Modeling Cell Size Regulation: From Single-Cell-Level Statistics to Molecular Mechanisms and Population-Level Effects.

PubMed

Ho, Po-Yi; Lin, Jie; Amir, Ariel

2018-05-20

Most microorganisms regulate their cell size. In this article, we review some of the mathematical formulations of the problem of cell size regulation. We focus on coarse-grained stochastic models and the statistics that they generate. We review the biologically relevant insights obtained from these models. We then describe cell cycle regulation and its molecular implementations, protein number regulation, and population growth, all in relation to size regulation. Finally, we discuss several future directions for developing understanding beyond phenomenological models of cell size regulation.

Modeling molecular mechanisms in the axon

NASA Astrophysics Data System (ADS)

de Rooij, R.; Miller, K. E.; Kuhl, E.

2017-03-01

Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

Semi-Automated Curation Allows Causal Network Model Building for the Quantification of Age-Dependent Plaque Progression in ApoE-/- Mouse.

PubMed

Szostak, Justyna; Martin, Florian; Talikka, Marja; Peitsch, Manuel C; Hoeng, Julia

2016-01-01

The cellular and molecular mechanisms behind the process of atherosclerotic plaque destabilization are complex, and molecular data from aortic plaques are difficult to interpret. Biological network models may overcome these difficulties and precisely quantify the molecular mechanisms impacted during disease progression. The atherosclerosis plaque destabilization biological network model was constructed with the semiautomated curation pipeline, BELIEF. Cellular and molecular mechanisms promoting plaque destabilization or rupture were captured in the network model. Public transcriptomic data sets were used to demonstrate the specificity of the network model and to capture the different mechanisms that were impacted in ApoE -/- mouse aorta at 6 and 32 weeks. We concluded that network models combined with the network perturbation amplitude algorithm provide a sensitive, quantitative method to follow disease progression at the molecular level. This approach can be used to investigate and quantify molecular mechanisms during plaque progression.

Mixing coarse-grained and fine-grained water in molecular dynamics simulations of a single system.

PubMed

Riniker, Sereina; van Gunsteren, Wilfred F

2012-07-28

The use of a supra-molecular coarse-grained (CG) model for liquid water as solvent in molecular dynamics simulations of biomolecules represented at the fine-grained (FG) atomic level of modelling may reduce the computational effort by one or two orders of magnitude. However, even if the pure FG model and the pure CG model represent the properties of the particular substance of interest rather well, their application in a hybrid FG/CG system containing varying ratios of FG versus CG particles is highly non-trivial, because it requires an appropriate balance between FG-FG, FG-CG, and CG-CG energies, and FG and CG entropies. Here, the properties of liquid water are used to calibrate the FG-CG interactions for the simple-point-charge water model at the FG level and a recently proposed supra-molecular water model at the CG level that represents five water molecules by one CG bead containing two interaction sites. Only two parameters are needed to reproduce different thermodynamic and dielectric properties of liquid water at physiological temperature and pressure for various mole fractions of CG water in FG water. The parametrisation strategy for the FG-CG interactions is simple and can be easily transferred to interactions between atomistic biomolecules and CG water.

Conceptual Model-Based Systems Biology: Mapping Knowledge and Discovering Gaps in the mRNA Transcription Cycle

PubMed Central

Somekh, Judith; Choder, Mordechai; Dori, Dov

2012-01-01

We propose a Conceptual Model-based Systems Biology framework for qualitative modeling, executing, and eliciting knowledge gaps in molecular biology systems. The framework is an adaptation of Object-Process Methodology (OPM), a graphical and textual executable modeling language. OPM enables concurrent representation of the system's structure—the objects that comprise the system, and behavior—how processes transform objects over time. Applying a top-down approach of recursively zooming into processes, we model a case in point—the mRNA transcription cycle. Starting with this high level cell function, we model increasingly detailed processes along with participating objects. Our modeling approach is capable of modeling molecular processes such as complex formation, localization and trafficking, molecular binding, enzymatic stimulation, and environmental intervention. At the lowest level, similar to the Gene Ontology, all biological processes boil down to three basic molecular functions: catalysis, binding/dissociation, and transporting. During modeling and execution of the mRNA transcription model, we discovered knowledge gaps, which we present and classify into various types. We also show how model execution enhances a coherent model construction. Identification and pinpointing knowledge gaps is an important feature of the framework, as it suggests where research should focus and whether conjectures about uncertain mechanisms fit into the already verified model. PMID:23308089

Computational Modeling of Airway and Pulmonary Vascular Structure and Function: Development of a “Lung Physiome”

PubMed Central

Tawhai, M. H.; Clark, A. R.; Donovan, G. M.; Burrowes, K. S.

