Young; Su, Yewang; Lee, Woosik; Xia, Jing; Cheng, Huanyu; Huang, Yonggang; Choi, Woon-Seop; Bretl, Timothy; Rogers, John A

2013-12-17

Thin, soft, and elastic electronics with physical properties well matched to the epidermis can be conformally and robustly integrated with the skin. Materials and optimized designs for such devices are presented for surface electromyography (sEMG). The findings enable sEMG from wide ranging areas of the body. The measurements have quality sufficient for advanced forms of human-machine interface. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Discovery and optimization of p38 inhibitors via computer-assisted drug design.

PubMed

Goldberg, Daniel R; Hao, Ming-Hong; Qian, Kevin C; Swinamer, Alan D; Gao, Donghong A; Xiong, Zhaoming; Sarko, Chris; Berry, Angela; Lord, John; Magolda, Ronald L; Fadra, Tazmeen; Kroe, Rachel R; Kukulka, Alison; Madwed, Jeffrey B; Martin, Leslie; Pargellis, Christopher; Skow, Donna; Song, Jinhua J; Tan, Zhulin; Torcellini, Carol A; Zimmitti, Clare S; Yee, Nathan K; Moss, Neil

2007-08-23

Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.

Modeling and optimization of atomic layer deposition processes on vertically aligned carbon nanotubes.

PubMed

Yazdani, Nuri; Chawla, Vipin; Edwards, Eve; Wood, Vanessa; Park, Hyung Gyu; Utke, Ivo

2014-01-01

Many energy conversion and storage devices exploit structured ceramics with large interfacial surface areas. Vertically aligned carbon nanotube (VACNT) arrays have emerged as possible scaffolds to support large surface area ceramic layers. However, obtaining conformal and uniform coatings of ceramics on structures with high aspect ratio morphologies is non-trivial, even with atomic layer deposition (ALD). Here we implement a diffusion model to investigate the effect of the ALD parameters on coating kinetics and use it to develop a guideline for achieving conformal and uniform thickness coatings throughout the depth of ultra-high aspect ratio structures. We validate the model predictions with experimental data from ALD coatings of VACNT arrays. However, the approach can be applied to predict film conformality as a function of depth for any porous topology, including nanopores and nanowire arrays.

Conformational Analysis of Free and Bound Retinoic Acid

PubMed Central

Fu, Zheng; Li, Xue; Merz, Kenneth M.

2012-01-01

The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and forty-eight 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single-point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the re-refined RA conformers the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug-target structural information for use in structure-based drug discovery applications. PMID:22844234

Structurally controlled deposition of silicon onto nanowires

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

Wang, Weijie; Liu, Zuqin; Han, Song

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

Food packing optimization

NASA Technical Reports Server (NTRS)

1981-01-01

The development of a universal closure lid for the space shuttle food package is reported. The revised lid needs a folded configuration which, when unfolded, fully conforms to the interior surfaces of the food cup. Experimental thermoform molds were fabricated and test lids formed. The lid material not in contact with the food conformed to the cup interior without wrinkles, permitting full nesting of the cups. The final lid design was established and thermoform tooling designed and fabricated. Lids formed on these molds were tested for strength. The heating elements were replaced and repositioned to eliminate any hot spots which may cause warpage.

Flattening maps for the visualization of multibranched vessels.

PubMed

Zhu, Lei; Haker, Steven; Tannenbaum, Allen

2005-02-01

In this paper, we present two novel algorithms which produce flattened visualizations of branched physiological surfaces, such as vessels. The first approach is a conformal mapping algorithm based on the minimization of two Dirichlet functionals. From a triangulated representation of vessel surfaces, we show how the algorithm can be implemented using a finite element technique. The second method is an algorithm which adjusts the conformal mapping to produce a flattened representation of the original surface while preserving areas. This approach employs the theory of optimal mass transport. Furthermore, a new way of extracting center lines for vessel fly-throughs is provided.

Flattening Maps for the Visualization of Multibranched Vessels

PubMed Central

Zhu, Lei; Haker, Steven; Tannenbaum, Allen

2013-01-01

In this paper, we present two novel algorithms which produce flattened visualizations of branched physiological surfaces, such as vessels. The first approach is a conformal mapping algorithm based on the minimization of two Dirichlet functionals. From a triangulated representation of vessel surfaces, we show how the algorithm can be implemented using a finite element technique. The second method is an algorithm which adjusts the conformal mapping to produce a flattened representation of the original surface while preserving areas. This approach employs the theory of optimal mass transport. Furthermore, a new way of extracting center lines for vessel fly-throughs is provided. PMID:15707245

Landau-type expansion for the energy landscape of the designed heteropolymer

NASA Astrophysics Data System (ADS)

Grosberg, Alexander; Pande, Vijay; Tanaka, Toyoichi

1997-03-01

The concept of evolutional optimization of heteropolymer sequences is used to construct the phenomenological theory describing folding/unfoolding kinetics of the polymers with designed sequences. The relevant energy landscape is described in terms of Landau expansion over the powers of the overlap parameter of the current and the native conformations. It is shown that only linear term is sequence (mutation) dependent, the rest being determined by the underlying conformational geometry. The theory os free of the assumptions of the uncorrelated energy landscape type. We demonstrate the power of the theory by comparing data to the simulations and experiments.

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

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

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

2016-03-28

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

Brain Morphometry on Congenital Hand Deformities based on Teichmüller Space Theory.

PubMed

Peng, Hao; Wang, Xu; Duan, Ye; Frey, Scott H; Gu, Xianfeng

2015-01-01

Congenital Hand Deformities (CHD) are usually occurred between fourth and eighth week after the embryo is formed. Failure of the transformation from arm bud cells to upper limb can lead to an abnormal appearing/functioning upper extremity which is presented at birth. Some causes are linked to genetics while others are affected by the environment, and the rest have remained unknown. CHD patients develop prehension through the use of their hands, which affect the brain as time passes. In recent years, CHD have gain increasing attention and researches have been conducted on CHD, both surgically and psychologically. However, the impacts of CHD on brain structure are not well-understood so far. Here, we propose a novel approach to apply Teichmüller space theory and conformal welding method to study brain morphometry in CHD patients. Conformal welding signature reflects the geometric relations among different functional areas on the cortex surface, which is intrinsic to the Riemannian metric, invariant under conformal deformation, and encodes complete information of the functional area boundaries. The computational algorithm is based on discrete surface Ricci flow, which has theoretic guarantees for the existence and uniqueness of the solutions. In practice, discrete Ricci flow is equivalent to a convex optimization problem, therefore has high numerically stability. In this paper, we compute the signatures of contours on general 3D surfaces with surface Ricci flow method, which encodes both global and local surface contour information. Then we evaluated the signatures of pre-central and post-central gyrus on healthy control and CHD subjects for analyzing brain cortical morphometry. Preliminary experimental results from 3D MRI data of CHD/control data demonstrate the effectiveness of our method. The statistical comparison between left and right brain gives us a better understanding on brain morphometry of subjects with Congenital Hand Deformities, in particular, missing the distal part of the upper limb.

The use of time-averaged 3JHH restrained molecular dynamics (tar-MD) simulations for the conformational analysis of five-membered ring systems: methodology and applications.

PubMed

Hendrickx, Pieter M S; Corzana, Francisco; Depraetere, Stefaan; Tourwé, Dirk A; Augustyns, Koen; Martins, José C

2010-02-01

Because of its presence in many molecules of biological relevance, the conformational analysis of five-membered rings using (3)J(HH) scalar coupling data from NMR is a topic of considerable interest. Typically, conformational analysis involves the use of a well-established mathematical procedure, originally developed by de Leeuw et al., that fits two rigid conformations to the available experimental data. This so-called pseudorotation analysis approach is not without problems, however, as chemically unrealistic conformations are sometimes generated from the data. Here, we present our investigations in the use of time-averaged restrained molecular dynamics simulations as a generic tool to determine the conformations that agree with experimental (3)J(HH) scalar coupling data. For this purpose, a set of six ribose-based molecules has been used as model compounds. The influence of several modeling parameters is assessed and optimized values are proposed. The results obtained with the tar-MD approach are compared to those obtained from the two conformer fitting procedure. Interpretation of the latter is facilitated by the introduction of a fitting error analysis that allows mapping the solution space of the fitting procedure. The relative merits of both methods and the advantages that result from the use of a force field and a time-averaged restraint potential for the experimental data are discussed. When combined, both techniques allow an enhanced understanding of the molecules' conformational behavior and prevent possible overinterpretation. In view of the very reasonable computational burden of a tar-MD simulation for the systems investigated here, the approach should be generally applicable. Copyright 2009 Wiley Periodicals, Inc.

Investigation of an "alternate water supply system" in enzymatic hydrolysis in the processive endocellulase Cel7A from Rasamsonia emersonii by molecular dynamics simulation.

PubMed

Sun, Xun; Qian, Meng-Dan; Guan, Shan-Shan; Shan, Ya-Ming; Dong, Ying; Zhang, Hao; Wang, Song; Han, Wei-Wei

2017-02-01

Cel7A from Rasamsonia emersonii is one of the processive endocellulases classified under family 7 glycoside hydrolase. Molecular dynamics simulations were carried out to obtain the optimized sliding and hydrolyzing conformations, in which the reducing ends of sugar chains are located on different sites. Hydrogen bonds are investigated to clarify the interactions between protein and substrate in either conformation. Nine hydrogen bonding interactions are identified in the sliding conformation, and six similar interactions are also found correspondingly in the hydrolyzing conformation. In addition, four strong hydrophobic interactions are also determined. The domain cross-correlation map analysis shows movement correlation of protein including autocorrelation between residues. The root mean square fluctuations analysis represents the various flexibilities of different fragment in the two conformations. Comparing the two conformations reveals the water-supply mechanism of selective hydrolysis of cellulose in Cel7A. The mechanism can be described as follow. When the reducing end of substrate slides from the unhydrolyzing site (sliding conformation) to the hydrolyzing site (hydrolyzing conformation), His225 is pushed down and rotated, the rotation leads to the movement of Glu209 with the interstrand hydrogen bonding in β-sheet. It further makes Asp211 close to the hydrolysis center and provides a water molecule bounding on its carboxyl in the previous unhydrolyzing site. After the hydrolysis takes place and the product is excluded from the enzyme, the Asp211 comes back to its initial position. In summary, Asp211 acts as an elevator to transport outer water molecules into the hydrolysis site for every other glycosidic bond. © 2016 Wiley Periodicals, Inc.

An optimized method to calculate error correction capability of tool influence function in frequency domain

NASA Astrophysics Data System (ADS)

Wang, Jia; Hou, Xi; Wan, Yongjian; Shi, Chunyan

2017-10-01

An optimized method to calculate error correction capability of tool influence function (TIF) in certain polishing conditions will be proposed based on smoothing spectral function. The basic mathematical model for this method will be established in theory. A set of polishing experimental data with rigid conformal tool is used to validate the optimized method. The calculated results can quantitatively indicate error correction capability of TIF for different spatial frequency errors in certain polishing conditions. The comparative analysis with previous method shows that the optimized method is simpler in form and can get the same accuracy results with less calculating time in contrast to previous method.

[Construction and operation status of management system of laboratories of schistosomiasis control institutions in Hubei Province].

PubMed

Zhao-Hui, Zheng; Jun, Qin; Li, Chen; Hong, Zhu; Li, Tang; Zu-Wu, Tu; Ming-Xing, Zeng; Qian, Sun; Shun-Xiang, Cai

2016-10-09

To analyze the construction and operation status of management system of laboratories of schistosomiasis control institutions in Hubei Province, so as to provide the reference for the standardized detection and management of schistosomiasis laboratories. According to the laboratory standard of schistosomiasis at provincial, municipal and county levels, the management system construction and operation status of 60 schistosomiasis control institutions was assessed by the acceptance examination method from 2013 to 2015. The management system was already occupied over all the laboratories of schistosomiasis control institutions and was officially running. There were 588 non-conformities and the inconsistency rate was 19.60%. The non-conformity rate of the management system of laboratory quality control was 38.10% (224 cases) and the non-conformity rate of requirements of instrument and equipment was 23.81% (140 cases). The management system has played an important role in the standardized management of schistosomiasis laboratories.

Strain conformation controls the specificity of cross-species prion transmission in the yeast model.

PubMed

Grizel, Anastasia V; Rubel, Aleksandr A; Chernoff, Yury O

2016-07-03

Transmissible self-assembled fibrous cross-β polymer infectious proteins (prions) cause neurodegenerative diseases in mammals and control non-Mendelian heritable traits in yeast. Cross-species prion transmission is frequently impaired, due to sequence differences in prion-forming proteins. Recent studies of prion species barrier on the model of closely related yeast species show that colocalization of divergent proteins is not sufficient for the cross-species prion transmission, and that an identity of specific amino acid sequences and a type of prion conformational variant (strain) play a major role in the control of transmission specificity. In contrast, chemical compounds primarily influence transmission specificity via favoring certain strain conformations, while the species origin of the host cell has only a relatively minor input. Strain alterations may occur during cross-species prion conversion in some combinations. The model is discussed which suggests that different recipient proteins can acquire different spectra of prion strain conformations, which could be either compatible or incompatible with a particular donor strain.

SU-E-T-621: Planning Methodologies for Cancer of the Anal Canal: Comparing IMRT, Rapid Arc, and Pencil Beam Scanning Proton Beam

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

McGlade, J; Kassaee, A

2015-06-15

Purpose: To evaluate planning methods for anal canal cancer and compare the results of 9-field Intensity Modulated Radiotherapy (IMRT), Volumetric Modulated Arc Therapy (Varian, RapidArc), and Proton Pencil Beam Scanning (PBS). Methods: We generated plans with IMRT, RapidArc (RA) and PBS for twenty patients for both initial phase including nodes and cone down phase of treatment using Eclipe (Varian). We evaluated the advantage of each technique for each phase. RA plans used 2 to 4 arcs and various collimator orientations. PBS used two posterior oblique fields. We evaluated the plans comparing dose volume histogram (DVH), locations of hot spots, andmore » PTV dose conformity. Results: Due to complex shape of target, for RA plans, multiple arcs (>2) are required to achieve optimal PTV conformity. When the PTV exceeds 15 cm in the superior-inferior direction, limitations of deliverability start to dominate. The PTV should be divided into a superior and an inferior structure. The optimization is performed with fixed jaws for each structure and collimator set to 90 degrees for the inferior PTV. Proton PBS plans show little advantage in small bowel sparing when treating the nodes. However, PBS plan reduces volumetric dose to the bladder at the cost of higher doses to the perineal skin. IMRT plans provide good target conformity, but they generate hot spots outside of the target volume. Conclusion: When using one planning technique for entire course of treatment, Multiple arc (>2) RA plans are better as compared to IMRT and PBS plans. When combining techniques, RA for the initial phase in combination with PBS for the cone down phase results in the most optimal plans.« less

FT-IR study and solvent-implicit and explicit effect on stepwise tautomerism of Guanylurea: M06-2X as a case of study

NASA Astrophysics Data System (ADS)

Karimzadeh, Morteza; Manouchehri, Neda; Saberi, Dariush; Niknam, Khodabakhsh

2018-06-01

All 66 conformers of guanylurea were optimized and frequency calculations were performed at M06-2X/6-311++G(d,p) level of theory. Theses conformers were categorized into five tautomers, and the most stable conformer of each tautomer were found. Geometrical parameters indicated that these tautomers have almost planar structure. Complete stepwise tautomerism were studied through both intramolecular proton transfer routs and internal rotations. Results indicated that the proton transfer routs involving four-membered heterocyclic structures were rate-determining steps. Also, intramolecular proton movement having six-membered transition state structures had very low energy barrier comparable to the transition states of internal rotation routs. Differentiation of studied tautomers could easily be done through their FT-IR spectra in the range of 3200 to 3900 cm-1 by comparing absorption bands and intensity of peaks. Solvent-implicit effects on the stability of tautomers were also studied through re-optimization and frequency calculation in four solvents. Water, DMSO, acetone and toluene had stabilization effect on all considered tautomers, but the order of stabilization effect was as follows: water > DMSO > acetone > toluene. Finally, solvent-explicit, base-explicit and acid-explicit effect were also studied by taking place of studied tautomer nearside of acid, base or solvent and optimization of them. Frequency calculation for proton movement by contribution of explicit effect showed that formic acid had a very strong effect on proton transfer from tautomer A1 to tautomer D8 by lowering the energy barrier from 42.57 to 0.8 kcal/mol. In addition, ammonia-explicit effect was found to lower the barrier from 42.57 to 22.46 kcal/mol, but this effect is lower than that of water and methanol-explicit effect.

Methods of Optimal Control of Laser-Plasma Instabilities Using Spike Trains of Uneven Duration and Delay (STUD Pulses)

NASA Astrophysics Data System (ADS)

Afeyan, Bedros

2013-10-01

We have recently introduced and extensively studied a new adaptive method of LPI control. It promises to extend the effectiveness of laser as inertial fusion drivers by allowing active control of stimulated Raman and Brillouin scattering and crossed beam energy transfer. It breaks multi-nanosecond pulses into a series of picosecond (ps) time scale spikes with comparable gaps in between. The height and width of each spike as well as their separations are optimization parameters. In addition, the spatial speckle patterns are changed after a number of successive spikes as needed (from every spike to never). The combination of these parameters allows the taming of parametric instabilities to conform to any desired reduced reflectivity profile, within the bounds of the performance limitations of the lasers. Instead of pulse shaping on hydrodynamical time scales, far faster (from 1 ps to 10 ps) modulations of the laser profile will be needed to implement the STUD pulse program for full LPI control. We will show theoretical and computational evidence for the effectiveness of the STUD pulse program to control LPI. The physics of why STUD pulses work and how optimization can be implemented efficiently using statistical nonlinear optical models and techniques will be explained. We will also discuss a novel diagnostic system employing STUD pulses that will allow the boosted measurement of velocity distribution function slopes on a ps time scale in the small crossing volume of a pump and a probe beam. Various regimes from weak to strong coupling and weak to strong damping will be treated. Novel pulse modulation schemes and diagnostic tools based on time-lenses used in both microscope and telescope modes will be suggested for the execution of the STUD pule program. Work Supported by the DOE NNSA-OFES Joint Program on HEDLP and DOE OFES SBIR Phase I Grants.

Synthetic-Type Control Charts for Time-Between-Events Monitoring

PubMed Central

Yen, Fang Yen; Chong, Khoo Michael Boon; Ha, Lee Ming

2013-01-01

This paper proposes three synthetic-type control charts to monitor the mean time-between-events of a homogenous Poisson process. The first proposed chart combines an Erlang (cumulative time between events, Tr) chart and a conforming run length (CRL) chart, denoted as Synth-Tr chart. The second proposed chart combines an exponential (or T) chart and a group conforming run length (GCRL) chart, denoted as GR-T chart. The third proposed chart combines an Erlang chart and a GCRL chart, denoted as GR-Tr chart. By using a Markov chain approach, the zero- and steady-state average number of observations to signal (ANOS) of the proposed charts are obtained, in order to evaluate the performance of the three charts. The optimal design of the proposed charts is shown in this paper. The proposed charts are superior to the existing T chart, Tr chart, and Synth-T chart. As compared to the EWMA-T chart, the GR-T chart performs better in detecting large shifts, in terms of the zero- and steady-state performances. The zero-state Synth-T4 and GR-Tr (r = 3 or 4) charts outperform the EWMA-T chart for all shifts, whereas the Synth-Tr (r = 2 or 3) and GR-T 2 charts perform better for moderate to large shifts. For the steady-state process, the Synth-Tr and GR-Tr charts are more efficient than the EWMA-T chart in detecting small to moderate shifts. PMID:23755231

The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET.

PubMed

Yang, Mengyi; Peng, Sijia; Sun, Ruirui; Lin, Jingdi; Wang, Nan; Chen, Chunlai

2018-01-09

Off-target binding and cleavage by Cas9 pose major challenges in its application. How the conformational dynamics of Cas9 govern its nuclease activity under on- and off-target conditions remains largely unknown. Here, using intra-molecular single-molecule fluorescence resonance energy transfer measurements, we revealed that Cas9 in apo, sgRNA-bound, and dsDNA/sgRNA-bound forms spontaneously transits among three major conformational states, mainly reflecting significant conformational mobility of the catalytic HNH domain. We also uncovered surprising long-range allosteric communication between the HNH domain and the RNA/DNA heteroduplex at the PAM-distal end to ensure correct positioning of the catalytic site, which demonstrated that a unique proofreading mechanism served as the last checkpoint before DNA cleavage. Several Cas9 residues were likely to mediate the allosteric communication and proofreading step. Modulating interactions between Cas9 and heteroduplex at the PAM-distal end by introducing mutations on these sites provides an alternative route to improve and optimize the CRISPR/Cas9 toolbox. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The great diversity of HMX conformers: probing the potential energy surface using CCSD(T).

PubMed

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

2013-04-25

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of what all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX.

Fluoxetine (Prozac) Binding to Serotonin Transporter Is Modulated by Chloride and Conformational Changes

PubMed Central

Tavoulari, Sotiria; Forrest, Lucy R.; Rudnick, Gary

2010-01-01

Serotonin transporter (SERT) is the main target for widely used antidepressant agents. Several of these drugs, including imipramine, citalopram, sertraline, and fluoxetine (Prozac), bound more avidly to SERT in the presence of Cl–. In contrast, Cl– did not enhance cocaine or paroxetine binding. A Cl– binding site recently identified in SERT, and shown to be important for Cl– dependent transport, was also critical for the Cl– dependence of antidepressant affinity. Mutation of the residues contributing to this site eliminated the Cl–-mediated affinity increase for imipramine and fluoxetine. Analysis of ligand docking to a single state of SERT indicated only small differences in the energy of interaction between bound ligands and Cl–. These differences in interaction energy cannot account for the affinity differences observed for Cl– dependence. However, fluoxetine binding led to a conformational change, detected by cysteine accessibility experiments, that was qualitatively different from that induced by cocaine or other ligands. Given the known Cl– requirement for serotonin-induced conformational changes, we propose that Cl– binding facilitates conformational changes required for optimal binding of fluoxetine and other antidepressant drugs. PMID:19641126

Performance evaluation and modeling of a conformal filter (CF) based real-time standoff hazardous material detection sensor

NASA Astrophysics Data System (ADS)

Nelson, Matthew P.; Tazik, Shawna K.; Bangalore, Arjun S.; Treado, Patrick J.; Klem, Ethan; Temple, Dorota

2017-05-01

Hyperspectral imaging (HSI) systems can provide detection and identification of a variety of targets in the presence of complex backgrounds. However, current generation sensors are typically large, costly to field, do not usually operate in real time and have limited sensitivity and specificity. Despite these shortcomings, HSI-based intelligence has proven to be a valuable tool, thus resulting in increased demand for this type of technology. By moving the next generation of HSI technology into a more adaptive configuration, and a smaller and more cost effective form factor, HSI technologies can help maintain a competitive advantage for the U.S. armed forces as well as local, state and federal law enforcement agencies. Operating near the physical limits of HSI system capability is often necessary and very challenging, but is often enabled by rigorous modeling of detection performance. Specific performance envelopes we consistently strive to improve include: operating under low signal to background conditions; at higher and higher frame rates; and under less than ideal motion control scenarios. An adaptable, low cost, low footprint, standoff sensor architecture we have been maturing includes the use of conformal liquid crystal tunable filters (LCTFs). These Conformal Filters (CFs) are electro-optically tunable, multivariate HSI spectrometers that, when combined with Dual Polarization (DP) optics, produce optimized spectral passbands on demand, which can readily be reconfigured, to discriminate targets from complex backgrounds in real-time. With DARPA support, ChemImage Sensor Systems (CISS™) in collaboration with Research Triangle Institute (RTI) International are developing a novel, real-time, adaptable, compressive sensing short-wave infrared (SWIR) hyperspectral imaging technology called the Reconfigurable Conformal Imaging Sensor (RCIS) based on DP-CF technology. RCIS will address many shortcomings of current generation systems and offer improvements in operational agility and detection performance, while addressing sensor weight, form factor and cost needs. This paper discusses recent test and performance modeling results of a RCIS breadboard apparatus.

SU-C-BRB-02: Automatic Planning as a Potential Strategy for Dose Escalation for Pancreas SBRT?

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

Wang, S; Zheng, D; Ma, R

Purpose: Stereotactic body radiation therapy (SBRT) has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process, and may impede further escalation of the prescription dose. The present study evaluates the potential of an automatic planning system as a dose escalation strategy. Methods: Ten pancreatic cancer patients treated with SBRT were studied retrospectively. SBRT was delivered over 5 consecutive fractions with 6 ∼ 8Gy/fraction. Two plans were generated by Pinnacle Auto-Planning with the original prescription and escalated prescription, respectively. Escalated prescriptionmore » adds 1 Gy/fraction to the original prescription. Manually-created planning volumes were excluded in the optimization goals in order to assess the planning efficiency and quality simultaneously. Critical organs with closest proximity were used to determine the plan normalization to ensure the OAR sparing. Dosimetric parameters including D100, and conformity index (CI) were assessed. Results: Auto-plans directly generate acceptable plans for 70% of the cases without necessity of further improvement, and two more iterations at most are necessary for the rest of the cases. For the pancreas SBRT plans with the original prescription, autoplans resulted in favorable target coverage and PTV conformity (D100 = 96.3% ± 1.48%; CI = 0.88 ± 0.06). For the plans with the escalated prescriptions, no significant target under-dosage was observed, and PTV conformity remains reasonable (D100 = 93.3% ± 3.8%, and CI = 0.84 ± 0.05). Conclusion: Automatic planning, without substantial human-intervention process, results in reasonable PTV coverage and PTV conformity on the premise of adequate OAR sparing for the pancreas SBRT plans with escalated prescription. The results highlight the potential of autoplanning as a dose escalation strategy for pancreas SBRT treatment planning. Further investigations with a larger number of patients are necessary. The project is partially supported by Philips Medical Systems.« less

Conformational and Thermal Stability Improvements for the Large-Scale Production of Yeast-Derived Rabbit Hemorrhagic Disease Virus-Like Particles as Multipurpose Vaccine

PubMed Central

Méndez, Lídice; González, Nemecio; Parra, Francisco; Martín-Alonso, José M.; Limonta, Miladys; Sánchez, Kosara; Cabrales, Ania; Estrada, Mario P.; Rodríguez-Mallón, Alina; Farnós, Omar

2013-01-01

Recombinant virus-like particles (VLP) antigenically similar to rabbit hemorrhagic disease virus (RHDV) were recently expressed at high levels inside Pichia pastoris cells. Based on the potential of RHDV VLP as platform for diverse vaccination purposes we undertook the design, development and scale-up of a production process. Conformational and stability issues were addressed to improve process control and optimization. Analyses on the structure, morphology and antigenicity of these multimers were carried out at different pH values during cell disruption and purification by size-exclusion chromatography. Process steps and environmental stresses in which aggregation or conformational instability can be detected were included. These analyses revealed higher stability and recoveries of properly assembled high-purity capsids at acidic and neutral pH in phosphate buffer. The use of stabilizers during long-term storage in solution showed that sucrose, sorbitol, trehalose and glycerol acted as useful aggregation-reducing agents. The VLP emulsified in an oil-based adjuvant were subjected to accelerated thermal stress treatments. None to slight variations were detected in the stability of formulations and in the structure of recovered capsids. A comprehensive analysis on scale-up strategies was accomplished and a nine steps large-scale production process was established. VLP produced after chromatographic separation protected rabbits against a lethal challenge. The minimum protective dose was identified. Stabilized particles were ultimately assayed as carriers of a foreign viral epitope from another pathogen affecting a larger animal species. For that purpose, a linear protective B-cell epitope from Classical Swine Fever Virus (CSFV) E2 envelope protein was chemically coupled to RHDV VLP. Conjugates were able to present the E2 peptide fragment for immune recognition and significantly enhanced the peptide-specific antibody response in vaccinated pigs. Overall these results allowed establishing improved conditions regarding conformational stability and recovery of these multimers for their production at large-scale and potential use on different animal species or humans. PMID:23460801

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.

MCCE2: improving protein pKa calculations with extensive side chain rotamer sampling.

PubMed

Song, Yifan; Mao, Junjun; Gunner, M R

2009-11-15

Multiconformation continuum electrostatics (MCCE) explores different conformational degrees of freedom in Monte Carlo calculations of protein residue and ligand pK(a)s. Explicit changes in side chain conformations throughout a titration create a position dependent, heterogeneous dielectric response giving a more accurate picture of coupled ionization and position changes. The MCCE2 methods for choosing a group of input heavy atom and proton positions are described. The pK(a)s calculated with different isosteric conformers, heavy atom rotamers and proton positions, with different degrees of optimization are tested against a curated group of 305 experimental pK(a)s in 33 proteins. QUICK calculations, with rotation around Asn and Gln termini, sampling His tautomers and torsion minimum hydroxyls yield an RMSD of 1.34 with 84% of the errors being <1.5 pH units. FULL calculations adding heavy atom rotamers and side chain optimization yield an RMSD of 0.90 with 90% of the errors <1.5 pH unit. Good results are also found for pK(a)s in the membrane protein bacteriorhodopsin. The inclusion of extra side chain positions distorts the dielectric boundary and also biases the calculated pK(a)s by creating more neutral than ionized conformers. Methods for correcting these errors are introduced. Calculations are compared with multiple X-ray and NMR derived structures in 36 soluble proteins. Calculations with X-ray structures give significantly better pK(a)s. Results with the default protein dielectric constant of 4 are as good as those using a value of 8. The MCCE2 program can be downloaded from http://www.sci.ccny.cuny.edu/~mcce. 2009 Wiley Periodicals, Inc.