2011-01-01

Computational models of lung structure and function necessarily span multiple spatial and temporal scales, i.e., dynamic molecular interactions give rise to whole organ function, and the link between these scales cannot be fully understood if only molecular or organ-level function is considered. Here, we review progress in constructing multiscale finite element models of lung structure and function that are aimed at providing a computational framework for bridging the spatial scales from molecular to whole organ. These include structural models of the intact lung, embedded models of the pulmonary airways that couple to model lung tissue, and models of the pulmonary vasculature that account for distinct structural differences at the extra- and intra-acinar levels. Biophysically based functional models for tissue deformation, pulmonary blood flow, and airway bronchoconstriction are also described. The development of these advanced multiscale models has led to a better understanding of complex physiological mechanisms that govern regional lung perfusion and emergent heterogeneity during bronchoconstriction. PMID:22011236

Electron Transport Modeling of Molecular Nanoscale Bridges Used in Energy Conversion Schemes

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

Dunietz, Barry D

2016-08-09

The goal of the research program is to reliably describe electron transport and transfer processes at the molecular level. Such insight is essential for improving molecular applications of solar and thermal energy conversion. We develop electronic structure models to study (1) photoinduced electron transfer and transport processes in organic semiconducting materials, and (2) charge and heat transport through molecular bridges. We seek fundamental understanding of key processes, which lead to design new experiments and ultimately to achieve systems with improved properties.

Computer Simulation of the Forces Acting on the Polystyrene Probe Submerged into the Succinonitrile Near Phase Transition

NASA Technical Reports Server (NTRS)

Bune, Andris V.; Kaukler, William F.; Whitaker, Ann F. (Technical Monitor)

2001-01-01

Modeling approach to simulate both mesoscale and microscopic forces acting in a typical AFM experiment is presented. At mesoscale level interaction between the cantilever tip and the sample surface is primarily described by the balance of attractive Van der Waals and repulsive forces. The model of cantilever oscillations is applicable to both non-contact and "tapping" AFM. This model can be farther enhanced to describe nanoparticle manipulation by cantilever. At microscopic level tip contamination and details of tip-surface interaction can be simulated using molecular dynamics approach. Integration of mesoscale model with molecular dynamic model is discussed.

A coupled two-dimensional main chain torsional potential for protein dynamics: generation and implementation.

PubMed

Li, Yongxiu; Gao, Ya; Zhang, Xuqiang; Wang, Xingyu; Mou, Lirong; Duan, Lili; He, Xiao; Mei, Ye; Zhang, John Z H

2013-09-01

Main chain torsions of alanine dipeptide are parameterized into coupled 2-dimensional Fourier expansions based on quantum mechanical (QM) calculations at M06 2X/aug-cc-pvtz//HF/6-31G** level. Solvation effect is considered by employing polarizable continuum model. Utilization of the M06 2X functional leads to precise potential energy surface that is comparable to or even better than MP2 level, but with much less computational demand. Parameterization of the 2D expansions is against the full main chain torsion space instead of just a few low energy conformations. This procedure is similar to that for the development of AMBER03 force field, except unique weighting factor was assigned to all the grid points. To avoid inconsistency between quantum mechanical calculations and molecular modeling, the model peptide is further optimized at molecular mechanics level with main chain dihedral angles fixed before the calculation of the conformational energy on molecular mechanical level at each grid point, during which generalized Born model is employed. Difference in solvation models at quantum mechanics and molecular mechanics levels makes this parameterization procedure less straightforward. All force field parameters other than main chain torsions are taken from existing AMBER force field. With this new main chain torsion terms, we have studied the main chain dihedral distributions of ALA dipeptide and pentapeptide in aqueous solution. The results demonstrate that 2D main chain torsion is effective in delineating the energy variation associated with rotations along main chain dihedrals. This work is an implication for the necessity of more accurate description of main chain torsions in the future development of ab initio force field and it also raises a challenge to the development of quantum mechanical methods, especially the quantum mechanical solvation models.

Ratios of molecular hydrogen line intensities in shocked gas - Evidence for cooling zones

NASA Technical Reports Server (NTRS)

Brand, P. W. J. L.; Moorhouse, A.; Bird, M.; Burton, M. G.; Geballe, T. R.

1988-01-01

Column densities of molecular hydrogen have been calculated from 19 infrared vibration-rotation and pure rotational line intensities measured at peak 1 of the Orion molecular outflow. The run of column density with energy level is similar to a simple coolng zone model of the line-emitting region, but is not well fitted by predictions of C-shock models current in the literature.

Computational Neuroscience.

ERIC Educational Resources Information Center

Sejnowski, Terrence J.; And Others

1988-01-01

Describes the use of brain models to connect the microscopic level accessible by molecular and cellular techniques with the systems level accessible by the study of behavior. Discusses classes of brain models, and specific examples of such models. Evaluates the strengths and weaknesses of using brain modelling to understand human brain function.…

Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations.

PubMed

Shen, Lin; Yang, Weitao

2016-04-12

We developed a new multiresolution method that spans three levels of resolution with quantum mechanical, atomistic molecular mechanical, and coarse-grained models. The resolution-adapted all-atom and coarse-grained water model, in which an all-atom structural description of the entire system is maintained during the simulations, is combined with the ab initio quantum mechanics and molecular mechanics method. We apply this model to calculate the redox potentials of the aqueous ruthenium and iron complexes by using the fractional number of electrons approach and thermodynamic integration simulations. The redox potentials are recovered in excellent accordance with the experimental data. The speed-up of the hybrid all-atom and coarse-grained water model renders it computationally more attractive. The accuracy depends on the hybrid all-atom and coarse-grained water model used in the combined quantum mechanical and molecular mechanical method. We have used another multiresolution model, in which an atomic-level layer of water molecules around redox center is solvated in supramolecular coarse-grained waters for the redox potential calculations. Compared with the experimental data, this alternative multilayer model leads to less accurate results when used with the coarse-grained polarizable MARTINI water or big multipole water model for the coarse-grained layer.

Challenge of representing entropy at different levels of resolution in molecular simulation.

PubMed

Huang, Wei; van Gunsteren, Wilfred F

2015-01-22

The role of entropic contributions in processes involving biomolecules is illustrated using the process of vaporization or condensation of the solvents water and methanol and the process of polypeptide folding in solution using molecular models at different levels of resolution: subatomic, atomic, supra-atomic, and supramolecular. For the folding process, a β-hexapeptide that adopts, as inferred from NMR experiments, both a right-handed 2.710/12-helical fold and a left-handed 314-helical fold in methanol, is used to illustrate the challenge of modeling thermodynamically driven processes at different levels of resolution.

Student Misapplication of a Gas-Like Model to Explain Particle Movement in Heated Solids: Implications for Curriculum and Instruction towards Students' Creation and Revision of Accurate Explanatory Models

ERIC Educational Resources Information Center

Bouwma-Gearhart, Jana; Stewart, James; Brown, Keffrelyn

2009-01-01

Understanding the particulate nature of matter (PNM) is vital for participating in many areas of science. We assessed 11 students' atomic/molecular-level explanations of real-world phenomena after their participation in a modelling-based PNM unit. All 11 students offered a scientifically acceptable model regarding atomic/molecular behaviour in…

A Stochastic Mixing Model for Predicting Emissions in a Direct Injection Diesel Engine.

DTIC Science & Technology

1986-09-01

of chemical reactors. The fundamental concept of these models is coalescence/dis- persion micromixing . C1] Details of this method are provided in Appen...Togby,A.H., "Monte Carlo Methods of Simulating Micromixing in Chemical Reactors", Chemical Engineering Science, Vol.27, p.1 4 97, 1972. 46. Kattan,A...on a molecular level. 2. Micromixing or stream mixing refers to the mixing of particles on a molecular level. Until the coalescence and dispersion

Designing an educative curriculum unit for teaching molecular geometry in high school chemistry

NASA Astrophysics Data System (ADS)

Makarious, Nader N.

Chemistry is a highly abstract discipline that is taught and learned with the aid of various models. Among the most challenging, yet a fundamental topic in general chemistry at the high school level, is molecular geometry. This study focused on developing exemplary educative curriculum materials pertaining to the topic of molecular geometry. The methodology used in this study consisted of several steps. First, a diverse set of models were analyzed to determine to what extent each model serves its purpose in teaching molecular geometry. Second, a number of high school teachers and college chemistry professors were asked to share their experiences on using models in teaching molecular geometry through an online questionnaire. Third, findings from the comparative analysis of models, teachers’ experiences, literature review on models and students’ misconceptions, the curriculum expectations of the Next Generation Science Standards and their emphasis on three-dimensional learning and nature of science (NOS) contributed to the development of the molecular geometry unit. Fourth, the developed unit was reviewed by fellow teachers and doctoral-level science education experts and was revised to further improve its coherence and clarity in support of teaching and learning of the molecular geometry concepts. The produced educative curriculum materials focus on the scientific practice of developing and using models as promoted in the Next Generations Science Standards (NGSS) while also addressing nature of science (NOS) goals. The educative features of the newly developed unit support teachers’ pedagogical knowledge (PK) and pedagogical content knowledge (PCK). The unit includes an overview, teacher’s guide, and eight detailed lesson plans with inquiry oriented modeling activities replete with models and suggestions for teachers, as well as formative and summative assessment tasks. The unit design process serves as a model for redesigning other instructional units in science disciplines in general and chemistry courses in particular.