Implementation of a volumetric modulated arc therapy treatment planning solution for kidney and adrenal stereotactic body radiation therapy

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

Sonier, Marcus, E-mail: Marcus.Sonier@bccancer.bc.ca; Chu, William; Department of Radiation Oncology, University of Toronto, Toronto, ON

To develop a volumetric modulated arc therapy (VMAT) treatment planning solution in the treatment of primary renal cell carcinoma and oligometastatic adrenal lesions with stereotactic body radiation therapy. Single-arc VMAT plans (n = 5) were compared with clinically delivered step-and-shoot intensity-modulated radiotherapy (IMRT) with planning target volume coverage normalized between techniques. Target volume conformity, organ-at-risk (OAR) dose, treatment time, and monitor units were compared. A VMAT planning solution, created from a combination of arc settings and optimization constraints, auto-generated treatment plans in a single optimization. The treatment planning solution was evaluated on 15 consecutive patients receiving kidney and adrenal stereotacticmore » body radiation therapy. Treatment time was reduced from 13.0 ± 2.6 to 4.0 ± 0.9 minutes for IMRT and VMAT, respectively. The VMAT planning solution generated treatment plans with increased target homogeneity, improved 95% conformity index, and a reduced maximum point dose to nearby OARs but with increased intermediate dose to distant OARs. The conformity of the 95% isodose improved from 1.32 ± 0.39 to 1.12 ± 0.05 for IMRT and VMAT treatment plans, respectively. Evaluation of the planning solution showed clinically acceptable dose distributions for 13 of 15 cases with tight conformity of the prescription isodose to the planning target volume of 1.07 ± 0.04, delivering minimal dose to OARs. The introduction of a stereotactic body radiation therapy VMAT treatment planning solution improves the efficiency of planning and delivery time, producing treatment plans of comparable or superior quality to IMRT in the case of primary renal cell carcinoma and oligometastatic adrenal lesions.« less

Microwave-Assisted Extraction, Chemical Structures, and Chain Conformation of Polysaccharides from a Novel Cordyceps Sinensis Fungus UM01.

PubMed

Cheong, Kit-Leong; Wang, Lan-Ying; Wu, Ding-Tao; Hu, De-Jun; Zhao, Jing; Li, Shao-Ping

2016-09-01

Cordyceps sinensis is a well-known tonic food with broad medicinal properties. The aim of the present study was to investigate the optimization of microwave-assisted extraction (MAE) and characterize chemical structures and chain conformation of polysaccharides from a novel C. sinensis fungus UM01. Ion-exchange and gel filtration chromatography were used to purify the polysaccharides. The chemical structure of purified polysaccharide was determined through gas chromatography-mass spectrometry. Moreover, high performance size exclusion chromatography combined with refractive index detector and multiangle laser light scattering were conducted to analyze the molecular weight (Mw ) and chain conformation of purified polysaccharide. Based on the orthogonal design L9 , optimal MAE conditions could be obtained through 1300 W of microwave power, with a 5-min irradiation time at a solid to water ratio of 1:60, generating the highest extraction yield of 6.20%. Subsequently, the polysaccharide UM01-S1 was purified. The UM01-S1 is a glucan-type polysaccharide with a (1→4)-β-d-glucosyl backbone and branching points located at O-3 of Glcp with a terminal-d-Glcp. The Mw , radius of gyration (Rg ) and hydrodynamic radius (Rh ) of UM01-S1 were determined as 5.442 × 10(6)  Da, 21.8 and 20.2 nm, respectively. Using the polymer solution theory, the exponent (ν) value of the power law function was calculated as 0.38, and the shape factor (ρ = Rg /Rh ) was 1.079, indicating that UM01-S1 has a sphere-like conformation with a branched structure in an aqueous solution. These results provide fundamental information for the future application of polysaccharides from cultured C. sinensis in health and functional food area. © 2016 Institute of Food Technologists®

TU-FG-201-10: Quality Management of Accelerated Partial Breast Irradiation (APBI) Plans

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

Ji, H; Lorio, V; Cernica, G

2016-06-15

Purpose: Since 2008, over 700 patients received high dose rate (HDR) APBI treatment at Virginia Hospital Center. The complexity involved in the planning process demonstrated a broad variation between patient geometry across all applicators, in relation to anatomical regions of interest. A quality management program instituting various metrics was implemented in March 2013 with the goal of ensuring an optimal plan is achieved for each patient. Methods: For each plan, an in-house complexity index, geometric conformity index, and plan quality index were defined. These indices were obtained for all patients treated. For patients treated after the implementation, the conformity indexmore » and quality index were maximized while other dosimetric limits, such as maximum skin and rib doses, were strictly kept. Subsequently, all evaluation parameters and applicator information were placed in a database for cross-evaluation with similar complexity. Results: Both the conformity and quality indices show good correlation with the complexity index. They decrease as complexity increases for all applicators. Multi lumen type balloon applicators demonstrate a minimal advantage over single lumen applicators in increasingly complex patient geometries, as compared to SAVI applicators which showed considerably greater advantage in these circumstances. After the implementation of the in-house planning protocol, there is a direct improvement of quality for SAVI plans. Conclusion: Due to their interstitial nature, SAVI devices show a better conformity in comparison to balloon-based devices regardless of the number of lumens, especially in complex cases. The quality management program focuses on optimizing indices by utilizing prior planning knowledge based on complexity levels. The database of indices assists in decision making and has subsequently aided in balancing the experience level among planners. This approach has made APBI planning more robust for patient care, with a measurable improvement in the plan quality.« less

Molecular Modeling of the Binding Structures in the Interlayer Adsorption of a Tetracycline Antibiotic by Smectite Clays

NASA Astrophysics Data System (ADS)

Aristilde, L.

2009-12-01

A controlling factor in the fate of antibiotics in the environment is their sequestration in soil particles including clay minerals. Of special interest is the interlayer adsorption by smectite clays, which has been shown to influence both the bioavailability and persistence of antibiotics in the soil environment. However, the interlayer structures of the bound antibiotics, essential to an accurate understanding of the adsorption mechanisms, are not well understood. Molecular simulations of oxytetracycline (OTC) with a model montmorillonite (MONT) clay were performed to gain insights into these structures for tetracycline antibiotics. Monte Carlo simulations were used for explorations of the clay layer spacing required for the adsorption of the antibiotic under different hydration states of the clay interlayer; these preliminary results were validated with previous X-ray diffraction patterns obtained following sorption experiments of OTC with MONT. Molecular dynamics relaxation simulations were performed subsequently in order to obtain geometry-optimized structures of the binding conformations of the intercalated antibiotic in the model MONT layers. This study contributes to a mechanistic understanding of the factors controlling the interlayer adsorption of the tetracycline antibiotics by the expandable smectite clay minerals. Figure 1. Optimized Monte Carlo simulation cell of OTC in the interlayer of MONT: perspective side view (top) and bottom view (bottom).

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

PubMed

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

2006-10-25

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

Modeling protein conformational changes by iterative fitting of distance constraints using reoriented normal modes.

PubMed

Zheng, Wenjun; Brooks, Bernard R

2006-06-15

Recently we have developed a normal-modes-based algorithm that predicts the direction of protein conformational changes given the initial state crystal structure together with a small number of pairwise distance constraints for the end state. Here we significantly extend this method to accurately model both the direction and amplitude of protein conformational changes. The new protocol implements a multisteps search in the conformational space that is driven by iteratively minimizing the error of fitting the given distance constraints and simultaneously enforcing the restraint of low elastic energy. At each step, an incremental structural displacement is computed as a linear combination of the lowest 10 normal modes derived from an elastic network model, whose eigenvectors are reorientated to correct for the distortions caused by the structural displacements in the previous steps. We test this method on a list of 16 pairs of protein structures for which relatively large conformational changes are observed (root mean square deviation >3 angstroms), using up to 10 pairwise distance constraints selected by a fluctuation analysis of the initial state structures. This method has achieved a near-optimal performance in almost all cases, and in many cases the final structural models lie within root mean square deviation of 1 approximately 2 angstroms from the native end state structures.

Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions.

PubMed

Twomey, Edward C; Cordasco, Dana F; Kozuch, Stephen D; Wei, Yufeng

2013-01-01

Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.

Differential Enzyme Flexibility Probed Using Solid-State Nanopores.

PubMed

Hu, Rui; Rodrigues, João V; Waduge, Pradeep; Yamazaki, Hirohito; Cressiot, Benjamin; Chishti, Yasmin; Makowski, Lee; Yu, Dapeng; Shakhnovich, Eugene; Zhao, Qing; Wanunu, Meni

2018-05-22

Enzymes and motor proteins are dynamic macromolecules that coexist in a number of conformations of similar energies. Protein function is usually accompanied by a change in structure and flexibility, often induced upon binding to ligands. However, while measuring protein flexibility changes between active and resting states is of therapeutic significance, it remains a challenge. Recently, our group has demonstrated that breadth of signal amplitudes in measured electrical signatures as an ensemble of individual protein molecules is driven through solid-state nanopores and correlates with protein conformational dynamics. Here, we extend our study to resolve subtle flexibility variation in dihydrofolate reductase mutants from unlabeled single molecules in solution. We first demonstrate using a canonical protein system, adenylate kinase, that both size and flexibility changes can be observed upon binding to a substrate that locks the protein in a closed conformation. Next, we investigate the influence of voltage bias and pore geometry on the measured electrical pulse statistics during protein transport. Finally, using the optimal experimental conditions, we systematically study a series of wild-type and mutant dihydrofolate reductase proteins, finding a good correlation between nanopore-measured protein conformational dynamics and equilibrium bulk fluorescence probe measurements. Our results unequivocally demonstrate that nanopore-based measurements reliably probe conformational diversity in native protein ensembles.

Elucidation of the active conformation of vancomycin dimers with antibacterial activity against vancomycin-resistant bacteria.

PubMed

Nakamura, Jun; Yamashiro, Hidenori; Hayashi, Sayaka; Yamamoto, Mami; Miura, Kenji; Xu, Shu; Doi, Takayuki; Maki, Hideki; Yoshida, Osamu; Arimoto, Hirokazu

2012-10-01

Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin-resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC-VV-linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin-resistant Staphylococcus aureus in vitro. In addition, double-disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin-resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin-resistant strains. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structural, vibrational spectroscopic and nonlinear optical activity studies on 2-hydroxy- 3, 5-dinitropyridine: A DFT approach

NASA Astrophysics Data System (ADS)

Asath, R. Mohamed; Premkumar, S.; Jawahar, A.; Mathavan, T.; Dhas, M. Kumara; Benial, A. Milton Franklin

2015-06-01

The conformational analysis was carried out for 2-Hydroxy- 3, 5-dinitropyridine molecule using potential energy surface scan and the most stable optimized conformer was predicted. The vibrational frequencies and Mulliken atomic charge distribution were calculated for the optimized geometry of the molecule using DFT/B3LYP cc-pVQZ basis set by Gaussian 09 Program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using VEDA 4.0 program. In the Frontier molecular orbitals analysis, the molecular reactivity, kinetic stability, intramolecular charge transfer studies and the calculation of ionization energy, electron affinity, global hardness, chemical potential, electrophilicity index and softness values of the title molecule were carried out. The nonlinear optical activity of the molecule was studied by means of first order hyperpolarizability, which was computed as 7.64 times greater than urea. The natural bond orbital analysis was performed to confirm the nonlinear optical activity of the molecule.

Near-horizon conformal symmetry and black hole entropy.

PubMed

Carlip, S

2002-06-17

Near an event horizon, the action of general relativity acquires a new asymptotic conformal symmetry. For two-dimensional dilaton gravity, this symmetry results in a chiral Virasoro algebra, and Cardy's formula for the density of states reproduces the Bekenstein-Hawking entropy. This lends support to the notion that black hole entropy is controlled universally by conformal symmetry near the horizon.

Prelude and Fugue, predicting local protein structure, early folding regions and structural weaknesses.

PubMed

Kwasigroch, Jean Marc; Rooman, Marianne

2006-07-15

Prelude&Fugue are bioinformatics tools aiming at predicting the local 3D structure of a protein from its amino acid sequence in terms of seven backbone torsion angle domains, using database-derived potentials. Prelude(&Fugue) computes all lowest free energy conformations of a protein or protein region, ranked by increasing energy, and possibly satisfying some interresidue distance constraints specified by the user. (Prelude&)Fugue detects sequence regions whose predicted structure is significantly preferred relative to other conformations in the absence of tertiary interactions. These programs can be used for predicting secondary structure, tertiary structure of short peptides, flickering early folding sequences and peptides that adopt a preferred conformation in solution. They can also be used for detecting structural weaknesses, i.e. sequence regions that are not optimal with respect to the tertiary fold. http://babylone.ulb.ac.be/Prelude_and_Fugue.

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

Battles, Michael B.; Langedijk, Johannes P.; Furmanova-Hollenstein, Polina

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitorsmore » or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.« less

Variational calculation of macrostate transition rates

NASA Astrophysics Data System (ADS)

Ulitsky, Alex; Shalloway, David

1998-08-01

We develop the macrostate variational method (MVM) for computing reaction rates of diffusive conformational transitions in multidimensional systems by a variational coarse-grained "macrostate" decomposition of the Smoluchowski equation. MVM uses multidimensional Gaussian packets to identify and focus computational effort on the "transition region," a localized, self-consistently determined region in conformational space positioned roughly between the macrostates. It also determines the "transition direction" which optimally specifies the projected potential of mean force for mean first-passage time calculations. MVM is complementary to variational transition state theory in that it can efficiently solve multidimensional problems but does not accommodate memory-friction effects. It has been tested on model 1- and 2-dimensional potentials and on the 12-dimensional conformational transition between the isoforms of a microcluster of six-atoms having only van der Waals interactions. Comparison with Brownian dynamics calculations shows that MVM obtains equivalent results at a fraction of the computational cost.

Analysis of vibrational, structural, and electronic properties of rivastigmine by density functional theory

NASA Astrophysics Data System (ADS)

Prasad, O.; Sinha, L.; Misra, N.; Narayan, V.; Kumar, N.; Kumar, A.

2010-09-01

The present work deals with the structural, electronic, and vibrational analysis of rivastigmine. Rivastigmine, an antidementia medicament, is credited with significant therapeutic effects on the cognitive, functional, and behavioural problems that are commonly associated with Alzheimer’s dementia. For rivastigmine, a number of minimum energy conformations are possible. The geometry of twelve possible conformers has been analyzed and the most stable conformer was further optimized at a higher basis set. The electronic properties and vibrational frequencies were then calculated using a density functional theory at the B3LYP level with the 6-311+G(d, p) basis set. The different molecular surfaces have also been drawn to understand the activity of the molecule. A narrower frontier orbital energy gap in rivastigmine makes it softer and more reactive than water and dimethylfuran. The calculated value of the dipole moment is 2.58 debye.

Molecular mechanism of respiratory syncytial virus fusion inhibitors

PubMed Central

Battles, Michael B; Langedijk, Johannes P; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H M; Koul, Anil; Arnoult, Eric; Peeples, Mark E; Roymans, Dirk; McLellan, Jason S

2016-01-01

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors. PMID:26641933

Complex formation and vectorization of a phosphorothioate oligonucleotide with an amphipathic leucine- and lysine-rich peptide: study at molecular and cellular levels.

PubMed

Boukhalfa-Heniche, Fatima-Zohra; Hernández, Belén; Gaillard, Stéphane; Coïc, Yves-Marie; Huynh-Dinh, Tam; Lecouvey, Marc; Seksek, Olivier; Ghomi, Mahmoud

2004-04-15

Optical spectroscopic techniques such as CD, Raman scattering, and fluorescence imaging allowed us to analyze the complex formation and vectorization of a single-stranded 20-mer phosphorothioate oligodeoxynucleotide with a 15-mer amphipathic peptide at molecular and cellular levels. Different solvent mixtures (methanol and water) and molecular ratios of peptide/oligodeoxynucleotide complexes were tested in order to overcome the problems related to solubility. Optimal conditions for both spectroscopic and cellular experiments were obtained with the molecular ratio peptide/oligodeoxynucleotide equal to 21:4, corresponding to a 7:5 ratio for their respective +/- charge ratio. At the molecular level, CD and Raman spectra were consistent with a alpha-helix conformation of the peptide in water or in a methanol-water mixture. The presence of methanol increased considerably the solubility of the peptide without altering its alpha-helix conformation, as evidenced by CD and Raman spectroscopies. UV absorption melting profile of the oligodeoxynucleotide gave rise to a flat melting profile, corresponding to its random structure in solution. Raman spectra of oligodeoxynucleotide/peptide complexes could only be studied in methanol/water mixture solutions. Drastic changes observed in Raman spectra have undoubtedly shown: (a) the perturbation occurred in the peptide secondary structure, and (b) possible interaction between the lysine residues of the peptide and the oligodeoxynucleotide. At the cellular level, the complex was prepared in a mixture of 10% methanol and 90% cell medium. Cellular uptake in optimal conditions for the oligodeoxynucleotide delivery with low cytotoxicity was controlled by fluorescence imaging allowing to specifically locate the compacted oligonucleotide labeled with fluorescein at its 5'-terminus with the peptide into human glioma cells after 1 h of incubation at 37 degrees C. Copyright 2004 Wiley Periodicals, Inc.

MO-F-CAMPUS-T-01: Radiosurgery of Multiple Brain Metastases with Single-Isocenter VMAT: Optimizing Treatment Geometry to Reduce Normal Brain Dose

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

Wu, Q; Snyder, K; Liu, C

Purpose: To develop an optimization algorithm to reduce normal brain dose by optimizing couch and collimator angles for single isocenter multiple targets treatment of stereotactic radiosurgery. Methods: Three metastatic brain lesions were retrospectively planned using single-isocenter volumetric modulated arc therapy (VMAT). Three matrices were developed to calculate the projection of each lesion on Beam’s Eye View (BEV) by the rotating couch, collimator and gantry respectively. The island blocking problem was addressed by computing the total area of open space between any two lesions with shared MLC leaf pairs. The couch and collimator angles resulting in the smallest open areas weremore » the optimized angles for each treatment arc. Two treatment plans with and without couch and collimator angle optimization were developed using the same objective functions and to achieve 99% of each target volume receiving full prescription dose of 18Gy. Plan quality was evaluated by calculating each target’s Conformity Index (CI), Gradient Index (GI), and Homogeneity index (HI), and absolute volume of normal brain V8Gy, V10Gy, V12Gy, and V14Gy. Results: Using the new couch/collimator optimization strategy, dose to normal brain tissue was reduced substantially. V8, V10, V12, and V14 decreased by 2.3%, 3.6%, 3.5%, and 6%, respectively. There were no significant differences in the conformity index, gradient index, and homogeneity index between two treatment plans with and without the new optimization algorithm. Conclusion: We have developed a solution to the island blocking problem in delivering radiation to multiple brain metastases with shared isocenter. Significant reduction in dose to normal brain was achieved by using optimal couch and collimator angles that minimize total area of open space between any of the two lesions with shared MLC leaf pairs. This technique has been integrated into Eclipse treatment system using scripting API.« less

40 CFR 89.511 - Suspension and revocation of certificates of conformity.

Code of Federal Regulations, 2010 CFR

2010-07-01

... ENGINES Selective Enforcement Auditing § 89.511 Suspension and revocation of certificates of conformity... proposed quality control and/or quality assurance measures to be taken by the manufacturer to prevent...

40 CFR 90.511 - Suspension and revocation of certificates of conformity.

Code of Federal Regulations, 2010 CFR

2010-07-01

... KILOWATTS Selective Enforcement Auditing § 90.511 Suspension and revocation of certificates of conformity... proposed quality control and/or quality assurance measures to be taken by the manufacturer to prevent...

Investigation of the binding of a carbohydrate-mimetic peptide to its complementary anticarbohydrate antibody by STD-NMR spectroscopy and molecular-dynamics simulations.

PubMed

Szczepina, Monica G; Bleile, Dustin W; Pinto, B Mario

2011-10-04

Saturation transfer difference (STD)-NMR spectroscopy was used to probe experimentally the bioactive solution conformation of the carbohydrate mimic MDWNMHAA 1 of the O-polysaccharide of Shigella flexneri Y when bound to its complementary antibody, mAb SYA/J6. Molecular dynamics simulations using the ZymeCAD™ Molecular Dynamics platform were also undertaken to give a more accurate picture of the conformational flexibility and the possibilities for bound ligand conformations. The ligand topology, or the dynamic epitope, was mapped with the CORCEMA-ST (COmplete Relaxation and Conformational Exchange Matrix Analysis of Saturation Transfer) program that calculates a total matrix analysis of relaxation and exchange effects to generate predicted STD-NMR intensities from simulation. The comparison of these predicted STD enhancements with experimental data was used to select a representative binding mode. A protocol that employed theoretical STD effects calculated at snapshots during the entire course of a molecular dynamics (MD) trajectory of the peptide bound to the Fv portion of the antibody, and not the averaged atomic positions of receptor-ligand complexes, was also examined. In addition, the R factor was calculated on the basis of STD (fit) to avoid T1 bias, and an effective R factor, R(eff), was defined such that if the calculated STD (fit) for proton k was within error of the experimental STD (fit) for proton k, then that calculated STD (fit) for proton k was not included in the calculation of the R factor. This protocol was effective in deriving the antibody-bound solution conformation of the peptide which also differed from the bound conformation determined by X-ray crystallography; however, several discrepancies between experimental and calculated STD (fit) values were observed. The bound conformation was therefore further refined with a simulated annealing refinement protocol known as STD-NMR intensity-restrained CORCEMA optimization (SICO) to give a more accurate representation of the bound peptide epitope. Further optimization was required in this case, but a satisfactory correlation between experimental and calculated STD values was obtained. Attempts were also made to obtain STD enhancements with a synthetic pentasaccharide hapten, corresponding to the O-polysaccharide, while bound to the antibody. However, unfavorable kinetics of binding in this system prevented sufficient STD build-up, which, in turn, hindered a rigorous analysis via full STD build-up curves. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The use of colloidal microgels for the controlled delivery of proteins and peptides

NASA Astrophysics Data System (ADS)

Cornelius, Victoria J.; Snowden, Martin J.; Mitchell, John C.

2007-01-01

Colloidal microgels may be used for the absorption and controlled release of confirmationally sensitive molecules such as proteins and peptides. These monodisperse microgels are easily prepared in a single pot reaction from e.g. Nisopropylacrylamide, butyl acrylate and methacrylic acid in the presence of a cross-linking agent and a suitable free radical initiator. The resultant materials display dramatic conformational changes in aqueous dispersion in response to changes in e.g. environmental pH. Colloidal microgels are capable of absorbing a range of different proteins and peptides at one pH, affording them protection by changing the conformation of the microgel following a pH change. A further change in environmental pH will allow the microgel to adopt a more extended confirmation and therefore allow the release of the encapsulated material. In the case of e.g. insulin this would offer the possibility of an oral delivery route. At the pH of stomach the microgel adopts a compact conformation, "protecting" the protein from denaturation. As the pH increases passing into the GI tract, the microgel changes its conformation to a more expanded form and thereby allows the protein to be released. Colloidal microgels offer an opportunity for the controlled release of conformationally sensitive protein and peptide molecules via an oral route.

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.

Highly Disordered Amyloid-β Monomer Probed by Single-Molecule FRET and MD Simulation.

PubMed

Meng, Fanjie; Bellaiche, Mathias M J; Kim, Jae-Yeol; Zerze, Gül H; Best, Robert B; Chung, Hoi Sung

2018-02-27

Monomers of amyloid-β (Aβ) protein are known to be disordered, but there is considerable controversy over the existence of residual or transient conformations that can potentially promote oligomerization and fibril formation. We employed single-molecule Förster resonance energy transfer (FRET) spectroscopy with site-specific dye labeling using an unnatural amino acid and molecular dynamics simulations to investigate conformations and dynamics of Aβ isoforms with 40 (Aβ40) and 42 residues (Aβ42). The FRET efficiency distributions of both proteins measured in phosphate-buffered saline at room temperature show a single peak with very similar FRET efficiencies, indicating there is apparently only one state. 2D FRET efficiency-donor lifetime analysis reveals, however, that there is a broad distribution of rapidly interconverting conformations. Using nanosecond fluorescence correlation spectroscopy, we measured the timescale of the fluctuations between these conformations to be ∼35 ns, similar to that of disordered proteins. These results suggest that both Aβ40 and Aβ42 populate an ensemble of rapidly reconfiguring unfolded states, with no long-lived conformational state distinguishable from that of the disordered ensemble. To gain molecular-level insights into these observations, we performed molecular dynamics simulations with a force field optimized to describe disordered proteins. We find, as in experiments, that both peptides populate configurations consistent with random polymer chains, with the vast majority of conformations lacking significant secondary structure, giving rise to very similar ensemble-averaged FRET efficiencies. Published by Elsevier Inc.

New parasite inhibitors encompassing novel conformationally-locked 5'-acyl sulfamoyl adenosines.

PubMed

Dixit, Shailesh S; Upadhayaya, Ram Shankar; Chattopadhyaya, Jyoti

2012-08-14

We describe the design, synthesis and biological evaluation of conformationally-locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North-type) nucleosides have been synthesized by covalently attaching a 4'-CH(2)-O-2' bridge () across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC(50) = 0.25-0.51 μM. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC(50) = 0.25 μM) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC(50) >4 μM) and in diploid human fibroblasts MRC-5 cell lines (CC(50) 4 μM). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5'-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.

Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)

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

Specht, Lena, E-mail: lena.specht@regionh.dk; Yahalom, Joachim; Illidge, Tim

2014-07-15

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solelymore » on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.« less

Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG).

PubMed

Specht, Lena; Yahalom, Joachim; Illidge, Tim; Berthelsen, Anne Kiil; Constine, Louis S; Eich, Hans Theodor; Girinsky, Theodore; Hoppe, Richard T; Mauch, Peter; Mikhaeel, N George; Ng, Andrea

2014-07-15

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines. Copyright © 2014 Elsevier Inc. All rights reserved.

On conforming mixed finite element methods for incompressible viscous flow problems

NASA Technical Reports Server (NTRS)

Gunzburger, M. D; Nicolaides, R. A.; Peterson, J. S.

1982-01-01

The application of conforming mixed finite element methods to obtain approximate solutions of linearized Navier-Stokes equations is examined. Attention is given to the convergence rates of various finite element approximations of the pressure and the velocity field. The optimality of the convergence rates are addressed in terms of comparisons of the approximation convergence to a smooth solution in relation to the best approximation available for the finite element space used. Consideration is also devoted to techniques for efficient use of a Gaussian elimination algorithm to obtain a solution to a system of linear algebraic equations derived by finite element discretizations of linear partial differential equations.

Full three-dimensional isotropic carpet cloak designed by quasi-conformal transformation optics.

PubMed

Silva, Daniely G; Teixeira, Poliane A; Gabrielli, Lucas H; Junqueira, Mateus A F C; Spadoti, Danilo H

2017-09-18

A fully three-dimensional carpet cloak presenting invisibility in all viewing angles is theoretically demonstrated. The design is developed using transformation optics and three-dimensional quasi-conformal mapping. Parametrization strategy and numerical optimization of the coordinate transformation deploying a quasi-Newton method is applied. A discussion about the minimum achievable anisotropy in the 3D transformation optics is presented. The method allows to reduce the anisotropy in the cloak and an isotropic medium could be considered. Numerical simulations confirm the strategy employed enabling the design of an isotropic reflectionless broadband carpet cloak independently of the incident light direction and polarization.

Three Dimensional Sector Design with Optimal Number of Sectors

NASA Technical Reports Server (NTRS)

Xue, Min

2010-01-01

In the national airspace system, sectors get overloaded due to high traffic demand and inefficient airspace designs. Overloads can be eliminated in some cases by redesigning sector boundaries. This paper extends the Voronoi-based sector design method by automatically selecting the number of sectors, allowing three-dimensional partitions, and enforcing traffic pattern conformance. The method was used to design sectors at Fort-Worth and Indianapolis centers for current traffic scenarios. Results show that new designs can eliminate overloaded sectors, although not in all cases, reduce the number of necessary sectors, and conform to major traffic patterns. Overall, the new methodology produces enhanced and efficient sector designs.

Man as the main component of the closed ecological system of the spacecraft or planetary station.

PubMed

Parin, V V; Adamovich, B A

1968-01-01

Current life-support systems of the spacecraft provide human requirements for food, water and oxygen only. Advanced life-support systems will involve man as their main component and will ensure completely his material and energy requirements. The design of individual components of such systems will assure their entire suitability and mutual control effects. Optimization of the performance of the crew and ecological system, on the basis of the information characterizing their function, demands efficient methods of collection and treatment of the information obtained through wireless recording of physiological parameters and their automatic treatment. Peculiarities of interplanetary missions and planetary stations make it necessary to conform the schedule of physiological recordings with the work-and-rest cycle of the space crew and inertness of components of the ecological system, especially of those responsible for oxygen regeneration. It is rational to model ecological systems and their components, taking into consideration the correction effect of the information on the health conditions and performance of the crewmen. Wide application of physiological data will allow the selection of optimal designs and sharply increase reliability of ecological systems.

Parameters optimization for magnetic resonance coupling wireless power transmission.

PubMed

Li, Changsheng; Zhang, He; Jiang, Xiaohua

2014-01-01

Taking maximum power transmission and power stable transmission as research objectives, optimal design for the wireless power transmission system based on magnetic resonance coupling is carried out in this paper. Firstly, based on the mutual coupling model, mathematical expressions of optimal coupling coefficients for the maximum power transmission target are deduced. Whereafter, methods of enhancing power transmission stability based on parameters optimal design are investigated. It is found that the sensitivity of the load power to the transmission parameters can be reduced and the power transmission stability can be enhanced by improving the system resonance frequency or coupling coefficient between the driving/pick-up coil and the transmission/receiving coil. Experiment results are well conformed to the theoretical analysis conclusions.