Monogenic Mouse Models of Autism Spectrum Disorders: Common Mechanisms and Missing Links

PubMed Central

Hulbert, Samuel W.; Jiang, Yong-hui

2016-01-01

Autism Spectrum Disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral analysis with circuit-level analysis in genetically modified models with strong construct validity. PMID:26733386

Molecular level in silico studies for oncology. Direct models review

NASA Astrophysics Data System (ADS)

Psakhie, S. G.; Tsukanov, A. A.

2017-09-01

The combination of therapy and diagnostics in one process "theranostics" is a trend in a modern medicine, especially in oncology. Such an approach requires development and usage of multifunctional hybrid nanoparticles with a hierarchical structure. Numerical methods and mathematical models play a significant role in the design of the hierarchical nanoparticles and allow looking inside the nanoscale mechanisms of agent-cell interactions. The current position of in silico approach in biomedicine and oncology is discussed. The review of the molecular level in silico studies in oncology, which are using the direct models, is presented.

Perspective: Reaches of chemical physics in biology.

PubMed

Gruebele, Martin; Thirumalai, D

2013-09-28

Chemical physics as a discipline contributes many experimental tools, algorithms, and fundamental theoretical models that can be applied to biological problems. This is especially true now as the molecular level and the systems level descriptions begin to connect, and multi-scale approaches are being developed to solve cutting edge problems in biology. In some cases, the concepts and tools got their start in non-biological fields, and migrated over, such as the idea of glassy landscapes, fluorescence spectroscopy, or master equation approaches. In other cases, the tools were specifically developed with biological physics applications in mind, such as modeling of single molecule trajectories or super-resolution laser techniques. In this introduction to the special topic section on chemical physics of biological systems, we consider a wide range of contributions, all the way from the molecular level, to molecular assemblies, chemical physics of the cell, and finally systems-level approaches, based on the contributions to this special issue. Chemical physicists can look forward to an exciting future where computational tools, analytical models, and new instrumentation will push the boundaries of biological inquiry.

Evaluation of Contamination Inspection and Analysis Methods through Modeling System Performance

NASA Technical Reports Server (NTRS)

Seasly, Elaine; Dever, Jason; Stuban, Steven M. F.

2016-01-01

Contamination is usually identified as a risk on the risk register for sensitive space systems hardware. Despite detailed, time-consuming, and costly contamination control efforts during assembly, integration, and test of space systems, contaminants are still found during visual inspections of hardware. Improved methods are needed to gather information during systems integration to catch potential contamination issues earlier and manage contamination risks better. This research explores evaluation of contamination inspection and analysis methods to determine optical system sensitivity to minimum detectable molecular contamination levels based on IEST-STD-CC1246E non-volatile residue (NVR) cleanliness levels. Potential future degradation of the system is modeled given chosen modules representative of optical elements in an optical system, minimum detectable molecular contamination levels for a chosen inspection and analysis method, and determining the effect of contamination on the system. By modeling system performance based on when molecular contamination is detected during systems integration and at what cleanliness level, the decision maker can perform trades amongst different inspection and analysis methods and determine if a planned method is adequate to meet system requirements and manage contamination risk.

Perspective: Reaches of chemical physics in biology

PubMed Central

Gruebele, Martin; Thirumalai, D.

2013-01-01

Chemical physics as a discipline contributes many experimental tools, algorithms, and fundamental theoretical models that can be applied to biological problems. This is especially true now as the molecular level and the systems level descriptions begin to connect, and multi-scale approaches are being developed to solve cutting edge problems in biology. In some cases, the concepts and tools got their start in non-biological fields, and migrated over, such as the idea of glassy landscapes, fluorescence spectroscopy, or master equation approaches. In other cases, the tools were specifically developed with biological physics applications in mind, such as modeling of single molecule trajectories or super-resolution laser techniques. In this introduction to the special topic section on chemical physics of biological systems, we consider a wide range of contributions, all the way from the molecular level, to molecular assemblies, chemical physics of the cell, and finally systems-level approaches, based on the contributions to this special issue. Chemical physicists can look forward to an exciting future where computational tools, analytical models, and new instrumentation will push the boundaries of biological inquiry. PMID:24089712

Molecular-Level Computational Investigation of Mechanical Transverse Behavior of p-Phenylene Terephthalamide (PPTA) Fibers

DTIC Science & Technology

2013-01-01

fabricated today are based on polymer matrix composites containing Kevlarw KM2 reinforcements , the present work will deal with generic PPTA fibers . In...Multi-length scale enriched continuum-level material model for Kevlarw- fiber reinforced polymer-matrix composites”, Journal of Materials...mechanical transverse behavior of p-phenylene terephthalamide (PPTA) fibers Purpose – A series of all-atom molecular-level computational analyses is

Computing by physical interaction in neurons.

PubMed

Aur, Dorian; Jog, Mandar; Poznanski, Roman R

2011-12-01

The electrodynamics of action potentials represents the fundamental level where information is integrated and processed in neurons. The Hodgkin-Huxley model cannot explain the non-stereotyped spatial charge density dynamics that occur during action potential propagation. Revealed in experiments as spike directivity, the non-uniform charge density dynamics within neurons carry meaningful information and suggest that fragments of information regarding our memories are endogenously stored in structural patterns at a molecular level and are revealed only during spiking activity. The main conceptual idea is that under the influence of electric fields, efficient computation by interaction occurs between charge densities embedded within molecular structures and the transient developed flow of electrical charges. This process of computation underlying electrical interactions and molecular mechanisms at the subcellular level is dissimilar from spiking neuron models that are completely devoid of physical interactions. Computation by interaction describes a more powerful continuous model of computation than the one that consists of discrete steps as represented in Turing machines.

Modeling of DNA and Protein Organization Levels with Cn3D Software

ERIC Educational Resources Information Center

Stasinakis, Panagiotis K.; Nicolaou, Despoina

2017-01-01

The molecular structure of living organisms and the complex interactions amongst its components are the basis for the diversity observed at the macroscopic level. Proteins and nucleic acids are some of the major molecular components, and play a key role in several biological functions, such as those of development and evolution. This article…

Molecular modeling: An open invitation for applied mathematics

NASA Astrophysics Data System (ADS)

Mezey, Paul G.

2013-10-01

Molecular modeling methods provide a very wide range of challenges for innovative mathematical and computational techniques, where often high dimensionality, large sets of data, and complicated interrelations imply a multitude of iterative approximations. The physical and chemical basis of these methodologies involves quantum mechanics with several non-intuitive aspects, where classical interpretation and classical analogies are often misleading or outright wrong. Hence, instead of the everyday, common sense approaches which work so well in engineering, in molecular modeling one often needs to rely on rather abstract mathematical constraints and conditions, again emphasizing the high level of reliance on applied mathematics. Yet, the interdisciplinary aspects of the field of molecular modeling also generates some inertia and perhaps too conservative reliance on tried and tested methodologies, that is at least partially caused by the less than up-to-date involvement in the newest developments in applied mathematics. It is expected that as more applied mathematicians take up the challenge of employing the latest advances of their field in molecular modeling, important breakthroughs may follow. In this presentation some of the current challenges of molecular modeling are discussed.

Deconstructing (and reconstructing) cell migration.

PubMed

Maheshwari, G; Lauffenburger, D A

1998-12-01

An overriding objective in cell biology is to be able to relate properties of particular molecular components to cell behavioral functions and even physiology. In the "traditional" mode of molecular cell biology, this objective has been tackled on a molecule-by-molecule basis, and in the "future" mode sometimes termed "functional genomics," it might be attacked in a high-throughput, parallel manner. Regardless of the manner of approach, the relationship between molecular-level properties and cell-level function is exceedingly difficult to elucidate because of the large number of relevant components involved, their high degree of interconnectedness, and the inescapable fact that they operate as physico-chemical entities-according to the laws of kinetics and mechanics-in space and time within the cell. Cell migration is a prominent representative example of such a cell behavioral function that requires increased understanding for both scientific and technological advance. This article presents a framework, derived from an engineering perspective regarding complex systems, intended to aid in developing improved understanding of how properties of molecular components influence the function of cell migration. That is, cell population migration behavior can be deconstructed as follows: first in terms of a mathematical model comprising cell population parameters (random motility, chemotaxis/haptotaxis, and chemokinesis/haptokinesis coefficients), which in turn depend on characteristics of individual cell paths that can be analyzed in terms of a mathematical model comprising individual cell parameters (translocation speed, directional persistence time, chemotactic/haptotactic index), which in turn depend on cell-level physical processes underlying motility (membrane extension and retraction, cell/substratum adhesion, cell contractile force, front-vs.-rear asymmetry), which in turn depend on molecular-level properties of the plethora of components involved in governance and regulation of these processes. Hence, the influence of any molecular component on cell population migration can be understood by reconstructing these relationships from the molecular level to the physical process level to the individual cell path level to the cell population distribution level. This approach requires combining experimental, theoretical, and computational methodologies from molecular biology, biochemistry, biophysics, and bioengineering.