Lattice Simulations and Infrared Conformality

DOE PAGES

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

2011-09-01

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

Closed form solutions of two time fractional nonlinear wave equations

NASA Astrophysics Data System (ADS)

Akbar, M. Ali; Ali, Norhashidah Hj. Mohd.; Roy, Ripan

2018-06-01

In this article, we investigate the exact traveling wave solutions of two nonlinear time fractional wave equations. The fractional derivatives are described in the sense of conformable fractional derivatives. In addition, the traveling wave solutions are accomplished in the form of hyperbolic, trigonometric, and rational functions involving free parameters. To investigate such types of solutions, we implement the new generalized (G‧ / G) -expansion method. The extracted solutions are reliable, useful and suitable to comprehend the optimal control problems, chaotic vibrations, global and local bifurcations and resonances, furthermore, fission and fusion phenomena occur in solitons, the relativistic energy-momentum relation, scalar electrodynamics, quantum relativistic one-particle theory, electromagnetic interactions etc. The results reveal that the method is very fruitful and convenient for exploring nonlinear differential equations of fractional order treated in theoretical physics.

Platinum-Based Nanocages with Subnanometer-Thick Walls and Well-Defined Facets

DOE PAGES

Zhang, Lei; Wang, Xue; Chi, Miaofang; ...

2015-07-24

A cost-effective catalyst should have a high dispersion of the active atoms, together with a controllable surface structure for the optimization of activity, selectivity, or both. We fabricated nanocages by depositing a few atomic layers of platinum (Pt) as conformal shells on palladium (Pd) nanocrystals with well-defined facets and then etching away the Pd templates. Density functional theory calculations suggest that the etching is initiated via a mechanism that involves the formation of vacancies through the removal of Pd atoms incorporated into the outermost layer during the deposition of Pt. With the use of Pd nanoscale cubes and octahedra asmore » templates, we obtained Pt cubic and octahedral nanocages enclosed by {100} and {111} facets, respectively, which exhibited distinctive catalytic activities toward oxygen reduction.« less

Dynamic and Progressive Control of DNA Origami Conformation by Modulating DNA Helicity with Chemical Adducts.

PubMed

Chen, Haorong; Zhang, Hanyu; Pan, Jing; Cha, Tae-Gon; Li, Shiming; Andréasson, Joakim; Choi, Jong Hyun

2016-05-24

DNA origami has received enormous attention for its ability to program complex nanostructures with a few nanometer precision. Dynamic origami structures that change conformation in response to environmental cues or external signals hold great promises in sensing and actuation at the nanoscale. The reconfiguration mechanism of existing dynamic origami structures is mostly limited to single-stranded hinges and relies almost exclusively on DNA hybridization or strand displacement. Here, we show an alternative approach by demonstrating on-demand conformation changes with DNA-binding molecules, which intercalate between base pairs and unwind DNA double helices. The unwinding effect modulates the helicity mismatch in DNA origami, which significantly influences the internal stress and the global conformation of the origami structure. We demonstrate the switching of a polymerized origami nanoribbon between different twisting states and a well-constrained torsional deformation in a monomeric origami shaft. The structural transformation is shown to be reversible, and binding isotherms confirm the reconfiguration mechanism. This approach provides a rapid and reversible means to change DNA origami conformation, which can be used for dynamic and progressive control at the nanoscale.

Conformal Nanocoatings with Uniform and Controllable Thickness on Microstructured Surfaces: A General Assembly Route.

PubMed

Hou, Yi; Wang, Zhen; Cai, Chao; Hao, Xi; Li, Dongdong; Zhao, Ning; Zhao, Yiping; Chen, Li; Ma, Hongwei; Xu, Jian

2018-02-01

Assembling nanoparticles (NPs) on various surfaces are intensively investigated for the construction of functional nanocoatings; however, it is still a challenge to fabricate conformal nanocoatings uniformly on surfaces having micro- or nanostructures. Herein, it is demonstrated that the negatively charged SiO 2 NPs and the positively charged silicon coupling agent can be assembled layer-by-layer on the microstructures based on the combination of electrostatic interaction and condensation reaction. Conformal nanocoatings with controllable thickness are formed on the microstructured surfaces with different compositions and morphologies. The formation mechanism is confirmed by using quartz crystal microbalance with dissipation (QCM-D) to study the assembly process in real time. The universality of this method is illustrated by using other reactive building blocks with opposite charge to build up the conformal nanocoatings. Application in the preparation of antireflective nanocoatings on nonplanar optical materials is demonstrated. This simple, versatile, and scalable strategy for the preparation of conformal nanocoatings is promising for practical applications. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modulation of phase transition of thermosensitive liposomes with leucine zipper-structured lipopeptides.

PubMed

Xu, Xiejun; Xiao, Xingqing; Wang, Yiming; Xu, Shouhong; Liu, Honglai

2018-06-13

Targeted therapy for cancer requires thermosensitive components in drug carriers for controlled drug release against viral cells. The conformational transition characteristic of leucine zipper-structured lipopeptides is utilized in our lab to modulate the phase transition temperature of liposomes, thus achieving temperature-responsive control. In this study, we computationally examined the conformational transition behaviors of leucine zipper-structured lipopeptides that were modified at the N-terminus by distinct functional groups. The conformational transition temperatures of these lipopeptides were determined by structural analysis of the implicit-solvent replica exchange molecular dynamics simulation trajectories using the dihedral angle principal component analysis and the dictionary of protein secondary structure method. Our calculations revealed that the computed transition temperatures of the lipopeptides are in good agreement with the experimental measurements. The effect of hydrogen bonds on the conformational stability of the lipopeptide dimers was examined in conventional explicit-solvent molecular dynamics simulations. A quantitative correlation of the degree of structural dissociation of the dimers and their binding strength is well described by an exponential fit of the binding free energies to the conformation transition temperatures of the lipopeptides.

Evolutionary Strategies for Protein Folding

NASA Astrophysics Data System (ADS)

Murthy Gopal, Srinivasa; Wenzel, Wolfgang

2006-03-01

The free energy approach for predicting the protein tertiary structure describes the native state of a protein as the global minimum of an appropriate free-energy forcefield. The low-energy region of the free-energy landscape of a protein is extremely rugged. Efficient optimization methods must therefore speed up the search for the global optimum by avoiding high energy transition states, adapt large scale moves or accept unphysical intermediates. Here we investigate an evolutionary strategies(ES) for optimizing a protein conformation in our all-atom free-energy force field([1],[2]). A set of random conformations is evolved using an ES to get a diverse population containing low energy structure. The ES is shown to balance energy improvement and yet maintain diversity in structures. The ES is implemented as a master-client model for distributed computing. Starting from random structures and by using this optimization technique, we were able to fold a 20 amino-acid helical protein and 16 amino-acid beta hairpin[3]. We compare ES to basin hopping method. [1]T. Herges and W. Wenzel,Biophys.J. 87,3100(2004) [2] A. Verma and W. Wenzel Stabilization and folding of beta-sheet and alpha-helical proteins in an all-atom free energy model(submitted)(2005) [3] S. M. Gopal and W. Wenzel Evolutionary Strategies for Protein Folding (in preparation)

Meeting Report: Structural Determination of Environmentally Responsive Proteins

PubMed Central

Reinlib, Leslie

2005-01-01

The three-dimensional structure of gene products continues to be a missing lynchpin between linear genome sequences and our understanding of the normal and abnormal function of proteins and pathways. Enhanced activity in this area is likely to lead to better understanding of how discrete changes in molecular patterns and conformation underlie functional changes in protein complexes and, with it, sensitivity of an individual to an exposure. The National Institute of Environmental Health Sciences convened a workshop of experts in structural determination and environmental health to solicit advice for future research in structural resolution relative to environmentally responsive proteins and pathways. The highest priorities recommended by the workshop were to support studies of structure, analysis, control, and design of conformational and functional states at molecular resolution for environmentally responsive molecules and complexes; promote understanding of dynamics, kinetics, and ligand responses; investigate the mechanisms and steps in posttranslational modifications, protein partnering, impact of genetic polymorphisms on structure/function, and ligand interactions; and encourage integrated experimental and computational approaches. The workshop participants also saw value in improving the throughput and purity of protein samples and macromolecular assemblies; developing optimal processes for design, production, and assembly of macromolecular complexes; encouraging studies on protein–protein and macromolecular interactions; and examining assemblies of individual proteins and their functions in pathways of interest for environmental health. PMID:16263521

SU-F-T-391: Comparative Study of Treatment Planning Between IMRT and IMAT for Malignant Pleural Mesothelioma

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

Duan, J

Purpose: The purpose of this study was to compare the dosimetric differences between intensitymodulated radiation therapy (IMRT) and intensity modulated arc therapy (IMAT) for malignant pleural mesothelioma (MPM) patients with regard to the sparing effect on organs at risk (OARs), plan quality, and delivery efficiency. Methods: Ten MPM patients were recruited in this study. To avoid the inter-operator variability, IMRT and IMAT plans for each patient were performed by one experienced dosimetrist. The treatment planning optimization process was carried out using the Eclipse 13.0 software. For a fair comparison, the planning target volume (PTV) coverage of the two plans wasmore » normalized to the same level. The treatment plans were evaluated on the following dosimetric variables: conformity index (CI) and homogeneity index (HI) for PTV, OARs dose, and the delivery efficiency for each plan. Results: All plans satisfied clinical requirements. The IMAT plans gained better CI and HI. The IMRT plans performed better sparing for heart and lung. Less MUs and control points were found in the IMAT plans. IMAT shortened delivery time compared with IMRT. Conclusion: For MPM, IMAT gains better conformity and homogeneity for PTV with IMRT, but increases the irradiation dose for OARs. IMAT shows an advantage in delivery efficiency.« less

Accurate structure prediction of peptide–MHC complexes for identifying highly immunogenic antigens

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

Park, Min-Sun; Park, Sung Yong; Miller, Keith R.

2013-11-01

Designing an optimal HIV-1 vaccine faces the challenge of identifying antigens that induce a broad immune capacity. One factor to control the breadth of T cell responses is the surface morphology of a peptide–MHC complex. Here, we present an in silico protocol for predicting peptide–MHC structure. A robust signature of a conformational transition was identified during all-atom molecular dynamics, which results in a model with high accuracy. A large test set was used in constructing our protocol and we went another step further using a blind test with a wild-type peptide and two highly immunogenic mutants, which predicted substantial conformationalmore » changes in both mutants. The center residues at position five of the analogs were configured to be accessible to solvent, forming a prominent surface, while the residue of the wild-type peptide was to point laterally toward the side of the binding cleft. We then experimentally determined the structures of the blind test set, using high resolution of X-ray crystallography, which verified predicted conformational changes. Our observation strongly supports a positive association of the surface morphology of a peptide–MHC complex to its immunogenicity. Our study offers the prospect of enhancing immunogenicity of vaccines by identifying MHC binding immunogens.« less

Redox-linked Conformational Dynamics in Apoptosis Inducing Factor

PubMed Central

Sevrioukova, Irina F.

2009-01-01

Apoptosis inducing factor (AIF) is a bifunctional mitochondrial flavoprotein critical for energy metabolism and induction of caspase-independent apoptosis, whose exact role in normal mitochondria remains unknown. Upon reduction with NADH, AIF undergoes dimerization and forms tight, long-lived FADH2-NAD charge-transfer complexes (CTC) proposed to be functionally important. To get a deeper insight into structure/function relations and redox mechanism of this vitally important protein, we determined the x-ray structures of oxidized and NADH-reduced forms of naturally folded recombinant murine AIF. Our structures reveal that CTC with the pyridine nucleotide is stabilized by (i) π-stacking interactions between coplanar nicotinamide, isoalloxazine and Phe309 rings, (ii) rearrangement of multiple aromatic residues in the C-terminal domain, likely serving as an electron delocalization site, and (iii) an extensive hydrogen-bonding network involving His453, a key residue undergoing a conformational switch to directly interact and orient the nicotinamide in position optimal for charge transfer. Via the His453-containing peptide, redox changes in the active site are transmitted to the surface, promoting AIF dimerization and restricting access to a primary nuclear localization signal through which the apoptogenic form is transported to the nucleus. Structural findings agree with the biochemical data and support the hypothesis that both normal and apoptogenic functions of AIF are controlled by NADH. PMID:19447115

An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1.

PubMed

Chen, Lu; Roake, Caitlin M; Freund, Adam; Batista, Pedro J; Tian, Siqi; Yin, Yi A; Gajera, Chandresh R; Lin, Shengda; Lee, Byron; Pech, Matthew F; Venteicher, Andrew S; Das, Rhiju; Chang, Howard Y; Artandi, Steven E

2018-05-18

Ribonucleoprotein enzymes require dynamic conformations of their RNA constituents for regulated catalysis. Human telomerase employs a non-coding RNA (hTR) with a bipartite arrangement of domains-a template-containing core and a distal three-way junction (CR4/5) that stimulates catalysis through unknown means. Here, we show that telomerase activity unexpectedly depends upon the holoenzyme protein TCAB1, which in turn controls conformation of CR4/5. Cells lacking TCAB1 exhibit a marked reduction in telomerase catalysis without affecting enzyme assembly. Instead, TCAB1 inactivation causes unfolding of CR4/5 helices that are required for catalysis and for association with the telomerase reverse-transcriptase (TERT). CR4/5 mutations derived from patients with telomere biology disorders provoke defects in catalysis and TERT binding similar to TCAB1 inactivation. These findings reveal a conformational "activity switch" in human telomerase RNA controlling catalysis and TERT engagement. The identification of two discrete catalytic states for telomerase suggests an intramolecular means for controlling telomerase in cancers and progenitor cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Final Rule for Control of Air Pollution From New Motor Vehicles and New Motor Vehicle Engines; Non-Conformance Penalties for 2004 and later Model Year Emission Standards for Heavy-Duty Diesel Engines and Heavy-Duty Diesel Vehicles

EPA Pesticide Factsheets

Final Rule for Control of Air Pollution From New Motor Vehicles and New Motor Vehicle Engines; Non-Conformance Penalties for 2004 and later Model Year Emission Standards for Heavy-Duty Diesel Engines and Heavy-Duty Diesel Vehicles

Differential Transmembrane Domain GXXXG Motif Pairing Impacts Major Histocompatibility Complex (MHC) Class II Structure*

PubMed Central

Dixon, Ann M.; Drake, Lisa; Hughes, Kelly T.; Sargent, Elizabeth; Hunt, Danielle; Harton, Jonathan A.; Drake, James R.

2014-01-01

Major histocompatibility complex (MHC) class II molecules exhibit conformational heterogeneity, which influences their ability to stimulate CD4 T cells and drive immune responses. Previous studies suggest a role for the transmembrane domain of the class II αβ heterodimer in determining molecular structure and function. Our previous studies identified an MHC class II conformer that is marked by the Ia.2 epitope. These Ia.2+ class II conformers are lipid raft-associated and able to drive both tyrosine kinase signaling and efficient antigen presentation to CD4 T cells. Here, we establish that the Ia.2+ I-Ak conformer is formed early in the class II biosynthetic pathway and that differential pairing of highly conserved transmembrane domain GXXXG dimerization motifs is responsible for formation of Ia.2+ versus Ia.2− I-Ak class II conformers and controlling lipid raft partitioning. These findings provide a molecular explanation for the formation of two distinct MHC class II conformers that differ in their inherent ability to signal and drive robust T cell activation, providing new insight into the role of MHC class II in regulating antigen-presenting cell-T cell interactions critical to the initiation and control of multiple aspects of the immune response. PMID:24619409

Patient specific optimization-based treatment planning for catheter-based ultrasound hyperthermia and thermal ablation

NASA Astrophysics Data System (ADS)

Prakash, Punit; Chen, Xin; Wootton, Jeffery; Pouliot, Jean; Hsu, I.-Chow; Diederich, Chris J.

2009-02-01

A 3D optimization-based thermal treatment planning platform has been developed for the application of catheter-based ultrasound hyperthermia in conjunction with high dose rate (HDR) brachytherapy for treating advanced pelvic tumors. Optimal selection of applied power levels to each independently controlled transducer segment can be used to conform and maximize therapeutic heating and thermal dose coverage to the target region, providing significant advantages over current hyperthermia technology and improving treatment response. Critical anatomic structures, clinical target outlines, and implant/applicator geometries were acquired from sequential multi-slice 2D images obtained from HDR treatment planning and used to reconstruct patient specific 3D biothermal models. A constrained optimization algorithm was devised and integrated within a finite element thermal solver to determine a priori the optimal applied power levels and the resulting 3D temperature distributions such that therapeutic heating is maximized within the target, while placing constraints on maximum tissue temperature and thermal exposure of surrounding non-targeted tissue. This optimizationbased treatment planning and modeling system was applied on representative cases of clinical implants for HDR treatment of cervix and prostate to evaluate the utility of this planning approach. The planning provided significant improvement in achievable temperature distributions for all cases, with substantial increase in T90 and thermal dose (CEM43T90) coverage to the hyperthermia target volume while decreasing maximum treatment temperature and reducing thermal dose exposure to surrounding non-targeted tissues and thermally sensitive rectum and bladder. This optimization based treatment planning platform with catheter-based ultrasound applicators is a useful tool that has potential to significantly improve the delivery of hyperthermia in conjunction with HDR brachytherapy. The planning platform has been extended to model thermal ablation, including the addition of temperature dependent attenuation, perfusion, and tissue damage. Pilot point control at the target boundaries was implemented to control power delivery to each transducer section, simulating an approach feasible for MR guided procedures. The computer model of thermal ablation was evaluated on representative patient anatomies to demonstrate the feasibility of using catheter-based ultrasound thermal ablation for treatment of benign prostate hyperplasia (BPH) and prostate cancer, and to assist in designing applicators and treatment delivery strategies.

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

PubMed Central

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

2006-01-01

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

Conformable actively multiplexed high-density surface electrode array for brain interfacing

DOEpatents

Rogers, John; Kim, Dae-Hyeong; Litt, Brian; Viventi, Jonathan

2015-01-13

Provided are methods and devices for interfacing with brain tissue, specifically for monitoring and/or actuation of spatio-temporal electrical waveforms. The device is conformable having a high electrode density and high spatial and temporal resolution. A conformable substrate supports a conformable electronic circuit and a barrier layer. Electrodes are positioned to provide electrical contact with a brain tissue. A controller monitors or actuates the electrodes, thereby interfacing with the brain tissue. In an aspect, methods are provided to monitor or actuate spatio-temporal electrical waveform over large brain surface areas by any of the devices disclosed herein.

Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography

DOE PAGES

Lei, Dongsheng; Marras, Alexander E.; Liu, Jianfang; ...

2018-02-09

Scaffolded DNA origami has proven to be a powerful and efficient technique to fabricate functional nanomachines by programming the folding of a single-stranded DNA template strand into three-dimensional (3D) nanostructures, designed to be precisely motion-controlled. Although two-dimensional (2D) imaging of DNA nanomachines using transmission electron microscopy and atomic force microscopy suggested these nanomachines are dynamic in 3D, geometric analysis based on 2D imaging was insufficient to uncover the exact motion in 3D. In this paper, we use the individual-particle electron tomography method and reconstruct 129 density maps from 129 individual DNA origami Bennett linkage mechanisms at ~6-14 nm resolution. The statisticalmore » analyses of these conformations lead to understanding the 3D structural dynamics of Bennett linkage mechanisms. Moreover, our effort provides experimental verification of a theoretical kinematics model of DNA origami, which can be used as feedback to improve the design and control of motion via optimized DNA sequences and routing.« less

Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography

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

Lei, Dongsheng; Marras, Alexander E.; Liu, Jianfang

Scaffolded DNA origami has proven to be a powerful and efficient technique to fabricate functional nanomachines by programming the folding of a single-stranded DNA template strand into three-dimensional (3D) nanostructures, designed to be precisely motion-controlled. Although two-dimensional (2D) imaging of DNA nanomachines using transmission electron microscopy and atomic force microscopy suggested these nanomachines are dynamic in 3D, geometric analysis based on 2D imaging was insufficient to uncover the exact motion in 3D. In this paper, we use the individual-particle electron tomography method and reconstruct 129 density maps from 129 individual DNA origami Bennett linkage mechanisms at ~6-14 nm resolution. The statisticalmore » analyses of these conformations lead to understanding the 3D structural dynamics of Bennett linkage mechanisms. Moreover, our effort provides experimental verification of a theoretical kinematics model of DNA origami, which can be used as feedback to improve the design and control of motion via optimized DNA sequences and routing.« less

Staggered-grid finite-difference acoustic modeling with the Time-Domain Atmospheric Acoustic Propagation Suite (TDAAPS).

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

Aldridge, David Franklin; Collier, Sandra L.; Marlin, David H.

2005-05-01

This document is intended to serve as a users guide for the time-domain atmospheric acoustic propagation suite (TDAAPS) program developed as part of the Department of Defense High-Performance Modernization Office (HPCMP) Common High-Performance Computing Scalable Software Initiative (CHSSI). TDAAPS performs staggered-grid finite-difference modeling of the acoustic velocity-pressure system with the incorporation of spatially inhomogeneous winds. Wherever practical the control structure of the codes are written in C++ using an object oriented design. Sections of code where a large number of calculations are required are written in C or F77 in order to enable better compiler optimization of these sections. Themore » TDAAPS program conforms to a UNIX style calling interface. Most of the actions of the codes are controlled by adding flags to the invoking command line. This document presents a large number of examples and provides new users with the necessary background to perform acoustic modeling with TDAAPS.« less

A new Gamma Knife radiosurgery paradigm: Tomosurgery

NASA Astrophysics Data System (ADS)

Hu, Xiaoliang

The Leksell (Elekta, Stockholm, Sweden) Gamma Knife(TM) (LGK) is the worldwide standard-of-care for the radiosurgical treatment of a wide variety of intracranial lesions. The current LGK utilizes a step-and-shoot dose delivery mechanism where the centroid of each conformal radiation dose (i.e., the shot isocenter) requires repositioning the patient outside of the irradiation field. Perhaps the greatest challenge the LGK treatment team faces is planning the treatment of large and/or complexly shaped lesions that may be in close proximity to critical neural or vascular structures. The standard manual treatment planning approach is a time consuming procedure where additional time spent does not guarantee the identification of an increasingly optimal treatment plan. I propose a new radiosurgery paradigm which I refer to as "Tomosurgery". The Tomosurgery paradigm begins with the division of the target volume into a series of adjacent treatment slices, each with a carefully determined optimal thickness. The use of a continuously moving disk-shaped radiation shot that moves through the lesion in a raster-scanning pattern is expected to improve overall radiation dose conformality and homogeneity. The Tomosurgery treatment planning algorithm recruits a two-stage optimization strategy, which first plans each treatment slice as a simplified 2D problem and secondly optimally assembles the 2D treatment plans into the final 3D treatment plan. Tested on 11 clinical LGK cases, the automated inversely-generated Tomosurgery treatment plans performed as well or better than the neurosurgeon's manually created treatment plans across all criteria: (a) dose volume histograms, (b) dose homogeneity, (c) dose conformality, and (d) critical structure damage, where applicable. LGK Tomosurgery inverse treatment planning required much less time than standard of care, manual (i.e., forward) LGK treatment planning procedures. These results suggest that Tomosurgery might provide an improvement over the current LGK radiosurgery treatment planning software. As regards treatment delivery, a Tomosurgery Investigational Platform (TIP) is proposed to perform the physical validation of radiation dose delivery. The TIP should facilitate translation of the Tomosurgery paradigm to several other radiosurgery and/or radiotherapy devices without the need for expensive modification of commercial devices until the feasibility of delivering Tomosurgical treatment plans has been well established.

Structure-based conformational preferences of amino acids

PubMed Central

Koehl, Patrice; Levitt, Michael

1999-01-01

Proteins can be very tolerant to amino acid substitution, even within their core. Understanding the factors responsible for this behavior is of critical importance for protein engineering and design. Mutations in proteins have been quantified in terms of the changes in stability they induce. For example, guest residues in specific secondary structures have been used as probes of conformational preferences of amino acids, yielding propensity scales. Predicting these amino acid propensities would be a good test of any new potential energy functions used to mimic protein stability. We have recently developed a protein design procedure that optimizes whole sequences for a given target conformation based on the knowledge of the template backbone and on a semiempirical potential energy function. This energy function is purely physical, including steric interactions based on a Lennard-Jones potential, electrostatics based on a Coulomb potential, and hydrophobicity in the form of an environment free energy based on accessible surface area and interatomic contact areas. Sequences designed by this procedure for 10 different proteins were analyzed to extract conformational preferences for amino acids. The resulting structure-based propensity scales show significant agreements with experimental propensity scale values, both for α-helices and β-sheets. These results indicate that amino acid conformational preferences are a natural consequence of the potential energy we use. This confirms the accuracy of our potential and indicates that such preferences should not be added as a design criterion. PMID:10535955

Conformation and structure of 3-methoxyphenyl-salicylaldimine

NASA Astrophysics Data System (ADS)

Elmali, A.; Kabak, M.; Elerman, Y.

1999-06-01

3-methoxyphenyl-salicylaldimine (C 14H 13NO 2) was studied by X-ray analysis and AM1 molecular orbital methods. It crystallises in the monoclinic space group P2 1/c with a=20.486(4) Å, b=4.7935(8) Å Å, c=12.310(5) Å, β=107.43(2)°, V=1153.3(6) Å 3, Z=4, D 0=1.309 g cm -3, Z=4, and μ(MoK α)=0.088 mm -1. The structure was solved by direct methods and refined to R=0.033 for 1635 reflections [ I<2(( I)]. The title molecule was nearly planar. There was a strong intramolecular hydrogen bond of distance 2.598(2) Å between the hydroxyl oxygen atom and imine nitrogen atom, the hydrogen atom essentially being bonded to the oxygen atom. Minimum energy conformations from AM1 were calculated as a function of the three torsion angles θ1(C8-N1-C7-C6), θ2(N1-C7-C6-C5), and θ3(C9-C8-N1-C7) varied every 10°. The theoretical calculations were carried out to compare with experimental results of the molecular conformations. The optimized geometry of the crystal structure corresponding to a non-planar conformation is the most stable conformation in all theoretical calculations.

Adsorption and conformations of lysozyme and α-lactalbumin at a water-octane interface

NASA Astrophysics Data System (ADS)

Cheung, David L.

2017-11-01

As proteins contain both hydrophobic and hydrophilic amino acids, they will readily adsorb onto interfaces between water and hydrophobic fluids such as oil. This adsorption normally causes changes in the protein structure, which can result in loss of protein function and irreversible adsorption, leading to the formation of protein interfacial films. While this can be advantageous in some applications (e.g., food technology), in most cases it limits our ability to exploit protein functionality at interfaces. To understand and control protein interfacial adsorption and function, it is necessary to understand the microscopic conformation of proteins at liquid interfaces. In this paper, molecular dynamics simulations are used to investigate the adsorption and conformation of two similar proteins, lysozyme and α-lactalbumin, at a water-octane interface. While they both adsorb onto the interface, α-lactalbumin does so in a specific orientation, mediated by two amphipathic helices, while lysozyme adsorbs in a non-specific manner. Using replica exchange simulations, both proteins are found to possess a number of distinct interfacial conformations, with compact states similar to the solution conformation being most common for both proteins. Decomposing the different contributions to the protein energy at oil-water interfaces suggests that conformational change for α-lactalbumin, unlike lysozyme, is driven by favourable protein-oil interactions. Revealing these differences between the factors that govern the conformational change at interfaces in otherwise similar proteins can give insight into the control of protein interfacial adsorption, aggregation, and function.

Implementing clinical protocols in oncology: quality gaps and the learning curve phenomenon.

PubMed

Kedikoglou, Simos; Syrigos, Konstantinos; Skalkidis, Yannis; Ploiarchopoulou, Fani; Dessypris, Nick; Petridou, Eleni

2005-08-01

The quality improvement effort in clinical practice has focused mostly on 'performance quality', i.e. on the development of comprehensive, evidence-based guidelines. This study aimed to assess the 'conformance quality', i.e. the extent to which guidelines once developed are correctly and consistently applied. It also aimed to assess the existence of quality gaps in the treatment of certain patient segments as defined by age or gender and to investigate methods to improve overall conformance quality. A retrospective audit of clinical practice in a well-defined oncology setting was undertaken and the results compared to those obtained from prospectively applying an internally developed clinical protocol in the same setting and using specific tools to increase conformance quality. All indicators showed improvement after the implementation of the protocol that in many cases reached statistical significance, while in the entire cohort advanced age was associated (although not significantly) with sub-optimal delivery of care. A 'learning curve' phenomenon in the implementation of quality initiatives was detected, with all indicators improving substantially in the second part of the prospective study. Clinicians should pay separate attention to the implementation of chosen protocols and employ specific tools to increase conformance quality in patient care.

Modulation of kinase-inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX-680 and with TPX2

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

Zhao, Baoguang; Smallwood, Angela; Yang, Jingsong

2008-10-24

VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 {angstrom} resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a {pi}-{pi} interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggestmore » that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.« less

Fisher information and steric effect: study of the internal rotation barrier of ethane.

PubMed

Esquivel, Rodolfo O; Liu, Shubin; Angulo, Juan Carlos; Dehesa, Jesús S; Antolín, Juan; Molina-Espíritu, Moyocoyani

2011-05-05

On the basis of a density-based quantification of the steric effect [Liu, S. B. J. Chem. Phys.2007, 126, 244103], the origin of the internal rotation barrier between the eclipsed and staggered conformers of ethane is systematically investigated in this work from an information-theoretical point of view by using the Fisher information measure in conjugated spaces. Two kinds of computational approaches are considered in this work: adiabatic (with optimal structure) and vertical (with fixed geometry). The analyses are performed systematically by following, in each case, the conformeric path by changing the dihedral angle from 0 to 180° . This is calculated at the HF, MP2, B3LYP, and CCSD(T) levels of theory and with several basis sets. Selected descriptors of the densities are utilized to support the observations. Our results show that in the adiabatic case the eclipsed conformer possesses a larger steric repulsion than the staggered conformer, but in the vertical cases the staggered conformer retains a larger steric repulsion. Our results verify the plausibility for defining and computing the steric effect in the post-Hartree-Fock level of theory according to the scheme proposed by Liu.

A spectroscopic and computational investigation of the conformational structural changes induced by hydrogen bonding networks in the glycidol-water complex.

PubMed

Conrad, A R; Teumelsan, N H; Wang, P E; Tubergen, M J

2010-01-14

Rotational spectra were recorded in natural abundance for the (13)C isotopomers of two conformers of glycidol. Moments of inertia from the (13)C isotopomers were used to calculate the substitution coordinates and C-C bond lengths of two glycidol monomer conformations. The structures of seven different conformational minima were found from ab initio (MP2/6-311++G(d,p)) optimizations of glycidol-water. The rotational spectrum of glycidol-water was recorded using microwave spectroscopy, and the rotational constants were determined to be A = 3902.331 (11) MHz, B = 2763.176 (3) MHz, and C = 1966.863 (3) MHz. Rotational spectra were also recorded for glycidol-H(2)(18)O, glycidol-D(b)OH, and glycidol-d(O)-D(2)O. The rotational spectra were assigned to the lowest-energy ab initio structure, and the structure was improved by fitting to the experimental moments of inertia. The best-fit structure shows evidence for structural changes in glycidol to accommodate formation of the intermolecular hydrogen bonding network: the O-C-C-O torsional angle in glycidol was found to increase from 40.8 degrees for the monomer to 49.9 degrees in the water complex.

Color deviation controlling of phosphor conformal coating by advanced spray painting technology for white LEDs.

PubMed

Yang, Liang; Wang, Simin; Lv, Zhicheng; Liu, Sheng

2013-04-01

An advanced phosphor conformal coating technology is proposed, good correlated color temperature (CCT) and chromaticity uniformity samples are fabricated through phosphor spray painting technology. Spray painting technology is also suitable for phosphor conformal coating of whole LED wafers. The samples of different CCTs are obtained through controlling the phosphor film thickness in the range of 6-80 μm; CCT variation of samples can be controlled in the range of ±200 K. The experimental Δuv reveals that the spray painting method can obtain a much smaller CCT variation (Δuv of 1.36e(-3)) than the conventional dispensing method (Δuv of 11.86e(-3)) when the light is emitted at angles from -90° to +90°, and chromaticity area uniformity is also improved significantly.

Theoretical study of hydrogen bond interactions of fluvastatin with ι-carrageenan and λ-carrageenan.

PubMed

Papadopoulos, Anastasios G; Sigalas, Michael P

2011-07-01

The binding of the reductase inhibitor drug fluvastatin, hydroxy-3-methylglutaryl coenzyme A, with the hydrophilic ι- or λ-carrageenan polymers, serving as potential controllers of the drug's release rate, have been studied at the density functional level of theory with the B3LYP exchange correlation functional. Three low energy conformers of fluvastatin have been calculated. The vibrational spectroscopic properties calculated for the most stable conformer were in satisfactory agreement with the experimental data. A series of hydrogen bonded complexes of the most stable conformer of fluvastatin anion with low molecular weight models of the polymers have been fully optimized. In almost all, intermolecular H-bonds are formed between the sulfate groups of ι- or λ-carrageenan and fluvastatin's hydroxyls, resulting in a red shift of the fluvastatin's O - H stretching vibrations. Cooperative intramolecular H-bonds within fluvastatin or ι-, λ-carrageenan are also present. The BSSE and ZPE corrected interaction energies were estimated in the range 281-318 kJ mol⁻¹ for ι-carrageenan - fluvastatin and 145-200 kJ mol⁻¹ for λ-carrageenan - fluvastatin complexes. The electron density (ρ (bcp)) and Laplacian (∇²ρ (bcp)) properties at critical points of the intermolecular hydrogen bonds, estimated by AIM (atoms in molecules) calculations, have a low and positive character (∇²ρ(bcp) > 0), consistent with the electrostatic character of the hydrogen bonds. The structural and energetic data observed, as well as the extent of the red shift of the fluvastatin's O - H stretching vibrations upon complex formation and the properties of electron density show a stronger binding of fluvastatin to ι- than to λ-carrageenan.

Downregulation of the posterior medial frontal cortex prevents social conformity.

PubMed

Klucharev, Vasily; Munneke, Moniek A M; Smidts, Ale; Fernández, Guillén

2011-08-17

We often change our behavior to conform to real or imagined group pressure. Social influence on our behavior has been extensively studied in social psychology, but its neural mechanisms have remained largely unknown. Here we demonstrate that the transient downregulation of the posterior medial frontal cortex by theta-burst transcranial magnetic stimulation reduces conformity, as indicated by reduced conformal adjustments in line with group opinion. Both the extent and probability of conformal behavioral adjustments decreased significantly relative to a sham and a control stimulation over another brain area. The posterior part of the medial frontal cortex has previously been implicated in behavioral and attitudinal adjustments. Here, we provide the first interventional evidence of its critical role in social influence on human behavior.

Single molecule views of Nature's nano-machines

NASA Astrophysics Data System (ADS)

Ha, Taekjip

2006-03-01

We are interested in the perturbational analysis of biological molecules to better understand their mechanisms. Our readout is the fluorescence signal from individual biomolecules, mainly in the form of single molecule fluorescence resonance energy transfer (FRET). We are pioneering approaches to perturb and control biomolecular conformations using external force (combination of single molecule FRET and optical trap) or other biological motifs (DNA hybridization, G-quadruplex, aptamers,.). In this talk, I will present our latest results on mapping the conformational energy landscape of the Holliday junction through simultaneous fluorescence and force measurements. In addition, a new nanomechanical device called single molecule nano-metronome will be discussed with an outlook toward controlling protein conformations using nucleic acids motifs.

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

Modulation of Cell Proliferation and Differentiation through Substrate-dependent Changes in Fibronectin Conformation

PubMed Central

García, Andrés J.; Vega, María D.; Boettiger, David

1999-01-01

Integrin-mediated cell adhesion to extracellular matrices provides signals essential for cell cycle progression and differentiation. We demonstrate that substrate-dependent changes in the conformation of adsorbed fibronectin (Fn) modulated integrin binding and controlled switching between proliferation and differentiation. Adsorption of Fn onto bacterial polystyrene (B), tissue culture polystyrene (T), and collagen (C) resulted in differences in Fn conformation as indicated by antibody binding. Using a biochemical method to quantify bound integrins in cultured cells, we found that differences in Fn conformation altered the quantity of bound α5 and β1 integrin subunits but not αv or β3. C2C12 myoblasts grown on these Fn-coated substrates proliferated to different levels (B > T > C). Immunostaining for muscle-specific myosin revealed minimal differentiation on B, significant levels on T, and extensive differentiation on C. Differentiation required binding to the RGD cell binding site in Fn and was blocked by antibodies specific for this site. Switching between proliferation and differentiation was controlled by the levels of α5β1 integrin bound to Fn, and differentiation was inhibited by anti-α5, but not anti-αv, antibodies, suggesting distinct integrin-mediated signaling pathways. Control of cell proliferation and differentiation through conformational changes in extracellular matrix proteins represents a versatile mechanism to elicit specific cellular responses for biological and biotechnological applications. PMID:10069818

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.

DNA origami based Au-Ag-core-shell nanoparticle dimers with single-molecule SERS sensitivity

NASA Astrophysics Data System (ADS)

Prinz, J.; Heck, C.; Ellerik, L.; Merk, V.; Bald, I.

2016-03-01

DNA origami nanostructures are a versatile tool to arrange metal nanostructures and other chemical entities with nanometer precision. In this way gold nanoparticle dimers with defined distance can be constructed, which can be exploited as novel substrates for surface enhanced Raman scattering (SERS). We have optimized the size, composition and arrangement of Au/Ag nanoparticles to create intense SERS hot spots, with Raman enhancement up to 1010, which is sufficient to detect single molecules by Raman scattering. This is demonstrated using single dye molecules (TAMRA and Cy3) placed into the center of the nanoparticle dimers. In conjunction with the DNA origami nanostructures novel SERS substrates are created, which can in the future be applied to the SERS analysis of more complex biomolecular targets, whose position and conformation within the SERS hot spot can be precisely controlled.DNA origami nanostructures are a versatile tool to arrange metal nanostructures and other chemical entities with nanometer precision. In this way gold nanoparticle dimers with defined distance can be constructed, which can be exploited as novel substrates for surface enhanced Raman scattering (SERS). We have optimized the size, composition and arrangement of Au/Ag nanoparticles to create intense SERS hot spots, with Raman enhancement up to 1010, which is sufficient to detect single molecules by Raman scattering. This is demonstrated using single dye molecules (TAMRA and Cy3) placed into the center of the nanoparticle dimers. In conjunction with the DNA origami nanostructures novel SERS substrates are created, which can in the future be applied to the SERS analysis of more complex biomolecular targets, whose position and conformation within the SERS hot spot can be precisely controlled. Electronic supplementary information (ESI) available: Additional information about materials and methods, designs of DNA origami templates, height profiles, additional SERS spectra, assignment of DNA bands, SEM images, additional AFM images, FDTD simulations, additional reference spectra for Cy3 and detailed description of EF estimation, simulated absorption and scattering spectra. See DOI: 10.1039/c5nr08674d

Formulation and experimental evaluation of closed-form control laws for the rapid maneuvering of reactor neutronic power

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

Bernard, J.A.

1989-09-01

This report describes both the theoretical development and the experimental evaluation of a novel, robust methodology for the time-optimal adjustment of a reactor's neutronic power under conditions of closed-loop digital control. Central to the approach are the MIT-SNL Period-Generated Minimum Time Control Laws' which determine the rate at which reactivity should be changed in order to cause a reactor's neutronic power to conform to a specified trajectory. Using these laws, reactor power can be safely raised by five to seven orders of magnitude in a few seconds. The MIT-SNL laws were developed to facilitate rapid increases of neutronic power onmore » spacecraft reactors operating in an SDI environment. However, these laws are generic and have other applications including the rapid recovery of research and test reactors subsequent to an unanticipated shutdown, power increases following the achievement of criticality on commercial reactors, power adjustments on commercial reactors so as to minimize thermal stress, and automated startups. The work reported here was performed by the Massachusetts Institute of Technology under contract to the Sandia National Laboratories. Support was also provided by the US Department of Energy's Division of University and Industry Programs. The work described in this report is significant in that a novel solution to the problem of time-optimal control of neutronic power was identified, in that a rigorous description of a reactor's dynamics was derived in that the rate of change of reactivity was recognized as the proper control signal, and in that extensive experimental trials were conducted of these newly developed concepts on actual nuclear reactors. 43 refs., 118 figs., 11 tabs.« less

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2015-07-01

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

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

PubMed

Saravanan, Kandasamy; Kalaiarasi, Chinnasamy; Kumaradhas, Poomani

2017-12-01

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

A collaborative filtering approach for protein-protein docking scoring functions.

PubMed

Bourquard, Thomas; Bernauer, Julie; Azé, Jérôme; Poupon, Anne

2011-04-22

A protein-protein docking procedure traditionally consists in two successive tasks: a search algorithm generates a large number of candidate conformations mimicking the complex existing in vivo between two proteins, and a scoring function is used to rank them in order to extract a native-like one. We have already shown that using Voronoi constructions and a well chosen set of parameters, an accurate scoring function could be designed and optimized. However to be able to perform large-scale in silico exploration of the interactome, a near-native solution has to be found in the ten best-ranked solutions. This cannot yet be guaranteed by any of the existing scoring functions. In this work, we introduce a new procedure for conformation ranking. We previously developed a set of scoring functions where learning was performed using a genetic algorithm. These functions were used to assign a rank to each possible conformation. We now have a refined rank using different classifiers (decision trees, rules and support vector machines) in a collaborative filtering scheme. The scoring function newly obtained is evaluated using 10 fold cross-validation, and compared to the functions obtained using either genetic algorithms or collaborative filtering taken separately. This new approach was successfully applied to the CAPRI scoring ensembles. We show that for 10 targets out of 12, we are able to find a near-native conformation in the 10 best ranked solutions. Moreover, for 6 of them, the near-native conformation selected is of high accuracy. Finally, we show that this function dramatically enriches the 100 best-ranking conformations in near-native structures.

A Collaborative Filtering Approach for Protein-Protein Docking Scoring Functions

PubMed Central

Bourquard, Thomas; Bernauer, Julie; Azé, Jérôme; Poupon, Anne

2011-01-01

A protein-protein docking procedure traditionally consists in two successive tasks: a search algorithm generates a large number of candidate conformations mimicking the complex existing in vivo between two proteins, and a scoring function is used to rank them in order to extract a native-like one. We have already shown that using Voronoi constructions and a well chosen set of parameters, an accurate scoring function could be designed and optimized. However to be able to perform large-scale in silico exploration of the interactome, a near-native solution has to be found in the ten best-ranked solutions. This cannot yet be guaranteed by any of the existing scoring functions. In this work, we introduce a new procedure for conformation ranking. We previously developed a set of scoring functions where learning was performed using a genetic algorithm. These functions were used to assign a rank to each possible conformation. We now have a refined rank using different classifiers (decision trees, rules and support vector machines) in a collaborative filtering scheme. The scoring function newly obtained is evaluated using 10 fold cross-validation, and compared to the functions obtained using either genetic algorithms or collaborative filtering taken separately. This new approach was successfully applied to the CAPRI scoring ensembles. We show that for 10 targets out of 12, we are able to find a near-native conformation in the 10 best ranked solutions. Moreover, for 6 of them, the near-native conformation selected is of high accuracy. Finally, we show that this function dramatically enriches the 100 best-ranking conformations in near-native structures. PMID:21526112

1,3-syn-Diaxial Repulsion of Typical Protecting Groups Used in Carbohydrate Chemistry in 3-O-Substituted Derivatives of Isopropyl d-Idopyranosides.

PubMed

Komarova, Bozhena S; Gerbst, Alexey G; Finogenova, Anastasiia M; Dmitrenok, Andrey S; Tsvetkov, Yury E; Nifantiev, Nikolay E

2017-09-01

The strength of 1,3-syn-diaxial repulsion was evaluated for main types of protecting groups (alkyl, silyl, and acyl) usually used in carbohydrate chemistry. As molecular probes for this study, derivatives of isopropyl 2-O-benzyl-4,6-O-benzylidene-α-d-idopyranoside bearing allyl, acetyl, and tert-butyldiphenylsilyl (TBDPS) protecting groups at O-3 were prepared from p-methoxyphenyl d-galactopyranoside. The equilibrium between O S 2 and 4 C 1 conformations in these compounds was investigated using 3 J H,H and 3 J C,H coupling constants that were determined from 1D 1 H NMR and 2D J-resolved HMBC spectra in various solvents. The analysis of the corresponding coupling constants calculated using DFT/B3LYP/pcJ-1 approximation applied to conformations optimized at DFT/B3LYP/6-311++G** level supported the investigation. Proportions of conformers in the equilibrium revealed the highest repulsion between the 3-allyloxy group and the isopropoxy aglycon and its dependence on the solvent polarity. Differences in the conformational behavior of 3-O-allyl and 3-O-acetyl-α-d-idopyranoside derivatives complied with the notion that higher electron density on O-3 increased 1,3-syn-diaxial repulsion. 3-O-TBDPS derivative existed mainly in 4 C 1 conformation. The attenuation of the 1,3-syn-diaxial repulsive interaction indicates that TBDPS has stereoelectronic properties that may have significance in context of fixing unnatural pyranoside conformation with the help of silyl groups but have been disregarded until now.

3D conformal planning using low segment multi-criteria IMRT optimization

PubMed Central

Khan, Fazal; Craft, David

2014-01-01

Purpose To evaluate automated multicriteria optimization (MCO) – designed for intensity modulated radiation therapy (IMRT), but invoked with limited segmentation – to efficiently produce high quality 3D conformal radiation therapy (3D-CRT) plans. Methods Ten patients previously planned with 3D-CRT to various disease sites (brain, breast, lung, abdomen, pelvis), were replanned with a low-segment inverse multicriteria optimized technique. The MCO-3D plans used the same beam geometry of the original 3D plans, but were limited to an energy of 6 MV. The MCO-3D plans were optimized using fluence-based MCO IMRT and then, after MCO navigation, segmented with a low number of segments. The 3D and MCO-3D plans were compared by evaluating mean dose for all structures, D95 (dose that 95% of the structure receives) and homogeneity indexes for targets, D1 and clinically appropriate dose volume objectives for individual organs at risk (OARs), monitor units (MUs), and physician preference. Results The MCO-3D plans reduced the OAR mean doses (41 out of a total of 45 OARs had a mean dose reduction, p<<0.01) and monitor units (seven out of ten plans have reduced MUs; the average reduction is 17%, p=0.08) while maintaining clinical standards on coverage and homogeneity of target volumes. All MCO-3D plans were preferred by physicians over their corresponding 3D plans. Conclusion High quality 3D plans can be produced using MCO-IMRT optimization, resulting in automated field-in-field type plans with good monitor unit efficiency. Adopting this technology in a clinic could improve plan quality, and streamline treatment plan production by utilizing a single system applicable to both IMRT and 3D planning. PMID:25413405

Agravity up to infinite energy

NASA Astrophysics Data System (ADS)

Salvio, Alberto; Strumia, Alessandro

2018-02-01

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

Statistical analysis of EGFR structures' performance in virtual screening

NASA Astrophysics Data System (ADS)

Li, Yan; Li, Xiang; Dong, Zigang

2015-11-01

In this work the ability of EGFR structures to distinguish true inhibitors from decoys in docking and MM-PBSA is assessed by statistical procedures. The docking performance depends critically on the receptor conformation and bound state. The enrichment of known inhibitors is well correlated with the difference between EGFR structures rather than the bound-ligand property. The optimal structures for virtual screening can be selected based purely on the complex information. And the mixed combination of distinct EGFR conformations is recommended for ensemble docking. In MM-PBSA, a variety of EGFR structures have identically good performance in the scoring and ranking of known inhibitors, indicating that the choice of the receptor structure has little effect on the screening.

Conformal Ablative Thermal Protection Systems (CA-TPS) for Venus and Saturn Backshells

NASA Technical Reports Server (NTRS)

Beck, R.; Gasch, M.; Stackpoole, M.; Wilder, M.; Boghozian, T.; Chavez-Garcia, J.; Prabhu, D.; Kazemba, C.; Venkatapathy, E.

2015-01-01

The new conformal ablator C-PICA, which was developed under STMD GCD, is an optimal candidate for use on the backshells for high velocity entry vehicles at both Venus and Saturn. The material has been tested at heat fluxes up to 400 Wcm2 in shear and over 1800 Wcm2 and 1.5 atm in stagnation with good results. C-PICA has similar density to PICA, but shows half the thermal penetration and similar recession at the same conditions, allowing for a lighter weight TPS to be flown. This poster for VEXAG will show the progress made in the development of the material and why it should be considered for use.

Vibrational and electronic spectroscopic studies of melatonin

NASA Astrophysics Data System (ADS)

Singh, Gurpreet; Abbas, J. M.; Dogra, Sukh Dev; Sachdeva, Ritika; Rai, Bimal; Tripathi, S. K.; Prakash, Satya; Sathe, Vasant; Saini, G. S. S.

2014-01-01

We report the infrared absorption and Raman spectra of melatonin recorded with 488 and 632.8 nm excitations in 3600-2700 and 1700-70 cm-1 regions. Further, we optimized molecular structure of the three conformers of melatonin within density functional theory calculations. Vibrational frequencies of all three conformers have also been calculated. Observed vibrational bands have been assigned to different vibrational motions of the molecules on the basis of potential energy distribution calculations and calculated vibrational frequencies. Observed band positions match well with the calculated values after scaling except Nsbnd H stretching mode frequencies. It is found that the observed and calculated frequencies mismatch of Nsbnd H stretching is due to intermolecular interactions between melatonin molecules.

A modular approach to intensity-modulated arc therapy optimization with noncoplanar trajectories

NASA Astrophysics Data System (ADS)

Papp, Dávid; Bortfeld, Thomas; Unkelbach, Jan

2015-07-01

Utilizing noncoplanar beam angles in volumetric modulated arc therapy (VMAT) has the potential to combine the benefits of arc therapy, such as short treatment times, with the benefits of noncoplanar intensity modulated radiotherapy (IMRT) plans, such as improved organ sparing. Recently, vendors introduced treatment machines that allow for simultaneous couch and gantry motion during beam delivery to make noncoplanar VMAT treatments possible. Our aim is to provide a reliable optimization method for noncoplanar isocentric arc therapy plan optimization. The proposed solution is modular in the sense that it can incorporate different existing beam angle selection and coplanar arc therapy optimization methods. Treatment planning is performed in three steps. First, a number of promising noncoplanar beam directions are selected using an iterative beam selection heuristic; these beams serve as anchor points of the arc therapy trajectory. In the second step, continuous gantry/couch angle trajectories are optimized using a simple combinatorial optimization model to define a beam trajectory that efficiently visits each of the anchor points. Treatment time is controlled by limiting the time the beam needs to trace the prescribed trajectory. In the third and final step, an optimal arc therapy plan is found along the prescribed beam trajectory. In principle any existing arc therapy optimization method could be incorporated into this step; for this work we use a sliding window VMAT algorithm. The approach is demonstrated using two particularly challenging cases. The first one is a lung SBRT patient whose planning goals could not be satisfied with fewer than nine noncoplanar IMRT fields when the patient was treated in the clinic. The second one is a brain tumor patient, where the target volume overlaps with the optic nerves and the chiasm and it is directly adjacent to the brainstem. Both cases illustrate that the large number of angles utilized by isocentric noncoplanar VMAT plans can help improve dose conformity, homogeneity, and organ sparing simultaneously using the same beam trajectory length and delivery time as a coplanar VMAT plan.

Development of a Synthetic Switch to Control Protein Stability in Eukaryotic Cells with Light.

PubMed

Taxis, Christof

2017-01-01

In eukaryotic cells, virtually all regulatory processes are influenced by proteolysis. Thus, synthetic control of protein stability is a powerful approach to influence cellular behavior. To achieve this, selected target proteins are modified with a conditional degradation sequence (degron) that responds to a distinct signal. For development of a synthetic degron, an appropriate sensor domain is fused with a degron such that activity of the degron is under control of the sensor. This chapter describes the development of a light-activated, synthetic degron in the model organism Saccharomyces cerevisiae. This photosensitive degron module is composed of the light-oxygen-voltage (LOV) 2 photoreceptor domain of Arabidopsis thaliana phototropin 1 and a degron derived from murine ornithine decarboxylase (ODC). Excitation of the photoreceptor with blue light induces a conformational change that leads to exposure and activation of the degron. Subsequently, the protein is targeted for degradation by the proteasome. Here, the strategy for degron module development and optimization is described in detail together with experimental aspects, which were pivotal for successful implementation of light-controlled proteolysis. The engineering of the photosensitive degron (psd) module may well serve as a blueprint for future development of sophisticated synthetic switches.

Brain and Surface Warping via Minimizing Lipschitz Extensions (PREPRINT)

DTIC Science & Technology

2006-01-01

Angenent, S. Haker , A. Tannenbaum, and R. Kikinis, “Conformal geometry and brain flattening,” Proc. MICCAI, pp. 271-278, 1999. 1 [2] G. Aronsson, M...surface mapping,” IEEE Transactions on Medical Imaging, 23:7, 2004. 1 [17] S. Haker , L. Zhu, A. Tannenbaum, and S. An- genent, “Optimal mass transport for

Vibrational spectroscopic, structural and nonlinear optical activity studies on 6-aminonicotinamide: A DFT approach

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

Asath, R. Mohamed; Premkumar, S.; Mathavan, T.

2016-05-23

The conformational analysis was carried out for 6-aminonicotinamide (ANA) using potential energy surface scan method and the most stable optimized conformer was predicted. The theoretical vibrational frequencies were calculated for the optimized geometry using DFT/B3LYP cc-pVQZ basis set by Gaussian 09 Program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using VEDA 4.0 program. The Mulliken atomic charge values were calculated. In the Frontier molecular orbitals analysis, the molecular reactivity, kinetic stability, intermolecular charge transfer studies and the related molecular properties were calculated. The ultraviolet-visible spectrum was simulated for both in the gas phase andmore » liquid phase (ethanol) and the π to π* electronic transition was predicted. The nonlinear optical (NLO) activity was studied by means of the first order hyperpolarizability value, which was 8.61 times greater than the urea and the natural bond orbital analysis was also performed to confirm the NLO activity of the molecule. Hence, the ANA molecule is a promising candidate for the NLO materials.« less

Preparation and characterization of a novel conformed bipolymer paclitaxel-nanoparticle using tea polysaccharides and zein.

PubMed

Li, Shuqin; Wang, Xiuming; Li, Weiwei; Yuan, Guoqi; Pan, Yuxiang; Chen, Haixia

2016-08-01

To improve the aqueous solubility of the anticancer agent paclitaxel (PTX), a newly conformed bipolymer paclitaxel-nanoparticle using tea polysaccharide (TPS) and zein was prepared and characterized. Tea polysaccharide was used as a biopolymer shell and zein was as the core and the optimal formula was subjected to the characteristic study by TEM, DSC, FTIR and in vitro release study. Results showed that the optimal particle was acquired with particle yield at 40.01%, drug loading at 0.12% and diameters around 165nm when the concentration of tea polysaccharide was set at 0.2%, and the amount of PTX:zein=1:10. The particle was a nanoparticle with spherical surface and the encapsulated PTX was in an amorphous form rather than cystalline form. PTX was interacted with zein and polysaccharide through O H and CO groups and it had a sustained release. The results suggested that the novel bipolymer might be a promising agent for PTX delivery and tea polysaccharide was demonstrated its function in drug delivery system. Copyright © 2016 Elsevier Ltd. All rights reserved.

Introducing folding stability into the score function for computational design of RNA-binding peptides boosts the probability of success.

PubMed

Xiao, Xingqing; Agris, Paul F; Hall, Carol K

2016-05-01

A computational strategy that integrates our peptide search algorithm with atomistic molecular dynamics simulation was used to design rational peptide drugs that recognize and bind to the anticodon stem and loop domain (ASL(Lys3)) of human tRNAUUULys3 for the purpose of interrupting HIV replication. The score function of the search algorithm was improved by adding a peptide stability term weighted by an adjustable factor λ to the peptide binding free energy. The five best peptide sequences associated with five different values of λ were determined using the search algorithm and then input in atomistic simulations to examine the stability of the peptides' folded conformations and their ability to bind to ASL(Lys3). Simulation results demonstrated that setting an intermediate value of λ achieves a good balance between optimizing the peptide's binding ability and stabilizing its folded conformation during the sequence evolution process, and hence leads to optimal binding to the target ASL(Lys3). Thus, addition of a peptide stability term significantly improves the success rate for our peptide design search. © 2016 Wiley Periodicals, Inc.

Vibrational spectroscopic, structural and nonlinear optical activity studies on 2-amino-3-chloro-5-trifluoromethyl pyridine: A DFT approach

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

Asath, R. Mohamed; Premkumar, S.; Mathavan, T.

2016-05-23

The conformational analysis was carried out for 2-amino-3-chloro-5-trifluoromethylpyridine using potential energy surface (PES) scan and the most stable optimized conformer was predicted. The theoretical vibrational frequencies were calculated for the optimized geometry using DFT/B3LYP cc-pVQZ basis set by Gaussian 09 Program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using VEDA 4.0 program package. The Mulliken atomic charge values were calculated. In the Frontier molecular orbitals analysis, the molecular reactivity, kinetic stability, intermolecular charge transfer studies and the calculation of ionization energy, electron affinity, global hardness, chemical potential, electrophilicity index and softness of the moleculemore » were carried out. The nonlinear optical (NLO) activity was studied and the first order hyperpolarizability value was computed, which was 3.48 times greater than the urea. The natural bond orbital analysis was also performed to confirm the NLO activity of the molecule. Hence, the ACTP molecule is a promising candidate for NLO materials.« less

Ligand Residence Time at G-protein-Coupled Receptors-Why We Should Take Our Time To Study It.

PubMed

Hoffmann, C; Castro, M; Rinken, A; Leurs, R; Hill, S J; Vischer, H F

2015-09-01

Over the past decade the kinetics of ligand binding to a receptor have received increasing interest. The concept of drug-target residence time is becoming an invaluable parameter for drug optimization. It holds great promise for drug development, and its optimization is thought to reduce off-target effects. The success of long-acting drugs like tiotropium support this hypothesis. Nonetheless, we know surprisingly little about the dynamics and the molecular detail of the drug binding process. Because protein dynamics and adaptation during the binding event will change the conformation of the protein, ligand binding will not be the static process that is often described. This can cause problems because simple mathematical models often fail to adequately describe the dynamics of the binding process. In this minireview we will discuss the current situation with an emphasis on G-protein-coupled receptors. These are important membrane protein drug targets that undergo conformational changes upon agonist binding to communicate signaling information across the plasma membrane of cells. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

DFT approach to (benzylthio)acetic acid: Conformational search, molecular (monomer and dimer) structure, vibrational spectroscopy and some electronic properties

NASA Astrophysics Data System (ADS)

Sienkiewicz-Gromiuk, Justyna

2018-01-01

The DFT studies were carried out with the B3LYP method utilizing the 6-31G and 6-311++G(d,p) basis sets depending on whether the aim of calculations was to gain the geometry at equilibrium, or to calculate the optimized molecular structure of (benzylthio)acetic acid (Hbta) in the forms of monomer and dimer. The minimum conformational energy search was followed by the potential energy surface (PES) scan of all rotary bonds existing in the acid molecule. The optimized geometrical monomeric and dimeric structures of the title compound were compared with the experimental structural data in the solid state. The detailed vibrational interpretation of experimental infrared and Raman bands was performed on the basis of theoretically simulated ESFF-scaled wavenumbers calculated for the monomer and dimer structures of Hbta. The electronic characteristics of Hbta is also presented in terms of Mulliken atomic charges, frontier molecular orbitals and global reactivity descriptors. Additionally, the MEP and ESP surfaces were computed to predict coordination sites for potential metal complex formation.