Nanoindentation of virus capsids in a molecular model

NASA Astrophysics Data System (ADS)

Cieplak, Marek; Robbins, Mark O.

2010-01-01

A molecular-level model is used to study the mechanical response of empty cowpea chlorotic mottle virus (CCMV) and cowpea mosaic virus (CPMV) capsids. The model is based on the native structure of the proteins that constitute the capsids and is described in terms of the Cα atoms. Nanoindentation by a large tip is modeled as compression between parallel plates. Plots of the compressive force versus plate separation for CCMV are qualitatively consistent with continuum models and experiments, showing an elastic region followed by an irreversible drop in force. The mechanical response of CPMV has not been studied, but the molecular model predicts an order of magnitude higher stiffness and a much shorter elastic region than for CCMV. These large changes result from small structural changes that increase the number of bonds by only 30% and would be difficult to capture in continuum models. Direct comparison of local deformations in continuum and molecular models of CCMV shows that the molecular model undergoes a gradual symmetry breaking rotation and accommodates more strain near the walls than the continuum model. The irreversible drop in force at small separations is associated with rupturing nearly all of the bonds between capsid proteins in the molecular model, while a buckling transition is observed in continuum models.

Automated chemical kinetic modeling via hybrid reactive molecular dynamics and quantum chemistry simulations.

PubMed

Döntgen, Malte; Schmalz, Felix; Kopp, Wassja A; Kröger, Leif C; Leonhard, Kai

2018-06-13

An automated scheme for obtaining chemical kinetic models from scratch using reactive molecular dynamics and quantum chemistry simulations is presented. This methodology combines the phase space sampling of reactive molecular dynamics with the thermochemistry and kinetics prediction capabilities of quantum mechanics. This scheme provides the NASA polynomial and modified Arrhenius equation parameters for all species and reactions that are observed during the simulation and supplies them in the ChemKin format. The ab initio level of theory for predictions is easily exchangeable and the presently used G3MP2 level of theory is found to reliably reproduce hydrogen and methane oxidation thermochemistry and kinetics data. Chemical kinetic models obtained with this approach are ready-to-use for, e.g., ignition delay time simulations, as shown for hydrogen combustion. The presented extension of the ChemTraYzer approach can be used as a basis for methodologically advancing chemical kinetic modeling schemes and as a black-box approach to generate chemical kinetic models.

Understanding valence-shell electron-pair repulsion (VSEPR) theory using origami molecular models

NASA Astrophysics Data System (ADS)

Endah Saraswati, Teguh; Saputro, Sulistyo; Ramli, Murni; Praseptiangga, Danar; Khasanah, Nurul; Marwati, Sri

2017-01-01

Valence-shell electron-pair repulsion (VSEPR) theory is conventionally used to predict molecular geometry. However, it is difficult to explore the full implications of this theory by simply drawing chemical structures. Here, we introduce origami modelling as a more accessible approach for exploration of the VSEPR theory. Our technique is simple, readily accessible and inexpensive compared with other sophisticated methods such as computer simulation or commercial three-dimensional modelling kits. This method can be implemented in chemistry education at both the high school and university levels. We discuss the example of a simple molecular structure prediction for ammonia (NH3). Using the origami model, both molecular shape and the scientific justification can be visualized easily. This ‘hands-on’ approach to building molecules will help promote understanding of VSEPR theory.

Modeling the polydomain-monodomain transition of liquid crystal elastomers.

PubMed

Whitmer, Jonathan K; Roberts, Tyler F; Shekhar, Raj; Abbott, Nicholas L; de Pablo, Juan J

2013-02-01

We study the mechanism of the polydomain-monodomain transition in liquid crystalline elastomers at the molecular scale. A coarse-grained model is proposed in which mesogens are described as ellipsoidal particles. Molecular dynamics simulations are used to examine the transition from a polydomain state to a monodomain state in the presence of uniaxial strain. Our model demonstrates soft elasticity, similar to that exhibited by side-chain elastomers in the literature. By analyzing the growth dynamics of nematic domains during uniaxial extension, we provide direct evidence that at a molecular level the polydomain-monodomain transition proceeds through cluster rotation and domain growth.

Modern Spectroscopy

ERIC Educational Resources Information Center

Barrow, Gordon M.

1970-01-01

Presents the basic ideas of modern spectroscopy. Both the angular momenta and wave-nature approaches to the determination of energy level patterns for atomic and molecular systems are discussed. The interpretation of spectra, based on atomic and molecular models, is considered. (LC)

Training New Technologists in the Basics of Molecular Pathology.

ERIC Educational Resources Information Center

Matta, Nahida

1993-01-01

Outlines a training model designed to help senior technologists ensure that the newly hired technologists in the clinical molecular pathology laboratory achieve the minimum level of knowledge needed to perform and progress on the job. (Author)

Relative complexation energies for Li(+) ion in solution: molecular level solvation versus polarizable continuum model study.

PubMed

Eilmes, Andrzej; Kubisiak, Piotr

2010-01-21

Relative complexation energies for the lithium cation in acetonitrile and diethyl ether have been studied. Quantum-chemical calculations explicitly describing the solvation of Li(+) have been performed based on structures obtained from molecular dynamics simulations. The effect of an increasing number of solvent molecules beyond the first solvation shell has been found to consist in reduction of the differences in complexation energies for different coordination numbers. Explicit-solvation data have served as a benchmark to the results of polarizable continuum model (PCM) calculations. It has been demonstrated that the PCM approach can yield relative complexation energies comparable to the predictions based on molecular-level solvation, but at significantly lower computational cost. The best agreement between the explicit-solvation and the PCM results has been obtained when the van der Waals surface was adopted to build the molecular cavity.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

PubMed

Martín-Rodríguez, Juan F; Muñoz-Bravo, Jose L; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M; Castaño, Justo P; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A

2015-11-09

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

PubMed Central

Martín-Rodríguez, Juan F.; Muñoz-Bravo, Jose L.; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M.; Castaño, Justo P.; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A.

2015-01-01

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors. PMID:26549306

A study of water uptake by selected superdisintegrants from the sub-molecular to the particulate level.

PubMed

Barmpalexis, P; Syllignaki, P; Kachrimanis, K

2018-06-01

Water diffusion through the matrix of three superdisintegrants, namely sodium starch glycolate (SSG), croscarmellose sodium (cCMC-Na) and crospovidone (cPVP), was studied at the sub-molecular level using Attenuated Total Reflectance (ATR)-FTIR spectroscopy and molecular dynamics simulations, and the results were correlated to water uptake studies conducted at the particulate level using Parallel Exponential Kinetics (PEK) modeling in dynamic moisture sorption studies and optical microscopy. ATR-FTIR studies indicated that water diffuses inside cPVP by a single fast acting process, while in SSG and cCMC-Na, a slow and a fast process acting simultaneously, were identified. The same pattern regarding the rate of water uptake for all superdisintegrants was found also at the particulate level by PEK modeling. Moreover, molecular dynamics simulation helped elucidate the hydrogen bonding patterns formed between water-SSG and water-cCMC-Na, mainly via their carboxylic oxygen atoms and secondarily via their hydroxyl groups, while cPVP formed hydrogen bonds only through carbonyl oxygen. Finally, cPVP chains showed significant flexibility during hydration, while cCMC-Na and SSG chains retain their conformation to some extent, explaining the extensive swelling observed also at the particulate level by optical microscopy hydration studies.

Modeling the chemistry of complex petroleum mixtures.

PubMed Central

Quann, R J

1998-01-01

Determining the complete molecular composition of petroleum and its refined products is not feasible with current analytical techniques because of the astronomical number of molecular components. Modeling the composition and behavior of such complex mixtures in refinery processes has accordingly evolved along a simplifying concept called lumping. Lumping reduces the complexity of the problem to a manageable form by grouping the entire set of molecular components into a handful of lumps. This traditional approach does not have a molecular basis and therefore excludes important aspects of process chemistry and molecular property fundamentals from the model's formulation. A new approach called structure-oriented lumping has been developed to model the composition and chemistry of complex mixtures at a molecular level. The central concept is to represent an individual molecular or a set of closely related isomers as a mathematical construct of certain specific and repeating structural groups. A complex mixture such as petroleum can then be represented as thousands of distinct molecular components, each having a mathematical identity. This enables the automated construction of large complex reaction networks with tens of thousands of specific reactions for simulating the chemistry of complex mixtures. Further, the method provides a convenient framework for incorporating molecular physical property correlations, existing group contribution methods, molecular thermodynamic properties, and the structure--activity relationships of chemical kinetics in the development of models. PMID:9860903