Vibrational spectroscopic, structural and nonlinear optical activity studies on 6-aminonicotinamide: A DFT approach

NASA Astrophysics Data System (ADS)

Asath, R. Mohamed; Premkumar, S.; Rekha, T. N.; Jawahar, A.; Mathavan, T.; Benial, A. Milton Franklin

2016-05-01

The conformational analysis was carried out for 6-aminonicotinamide (ANA) using potential energy surface scan method and the most stable optimized conformer was predicted. The theoretical vibrational frequencies were calculated for the optimized geometry using DFT/B3LYP cc-pVQZ basis set by Gaussian 09 Program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using VEDA 4.0 program. The Mulliken atomic charge values were calculated. In the Frontier molecular orbitals analysis, the molecular reactivity, kinetic stability, intermolecular charge transfer studies and the related molecular properties were calculated. The ultraviolet-visible spectrum was simulated for both in the gas phase and liquid phase (ethanol) and the л to л* electronic transition was predicted. The nonlinear optical (NLO) activity was studied by means of the first order hyperpolarizability value, which was 8.61 times greater than the urea and the natural bond orbital analysis was also performed to confirm the NLO activity of the molecule. Hence, the ANA molecule is a promising candidate for the NLO materials.

Vibrational spectroscopic, structural and nonlinear optical activity studies on 2-amino-3-chloro-5-trifluoromethyl pyridine: A DFT approach

NASA Astrophysics Data System (ADS)

Asath, R. Mohamed; Premkumar, S.; Rekha, T. N.; Jawahar, A.; Mathavan, T.; Benial, A. Milton Franklin

2016-05-01

The conformational analysis was carried out for 2-amino-3-chloro-5-trifluoromethylpyridine using potential energy surface (PES) scan and the most stable optimized conformer was predicted. The theoretical vibrational frequencies were calculated for the optimized geometry using DFT/B3LYP cc-pVQZ basis set by Gaussian 09 Program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using VEDA 4.0 program package. The Mulliken atomic charge values were calculated. In the Frontier molecular orbitals analysis, the molecular reactivity, kinetic stability, intermolecular charge transfer studies and the calculation of ionization energy, electron affinity, global hardness, chemical potential, electrophilicity index and softness of the molecule were carried out. The nonlinear optical (NLO) activity was studied and the first order hyperpolarizability value was computed, which was 3.48 times greater than the urea. The natural bond orbital analysis was also performed to confirm the NLO activity of the molecule. Hence, the ACTP molecule is a promising candidate for NLO materials.

Implant strategies for endocervical and interstitial ultrasound hyperthermia adjunct to HDR brachytherapy for the treatment of cervical cancer

NASA Astrophysics Data System (ADS)

Wootton, Jeffery H.; Prakash, Punit; Hsu, I.-Chow Joe; Diederich, Chris J.

2011-07-01

Catheter-based ultrasound devices provide a method to deliver 3D conformable heating integrated with HDR brachytherapy delivery. Theoretical characterization of heating patterns was performed to identify implant strategies for these devices which can best be used to apply hyperthermia to cervical cancer. A constrained optimization-based hyperthermia treatment planning platform was used for the analysis. The proportion of tissue >=41 °C in a hyperthermia treatment volume was maximized with constraints Tmax <= 47 °C, Trectum <= 41.5 °C, and Tbladder <= 42.5 °C. Hyperthermia treatment was modeled for generalized implant configurations and complex configurations from a database of patients (n = 14) treated with HDR brachytherapy. Various combinations of endocervical (360° or 2 × 180° output; 6 mm OD) and interstitial (180°, 270°, or 360° output; 2.4 mm OD) applicators within catheter locations from brachytherapy implants were modeled, with perfusion constant (1 or 3 kg m-3 s-1) or varying with location or temperature. Device positioning, sectoring, active length and aiming were empirically optimized to maximize thermal coverage. Conformable heating of appreciable volumes (>200 cm3) is possible using multiple sectored interstitial and endocervical ultrasound devices. The endocervical device can heat >41 °C to 4.6 cm diameter compared to 3.6 cm for the interstitial. Sectored applicators afford tight control of heating that is robust to perfusion changes in most regularly spaced configurations. T90 in example patient cases was 40.5-42.7 °C (1.9-39.6 EM43 °C) at 1 kg m-3 s-1 with 10/14 patients >=41 °C. Guidelines are presented for positioning of implant catheters during the initial surgery, selection of ultrasound applicator configurations, and tailored power schemes for achieving T90 >= 41 °C in clinically practical implant configurations. Catheter-based ultrasound devices, when adhering to the guidelines, show potential to generate conformal therapeutic heating ranging from a single endocervical device targeting small volumes local to the cervix (<2 cm radial) to a combination of a 2 × 180° endocervical and directional interstitial applicators in the lateral periphery to target much larger volumes (6 cm radial), while preferentially limiting heating of the bladder and rectum.

SU-F-T-520: Dosimetric Comparison of Radiation Treatment Plans for Whole Breast Irradiation Between 3D Conformal in Prone and Supine Positions Vs. VMAT and IMRT in Supine Positions

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

Bejarano Buele, A; Parsai, E

Purpose: The target volume for Whole Breast Irradiation (WBI) is dictated by location of tumor mass, breast tissue distribution, and involvement of lymph nodes. Dose coverage and Organs at Risk (OARs) sparing can be difficult to achieve in patients with unfavorable thoracic geometries. For these cases, inverse-planned and 3D-conformal prone treatments can be alternatives to traditional supine 3D-conformal plans. A dosimetric comparison can determine which of these techniques achieve optimal target coverage while sparing OARs. Methods: This study included simulation datasets for 8 patients, 5 of whom were simulated in both supine and prone positions. Positioning devices included breast boardsmore » and Vaclok bags for the supine position, and prone breast boards for the prone position. WBI 3-D conformal plans were created for patients simulated in both positions. Additional VMAT and IMRT WBI plans were made for all patients in the supine position. Results: Prone and supine 3D conformal plans had comparable PTV coverage. Prone 3D conformal plans received a significant 50% decrease to V20, V10, V5 and V30% for the ipsilateral lung in contrast to the supine plans. The heart also experienced a 10% decrease in maximum dose in the prone position, and V20, V10, V5 and V2 had significantly lower values than the supine plan. Supine IMRT and VMAT breast plans obtained comparable PTV coverage. The heart experienced a 10% decrease in maximum dose with inverse modulated plans when compared to the supine 3D conformal plan, while V20, V10, V5 and V2 showed higher values with inverse modulated plans than with supine 3D conformal plans. Conclusion: Prone 3D-conformal, and supine inverse planned treatments were generally superior in sparing OARs to supine plans with comparable PTV coverage. IMRT and VMAT plans offer sparing of OARs from high dose regions with an increase of irradiated volume in the low dose regions.« less

Spectroscopic and molecular structure investigation of the phosphorus-containing G‧2 dendrimer with terminal aldehyde groups using DFT method

NASA Astrophysics Data System (ADS)

Furer, V. L.; Vandyukov, A. E.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

2015-02-01

The FTIR and FT Raman spectra of the second generation dendrimer G‧2 built from thiophosphoryl core with terminal aldehyde groups have been recorded. The structural optimization and normal mode analysis were performed for model compound C, consisting of thiophosphoryl core, one branch with three repeated units, and four 4-oxybenzaldehyde terminal groups on the basis of the density functional theory (DFT) at the PBE/TZ2P level. The vibrational frequencies, infrared and Raman intensities for the t,g,g- and t,-g,g-conformers of the terminal groups were calculated. The t,g,g-conformer is 2.0 kcal/mol less stable compared to t,-g,g-conformer. A reliable assignment of the fundamental bands observed in the experimental IR and Raman spectra of dendrimer was achieved. For the low generations (G‧1 to G‧3) the disk form of studied dendrimer molecules is the most probable. For higher generations, the shape of dendrimer molecules will be that of a cauliflower.

3D printing of shape-conformable thermoelectric materials using all-inorganic Bi2Te3-based inks

NASA Astrophysics Data System (ADS)

Kim, Fredrick; Kwon, Beomjin; Eom, Youngho; Lee, Ji Eun; Park, Sangmin; Jo, Seungki; Park, Sung Hoon; Kim, Bong-Seo; Im, Hye Jin; Lee, Min Ho; Min, Tae Sik; Kim, Kyung Tae; Chae, Han Gi; King, William P.; Son, Jae Sung

2018-04-01

Thermoelectric energy conversion offers a unique solution for generating electricity from waste heat. However, despite recent improvements in the efficiency of thermoelectric materials, the widespread application of thermoelectric generators has been hampered by challenges in fabricating thermoelectric materials with appropriate dimensions to perfectly fit heat sources. Herein, we report an extrusion-based three-dimensional printing method to produce thermoelectric materials with geometries suitable for heat sources. All-inorganic viscoelastic inks were synthesized using Sb2Te3 chalcogenidometallate ions as inorganic binders for Bi2Te3-based particles. Three-dimensional printed materials with various geometries showed homogenous thermoelectric properties, and their dimensionless figure-of-merit values of 0.9 (p-type) and 0.6 (n-type) were comparable to the bulk values. Conformal cylindrical thermoelectric generators made of 3D-printed half rings mounted on an alumina pipe were studied both experimentally and computationally. Simulations show that the power output of the conformal, shape-optimized generator is higher than that of conventional planar generators.

Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding

PubMed Central

Koenig, Patrick; Lee, Chingwei V.; Walters, Benjamin T.; Janakiraman, Vasantharajan; Stinson, Jeremy; Patapoff, Thomas W.; Fuh, Germaine

2017-01-01

Somatic mutations within the antibody variable domains are critical to the immense capacity of the immune repertoire. Here, via a deep mutational scan, we dissect how mutations at all positions of the variable domains of a high-affinity anti-VEGF antibody G6.31 impact its antigen-binding function. The resulting mutational landscape demonstrates that large portions of antibody variable domain positions are open to mutation, and that beneficial mutations can be found throughout the variable domains. We determine the role of one antigen-distal light chain position 83, demonstrating that mutation at this site optimizes both antigen affinity and thermostability by modulating the interdomain conformational dynamics of the antigen-binding fragment. Furthermore, by analyzing a large number of human antibody sequences and structures, we demonstrate that somatic mutations occur frequently at position 83, with corresponding domain conformations observed for G6.31. Therefore, the modulation of interdomain dynamics represents an important mechanism during antibody maturation in vivo. PMID:28057863

Molecular mechanism of respiratory syncytial virus fusion inhibitors

DOE PAGES

Battles, Michael B.; Langedijk, Johannes P.; Furmanova-Hollenstein, Polina; ...

2015-12-07

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitorsmore » or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.« less

A coarse-grained model for DNA origami.

PubMed

Reshetnikov, Roman V; Stolyarova, Anastasia V; Zalevsky, Arthur O; Panteleev, Dmitry Y; Pavlova, Galina V; Klinov, Dmitry V; Golovin, Andrey V; Protopopova, Anna D

2018-02-16

Modeling tools provide a valuable support for DNA origami design. However, current solutions have limited application for conformational analysis of the designs. In this work we present a tool for a thorough study of DNA origami structure and dynamics. The tool is based on a novel coarse-grained model dedicated to geometry optimization and conformational analysis of DNA origami. We explored the ability of the model to predict dynamic behavior, global shapes, and fine details of two single-layer systems designed in hexagonal and square lattices using atomic force microscopy, Förster resonance energy transfer spectroscopy, and all-atom molecular dynamic simulations for validation of the results. We also examined the performance of the model for multilayer systems by simulation of DNA origami with published cryo-electron microscopy and atomic force microscopy structures. A good agreement between the simulated and experimental data makes the model suitable for conformational analysis of DNA origami objects. The tool is available at http://vsb.fbb.msu.ru/cosm as a web-service and as a standalone version.

Inkjet-Printed Graphene/PEDOT:PSS Temperature Sensors on a Skin-Conformable Polyurethane Substrate.

PubMed

Vuorinen, Tiina; Niittynen, Juha; Kankkunen, Timo; Kraft, Thomas M; Mäntysalo, Matti

2016-10-18

Epidermal electronic systems (EESs) are skin-like electronic systems, which can be used to measure several physiological parameters from the skin. This paper presents materials and a simple, straightforward fabrication process for skin-conformable inkjet-printed temperature sensors. Epidermal temperature sensors are already presented in some studies, but they are mainly fabricated using traditional photolithography processes. These traditional fabrication routes have several processing steps and they create a substantial amount of material waste. Hence utilizing printing processes, the EES may become attractive for disposable systems by decreasing the manufacturing costs and reducing the wasted materials. In this study, the sensors are fabricated with inkjet-printed graphene/PEDOT:PSS ink and the printing is done on top of a skin-conformable polyurethane plaster (adhesive bandage). Sensor characterization was conducted both in inert and ambient atmosphere and the graphene/PEDOT:PSS temperature sensors (thermistors) were able reach higher than 0.06% per degree Celsius sensitivity in an optimal environment exhibiting negative temperature dependence.

A coarse-grained model for DNA origami

PubMed Central

Stolyarova, Anastasia V; Zalevsky, Arthur O; Panteleev, Dmitry Y; Pavlova, Galina V; Klinov, Dmitry V; Golovin, Andrey V; Protopopova, Anna D

2018-01-01

Abstract Modeling tools provide a valuable support for DNA origami design. However, current solutions have limited application for conformational analysis of the designs. In this work we present a tool for a thorough study of DNA origami structure and dynamics. The tool is based on a novel coarse-grained model dedicated to geometry optimization and conformational analysis of DNA origami. We explored the ability of the model to predict dynamic behavior, global shapes, and fine details of two single-layer systems designed in hexagonal and square lattices using atomic force microscopy, Förster resonance energy transfer spectroscopy, and all-atom molecular dynamic simulations for validation of the results. We also examined the performance of the model for multilayer systems by simulation of DNA origami with published cryo-electron microscopy and atomic force microscopy structures. A good agreement between the simulated and experimental data makes the model suitable for conformational analysis of DNA origami objects. The tool is available at http://vsb.fbb.msu.ru/cosm as a web-service and as a standalone version. PMID:29267876

Cluster analysis of molecular simulation trajectories for systems where both conformation and orientation of the sampled states are important.

PubMed

Abramyan, Tigran M; Snyder, James A; Thyparambil, Aby A; Stuart, Steven J; Latour, Robert A

2016-08-05

Clustering methods have been widely used to group together similar conformational states from molecular simulations of biomolecules in solution. For applications such as the interaction of a protein with a surface, the orientation of the protein relative to the surface is also an important clustering parameter because of its potential effect on adsorbed-state bioactivity. This study presents cluster analysis methods that are specifically designed for systems where both molecular orientation and conformation are important, and the methods are demonstrated using test cases of adsorbed proteins for validation. Additionally, because cluster analysis can be a very subjective process, an objective procedure for identifying both the optimal number of clusters and the best clustering algorithm to be applied to analyze a given dataset is presented. The method is demonstrated for several agglomerative hierarchical clustering algorithms used in conjunction with three cluster validation techniques. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Optimization of a Nucleic Acids united-RESidue 2-Point model (NARES-2P) with a maximum-likelihood approach

NASA Astrophysics Data System (ADS)

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

2015-12-01

Coarse-grained models are useful tools to investigate the structural and thermodynamic properties of biomolecules. They are obtained by merging several atoms into one interaction site. Such simplified models try to capture as much as possible information of the original biomolecular system in all-atom representation but the resulting parameters of these coarse-grained force fields still need further optimization. In this paper, a force field optimization method, which is based on maximum-likelihood fitting of the simulated to the experimental conformational ensembles and least-squares fitting of the simulated to the experimental heat-capacity curves, is applied to optimize the Nucleic Acid united-RESidue 2-point (NARES-2P) model for coarse-grained simulations of nucleic acids recently developed in our laboratory. The optimized NARES-2P force field reproduces the structural and thermodynamic data of small DNA molecules much better than the original force field.

40 CFR 93.109 - Criteria and procedures for determining conformity of transportation plans, programs, and...

Code of Federal Regulations, 2011 CFR

2011-07-01

...) through (k) of this section explain when the budget, interim emissions, and hot-spot tests are required... § 93.115 Project from a conforming plan and TIP § 93.116 CO, PM10, and PM2.5 hot-spots. § 93.117 PM10... Currently conforming plan and TIP § 93.116 CO, PM10, and PM2.5 hot-spots. § 93.117 PM10 and PM2.5 control...

40 CFR 93.109 - Criteria and procedures for determining conformity of transportation plans, programs, and...

Code of Federal Regulations, 2010 CFR

2010-07-01

...) through (k) of this section explain when the budget, interim emissions, and hot-spot tests are required... § 93.115 Project from a conforming plan and TIP § 93.116 CO, PM10, and PM2.5 hot-spots. § 93.117 PM10... Currently conforming plan and TIP § 93.116 CO, PM10, and PM2.5 hot-spots. § 93.117 PM10 and PM2.5 control...

Allosteric activation via kinetic control: Potassium accelerates a conformational change in IMP dehydrogenase†

PubMed Central

Riera, Thomas V.; Zheng, Lianqing; Josephine, Helen R.; Min, Donghong; Yang, Wei; Hedstrom, Lizbeth

2011-01-01

Allosteric activators are generally believed to shift the equilibrium distribution of enzyme conformations to favor a catalytically productive structure; the kinetics of conformational exchange is seldom addressed. Several observations suggested that the usual allosteric mechanism might not apply to the activation of IMP dehydrogenase (IMPDH) by monovalent cations. Therefore we investigated the mechanism of K+ activation in IMPDH by delineating the kinetic mechanism in the absence of monovalent cations. Surprisingly, the K+-dependence of kcat derives from the rate of flap closure, which increases by ≥65-fold in the presence of K+. We performed both alchemical free energy simulations and potential of mean force calculations using the orthogonal space random walk strategy to computationally analyze how K+ accelerates this conformational change. The simulations recapitulate the preference of IMPDH for K+, validating the computational models. When K+ is replaced with a dummy ion, the residues of the K+ binding site relax into ordered secondary structure, creating a barrier to conformational exchange. K+ mobilizes these residues by providing alternate interactions for the main chain carbonyls. Potential of mean force calculations indicate that K+ changes the shape of the energy well, shrinking the reaction coordinate by shifting the closed conformation toward the open state. This work suggests that allosteric regulation can be under kinetic as well as thermodynamic control. PMID:21870820

Probing Conformational Change of Bovine Serum Albumin–Dextran Conjugates under Controlled Dry Heating

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

Xia, Shuqin; Li, Yunqi; Zhao, Qin

2015-04-29

The time-dependent conformational change of bovine serum album (BSA) during Maillard reaction with dextran under controlled dry heating has been studied by small-angle X-ray scattering, fluorescence spectroscopy, dynamic light scattering, and circular dichroism analysis. Through the research on the radii of gyration (R g), intrinsic fluorescence, and secondary structure, conjugates with dextran coating were found to inhibit BSA aggregation and preserve the secondary structure of native BSA against long-time heat treatment during Maillard reaction. The results suggested that the hydrophilic dextran was conjugated to the compact protein surface and enclosed it and more dextran chains were attached to BSA withmore » the increase of the heating time. The study presented here will be beneficial to the understanding of the conformational evolution of BSA molecules during the dry-heating Maillard reaction and to the control of the protein–polysaccharide conjugate structure.« less

Temperature dependence of nonlinear optical properties in Li doped nano-carbon bowl material

NASA Astrophysics Data System (ADS)

Li, Wei-qi; Zhou, Xin; Chang, Ying; Quan Tian, Wei; Sun, Xiu-Dong

2013-04-01

The mechanism for change of nonlinear optical (NLO) properties with temperature is proposed for a nonlinear optical material, Li doped curved nano-carbon bowl. Four stable conformations of Li doped corannulene were located and their electronic properties were investigated in detail. The NLO response of those Li doped conformations varies with relative position of doping agent on the curved carbon surface of corannulene. Conversion among those Li doped conformations, which could be controlled by temperature, changes the NLO response of bulk material. Thus, conformation change of alkali metal doped carbon nano-material with temperature rationalizes the variation of NLO properties of those materials.

Neurotransmitters in the Gas Phase: La-Mb Studies

NASA Astrophysics Data System (ADS)

Cabezas, C.; Mata, S.; López, J. C.; Alonso, J. L.

2011-06-01

LA-MB-FTMW spectroscopy combines laser ablation with Fourier transform microwave spectroscopy in supersonic jets overcoming the problems of thermal decomposition associated with conventional heating methods. We present here the results on LA-MB-FTMW studies of some neurotransmitters. Six conformers of dopamine, four of adrenaline, five of noradrenaline and three conformers of serotonin have been characterized in the gas phase. The rotational and nuclear quadrupole coupling constants extracted from the analysis of the rotational spectrum are directly compared with those predicted by ab initio methods to achieve the conclusive identification of different conformers and the experimental characterization of the intramolecular forces at play which control conformational preferences.

Conformational Control of Ultrafast Molecular Rotor Property: Tuning Viscosity Sensing Efficiency by Twist Angle Variation.

PubMed

Ghosh, Rajib; Kushwaha, Archana; Das, Dipanwita

2017-09-21

Fluorescent molecular rotors find widespread application in sensing and imaging of microscopic viscosity in complex chemical and biological media. Development of viscosity-sensitive ultrafast molecular rotor (UMR) relies upon the understanding of the excited-state dynamics and their implications for viscosity-dependent fluorescence signaling. Unraveling the structure-property relationship of UMR behavior is of significance toward development of an ultrasensitive fluorescence microviscosity sensor. Herein we show that the ground-state equilibrium conformation has an important role in the ultrafast twisting dynamics of UMRs and consequent viscosity sensing efficiency. Synthesis, photophysics, and ultrafast spectroscopic experiments in conjunction with quantum chemical calculation of a series of UMRs based on dimethylaniline donor and benzimidazolium acceptor with predefined ground-state torsion angle led us to unravel that the ultrafast torsional dynamics around the bond connecting donor and acceptor groups profoundly influences the molecular rotor efficiency. This is the first experimental demonstration of conformational control of small-molecule-based UMR efficiencies which can have wider implication toward development of fluorescence sensors based on the UMR principle. Conformation-controlled UMR efficiency has been shown to exhibit commensurate fluorescence enhancement upon DNA binding.

Investigation of the pH-dependence of dye-doped protein-protein interactions.

PubMed

Nudelman, Roman; Gloukhikh, Ekaterina; Rekun, Antonina; Richter, Shachar

2016-11-01

Proteins can dramatically change their conformation under environmental conditions such as temperature and pH. In this context, Glycoprotein's conformational determination is challenging. This is due to the variety of domains which contain rich chemical characters existing within this complex. Here we demonstrate a new, straightforward and efficient technique that uses the pH-dependent properties of dyes-doped Pig Gastric Mucin (PGM) for predicting and controlling protein-protein interaction and conformation. We utilize the PGM as natural host matrix which is capable of dynamically changing its conformational shape and adsorbing hydrophobic and hydrophilic dyes under different pH conditions and investigate and control the fluorescent properties of these composites in solution. It is shown at various pH conditions, a large variety of light emission from these complexes such as red, green and white is obtained. This phenomenon is explained by pH-dependent protein folding and protein-protein interactions that induce different emission spectra which are mediated and controlled by means of dye-dye interactions and surrounding environment. This process is used to form the technologically challenging white light-emitting liquid or solid coating for LED devices. © 2016 The Protein Society.

FT-IR study and solvent-implicit and explicit effect on stepwise tautomerism of Guanylurea: M06-2X as a case of study.

PubMed

Karimzadeh, Morteza; Manouchehri, Neda; Saberi, Dariush; Niknam, Khodabakhsh

2018-06-15

All 66 conformers of guanylurea were optimized and frequency calculations were performed at M06-2X/6-311++G(d,p) level of theory. Theses conformers were categorized into five tautomers, and the most stable conformer of each tautomer were found. Geometrical parameters indicated that these tautomers have almost planar structure. Complete stepwise tautomerism were studied through both intramolecular proton transfer routs and internal rotations. Results indicated that the proton transfer routs involving four-membered heterocyclic structures were rate-determining steps. Also, intramolecular proton movement having six-membered transition state structures had very low energy barrier comparable to the transition states of internal rotation routs. Differentiation of studied tautomers could easily be done through their FT-IR spectra in the range of 3200 to 3900cm -1 by comparing absorption bands and intensity of peaks. Solvent-implicit effects on the stability of tautomers were also studied through re-optimization and frequency calculation in four solvents. Water, DMSO, acetone and toluene had stabilization effect on all considered tautomers, but the order of stabilization effect was as follows: water>DMSO>acetone>toluene. Finally, solvent-explicit, base-explicit and acid-explicit effect were also studied by taking place of studied tautomer nearside of acid, base or solvent and optimization of them. Frequency calculation for proton movement by contribution of explicit effect showed that formic acid had a very strong effect on proton transfer from tautomer A1 to tautomer D8 by lowering the energy barrier from 42.57 to 0.8kcal/mol. In addition, ammonia-explicit effect was found to lower the barrier from 42.57 to 22.46kcal/mol, but this effect is lower than that of water and methanol-explicit effect. Copyright © 2018 Elsevier B.V. All rights reserved.

Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane.

PubMed

Bailey, William F; Lambert, Kyle M; Stempel, Zachary D; Wiberg, Kenneth B; Mercado, Brandon Q

2016-12-16

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF 3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

A phenylalanine rotameric switch for signal-state control in bacterial chemoreceptors

NASA Astrophysics Data System (ADS)

Ortega, Davi R.; Yang, Chen; Ames, Peter; Baudry, Jerome; Parkinson, John S.; Zhulin, Igor B.

2013-12-01

Bacterial chemoreceptors are widely used as a model system for elucidating the molecular mechanisms of transmembrane signalling and have provided a detailed understanding of how ligand binding by the receptor modulates the activity of its associated kinase CheA. However, the mechanisms by which conformational signals move between signalling elements within a receptor dimer and how they control kinase activity remain unknown. Here, using long molecular dynamics simulations, we show that the kinase-activating cytoplasmic tip of the chemoreceptor fluctuates between two stable conformations in a signal-dependent manner. A highly conserved residue, Phe396, appears to serve as the conformational switch, because flipping of the stacked aromatic rings of an interacting F396-F396‧ pair in the receptor homodimer takes place concomitantly with the signal-related conformational changes. We suggest that interacting aromatic residues, which are common stabilizers of protein tertiary structure, might serve as rotameric molecular switches in other biological processes as well.

Hsp90 dependence of a kinase is determined by its conformational landscape

PubMed Central

Luo, Qi; Boczek, Edgar E.; Wang, Qi; Buchner, Johannes; Kaila, Ville R. I.

2017-01-01

Heat shock protein 90 (Hsp90) is an abundant molecular chaperone, involved in the folding and activation of 60% of the human kinome. The oncogenic tyrosine kinase v-Src is one of the most stringent client proteins of Hsp90, whereas its almost identical homolog c-Src is only weakly affected by the chaperone. Here, we perform atomistic molecular simulations and in vitro kinase assays to explore the mechanistic differences in the activation of v-Src and c-Src. While activation in c-Src is strictly controlled by ATP-binding and phosphorylation, we find that activating conformational transitions are spontaneously sampled in Hsp90-dependent Src mutants. Phosphorylation results in an enrichment of the active conformation and in an increased affinity for Hsp90. Thus, the conformational landscape of the mutated kinase is reshaped by a broken “control switch”, resulting in perturbations of long-range electrostatics, higher activity and increased Hsp90-dependence. PMID:28290541

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

PubMed

Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-06

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer.

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

PubMed

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

2016-10-01

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

I-SWOT as instrument to individually optimize therapy of thoracoabdominal aortic aneurysms: Effective, norm-compliant and meeting the needs.

PubMed

Sachweh, A; von Kodolitsch, Y; Kölbel, T; Larena-Avellaneda, A; Wipper, S; Bernhardt, A M; Girdauskas, E; Detter, C; Reichenspurner, H; Blankart, C R; Debus, E S

2017-01-01

Guidelines summarize medical evidence, they identify the most efficient therapy under study conditions and recommend this therapy for use. The physician now has the challenge to translate a therapy that is efficient under laboratory conditions to a patient who is an individual person. To accomplish this task the physician has to make sure that (I) the ideal typical therapy is applicable and effective in this individual patient taking the special features into consideration, that (II) therapy is compliant with the norm including guidelines, laws and ethical requirements (conformity) and that (III) the therapy meets the patient's needs. How can physicians together with the patients translate the medical evidence into an individually optimized therapy? At the German Aortic Center in Hamburg we use I‑SWOT as an instrument to identify such individually optimized therapy. With I‑SWOT, we present an instrument with which we have developed an (I) efficient, (II) conform and (III) needs-oriented therapeutic strategy for individual patients. I-SWOT cross-tabulates strengths (S) and weaknesses (W) related to therapy with opportunities (O) and threats (T) related to individual patients. This I‑SWOT matrix identifies four fundamental types of strategy, which comprise "SO" maximizing strengths and opportunities, "WT" minimizing weaknesses and threats, "WO" minimizing weaknesses and maximizing opportunities and "ST" maximizing strengths and minimizing threats. We discuss the case of a patient with asymptomatic thoracoabdominal aneurysm to show how I‑SWOT is used to identify an individually optimized therapy strategy.

Conformal Radiotherapy in the Treatment of Advanced Juvenile Nasopharyngeal Angiofibroma With Intracranial Extension: An Institutional Experience

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

Chakraborty, Santam, E-mail: drsantam@gmail.com; Ghoshal, Sushmita; Patil, Vijay Maruti

2011-08-01

Purpose: To describe the results of conformal radiotherapy in advanced juvenile nasopharyngeal angiofibroma in a tertiary care institution. Methods and Materials: Retrospective chart review was conducted for 8 patients treated with conformal radiotherapy between 2006 and 2009. The median follow-up was 17 months. All patients had Stage IIIB disease with intracranial extension. Radiotherapy was considered as treatment because patients were deemed inoperable owing to extensive intracranial/intraorbital extension or proximity to optic nerve. All but 1 patient were treated with intensity-modulated radiotherapy using seven coplanar fields. Median (range) dose prescribed was 39.6 (30-46) Gy. Actuarial analysis of local control and descriptivemore » analysis of toxicity profile was conducted. Results: Despite the large and complex target volume (median planning target volume, 292 cm{sup 3}), intensity-modulated radiotherapy achieved conformal dose distributions (median van't Reit index, 0.66). Significant sparing of the surrounding organs at risk was obtained. No significant Grade 3/4 toxicities were experienced during or after treatment. Actual local control at 2 years was 87.5%. One patient died 1 month after radiotherapy secondary to massive epistaxis. The remaining 7 patients had progressive resolution of disease and were symptom-free at last follow-up. Persistent rhinitis was the only significant toxicity, seen in 1 patient. Conclusions: Conformal radiotherapy results in good local control with minimal acute and late side effects in juvenile nasopharyngeal angiofibromas, even in the presence of advanced disease.« less

Employing Synergetic Effect of Doping and Thin Film Coating to Boost the Performance of Lithium-Ion Battery Cathode Particles

PubMed Central

Patel, Rajankumar L.; Jiang, Ying-Bing; Choudhury, Amitava; Liang, Xinhua

2016-01-01

Atomic layer deposition (ALD) has evolved as an important technique to coat conformal protective thin films on cathode and anode particles of lithium ion batteries to enhance their electrochemical performance. Coating a conformal, conductive and optimal ultrathin film on cathode particles has significantly increased the capacity retention and cycle life as demonstrated in our previous work. In this work, we have unearthed the synergetic effect of electrochemically active iron oxide films coating and partial doping of iron on LiMn1.5Ni0.5O4 (LMNO) particles. The ionic Fe penetrates into the lattice structure of LMNO during the ALD process. After the structural defects were saturated, the iron started participating in formation of ultrathin oxide films on LMNO particle surface. Owing to the conductive nature of iron oxide films, with an optimal film thickness of ~0.6 nm, the initial capacity improved by ~25% at room temperature and by ~26% at an elevated temperature of 55 °C at a 1C cycling rate. The synergy of doping of LMNO with iron combined with the conductive and protective nature of the optimal iron oxide film led to a high capacity retention (~93% at room temperature and ~91% at 55 °C) even after 1,000 cycles at a 1C cycling rate. PMID:27142704

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

A global optimization algorithm for protein surface alignment

PubMed Central

2010-01-01

Background A relevant problem in drug design is the comparison and recognition of protein binding sites. Binding sites recognition is generally based on geometry often combined with physico-chemical properties of the site since the conformation, size and chemical composition of the protein surface are all relevant for the interaction with a specific ligand. Several matching strategies have been designed for the recognition of protein-ligand binding sites and of protein-protein interfaces but the problem cannot be considered solved. Results In this paper we propose a new method for local structural alignment of protein surfaces based on continuous global optimization techniques. Given the three-dimensional structures of two proteins, the method finds the isometric transformation (rotation plus translation) that best superimposes active regions of two structures. We draw our inspiration from the well-known Iterative Closest Point (ICP) method for three-dimensional (3D) shapes registration. Our main contribution is in the adoption of a controlled random search as a more efficient global optimization approach along with a new dissimilarity measure. The reported computational experience and comparison show viability of the proposed approach. Conclusions Our method performs well to detect similarity in binding sites when this in fact exists. In the future we plan to do a more comprehensive evaluation of the method by considering large datasets of non-redundant proteins and applying a clustering technique to the results of all comparisons to classify binding sites. PMID:20920230

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

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

PubMed

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

2014-01-01

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

40 CFR 1027.150 - What definitions apply to this part?

Code of Federal Regulations, 2012 CFR

2012-07-01

... POLLUTION CONTROLS FEES FOR ENGINE, VEHICLE, AND EQUIPMENT COMPLIANCE PROGRAMS § 1027.150 What definitions.... California-only certificate is a certificate of conformity issued by EPA showing compliance with emission standards established by California. Federal certificate is a certificate of conformity issued by EPA...

40 CFR 1027.150 - What definitions apply to this part?

Code of Federal Regulations, 2014 CFR

2014-07-01

... POLLUTION CONTROLS FEES FOR ENGINE, VEHICLE, AND EQUIPMENT COMPLIANCE PROGRAMS § 1027.150 What definitions.... California-only certificate is a certificate of conformity issued by EPA showing compliance with emission standards established by California. Federal certificate is a certificate of conformity issued by EPA...

40 CFR 1027.150 - What definitions apply to this part?

Code of Federal Regulations, 2011 CFR

2011-07-01

... POLLUTION CONTROLS FEES FOR ENGINE, VEHICLE, AND EQUIPMENT COMPLIANCE PROGRAMS § 1027.150 What definitions.... California-only certificate is a certificate of conformity issued by EPA showing compliance with emission standards established by California. Federal certificate is a certificate of conformity issued by EPA...

40 CFR 1027.150 - What definitions apply to this part?

Code of Federal Regulations, 2010 CFR

2010-07-01

... POLLUTION CONTROLS FEES FOR ENGINE, VEHICLE, AND EQUIPMENT COMPLIANCE PROGRAMS § 1027.150 What definitions.... California-only certificate is a certificate of conformity issued by EPA showing compliance with emission standards established by California. Federal certificate is a certificate of conformity issued by EPA...

40 CFR 1027.150 - What definitions apply to this part?

Code of Federal Regulations, 2013 CFR

2013-07-01

... POLLUTION CONTROLS FEES FOR ENGINE, VEHICLE, AND EQUIPMENT COMPLIANCE PROGRAMS § 1027.150 What definitions.... California-only certificate is a certificate of conformity issued by EPA showing compliance with emission standards established by California. Federal certificate is a certificate of conformity issued by EPA...

Political Correctness and American Academe.

ERIC Educational Resources Information Center

Drucker, Peter F.

1994-01-01

Argues that today's political correctness atmosphere is a throwback to attempts made by the Nazis and Stalinists to force society into conformity. Academia, it is claimed, is being forced to conform to gain control of the institution of higher education. It is predicted that this effort will fail. (GR)

77 FR 35866 - Approval and Promulgation of Implementation Plans; Revisions to the Georgia State Implementation...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-15

... (GA DNR), on November 16, 2010. This revision consists of transportation conformity criteria and procedures related to interagency consultation and enforceability of certain transportation-related control measures and mitigation measures. The intended effect is to update the transportation conformity criteria...

75 FR 20780 - Approval and Promulgation of Implementation Plans; Revisions to the Kentucky State Implementation...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-21

... transportation conformity revisions to the Kentucky State Implementation Plan (SIP) submitted by the Commonwealth...). This addition consists of transportation conformity criteria and procedures related to interagency consultation and enforceability of certain transportation-related control measures and mitigation measures. The...

Engineering acyclic stereocontrol in the alkylation of vinylglycine-derived dianions: asymmetric synthesis of higher alpha-vinyl amino acids.

PubMed

Berkowitz, D B; McFadden, J M; Sloss, M K

2000-05-19

A generalizable synthesis of higher L-alpha-vinyl amino acids is presented. The strategy pursued here involves the introduction of the amino acid side chain via the alkylation of a chiral, vinylglycine-derived dianionic dienolate, bearing the (-)-8-(beta-naphthyl)menthyl (d'Angelo) auxiliary. A model is presented that postulates a favored "exo-entended" conformation for this dienolate, leading to C(alpha)-alkylation at the si face. The model invokes internal amidate chelation to control ester enolate geometry and soft-soft interactions between the polarizable beta-naphthyl ring of the auxiliary and the extended pi-system of the dienolate to shield the re face. Heats of formation for four conformers of this dianion were calculated for their semiempirical optimized geometries (PM3). The results support the notion that in these vinylglycine-derived dianionic dienolates, "exo" conformations are considerable lower in energy than their "endo" counterparts, with the "exo-entended" conformation being most favorable. In fact, the d'Angelo auxiliary gives a greater degree of acyclic stereocontrol in this system when compared with the (-)-8-phenylmenthyl (Corey) and trans-2-(beta-naphthyl)cyclohexyl auxiliaries, using isobutyl iodide and benzyl bromide as model electrophiles. These dianions are generated from the corresponding dehydrobutyrine esters via sequential deprotonation with LDA and n-BuLi (2 equiv). When alkylations are carried out at -78 degrees C in THF-HMPA, they proceed in 65-81% yields, with both regiocontrol (deconjugative alpha-alkylation is preferred over gamma-alkylation) and a great degree of acyclic stereocontrol [91:9 to >/=98:2 diastereomeric ratios (10 examples)]. The auxiliary may be recovered in high yield (generally 90%) using a modification of Gassman's "anhydrous hydroxide" conditions, in which considerably higher temperatures are employed. Among the side chains introduced directly are those of butyrine, leucine, ornithine, phenylalanine, aspartate, valine, and norvaline. The lysine side chain is elaborated via a 4-step sequence from the alkylation product obtained with 1-chloro-4-iodobutane as electrophile. Importantly, to our knowledge, this work represents the first asymmetric synthesis of L-alpha-vinyl analogues of m-tyrosine, ornithine, and lysine, known time-dependent inhibitors for amino acid decarboxylases.

Component-based integration of chemistry and optimization software.

PubMed

Kenny, Joseph P; Benson, Steven J; Alexeev, Yuri; Sarich, Jason; Janssen, Curtis L; McInnes, Lois Curfman; Krishnan, Manojkumar; Nieplocha, Jarek; Jurrus, Elizabeth; Fahlstrom, Carl; Windus, Theresa L

2004-11-15

Typical scientific software designs make rigid assumptions regarding programming language and data structures, frustrating software interoperability and scientific collaboration. Component-based software engineering is an emerging approach to managing the increasing complexity of scientific software. Component technology facilitates code interoperability and reuse. Through the adoption of methodology and tools developed by the Common Component Architecture Forum, we have developed a component architecture for molecular structure optimization. Using the NWChem and Massively Parallel Quantum Chemistry packages, we have produced chemistry components that provide capacity for energy and energy derivative evaluation. We have constructed geometry optimization applications by integrating the Toolkit for Advanced Optimization, Portable Extensible Toolkit for Scientific Computation, and Global Arrays packages, which provide optimization and linear algebra capabilities. We present a brief overview of the component development process and a description of abstract interfaces for chemical optimizations. The components conforming to these abstract interfaces allow the construction of applications using different chemistry and mathematics packages interchangeably. Initial numerical results for the component software demonstrate good performance, and highlight potential research enabled by this platform.

Conformational study and structure of N-(2,5-methylphenyl)salicylaldimine

NASA Astrophysics Data System (ADS)

Elmali, A.; Elerman, Y.; Zeyrek, C. T.

1998-02-01

N-(2,5-methylphenyl)salicylaldimine (C 15H 15NO) has been investigated by X-ray analysis and AM1 semi-empirical quantum mechanical method. The crystal is in the orthorhombic space group P2 12 12 1 with a = 6.839(1), b = 7.720(4), c = 23.183(3) Å, V = 1224.1(2) Å3, Z = 4, Dc = 1.222 g cm -3 and μ(Mo K α) = 0.076 mm -1. The title structure was solved by direct methods and refined to R = 0.0364 for 1489 reflections [ I > 2 σ( I)] by full-matrix anisotropic least-squares methods. The title compound is photochromic and the molecule is not planar. There is a strong intramolecular hydrogen bond of distance 2.604(2) Å between the hydroxyl oxygen atom and imine nitrogen atom, the hydrogen atom essentially being bonded to the oxygen atom. Minimum energy conformations from AM1 were calculated as a function of three torsion angles, θ1 (C8N1C7C6), θ2 (C9C8N1C7) and θ3 (N1C7C6C5), varied every 10°. The optimized geometry of the crystal structure corresponding to non-planar conformation is the most stable conformation in all calculations. The results strongly indicate that the minimum energy conformation is primarily determined by non-bonded hydrogen-hydrogen repulsions.

How Does (E)-2-(Acetamidomethylene)succinate Bind to Its Hydrolase? From the Binding Process to the Final Result

PubMed Central

Zhang, Ji-Long; Zheng, Qing-Chuan; Li, Zheng-Qiang; Zhang, Hong-Xing

2013-01-01

The binding of (E)-2-(acetamidomethylene)succinate (E-2AMS) to E-2AMS hydrolase is crucial for biological function of the enzyme and the last step reaction of vitamin B6 biological degradation. In the present study, several molecular simulation methods, including molecular docking, conventional molecular dynamics (MD), steered MD (SMD), and free energy calculation methods, were properly integrated to investigate the detailed binding process of E-2AMS to its hydrolase and to assign the optimal enzyme-substrate complex conformation. It was demonstrated that the substrate binding conformation with trans-form amide bond is energetically preferred conformation, in which E-2AMS's pose not only ensures hydrogen bond formation of its amide oxygen atom with the vicinal oxyanion hole but also provides probability of the hydrophobic interaction between its methyl moiety and the related enzyme's hydrophobic cavity. Several key residues, Arg146, Arg167, Tyr168, Arg179, and Tyr259, orientate the E-2AMS's pose and stabilize its conformation in the active site via the hydrogen bond interaction with E-2AMS. Sequentially, the binding process of E-2AMS to E-2AMS hydrolase was studied by SMD simulation, which shows the surprising conformational reversal of E-2AMS. Several important intermediate structures and some significant residues were identified in the simulation. It is stressed that Arg146 and Arg167 are two pivotal residues responsible for the conformational reversal of E-2AMS in the binding or unbinding. Our research has shed light onto the full binding process of the substrate to E-2AMS hydrolase, which could provide more penetrating insight into the interaction of E-2AMS with the enzyme and would help in the further exploration on the catalysis mechanism. PMID:23308285

BWM*: A Novel, Provable, Ensemble-based Dynamic Programming Algorithm for Sparse Approximations of Computational Protein Design.

PubMed

Jou, Jonathan D; Jain, Swati; Georgiev, Ivelin S; Donald, Bruce R

2016-06-01

Sparse energy functions that ignore long range interactions between residue pairs are frequently used by protein design algorithms to reduce computational cost. Current dynamic programming algorithms that fully exploit the optimal substructure produced by these energy functions only compute the GMEC. This disproportionately favors the sequence of a single, static conformation and overlooks better binding sequences with multiple low-energy conformations. Provable, ensemble-based algorithms such as A* avoid this problem, but A* cannot guarantee better performance than exhaustive enumeration. We propose a novel, provable, dynamic programming algorithm called Branch-Width Minimization* (BWM*) to enumerate a gap-free ensemble of conformations in order of increasing energy. Given a branch-decomposition of branch-width w for an n-residue protein design with at most q discrete side-chain conformations per residue, BWM* returns the sparse GMEC in O([Formula: see text]) time and enumerates each additional conformation in merely O([Formula: see text]) time. We define a new measure, Total Effective Search Space (TESS), which can be computed efficiently a priori before BWM* or A* is run. We ran BWM* on 67 protein design problems and found that TESS discriminated between BWM*-efficient and A*-efficient cases with 100% accuracy. As predicted by TESS and validated experimentally, BWM* outperforms A* in 73% of the cases and computes the full ensemble or a close approximation faster than A*, enumerating each additional conformation in milliseconds. Unlike A*, the performance of BWM* can be predicted in polynomial time before running the algorithm, which gives protein designers the power to choose the most efficient algorithm for their particular design problem.

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.

Nanoscale Probing of Electrical Signals in Biological Systems

DTIC Science & Technology

2012-03-18

Membranes Anodized aluminum oxide ( AAO ) is an ideal prototype substrate for studying ion transport through nanoporous membranes . For optimal...electrochemical microscopy, scanning ion conductance microscopy, nanoporous membranes , anodized aluminum oxide , atomic layer deposition, focused ion beam...capacity. This approach utilizes atomic layer deposition (ALD) of a thin conformal Ir film into a nanoporous anodized aluminum oxide (

Numerical Sensitivity of Trajectories Across Conformational Energy Hypersurfaces from Geometry Optimized Molecular Orbital Calculations: AM1, MNDO, and MINDO/3

DTIC Science & Technology

1988-01-01

relationship studies, it became corn- surfaces are being traversed, the molecule monly believed that compounds with higher h can go along different paths on...1975). AMPAC, and consanguineous programs 15. W. Thiel, Quantum Chem. Prog. Exchange Cata- should be done with the tightest available log, 11, 353

Evidence Evaluation: Measure "Z" Corresponds to Human Utility Judgments Better than Measure "L" and Optimal-Experimental-Design Models

ERIC Educational Resources Information Center

Rusconi, Patrice; Marelli, Marco; D'Addario, Marco; Russo, Selena; Cherubini, Paolo

2014-01-01

Evidence evaluation is a crucial process in many human activities, spanning from medical diagnosis to impression formation. The present experiments investigated which, if any, normative model best conforms to people's intuition about the value of the obtained evidence. Psychologists, epistemologists, and philosophers of science have proposed…

Crystal structure and theoretical studies of derivative of imidazo-1,2,4-triazine

NASA Astrophysics Data System (ADS)

Dybała, Izabela; Sztanke, Krzysztof

2016-09-01

In this study, we present the result of X-ray structure analysis of methyl [8-(3-chlorophenyl)-4-oxo-2,3,4,6,7,8-heksahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetate (1). The molecule conformation is flat, with a chlorophenyl substituent and the ester moiety lying in the plain of the heterobicyclic scaffold. Its conformation is stabilized by an intramolecular Nsbnd H…O hydrogen bond. Within the crystalline structure of 1, molecules associate with one another by weak Csbnd H…O, Csbnd H…Cl and Csbnd H…π bonds. The molecular and crystal structure of 1 was compared with the previously described structurally similar compound possessing the same bicyclic rigid core and similar chemical nature of the functional ester moiety. Very interesting differences in molecules geometry and association were observed. Non-covalent bonds within the crystals are additionally visualized by determination of Hirshfeld surfaces. Moreover, the quantum chemical calculation for 1 in the gas phase were carried out. The DFT calculation methods was used to optimize of molecule geometry and obtain molecular energy profiles with respect to selected torsion angles. The quantum chemical conformational analysis that was carried out for compound 1 in the gas phase suggests that in the solid state the molecules adopt the minimum energy conformation.

Biophysical characterization and conformational stability of Ebola and Marburg virus-like particles.

PubMed

Hu, Lei; Trefethen, Jared M; Zeng, Yuhong; Yee, Luisa; Ohtake, Satoshi; Lechuga-Ballesteros, David; Warfield, Kelly L; Aman, M Javad; Shulenin, Sergey; Unfer, Robert; Enterlein, Sven G; Truong-Le, Vu; Volkin, David B; Joshi, Sangeeta B; Middaugh, C Russell

2011-12-01

The filoviruses, Ebola virus and Marburg virus, cause severe hemorrhagic fever with up to 90% human mortality. Virus-like particles of EBOV (eVLPs) and MARV (mVLPs) are attractive vaccine candidates. For the development of stable vaccines, the conformational stability of these two enveloped VLPs produced in insect cells was characterized by various spectroscopic techniques over a wide pH and temperature range. Temperature-induced aggregation of the VLPs at various pH values was monitored by light scattering. Temperature/pH empirical phase diagrams (EPDs) of the two VLPs were constructed to summarize the large volume of data generated. The EPDs show that both VLPs lose their conformational integrity above about 50°C-60°C, depending on solution pH. The VLPs were maximally thermal stable in solution at pH 7-8, with a significant reduction in stability at pH 5 and 6. They were much less stable in solution at pH 3-4 due to increased susceptibility of the VLPs to aggregation. The characterization data and conformational stability profiles from these studies provide a basis for selection of optimized solution conditions for further vaccine formulation and long-term stability studies of eVLPs and mVLPs. Copyright © 2011 Wiley-Liss, Inc.

Excited state conformational dynamics in carotenoids: dark intermediates and excitation energy transfer.

PubMed

Beck, Warren F; Bishop, Michael M; Roscioli, Jerome D; Ghosh, Soumen; Frank, Harry A

2015-04-15

A consideration of the excited state potential energy surfaces of carotenoids develops a new hypothesis for the nature of the conformational motions that follow optical preparation of the S2 (1(1)Bu(+)) state. After an initial displacement from the Franck-Condon geometry along bond length alternation coordinates, it is suggested that carotenoids pass over a transition-state barrier leading to twisted conformations. This hypothesis leads to assignments for several dark intermediate states encountered in femtosecond spectroscopic studies. The Sx state is assigned to the structure reached upon the onset of torsional motions near the transition state barrier that divides planar and twisted structures on the S2 state potential energy surface. The X state, detected recently in two-dimensional electronic spectra, corresponds to a twisted structure well past the barrier and approaching the S2 state torsional minimum. Lastly, the S(∗) state is assigned to a low lying S1 state structure with intramolecular charge transfer character (ICT) and a pyramidal conformation. It follows that the bent and twisted structures of carotenoids that are found in photosynthetic light-harvesting proteins yield excited-state structures that favor the development of an ICT character and optimized energy transfer yields to (bacterio)chlorophyll acceptors. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of ionic strength and sugars on the aggregation propensity of monoclonal antibodies: influence of colloidal and conformational stabilities.

PubMed

Saito, Shuntaro; Hasegawa, Jun; Kobayashi, Naoki; Tomitsuka, Toshiaki; Uchiyama, Susumu; Fukui, Kiichi

2013-05-01

To develop a general strategy for optimizing monoclonal antibody (MAb) formulations. Colloidal stabilities of four representative MAbs solutions were assessed based on the second virial coefficient (B 2) at 20°C and 40°C, and net charges at different NaCl concentrations, and/or in the presence of sugars. Conformational stabilities were evaluated from the unfolding temperatures. The aggregation propensities were determined at 40°C and after freeze-thawing. The electrostatic potential of antibody surfaces was simulated for the development of rational formulations. Similar B 2 values were obtained at 20°C and 40°C, implying little dependence on temperature. B 2 correlated quantitatively with aggregation propensities at 40°C. The net charge partly correlated with colloidal stability. Salts stabilized or destabilized MAbs, depending on repulsive or attractive interactions. Sugars improved the aggregation propensity under freeze-thaw stress through improved conformational stability. Uneven and even distributions of potential surfaces were attributed to attractive and strong repulsive electrostatic interactions. Assessment of colloidal stability at the lowest ionic strength is particularly effective for the development of formulations. If necessary, salts are added to enhance the colloidal stability. Sugars further improved aggregation propensities by enhancing conformational stability. These behaviors are rationally predictable according to the surface potentials of MAbs.

Combine experimental and theoretical investigation on an alkaloid-Dimethylisoborreverine

NASA Astrophysics Data System (ADS)

Singh, Swapnil; Singh, Harshita; Karthick, T.; Agarwal, Parag; Erande, Rohan D.; Dethe, Dattatraya H.; Tandon, Poonam

2016-01-01

A combined experimental (FT-IR, 1H and 13C NMR) and theoretical approach is used to study the structure and properties of antimalarial drug dimethylisoborreverine (DMIB). Conformational analysis, has been performed by plotting one dimensional potential energy curve that was computed using density functional theory (DFT) with B3LYP/6-31G method and predicted conformer A1 as the most stable conformer. After full geometry optimization, harmonic wavenumbers were computed for conformer A1 at the DFT/B3LYP/6-311++G(d,P) level. A complete vibrational assignment of all the vibrational modes have been performed on the bases of the potential energy distribution (PED) and theoretical results were found to be in good agreement with the observed data. To predict the solvent effect, the UV-Vis spectra were calculated in different solvents by polarizable continuum model using TD-DFT method. Molecular docking studies were performed to test the biological activity of the sample using SWISSDOCK web server and Hex 8.0.0 software. The molecular electrostatic potential (MESP) was plotted to identify the reactive sites of the molecule. Natural bond orbital (NBO) analysis was performed to get a deep insight of intramolecular charge transfer. Thermodynamical parameters were calculated to predict the direction of chemical reaction.

Localized frustration and binding-induced conformational change in recognition of 5S RNA by TFIIIA zinc finger.

PubMed

Tan, Cheng; Li, Wenfei; Wang, Wei

2013-12-19

Protein TFIIIA is composed of nine tandemly arranged Cys2His2 zinc fingers. It can bind either to the 5S RNA gene as a transcription factor or to the 5S RNA transcript as a chaperone. Although structural and biochemical data provided valuable information on the recognition between the TFIIIIA and the 5S DNA/RNA, the involved conformational motions and energetic factors contributing to the binding affinity and specificity remain unclear. In this work, we conducted MD simulations and MM/GBSA calculations to investigate the binding-induced conformational changes in the recognition of the 5S RNA by the central three zinc fingers of TFIIIA and the energetic factors that influence the binding affinity and specificity at an atomistic level. Our results revealed drastic interdomain conformational changes between these three zinc fingers, involving the exposure/burial of several crucial DNA/RNA binding residues, which can be related to the competition between DNA and RNA for the binding of TFIIIA. We also showed that the specific recognition between finger 4/finger 6 and the 5S RNA introduces frustrations to the nonspecific interactions between finger 5 and the 5S RNA, which may be important to achieve optimal binding affinity and specificity.

Absolute Configuration of 3-METHYLCYCLOHEXANONE by Chiral Tag Rotational Spectroscopy and Vibrational Circular Dichroism

NASA Astrophysics Data System (ADS)

Evangelisti, Luca; Holdren, Martin S.; Mayer, Kevin J.; Smart, Taylor; West, Channing; Pate, Brooks

2017-06-01

The absolute configuration of 3-methylcyclohexanone was established by chiral tag rotational spectroscopy measurements using 3-butyn-2-ol as the tag partner. This molecule was chosen because it is a benchmark measurement for vibrational circular dichroism (VCD). A comparison of the analysis approaches of chiral tag rotational spectroscopy and VCD will be presented. One important issue in chiral analysis by both methods is the conformational flexibility of the molecule being analyzed. The analysis of conformational composition of samples will be illustrated. In this case, the high spectral resolution of molecular rotational spectroscopy and potential for spectral simplification by conformational cooling in the pulsed jet expansion are advantages for chiral tag spectroscopy. The computational chemistry requirements for the two methods will also be discussed. In this case, the need to perform conformer searches for weakly bound complexes and to perform reasonably high level quantum chemistry geometry optimizations on these complexes makes the computational time requirements less favorable for chiral tag rotational spectroscopy. Finally, the issue of reliability of the determination of the absolute configuration will be considered. In this case, rotational spectroscopy offers a "gold standard" analysis method through the determination of the ^{13}C-subsitution structure of the complex between 3-methylcyclohexanone and an enantiopure sample of the 3-butyn-2-ol tag.

High-Throughput Biophysical Analysis and Data Visualization of Conformational Stability of an IgG1 Monoclonal Antibody (mAb) After Deglycosylation

PubMed Central

Alsenaidy, Mohammad A.; Kim, Jae Hyun; Majumdar, Ranajoy; Weis, David D.; Joshi, Sangeeta B.; Tolbert, Thomas J.; Middaugh, C. Russell; Volkin, David B.

2013-01-01

The structural integrity and conformational stability of an IgG1 monoclonal antibody (mAb), after partial and complete enzymatic removal of the N-linked Fc glycan, was compared to the untreated mAb over a wide range of temperature (10° to 90°C) and solution pH (3 to 8) using circular dichroism, fluorescence spectroscopy, and static light scattering combined with data visualization employing empirical phase diagrams (EPDs). Subtle to larger stability differences between the different glycoforms were observed. Improved detection of physical stability differences was then demonstrated over narrower pH range (4.0-6.0) using smaller temperature increments, especially when combined with an alternative data visualization method (radar plots). Differential scanning calorimetry and differential scanning fluorimetry were then utilized and also showed an improved ability to detect differences in mAb glycoform physical stability. Based on these results, a two-step methodology was used in which mAb glycoform conformational stability is first screened with a wide variety of instruments and environmental stresses, followed by a second evaluation with optimally sensitive experimental conditions, analytical techniques and data visualization methods. With this approach, high-throughput biophysical analysis to assess relatively subtle conformational stability differences in protein glycoforms is demonstrated. PMID:24114789

An improved method for the calculation of Near-Field Acoustic Radiation Modes

NASA Astrophysics Data System (ADS)

Liu, Zu-Bin; Maury, Cédric

2016-02-01

Sensing and controlling Acoustic Radiation Modes (ARMs) in the near-field of vibrating structures is of great interest for broadband noise reduction or enhancement, as ARMs are velocity distributions defined over a vibrating surface, that independently and optimally contribute to the acoustic power in the acoustic field. But present methods only provide far-field ARMs (FFARMs) that are inadequate for the acoustic near-field problem. The Near-Field Acoustic Radiation Modes (NFARMs) are firstly studied with an improved numerical method, the Pressure-Velocity method, which rely on the eigen decomposition of the acoustic transfers between the vibrating source and a conformal observation surface, including sound pressure and velocity transfer matrices. The active and reactive parts of the sound power are separated and lead to the active and reactive ARMs. NFARMs are studied for a 2D baffled beam and for a 3D baffled plate, and so as differences between the NFARMS and the classical FFARMs. Comparisons of the NFARMs are analyzed when varying frequency and observation distance to the source. It is found that the efficiencies and shapes of the optimal active ARMs are independent on the distance while that of the reactive ones are distinctly related on.

Pyranopterin conformation defines the function of molybdenum and tungsten enzymes.

PubMed

Rothery, Richard A; Stein, Benjamin; Solomonson, Matthew; Kirk, Martin L; Weiner, Joel H

2012-09-11

We have analyzed the conformations of 319 pyranopterins in 102 protein structures of mononuclear molybdenum and tungsten enzymes. These span a continuum between geometries anticipated for quinonoid dihydro, tetrahydro, and dihydro oxidation states. We demonstrate that pyranopterin conformation is correlated with the protein folds defining the three major mononuclear molybdenum and tungsten enzyme families, and that binding-site micro-tuning controls pyranopterin oxidation state. Enzymes belonging to the bacterial dimethyl sulfoxide reductase (DMSOR) family contain a metal-bis-pyranopterin cofactor, the two pyranopterins of which have distinct conformations, with one similar to the predicted tetrahydro form, and the other similar to the predicted dihydro form. Enzymes containing a single pyranopterin belong to either the xanthine dehydrogenase (XDH) or sulfite oxidase (SUOX) families, and these have pyranopterin conformations similar to those predicted for tetrahydro and dihydro forms, respectively. This work provides keen insight into the roles of pyranopterin conformation and oxidation state in catalysis, redox potential modulation of the metal site, and catalytic function.

Technical Standards for Command and Control Information Systems (CCISs)

DTIC Science & Technology

1992-01-01

initiation, Conformance Testing 149 management, scheduling, resource allocation , logical and IEEE P1 003 146 physical device access, interrupt handling...70 5.2.3 Remote Data Access (RDA) ........................................... 72 5.2.4 Information Resource Dictionary...146 7.2.1.2 POSIX Conformance Testing .............................. 149 7.2.2 Consortia Recommendations

Being Imitated, Conformity, and Social Influence: An Integrative Review.

ERIC Educational Resources Information Center

Thelen, Mark H.; And Others

1981-01-01

Reviews literature on effects of being imitated and the social influence function of imitation, plus related literature on conformity from social psychology. Considers this research within a number of theoretical contexts, especially within the conceptual framework of effectance motivation. Suggests imitation may facilitate mastery and control of…

21 CFR 172.755 - Stearyl monoglyceridyl citrate.

Code of Federal Regulations, 2010 CFR

2010-04-01

... is prepared by controlled chemical reaction of the following: Reactant Limitations Citric acid Monoglycerides of fatty acids Prepared by the glycerolysis of edible fats and oils or derived from fatty acids conforming with § 172.860. Stearyl alcohol Derived from fatty acids conforming with § 172.860, or derived...

Molecular models of alginic acid: Interactions with calcium ions and calcite surfaces

NASA Astrophysics Data System (ADS)

Perry, Thomas D.; Cygan, Randall T.; Mitchell, Ralph

2006-07-01

Cation binding by polysaccharides is observed in many environments and is important for predictive environmental modeling, and numerous industrial and food technology applications. The complexities of these cation-organic interactions are well suited for predictive molecular modeling and the analysis of conformation and configuration of polysaccharides and their influence on cation binding. In this study, alginic acid was chosen as a model polymer system and representative disaccharide and polysaccharide subunits were developed. Molecular dynamics simulation of the torsion angles of the ether linkage between various monomeric subunits identified local and global energy minima for selected disaccharides. The simulations indicate stable disaccharide configurations and a common global energy minimum for all disaccharide models at Φ = 274 ± 7°, Ψ = 227 ± 5°, where Φ and Ψ are the torsion angles about the ether linkage. The ability of disaccharide subunits to bind calcium ions and to associate with the (101¯4) surface of calcite was also investigated. Molecular models of disaccharide interactions with calcite provide binding energy differences for conformations that are related to the proximity and residence densities of the electron-donating moieties with calcium ions on the calcite surface, which are controlled, in part, by the torsion of the ether linkage between monosaccharide units. Dynamically optimized configurations for polymer alginate models with calcium ions were also derived.

Uncoupling of Protease trans-Cleavage and Helicase Activities in Pestivirus NS3

PubMed Central

Zheng, Fengwei; Lu, Guoliang; Li, Ling

2017-01-01

ABSTRACT The nonstructural protein NS3 from the Flaviviridae family is a multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and genome replication. Here we report a full-length crystal structure of the classical swine fever virus (CSFV) NS3 in complex with its NS4A protease cofactor segment (PCS) at a 2.35-Å resolution. The structure reveals a previously unidentified ∼2,200-Å2 intramolecular protease-helicase interface comprising three clusters of interactions, representing a “closed” global conformation related to the NS3-NS4A cis-cleavage event. Although this conformation is incompatible with protease trans-cleavage, it appears to be functionally important and beneficial to the helicase activity, as the mutations designed to perturb this conformation impaired both the helicase activities in vitro and virus production in vivo. Our work reveals important features of protease-helicase coordination in pestivirus NS3 and provides a key basis for how different conformational states may explicitly contribute to certain functions of this natural protease-helicase fusion protein. IMPORTANCE Many RNA viruses encode helicases to aid their RNA genome replication and transcription by unwinding structured RNA. Being naturally fused to a protease participating in viral polyprotein processing, the NS3 helicases encoded by the Flaviviridae family viruses are unique. Therefore, how these two enzyme modules coordinate in a single polypeptide is of particular interest. Here we report a previously unidentified conformation of pestivirus NS3 in complex with its NS4A protease cofactor segment (PCS). This conformational state is related to the protease cis-cleavage event and is optimal for the function of helicase. This work provides an important basis to understand how different enzymatic activities of NS3 may be achieved by the coordination between the protease and helicase through different conformational states. PMID:28835495

Effects of side-chain orientation on the backbone conformation of the dehydrophenylalanine residue. Theoretical and X-ray study.

PubMed

Buczek, Aneta; Siodłak, Dawid; Bujak, Maciej; Broda, Małgorzata A

2011-04-21

Two E isomers of α,β-dehydro-phenylalanine, Ac-(E)-ΔPhe-NHMe (1a) and Ac-(E)-ΔPhe-NMe(2) (2a), have been synthesized and their low temperature structures determined by single-crystal X-ray diffraction. A systematic theoretical analysis was performed on these molecules and their Z isomers (1b and 2b). The ϕ,ψ potential energy surfaces were calculated at the MP2/6-31+G(d,p) and B3LYP/6-31+G(d,p) levels in the gas phase and at the B3LYP/6-31+G(d,p) level in the chloroform and water solutions with the SCRF-PCM method. All minima were fully optimized by the MP2 and DFT methods, and their relative stabilities were analyzed in terms of π-conjugation, internal H-bonds, and dipole-dipole interactions between carbonyl groups. The results indicate that all the studied compounds can adopt the conformation H (ϕ, ψ ≈ ±40°, ∓120°) which is atypical for standard amino acids residues. A different arrangement of the side chain in the E and Z isomers causes them to have different conformational preferences. In the presence of a polar solvent both Z isomers of ΔPhe (1b and 2b) are found to adopt the 3(10)-helical conformation (left- and right-handed are equally likely). On the other hand, this conformation is not accessible or highly energetic for E isomers of ΔPhe (1a and 2a). Those isomers have an intrinsic inclination to have an extended conformation. The conformational space of the Z isomers is much more restricted than that of the E derivative both in the gas phase and in solution. In the gas phase the E isomers of ΔPhe have lower energies than the Z ones, but in the aqueous solution the energy order is reversed.

DNA-controlled dynamic colloidal nanoparticle systems for mediating cellular interaction

NASA Astrophysics Data System (ADS)

Ohta, Seiichi; Glancy, Dylan; Chan, Warren C. W.

2016-02-01

Precise control of biosystems requires development of materials that can dynamically change physicochemical properties. Inspired by the ability of proteins to alter their conformation to mediate function, we explored the use of DNA as molecular keys to assemble and transform colloidal nanoparticle systems. The systems consist of a core nanoparticle surrounded by small satellites, the conformation of which can be transformed in response to DNA via a toe-hold displacement mechanism. The conformational changes can alter the optical properties and biological interactions of the assembled nanosystem. Photoluminescent signal is altered by changes in fluorophore-modified particle distance, whereas cellular targeting efficiency is increased 2.5 times by changing the surface display of targeting ligands. These concepts provide strategies for engineering dynamic nanotechnology systems for navigating complex biological environments.

Application of statistical process control and process capability analysis procedures in orbiter processing activities at the Kennedy Space Center

NASA Technical Reports Server (NTRS)

Safford, Robert R.; Jackson, Andrew E.; Swart, William W.; Barth, Timothy S.

1994-01-01

Successful ground processing at KSC requires that flight hardware and ground support equipment conform to specifications at tens of thousands of checkpoints. Knowledge of conformance is an essential requirement for launch. That knowledge of conformance at every requisite point does not, however, enable identification of past problems with equipment, or potential problem areas. This paper describes how the introduction of Statistical Process Control and Process Capability Analysis identification procedures into existing shuttle processing procedures can enable identification of potential problem areas and candidates for improvements to increase processing performance measures. Results of a case study describing application of the analysis procedures to Thermal Protection System processing are used to illustrate the benefits of the approaches described in the paper.

Intracranial stereotactic radiosurgery with an adapted linear accelerator vs. robotic radiosurgery: Comparison of dosimetric treatment plan quality.

PubMed

Treuer, Harald; Hoevels, Moritz; Luyken, Klaus; Visser-Vandewalle, Veerle; Wirths, Jochen; Kocher, Martin; Ruge, Maximilian

2015-06-01

Stereotactic radiosurgery with an adapted linear accelerator (linac-SRS) is an established therapy option for brain metastases, benign brain tumors, and arteriovenous malformations. We intended to investigate whether the dosimetric quality of treatment plans achieved with a CyberKnife (CK) is at least equivalent to that for linac-SRS with circular or micromultileaf collimators (microMLC). A random sample of 16 patients with 23 target volumes, previously treated with linac-SRS, was replanned with CK. Planning constraints were identical dose prescription and clinical applicability. In all cases uniform optimization scripts and inverse planning objectives were used. Plans were compared with respect to coverage, minimal dose within target volume, conformity index, and volume of brain tissue irradiated with ≥ 10 Gy. Generating the CK plan was unproblematic with simple optimization scripts in all cases. With the CK plans, coverage, minimal target volume dosage, and conformity index were significantly better, while no significant improvement could be shown regarding the 10 Gy volume. Multiobjective comparison for the irradiated target volumes was superior in the CK plan in 20 out of 23 cases and equivalent in 3 out of 23 cases. Multiobjective comparison for the treated patients was superior in the CK plan in all 16 cases. The results clearly demonstrate the superiority of the irradiation plan for CK compared to classical linac-SRS with circular collimators and microMLC. In particular, the average minimal target volume dose per patient, increased by 1.9 Gy, and at the same time a 14% better conformation index seems to be an improvement with clinical relevance.

Atomistic details of the disordered states of KID and pKID. Implications in coupled binding and folding.

PubMed

Ganguly, Debabani; Chen, Jianhan

2009-04-15

Intrinsically disordered proteins (IDPs) are a newly recognized class of functional proteins for which a lack of stable tertiary fold is required for function. Because of the heterogeneous and dynamical nature, molecular modeling is necessary to provide the missing details of disordered states of IDP that are crucial for understanding their functions. In particular, generalized Born (GB) implicit solvent, combined with replica exchange (REX), might offer an optimal balance between accuracy and efficiency for modeling IDPs. We carried out extensive REX simulations in an optimized GB force field to characterize the disordered states of a regulatory IDP, KID domain of transcription factor CREB, and its phosphorylated form, pKID. The results revealed that both KID and pKID, though highly disordered on the tertiary level, are compact and mainly occupy a small number of helical substates. Interestingly, although phosphorylation of KID Ser133 leads only to marginal changes in average helicities on the ensemble level, underlying conformational substates differ significantly. In particular, pSer133 appears to restrict the accessible conformational space of the loop region and thus reduces the entropic cost of KID folding upon binding to the KIX domain of CREB-binding protein. Such an expanded role of phosphorylation in the KID:KIX recognition was not previously recognized because of a lack of substantial conformational changes on the ensemble level and inaccessibility of the structural details from experiments. The results also suggest that an implicit solvent-based modeling framework, despite various existing limitations, might be feasible for accurate atomistic simulation of small IDPs in general.

Children's memory distortions following social contact with a co-witness: disentangling social and cognitive mechanisms.

PubMed

Bright-Paul, Alexandra; Jarrold, Christopher; Wright, Daniel B; Guillaume, Stephanie

2012-01-01

This study examined whether recalling an event with a co-witness influences children's recall. Individual 3-5-year-olds (n = 48) watched a film with a co-witness. Unbeknown to participants, the co-witness was watching an alternative version of the film. Afterwards both the co-witness and the participant answered questions about the film together (public recall), and the degree to which children conformed to the co-witness's alternative version of events was measured. Subsequently participants were questioned again individually (private recall). Children also completed false belief and inhibitory control tasks. By separating errors made in public and private, the results indicated that both social conformity (32% of errors) and memory distortion (68% of errors) played a role in co-witness influence. Inhibitory control predicted the likelihood of retracting errors in private, but only for children who failed (r = .66) rather than passed false belief tasks (r = -.10). The results suggest that children with a theory of mind conform in the company of the co-witness to avoid social embarrassment, while those a poor theory of mind conform on the basis of an inability to inhibit the co-witness's response. The findings contribute to our understanding of the motivations responsible for co-witness conformity across early childhood.

TH-CD-209-10: Scanning Proton Arc Therapy (SPArc) - The First Robust and Delivery-Efficient Spot Scanning Proton Arc Therapy

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

Ding, X; Li, X; Zhang, J

Purpose: To develop a delivery-efficient proton spot-scanning arc therapy technique with robust plan quality. Methods: We developed a Scanning Proton Arc(SPArc) optimization algorithm integrated with (1)Control point re-sampling by splitting control point into adjacent sub-control points; (2)Energy layer re-distribution by assigning the original energy layers to the new sub-control points; (3)Energy layer filtration by deleting low MU weighting energy layers; (4)Energy layer re-sampling by sampling additional layers to ensure the optimal solution. A bilateral head and neck oropharynx case and a non-mobile lung target case were tested. Plan quality and total estimated delivery time were compared to original robust optimizedmore » multi-field step-and-shoot arc plan without SPArc optimization (Arcmulti-field) and standard robust optimized Intensity Modulated Proton Therapy(IMPT) plans. Dose-Volume-Histograms (DVH) of target and Organ-at-Risks (OARs) were analyzed along with all worst case scenarios. Total delivery time was calculated based on the assumption of a 360 degree gantry room with 1 RPM rotation speed, 2ms spot switching time, beam current 1nA, minimum spot weighting 0.01 MU, energy-layer-switching-time (ELST) from 0.5 to 4s. Results: Compared to IMPT, SPArc delivered less integral dose(−14% lung and −8% oropharynx). For lung case, SPArc reduced 60% of skin max dose, 35% of rib max dose and 15% of lung mean dose. Conformity Index is improved from 7.6(IMPT) to 4.0(SPArc). Compared to Arcmulti-field, SPArc reduced number of energy layers by 61%(276 layers in lung) and 80%(1008 layers in oropharynx) while kept the same robust plan quality. With ELST from 0.5s to 4s, it reduced 55%–60% of Arcmulti-field delivery time for the lung case and 56%–67% for the oropharynx case. Conclusion: SPArc is the first robust and delivery-efficient proton spot-scanning arc therapy technique which could be implemented in routine clinic. For modern proton machine with ELST close to 0.5s, SPArc would be a popular treatment option for both single and multi-room center.« less

Cerium chloride stimulated controlled conversion of B-to-Z DNA in self-assembled nanostructures

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

Bhanjadeo, Madhabi M.; Academy of Scientific & Innovative Research; Nayak, Ashok K.

DNA adopts different conformation not only because of novel base pairs but also while interacting with inorganic or organic compounds. Self-assembled branched DNA (bDNA) structures or DNA origami that change conformation in response to environmental cues hold great promises in sensing and actuation at the nanoscale. Recently, the B-Z transition in DNA is being explored to design various nanomechanical devices. In this communication we have demonstrated that Cerium chloride binds to the phosphate backbone of self-assembled bDNA structure and induce B-to-Z transition at physiological concentration. The mechanism of controlled conversion from right-handed to left-handed has been assayed by various dyemore » binding studies using CD and fluorescence spectroscopy. Three different bDNA structures have been identified to display B-Z transition. This approach provides a rapid and reversible means to change bDNA conformation, which can be used for dynamic and progressive control at the nanoscale. - Highlights: • Cerium-induced B-to-Z DNA transition in self-assembled nanostructures. • Lower melting temperature of Z-DNA than B-DNA confirmed by CD spectroscopy. • Binding mechanism of cerium chloride is explained using fluorescence spectroscopy. • Right-handed to left-handed DNA conformation is also noticed in modified bDNA structure.« less

Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins.

PubMed

Firman, Taylor; Ghosh, Kingshuk

2018-03-28

We present an analytical theory to compute conformations of heteropolymers-applicable to describe disordered proteins-as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence-while maintaining the same charge composition-can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at a high-throughput level can provide valuable insights into the different mechanisms by which phosphorylation/charge mutation controls IDP function.

Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins

NASA Astrophysics Data System (ADS)

Firman, Taylor; Ghosh, Kingshuk

2018-03-01

We present an analytical theory to compute conformations of heteropolymers—applicable to describe disordered proteins—as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence—while maintaining the same charge composition—can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at a high-throughput level can provide valuable insights into the different mechanisms by which phosphorylation/charge mutation controls IDP function.

Poster — Thur Eve — 61: A new framework for MPERT plan optimization using MC-DAO

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

Baker, M; Lloyd, S AM; Townson, R

2014-08-15

This work combines the inverse planning technique known as Direct Aperture Optimization (DAO) with Intensity Modulated Radiation Therapy (IMRT) and combined electron and photon therapy plans. In particular, determining conditions under which Modulated Photon/Electron Radiation Therapy (MPERT) produces better dose conformality and sparing of organs at risk than traditional IMRT plans is central to the project. Presented here are the materials and methods used to generate and manipulate the DAO procedure. Included is the introduction of a powerful Java-based toolkit, the Aperture-based Monte Carlo (MC) MPERT Optimizer (AMMO), that serves as a framework for optimization and provides streamlined access tomore » underlying particle transport packages. Comparison of the toolkit's dose calculations to those produced by the Eclipse TPS and the demonstration of a preliminary optimization are presented as first benchmarks. Excellent agreement is illustrated between the Eclipse TPS and AMMO for a 6MV photon field. The results of a simple optimization shows the functioning of the optimization framework, while significant research remains to characterize appropriate constraints.« less

WE-G-16A-01: Evolution of Radiation Treatment Planning

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

Rothenberg, L; Mohan, R; Van Dyk, J

Welcome and Introduction - Lawrence N. Rothenberg This symposium is one a continuing series of presentations at AAPM Annual Meetings on the historical aspects of medical physics, radiology, and radiation oncology that have been organized by the AAPM History Committee. Information on previous presentations including “Early Developments in Teletherapy” (Indianapolis 2013), “Historical Aspects of Cross-Sectional Imaging” (Charlotte 2012), “Historical Aspects of Brachytherapy” (Vancouver 2011), “50 Years of Women in Medical Physics” (Houston 2008), and “Roentgen's Early Investigations” (Minneapolis 2007) can be found in the Education Section of the AAPM Website. The Austin 2014 History Symposium will be on “Evolution ofmore » Radiation Treatment Planning.” Overview - Radhe Mohan Treatment planning is one of the most critical components in the chain of radiation therapy of cancers. Treatment plans of today contain a wide variety of sophisticated information conveying the potential clinical effectiveness of the designed treatment to practitioners. Examples of such information include dose distributions superimposed on three- or even four-dimensional anatomic images; dose volume histograms, dose, dose-volume and dose-response indices for anatomic structures of interest; etc. These data are used for evaluating treatment plans and for making treatment decisions. The current state-of-the-art has evolved from the 1940s era when the dose to the tumor and normal tissues was estimated approximately by manual means. However, the symposium will cover the history of the field from the late-1950's, when computers were first introduced for treatment planning, to the present state involving the use of high performance computing and advanced multi-dimensional anatomic, functional and biological imaging, focusing only on external beam treatment planning. The symposium will start with a general overview of the treatment planning process including imaging, structure delineation, assignment of dose requirements, consideration of uncertainties, selection of beam configurations and shaping of beams, and calculations, optimization and evaluation of dose distributions. This will be followed by three presentations covering the evolution of treatment planning, which parallels the evolution of computers, availability of advanced volumetric imaging and the development of novel technologies such as dynamic multi-leaf collimators and online image guidance. This evolution will be divided over three distinct periods - prior to 1970's, the 2D era; from 1980 to the mid-1990's, the 3D era; and from the mid 1990's to today, the IMRT era. When the World was Flat: The Two-Dimensional Radiation Therapy Era” - Jacob Van Dyk In the 2D era, anatomy was defined with the aid of solder wires, special contouring devices and projection x-rays. Dose distributions were calculated manually from single field, flat surface isodoses on transparencies. Precalculated atlases of generic dose distributions were produced by the International Atomic Energy Agency. Massive time-shared main frames and mini-computers were used to compute doses at individual points or dose distributions in a single plane. Beam shapes were generally rectangular, with wedges, missing tissue compensators and occasional blocks to shield critical structures. Dose calculations were measurement-based or they used primary and scatter calculations based on scatter-air ratio methodologies. Dose distributions were displayed on line printers as alpha-numeric character maps or isodose patterns made with pen plotters. More than Pretty Pictures: 3D Treatment Planning and Conformal Therapy - Benedick A. Fraass The introduction of computed tomography allowed the delineation of anatomy three-dimensionally and, supported partly by contracts from the National Cancer Institute, made possible the introduction and clinical use of 3D treatment planning, leading to development and use of 3D conformal therapy in the 1980's. 3D computer graphics and 3D anatomical structure definitions made possible Beam's Eye View (BEV) displays, making conformal beam shaping and much more sophisticated beam arrangements possible. These conformal plans significantly improved target dose coverage as well as normal tissue sparing. The use of dose volume histograms, gross/clinical/planning target volumes, MRI and PET imaging, multileaf collimators, and computer-controlled treatment delivery made sophisticated planning approaches practical. The significant improvements in dose distributions and analysis achievable with 3D conformal therapy made possible formal dose escalation and normal tissue tolerance clinical studies that set new and improved expectations for improved local control and decreasing complications in many clinical sites. From the Art to the State of the Art: Inverse Planning and IMRT - Thomas R. Bortfeld While the potential of intensity modulation was recognized in the mid- 1980's, intensity-modulated radiotherapy (IMRT) did not become a reality until the mid-1990's. Broad beams of photons could be sub-divided into narrow beamlets whose intensities could be determined using sophisticated optimization algorithms to appropriately balance tumor dose with normal tissue sparing. The development of dynamic multi-leaf collimators (on conventional linear accelerators as well as in helical delivery devices) enabled the efficient delivery of IMRT. The evolution of IMRT planning is continuing in the form of Volumetric Modulated Arc Therapy (VMAT) and through advanced optimization tools, such as multi-criteria optimization, automated IMRT planning, and robust optimization to protect dose distributions against uncertainties. IMRT also facilitates “dose painting” in which different sub-volumes of the target are prescribed different doses. Clearly, these advancements are being made possible by the increasing power and lower cost of computers and developments in other fields such as imaging and operations research. Summary - Radhe Mohan The history does not end here. The advancement of treatment planning is expected to continue, leading to further automation and improvements in conformality and robustness of dose distributions, particularly in the area of particle therapy. Radiobiological modeling will gain emphasis as part of the planning process. Learning Objectives: The scope of changes in technology and the capabilities of radiation treatment planning The impact of these changes in the quality of treatment plans and optimality of dose distributions The impact of development in other fields (imaging, computers, operations research, etc.) on the evolution of radiation treatment planning.« less

Fine-tuning the release of molecular guests from mesoporous silicas by controlling the orientation and mobility of surface phenyl substituents

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

Manzano, J. Sebastian; Singappuli-Arachchige, Dilini; Parikh, Bosky L.

Phenyl-functionalized mesoporous silica materials were used to explore the effect of non-covalent interactions on the release of Ibuprofen into simulated body fluid. Variations in orientation and conformational mobility of the surface phenyl groups were introduced by selecting different structural precursors: a rigid upright orientation was obtained using phenyl groups directly bound to surface Si atoms (Ph-MSN), mobile groups were produced by using ethylene linkers to connect phenyl groups to the surface (PhEt-MSN), and groups co-planar to the surface were obtained by synthesizing a phenylene-bridged periodic mesoporous organosilica (Ph-PMO). The Ibuprofen release profiles from these materials and non-functionalized mesoporous silica nanoparticlesmore » (MSN) were analyzed using an adsorption-diffusion model. The model provided kinetic and thermodynamic parameters that evidenced fundamental differences in drug-surface interactions between the materials. All phenyl-bearing materials show lower Ibuprofen initial release rates than bare MSN. The conformationally locked Ph-MSN and Ph-PMO have stronger interactions with the drug (negative ΔG of adsorption) than the flexible PhEt-MSN and bare MSN (positive ΔG of adsorption). These differences in strength of adsorption are consistent with differences between interaction geometries obtained from DFT calculations. B3LYP-D3-optimized models show that π-π interactions contribute more to drug adsorption than H-bonding with silanol groups. Here, the results suggest that the type and geometry of interactions control the kinetics and extent of drug release, and should therefore serve as a guide to design new drug delivery systems with precise release behaviors customized to any desired target.« less

Fine-tuning the release of molecular guests from mesoporous silicas by controlling the orientation and mobility of surface phenyl substituents

DOE PAGES

Manzano, J. Sebastian; Singappuli-Arachchige, Dilini; Parikh, Bosky L.; ...

2017-12-05

Phenyl-functionalized mesoporous silica materials were used to explore the effect of non-covalent interactions on the release of Ibuprofen into simulated body fluid. Variations in orientation and conformational mobility of the surface phenyl groups were introduced by selecting different structural precursors: a rigid upright orientation was obtained using phenyl groups directly bound to surface Si atoms (Ph-MSN), mobile groups were produced by using ethylene linkers to connect phenyl groups to the surface (PhEt-MSN), and groups co-planar to the surface were obtained by synthesizing a phenylene-bridged periodic mesoporous organosilica (Ph-PMO). The Ibuprofen release profiles from these materials and non-functionalized mesoporous silica nanoparticlesmore » (MSN) were analyzed using an adsorption-diffusion model. The model provided kinetic and thermodynamic parameters that evidenced fundamental differences in drug-surface interactions between the materials. All phenyl-bearing materials show lower Ibuprofen initial release rates than bare MSN. The conformationally locked Ph-MSN and Ph-PMO have stronger interactions with the drug (negative ΔG of adsorption) than the flexible PhEt-MSN and bare MSN (positive ΔG of adsorption). These differences in strength of adsorption are consistent with differences between interaction geometries obtained from DFT calculations. B3LYP-D3-optimized models show that π-π interactions contribute more to drug adsorption than H-bonding with silanol groups. Here, the results suggest that the type and geometry of interactions control the kinetics and extent of drug release, and should therefore serve as a guide to design new drug delivery systems with precise release behaviors customized to any desired target.« less

Spot Scanning Proton Therapy for Malignancies of the Base of Skull: Treatment Planning, Acute Toxicities, and Preliminary Clinical Outcomes

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

Grosshans, David R., E-mail: dgrossha@mdanderson.org; Zhu, X. Ronald; Melancon, Adam

2014-11-01

Purpose: To describe treatment planning techniques and early clinical outcomes in patients treated with spot scanning proton therapy for chordoma or chondrosarcoma of the skull base. Methods and Materials: From June 2010 through August 2011, 15 patients were treated with spot scanning proton therapy for chordoma (n=10) or chondrosarcoma (n=5) at a single institution. Toxicity was prospectively evaluated and scored weekly and at all follow-up visits according to Common Terminology Criteria for Adverse Events, version 3.0. Treatment planning techniques and dosimetric data were recorded and compared with those of passive scattering plans created with clinically applicable dose constraints. Results: Tenmore » patients were treated with single-field-optimized scanning beam plans and 5 with multifield-optimized intensity modulated proton therapy. All but 2 patients received a simultaneous integrated boost as well. The mean prescribed radiation doses were 69.8 Gy (relative biological effectiveness [RBE]; range, 68-70 Gy [RBE]) for chordoma and 68.4 Gy (RBE) (range, 66-70) for chondrosarcoma. In comparison with passive scattering plans, spot scanning plans demonstrated improved high-dose conformality and sparing of temporal lobes and brainstem. Clinically, the most common acute toxicities included fatigue (grade 2 for 2 patients, grade 1 for 8 patients) and nausea (grade 2 for 2 patients, grade 1 for 6 patients). No toxicities of grades 3 to 5 were recorded. At a median follow-up time of 27 months (range, 13-42 months), 1 patient had experienced local recurrence and a second developed distant metastatic disease. Two patients had magnetic resonance imaging-documented temporal lobe changes, and a third patient developed facial numbness. No other subacute or late effects were recorded. Conclusions: In comparison to passive scattering, treatment plans for spot scanning proton therapy displayed improved high-dose conformality. Clinically, the treatment was well tolerated, and with short-term follow-up, disease control rates and toxicity profiles were favorable.« less

Core-shell silk hydrogels with spatially tuned conformations as drug-delivery system.

PubMed

Yan, Le-Ping; Oliveira, Joaquim M; Oliveira, Ana L; Reis, Rui L

2017-11-01

Hydrogels of spatially controlled physicochemical properties are appealing platforms for tissue engineering and drug delivery. In this study, core-shell silk fibroin (SF) hydrogels of spatially controlled conformation were developed. The core-shell structure in the hydrogels was formed by means of soaking the preformed (enzymatically crosslinked) random coil SF hydrogels in methanol. When increasing the methanol treatment time from 1 to 10 min, the thickness of the shell layer can be tuned from about 200 to about 850 μm as measured in wet status. After lyophilization of the rehydrated core-shell hydrogels, the shell layer displayed compact morphology and the core layer presented porous structure, when observed by scanning electron microscopy. The conformation of the hydrogels was evaluated by Fourier transform infrared spectroscopy in wet status. The results revealed that the shell layer possessed dominant β-sheet conformation and the core layer maintained mainly random coil conformation. Enzymatic degradation data showed that the shell layers presented superior stability to the core layer. The mechanical analysis displayed that the compressive modulus of the core-shell hydrogels ranged from about 25 kPa to about 1.1 MPa by increasing the immersion time in methanol. When incorporated with albumin, the core-shell SF hydrogels demonstrated slower and more controllable release profiles compared with the non-treated hydrogel. These core-shell SF hydrogels of highly tuned properties are useful systems as drug-delivery system and may be applied as cartilage substitute. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Direct observation of bis(dicarbollyl)nickel conformers in solution by fluorescence spectroscopy: an approach to redox-controlled metallacarborane molecular motors.

PubMed

Safronov, Alexander V; Shlyakhtina, Natalia I; Everett, Thomas A; VanGordon, Monika R; Sevryugina, Yulia V; Jalisatgi, Satish S; Hawthorne, M Frederick

2014-10-06

As a continuation of work on metallacarborane-based molecular motors, the structures of substituted bis(dicarbollyl)nickel complexes in Ni(III) and Ni(IV) oxidation states were investigated in solution by fluorescence spectroscopy. Symmetrically positioned cage-linked pyrene molecules served as fluorescent probes to enable the observation of mixed meso-trans/dl-gauche (pyrene monomer fluorescence) and dl-cis/dl-gauche (intramolecular pyrene excimer fluorescence with residual monomer fluorescence) cage conformations of the nickelacarboranes in the Ni(III) and Ni(IV) oxidation states, respectively. The absence of energetically disfavored conformers in solution--dl-cis in the case of nickel(III) complexes and meso-trans in the case of nickel(IV)--was demonstrated based on spectroscopic data and conformer energy calculations in solution. The conformational persistence observed in solution indicates that bis(dicarbollyl)nickel complexes may provide attractive templates for building electrically driven and/or photodriven molecular motors.

Inter-ring rotations of AAA ATPase p97 revealed by electron cryomicroscopy

PubMed Central

Yeung, Heidi O.; Förster, Andreas; Bebeacua, Cecilia; Niwa, Hajime; Ewens, Caroline; McKeown, Ciarán; Zhang, Xiaodong; Freemont, Paul S.

2014-01-01

The type II AAA+ protein p97 is involved in numerous cellular activities, including endoplasmic reticulum-associated degradation, transcription activation, membrane fusion and cell-cycle control. These activities are at least in part regulated by the ubiquitin system, in which p97 is thought to target ubiquitylated protein substrates within macromolecular complexes and assist in their extraction or disassembly. Although ATPase activity is essential for p97 function, little is known about how ATP binding or hydrolysis is coupled with p97 conformational changes and substrate remodelling. Here, we have used single-particle electron cryomicroscopy (cryo-EM) to study the effect of nucleotides on p97 conformation. We have identified conformational heterogeneity within the cryo-EM datasets from which we have resolved two major p97 conformations. A comparison of conformations reveals inter-ring rotations upon nucleotide binding and hydrolysis that may be linked to the remodelling of target protein complexes. PMID:24598262

Loop-driven conformational transition between the alternative and collapsed form of prethrombin-2: targeted molecular dynamics study.

PubMed

Wu, Sangwook

2017-01-01

Two distinct crystal structures of prethrombin-2, the alternative and collapsed forms, are elucidated by X-ray crystallogrphy. We analyzed the conformational transition from the alternative to the collapsed form employing targeted molecular dynamics (TMD) simulation. Despite small RMSD difference in the two X-ray crystal structures, some hydrophobic residues (W60d, W148, W215, and F227) show a significant difference between the two conformations. TMD simulation shows that the four hydrophobic residues undergo concerted movement from dimer to trimer transition via tetramer state in the conformational change from the alternative to the collapsed form. We reveal that the concerted movement of the four hydrophobic residues is controlled by movement of specific loop regions behind. In this paper, we propose a sequential scenario for the conformational transition from the alternative form to the collapsed form, which is partially supported by the mutant W148A simulation.

Automated treatment planning for a dedicated multi-source intracranial radiosurgery treatment unit using projected gradient and grassfire algorithms.

PubMed

Ghobadi, Kimia; Ghaffari, Hamid R; Aleman, Dionne M; Jaffray, David A; Ruschin, Mark

2012-06-01

The purpose of this work is to develop a framework to the inverse problem for radiosurgery treatment planning on the Gamma Knife(®) Perfexion™ (PFX) for intracranial targets. The approach taken in the present study consists of two parts. First, a hybrid grassfire and sphere-packing algorithm is used to obtain shot positions (isocenters) based on the geometry of the target to be treated. For the selected isocenters, a sector duration optimization (SDO) model is used to optimize the duration of radiation delivery from each collimator size from each individual source bank. The SDO model is solved using a projected gradient algorithm. This approach has been retrospectively tested on seven manually planned clinical cases (comprising 11 lesions) including acoustic neuromas and brain metastases. In terms of conformity and organ-at-risk (OAR) sparing, the quality of plans achieved with the inverse planning approach were, on average, improved compared to the manually generated plans. The mean difference in conformity index between inverse and forward plans was -0.12 (range: -0.27 to +0.03) and +0.08 (range: 0.00-0.17) for classic and Paddick definitions, respectively, favoring the inverse plans. The mean difference in volume receiving the prescribed dose (V(100)) between forward and inverse plans was 0.2% (range: -2.4% to +2.0%). After plan renormalization for equivalent coverage (i.e., V(100)), the mean difference in dose to 1 mm(3) of brainstem between forward and inverse plans was -0.24 Gy (range: -2.40 to +2.02 Gy) favoring the inverse plans. Beam-on time varied with the number of isocenters but for the most optimal plans was on average 33 min longer than manual plans (range: -17 to +91 min) when normalized to a calibration dose rate of 3.5 Gy/min. In terms of algorithm performance, the isocenter selection for all the presented plans was performed in less than 3 s, while the SDO was performed in an average of 215 min. PFX inverse planning can be performed using geometric isocenter selection and mathematical modeling and optimization techniques. The obtained treatment plans all meet or exceed clinical guidelines while displaying high conformity. © 2012 American Association of Physicists in Medicine.

Comparing photon and proton-based hypofractioned SBRT for prostate cancer accounting for robustness and realistic treatment deliverability.

PubMed

Goddard, Lee C; Brodin, N Patrik; Bodner, William R; Garg, Madhur K; Tomé, Wolfgang A

2018-05-01

To investigate whether photon or proton-based stereotactic body radiation therapy (SBRT is the preferred modality for high dose hypofractionation prostate cancer treatment. Achievable dose distributions were compared when uncertainties in target positioning and range uncertainties were appropriately accounted for. 10 patients with prostate cancer previously treated at our institution (Montefiore Medical Center) with photon SBRT using volumetric modulated arc therapy (VMAT) were identified. MRI images fused to the treatment planning CT allowed for accurate target and organ at risk (OAR) delineation. The clinical target volume was defined as the prostate gland plus the proximal seminal vesicles. Critical OARs include the bladder wall, bowel, femoral heads, neurovascular bundle, penile bulb, rectal wall, urethra and urogenital diaphragm. Photon plan robustness was evaluated by simulating 2 mm isotropic setup variations. Comparative proton SBRT plans employing intensity modulated proton therapy (IMPT) were generated using robust optimization. Plan robustness was evaluated by simulating 2 mm setup variations and 3% or 1% Hounsfield unit (HU) calibration uncertainties. Comparable maximum OAR doses are achievable between photon and proton SBRT, however, robust optimization results in higher maximum doses for proton SBRT. Rectal maximum doses are significantly higher for Robust proton SBRT with 1% HU uncertainty compared to photon SBRT (p = 0.03), whereas maximum doses were comparable for bladder wall (p = 0.43), urethra (p = 0.82) and urogenital diaphragm (p = 0.50). Mean doses to bladder and rectal wall are lower for proton SBRT, but higher for neurovascular bundle, urethra and urogenital diaphragm due to increased lateral scatter. Similar target conformality is achieved, albeit with slightly larger treated volume ratios for proton SBRT, >1.4 compared to 1.2 for photon SBRT. Similar treatment plans can be generated with IMPT compared to VMAT in terms of target coverage, target conformality, and OAR sparing when range and HU uncertainties are neglected. However, when accounting for these uncertainties during robust optimization, VMAT outperforms IMPT in terms of achievable target conformity and OAR sparing. Advances in knowledge: Comparison between achievable dose distributions using modern, robust optimization of IMPT for high dose per fraction SBRT regimens for the prostate has not been previously investigated.

Very high-energy electron (VHEE) beams in radiation therapy; Treatment plan comparison between VHEE, VMAT, and PPBS.

PubMed

Schüler, Emil; Eriksson, Kjell; Hynning, Elin; Hancock, Steven L; Hiniker, Susan M; Bazalova-Carter, Magdalena; Wong, Tony; Le, Quynh-Thu; Loo, Billy W; Maxim, Peter G

2017-06-01

The aim of this study was to evaluate the performance of very high-energy electron beams (VHEE) in comparison to clinically derived treatment plans generated with volumetric modulated arc therapy (VMAT) and proton pencil beam scanning (PPBS) technology. We developed a custom optimization script that could be applied automatically across modalities to eliminate operator bias during IMRT optimization. Four clinical cases were selected (prostate cancer, lung cancer, pediatric brain tumor, and head and neck cancer (HNC)). The VHEE beams were calculated in the EGSnrc/DOSXYZnrc Monte Carlo code for 100 and 200 MeV beams. Treatment plans with VHEE, VMAT, and PPBS were optimized in a research version of RayStation using an in-house developed script to minimize operator bias between the different techniques. The in-house developed script generated similar or superior plans to the clinically used plans. In the comparisons between the modalities, the integral dose was lowest for the PPBS-generated plans in all cases. For the prostate case, the 200 MeV VHEE plan showed reduced integral dose and reduced organ at risk (OAR) dose compared to the VMAT plan. For all other cases, both the 100 and the 200 MeV VHEE plans were superior to the VMAT plans, and the VHEE plans showed better conformity and lower spinal cord dose in the pediatric brain case and lower brain stem dose in the HNC case when compared to the PPBS plan. The automated optimization developed in this study generated similar or superior plans as compared to the clinically used plan and represents an unbiased approach to compare treatment plans generated for different modalities. In the present study, we also show that VHEE plans are similar or superior to VMAT plans with reduced mean OAR dose and increased target conformity for a variety of clinical cases, and VHEE plans can even achieve reductions in OAR doses compared to PPBS plans for shallow targets. With increased VHEE energy, better conformity and even higher reductions in mean OAR doses are achieved. On the whole, VHEE was intermediate between photon VMAT and PPBS for OAR sparing. © 2017 American Association of Physicists in Medicine.

Conformational Transitions and Stop-and-Go Nanopore Transport of Single Stranded DNA on Charged Graphene

PubMed Central

Shankla, Manish; Aksimentiev, Aleksei

2014-01-01

Control over interactions with biomolecules holds the key to applications of graphene in biotechnology. One such application is nanopore sequencing, where a DNA molecule is electrophoretically driven through a graphene nanopore. Here, we investigate how interactions of single-stranded DNA and a graphene membrane can be controlled by electrically biasing the membrane. The results of our molecular dynamics simulations suggest that electric charge on graphene can force a DNA homopolymer to adopt a range of strikingly different conformations. The conformational response is sensitive to even very subtle nucleotide modifications, such as DNA methylation. The speed of DNA motion through a graphene nanopore is strongly affected by the graphene charge: a positive charge accelerates the motion whereas a negative charge arrests it. As a possible application of the effect, we demonstrate stop-and-go transport of DNA controlled by the charge of graphene. Such on-demand transport of DNA is essential for realizing nanopore sequencing. PMID:25296960

Cerium chloride stimulated controlled conversion of B-to-Z DNA in self-assembled nanostructures.

PubMed

Bhanjadeo, Madhabi M; Nayak, Ashok K; Subudhi, Umakanta

2017-01-22

DNA adopts different conformation not only because of novel base pairs but also while interacting with inorganic or organic compounds. Self-assembled branched DNA (bDNA) structures or DNA origami that change conformation in response to environmental cues hold great promises in sensing and actuation at the nanoscale. Recently, the B-Z transition in DNA is being explored to design various nanomechanical devices. In this communication we have demonstrated that Cerium chloride binds to the phosphate backbone of self-assembled bDNA structure and induce B-to-Z transition at physiological concentration. The mechanism of controlled conversion from right-handed to left-handed has been assayed by various dye binding studies using CD and fluorescence spectroscopy. Three different bDNA structures have been identified to display B-Z transition. This approach provides a rapid and reversible means to change bDNA conformation, which can be used for dynamic and progressive control at the nanoscale. Copyright © 2016 Elsevier Inc. All rights reserved.

Conformational transitions and stop-and-go nanopore transport of single-stranded DNA on charged graphene

NASA Astrophysics Data System (ADS)

Shankla, Manish; Aksimentiev, Aleksei

2014-10-01

Control over interactions with biomolecules holds the key to applications of graphene in biotechnology. One such application is nanopore sequencing, where a DNA molecule is electrophoretically driven through a graphene nanopore. Here we investigate how interactions of single-stranded DNA and a graphene membrane can be controlled by electrically biasing the membrane. The results of our molecular dynamics simulations suggest that electric charge on graphene can force a DNA homopolymer to adopt a range of strikingly different conformations. The conformational response is sensitive to even very subtle nucleotide modifications, such as DNA methylation. The speed of DNA motion through a graphene nanopore is strongly affected by the graphene charge: a positive charge accelerates the motion, whereas a negative charge arrests it. As a possible application of the effect, we demonstrate stop-and-go transport of DNA controlled by the charge of graphene. Such on-demand transport of DNA is essential for realizing nanopore sequencing.

Conformational landscape of a virus by single-particle X-ray scattering

DOE PAGES

Hosseinizadeh, Ahmad; Mashayekhi, Ghoncheh; Copperman, Jeremy; ...

2017-08-14

Using a manifold-based analysis of experimental diffraction snapshots from an X-ray free electron laser, we determine the three-dimensional structure and conformational landscape of the PR772 virus to a detector-limited resolution of 9 nm. Our results indicate that a single conformational coordinate controls reorganization of the genome, growth of a tubular structure from a portal vertex and release of the genome. Furthermore, these results demonstrate that single-particle X-ray scattering has the potential to shed light on key biological processes.

An overview of the serpin superfamily

PubMed Central

Law, Ruby HP; Zhang, Qingwei; McGowan, Sheena; Buckle, Ashley M; Silverman, Gary A; Wong, Wilson; Rosado, Carlos J; Langendorf, Chris G; Pike, Rob N; Bird, Philip I; Whisstock, James C

2006-01-01

Serpins are a broadly distributed family of protease inhibitors that use a conformational change to inhibit target enzymes. They are central in controlling many important proteolytic cascades, including the mammalian coagulation pathways. Serpins are conformationally labile and many of the disease-linked mutations of serpins result in misfolding or in pathogenic, inactive polymers. PMID:16737556

Strand swapping regulates the iron-sulfur cluster in the diabetes drug target mitoNEET

PubMed Central

Baxter, Elizabeth Leigh; Jennings, Patricia A.; Onuchic, José N.

2012-01-01

MitoNEET is a recently identified diabetes drug target that coordinates a transferable 2Fe-2S cluster, and additionally contains an unusual strand swap. In this manuscript, we use a dual basin structure-based model to predict and characterize the folding and functionality of strand swapping in mitoNEET. We demonstrate that a strand unswapped conformation is kinetically accessible and that multiple levels of control are employed to regulate the conformational dynamics of the system. Environmental factors such as temperature can shift route preference toward the unswapped pathway. Additionally we see that a region recently identified as contributing to frustration in folding acts as a regulatory hinge loop that modulates conformational balance. Interestingly, strand unswapping transfers strain specifically to cluster-coordinating residues, opening the cluster-coordinating pocket. Strengthening contacts within the cluster-coordinating pocket opens a new pathway between the swapped and unswapped conformation that utilizes cracking to bypass the unfolded basin. These results suggest that local control within distinct regions affect motions important in regulating mitoNEET’s 2Fe-2S clusters. PMID:22308404

Temporal switching of an amphiphilic self-assembly by a chemical fuel-driven conformational response† †Electronic supplementary information (ESI) available: Experimental section, synthetic procedures and supporting figures. See DOI: 10.1039/c7sc01730h Click here for additional data file.

PubMed Central

Jalani, Krishnendu; Dhiman, Shikha

2017-01-01

The spatial and temporal control of self-assemblies is the latest scientific hurdle in supramolecular chemistry which is inspired by the functioning of biological systems fueled by chemical signals. In this study, we work towards alleviating this scenario by employing a unique amphiphilic foldamer that operates under the effect of a chemical fuel. The conformational changes in the foldamer amplify into observable morphological changes in its amphiphilic assembly that are controlled by external molecular cues (fuel). We take advantage of this redox responsive foldamer to affect its conformation in a temporal manner by an enzymatic pathway. The temporal characteristics of the transient conformation/assembly can be modulated by varying the concentrations of the fuel and enzyme. We believe that such a design strategy can have positive consequences in designing molecular and supramolecular systems for future active, adaptive and autonomous materials. PMID:28989632

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.

Conformational flexibility of human casein kinase catalytic subunit explored by metadynamics.

PubMed

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-03-04

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the γ phosphate from ATP to serine and threonine residues on protein substrates. In a number of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2α catalytic subunit. This variability reflects a high flexibility for two regions of CK2α: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, we present a computational study simulating the equilibrium between three conformations involving these regions. Simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provides a reference pathway describing the conformational changes being studied, based on analysis of free energy surfaces. The free energies of the three conformations were found to be close and the paths proposed had low activation barriers. Our results indicate that these conformations can exist in water. This information should be useful when designing inhibitors specific to one conformation. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Thermodynamic contribution of backbone conformational entropy in the binding between SH3 domain and proline-rich motif.

PubMed

Zeng, Danyun; Shen, Qingliang; Cho, Jae-Hyun

2017-02-26

Biological functions of intrinsically disordered proteins (IDPs), and proteins containing intrinsically disordered regions (IDRs) are often mediated by short linear motifs, like proline-rich motifs (PRMs). Upon binding to their target proteins, IDPs undergo a disorder-to-order transition which is accompanied by a large conformational entropy penalty. Hence, the molecular mechanisms underlying control of conformational entropy are critical for understanding the binding affinity and selectivity of IDPs-mediated protein-protein interactions (PPIs). Here, we investigated the backbone conformational entropy change accompanied by binding of the N-terminal SH3 domain (nSH3) of CrkII and PRM derived from guanine nucleotide exchange factor 1 (C3G). In particular, we focused on the estimation of conformational entropy change of disordered PRM upon binding to the nSH3 domain. Quantitative characterization of conformational dynamics of disordered peptides like PRMs is limited. Hence, we combined various methods, including NMR model-free analysis, δ2D, DynaMine, and structure-based calculation of entropy loss. This study demonstrates that the contribution of backbone conformational entropy change is significant in the PPIs mediated by IDPs/IDRs. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

PubMed Central

Preiswerk, Nathalie; Beck, Tobias; Schulz, Jessica D.; Milovník, Peter; Mayer, Clemens; Siegel, Justin B.; Baker, David; Hilvert, Donald

2014-01-01

By combining targeted mutagenesis, computational refinement, and directed evolution, a modestly active, computationally designed Diels-Alderase was converted into the most proficient biocatalyst for [4+2] cycloadditions known. The high stereoselectivity and minimal product inhibition of the evolved enzyme enabled preparative scale synthesis of a single product diastereomer. X-ray crystallography of the enzyme–product complex shows that the molecular changes introduced over the course of optimization, including addition of a lid structure, gradually reshaped the pocket for more effective substrate preorganization and transition state stabilization. The good overall agreement between the experimental structure and the original design model with respect to the orientations of both the bound product and the catalytic side chains contrasts with other computationally designed enzymes. Because design accuracy appears to correlate with scaffold rigidity, improved control over backbone conformation will likely be the key to future efforts to design more efficient enzymes for diverse chemical reactions. PMID:24847076

Hydrogen tunneling links protein dynamics to enzyme catalysis.

PubMed

Klinman, Judith P; Kohen, Amnon

2013-01-01

The relationship between protein dynamics and function is a subject of considerable contemporary interest. Although protein motions are frequently observed during ligand binding and release steps, the contribution of protein motions to the catalysis of bond making/breaking processes is more difficult to probe and verify. Here, we show how the quantum mechanical hydrogen tunneling associated with enzymatic C-H bond cleavage provides a unique window into the necessity of protein dynamics for achieving optimal catalysis. Experimental findings support a hierarchy of thermodynamically equilibrated motions that control the H-donor and -acceptor distance and active-site electrostatics, creating an ensemble of conformations suitable for H-tunneling. A possible extension of this view to methyl transfer and other catalyzed reactions is also presented. The impact of understanding these dynamics on the conceptual framework for enzyme activity, inhibitor/drug design, and biomimetic catalyst design is likely to be substantial.

Hydrogen Tunneling Links Protein Dynamics to Enzyme Catalysis

PubMed Central

Klinman, Judith P.; Kohen, Amnon

2014-01-01

The relationship between protein dynamics and function is a subject of considerable contemporary interest. Although protein motions are frequently observed during ligand binding and release steps, the contribution of protein motions to the catalysis of bond making/breaking processes is more difficult to probe and verify. Here, we show how the quantum mechanical hydrogen tunneling associated with enzymatic C–H bond cleavage provides a unique window into the necessity of protein dynamics for achieving optimal catalysis. Experimental findings support a hierarchy of thermodynamically equilibrated motions that control the H-donor and -acceptor distance and active-site electrostatics, creating an ensemble of conformations suitable for H-tunneling. A possible extension of this view to methyl transfer and other catalyzed reactions is also presented. The impact of understanding these dynamics on the conceptual framework for enzyme activity, inhibitor/drug design, and biomimetic catalyst design is likely to be substantial. PMID:23746260

Frontiers in planning optimization for lung SBRT.

PubMed

Giglioli, Francesca Romana; Clemente, Stefania; Esposito, Marco; Fiandra, Christian; Marino, Carmelo; Russo, Serenella; Strigari, Lidia; Villaggi, Elena; Stasi, Michele; Mancosu, Pietro

2017-12-01

Emerging data are showing the safety and the efficacy of Stereotactic Body Radiation therapy (SBRT) in lung cancer management. In this context, the very high doses delivered to the Planning Target Volume, make the planning phase essential for achieving high dose levels conformed to the shape of the target in order to have a good prognosis for tumor control and to avoid an overdose in relevant healthy adjacent tissue. In this non-systematic review we analyzed the technological and the physics aspects of SBRT planning for lung cancer. In particular, the aims of the study were: (i) to evaluate prescription strategies (homogeneous or inhomogeneous), (ii) to outline possible geometrical solutions by comparing the dosimetric results (iii) to describe the technological possibilities for a safe and effective treatment, (iv) to present the issues concerning radiobiological planning and the automation of the planning process. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Optimizing the Compatibility between Rating Scales and Measures of Productive Second Language Competence

ERIC Educational Resources Information Center

Weaver, Christopher

2011-01-01

This study presents a systematic investigation concerning the performance of different rating scales used in the English section of a university entrance examination to assess 1,287 Japanese test takers' ability to write a third-person introduction speech. Although the rating scales did not conform to all of the expectations of the Rasch model,…

Computational prediction of atomic structures of helical membrane proteins aided by EM maps.

PubMed

Kovacs, Julio A; Yeager, Mark; Abagyan, Ruben

2007-09-15

Integral membrane proteins pose a major challenge for protein-structure prediction because only approximately 100 high-resolution structures are available currently, thereby impeding the development of rules or empirical potentials to predict the packing of transmembrane alpha-helices. However, when an intermediate-resolution electron microscopy (EM) map is available, it can be used to provide restraints which, in combination with a suitable computational protocol, make structure prediction feasible. In this work we present such a protocol, which proceeds in three stages: 1), generation of an ensemble of alpha-helices by flexible fitting into each of the density rods in the low-resolution EM map, spanning a range of rotational angles around the main helical axes and translational shifts along the density rods; 2), fast optimization of side chains and scoring of the resulting conformations; and 3), refinement of the lowest-scoring conformations with internal coordinate mechanics, by optimizing the van der Waals, electrostatics, hydrogen bonding, torsional, and solvation energy contributions. In addition, our method implements a penalty term through a so-called tethering map, derived from the EM map, which restrains the positions of the alpha-helices. The protocol was validated on three test cases: GpA, KcsA, and MscL.

Kilovoltage radiotherapy for companion animals: dosimetric comparison of 300 kV, 450 kV, and 6 MV X-ray beams.

PubMed

Seo, Jaehyeon; Son, Jaeman; Cho, Yeona; Park, Nohwon; Kim, Dong Wook; Kim, Jinsung; Yoon, Myonggeun

2018-04-12

Radiotherapy for the treatment of cancer in companion animals is currently administered using megavoltage X-ray machines. Because these machines are expensive, most animal hospitals do not perform radiotherapy. This study evaluated the ability of relatively inexpensive kilovoltage X-ray machines to treat companion animals. A simulation study based on a treatment planning system was performed for tumors of the brain (non-infectious meningoencephalitis), nasal cavity (malignant nasal tumors), forefoot (malignant muscular tumors), and abdomen (malignant intestinal tumors). The results of kilovoltage (300 kV and 450 kV) and megavoltage (6 MV) X-ray beams were compared. Whereas 300 kV and 6 MV X-ray beams provided optimal radiation dose homogeneity and conformity, respectively, for brain tumors, 6 MV X-rays provided optimal homogeneity and radiation conformity for nasal cavity, forefoot and abdominal tumors. Although megavoltage X-ray beams provided better radiation dose distribution in most treated animals, the differences between megavoltage and kilovoltage X-ray beams were relatively small. The similar therapeutic effects of kilovoltage and 6 MV X-ray beams suggest that kilovoltage X-ray beams may be effective alternatives to megavoltage X-ray beams in treating cancers in companion animals.

Guideline implementation in clinical practice: use of statistical process control charts as visual feedback devices.

PubMed

Al-Hussein, Fahad A

2009-01-01

To use statistical control charts in a series of audits to improve the acceptance and consistant use of guidelines, and reduce the variations in prescription processing in primary health care. A series of audits were done at the main satellite of King Saud Housing Family and Community Medicine Center, National Guard Health Affairs, Riyadh, where three general practitioners and six pharmacists provide outpatient care to about 3000 residents. Audits were carried out every fortnight to calculate the proportion of prescriptions that did not conform to the given guidelines of prescribing and dispensing. Simple random samples of thirty were chosen from a sampling frame of all prescriptions given in the two previous weeks. Thirty six audits were carried out from September 2004 to February 2006. P-charts were constructed around a parametric specification of non-conformities not exceeding 25%. Of the 1081 prescriptions, the most frequent non-conformity was failure to write generic names (35.5%), followed by the failure to record patient's weight (16.4%), pharmacist's name (14.3%), duration of therapy (9.1%), and the use of inappropriate abbreviations (6.0%). Initially, 100% of prescriptions did not conform to the guidelines, but within a period of three months, this came down to 40%. A process of audits in the context of statistical process control is necessary for any improvement in the implementation of guidelines in primary care. Statistical process control charts are an effective means of visual feedback to the care providers.

A proposed simulation optimization model framework for emergency department problems in public hospital

NASA Astrophysics Data System (ADS)

Ibrahim, Ireen Munira; Liong, Choong-Yeun; Bakar, Sakhinah Abu; Ahmad, Norazura; Najmuddin, Ahmad Farid

2015-12-01

The Emergency Department (ED) is a very complex system with limited resources to support increase in demand. ED services are considered as good quality if they can meet the patient's expectation. Long waiting times and length of stay is always the main problem faced by the management. The management of ED should give greater emphasis on their capacity of resources in order to increase the quality of services, which conforms to patient satisfaction. This paper is a review of work in progress of a study being conducted in a government hospital in Selangor, Malaysia. This paper proposed a simulation optimization model framework which is used to study ED operations and problems as well as to find an optimal solution to the problems. The integration of simulation and optimization is hoped can assist management in decision making process regarding their resource capacity planning in order to improve current and future ED operations.