Evaluation of the molecular level visualisation approach for teaching and learning chemistry in Thailand

NASA Astrophysics Data System (ADS)

Phenglengdi, Butsari

This research evaluates the use of a molecular level visualisation approach in Thai secondary schools. The goal is to obtain insights about the usefulness of this approach, and to examine possible improvements in how the approach might be applied in the future. The methodology used for this research used both qualitative and quantitative approaches. Data were collected in the form of pre- and post-intervention multiple choice questions, open-ended-questions, drawing exercises, one-to-one interviews and video recordings of class activity. The research was conducted in two phases, involving a total of 261 students from the 11th Grade in Thailand. The use of VisChem animations in three studies was evaluated in Phase I. Study 1 was a pilot study exploring the benefits of incorporating VisChem animations to portray the molecular level. Study 2 compared test results between students exposed to these animations of molecular level events, and those not. Finally, in Study 3, test results were gathered from different types of schools (a rural school, a city school, and a university school). The results showed that students (and teachers) had misconceptions at the molecular level, and VisChem animations could help students understand chemistry concepts at the molecular level across all three types of schools. While the animation treatment group had a better score on the topic of states of water, the non-animation treatment group had a better score on the topic of dissolving sodium chloride in water than the animation group. The molecular level visualisation approach as a learning design was evaluated in Phase II. This approach involved a combination of VisChem animations, pictures, and diagrams together with the seven-step VisChem learning design. The study involved three classes of students, each with a different treatment, described as Class A - Traditional approach; Class B - VisChem animations with traditional approach; and Class C - Molecular level visualisation approach. Pre-test and post-test scores were compared across the three classes. The results from the multiple choice and calculation tests showed that the Class C - molecular level visualisation approach group demonstrated a deeper understanding of chemistry concepts than students in Classes A and B. However, the results showed that all the students were unable to perform satisfactorily on the calculation tests because the students had insufficient prior knowledge about stoichiometry to connect with the new knowledge. In the drawing tests the students exposed to the molecular level visualisation approach had a better mental model than the other classes, albeit with some remaining misconceptions. The findings highlight the intersecting nature of the teacher, student, and modelling in chemistry teaching. Use of a multi-step molecular level visualisation approach that encourages observation, reflection of prior understanding, and multiple opportunities at viewing (and using various visualisation elements), are key elements leading to a deeper understanding of chemistry. Presentation of the multi-step molecular level visualisation approach must be coupled with careful consideration of student prior knowledge, and with adequate guidance from a teacher who understands the topics at a deep level.

Modeling Aromatic Liquids:  Toluene, Phenol, and Pyridine.

PubMed

Baker, Christopher M; Grant, Guy H

2007-03-01

Aromatic groups are now acknowledged to play an important role in many systems of interest. However, existing molecular mechanics methods provide a poor representation of these groups. In a previous paper, we have shown that the molecular mechanics treatment of benzene can be improved by the incorporation of an explicit representation of the aromatic π electrons. Here, we develop this concept further, developing charge-separation models for toluene, phenol, and pyridine. Monte Carlo simulations are used to parametrize the models, via the reproduction of experimental thermodynamic data, and our models are shown to outperform an existing atom-centered model. The models are then used to make predictions about the structures of the liquids at the molecular level and are tested further through their application to the modeling of gas-phase dimers and cation-π interactions.

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

Antonelli, Perry Edward

A low-level model-to-model interface is presented that will enable independent models to be linked into an integrated system of models. The interface is based on a standard set of functions that contain appropriate export and import schemas that enable models to be linked with no changes to the models themselves. These ideas are presented in the context of a specific multiscale material problem that couples atomistic-based molecular dynamics calculations to continuum calculations of fluid ow. These simulations will be used to examine the influence of interactions of the fluid with an adjacent solid on the fluid ow. The interface willmore » also be examined by adding it to an already existing modeling code, Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) and comparing it with our own molecular dynamics code.« less

A logic-based dynamic modeling approach to explicate the evolution of the central dogma of molecular biology.

PubMed

Jafari, Mohieddin; Ansari-Pour, Naser; Azimzadeh, Sadegh; Mirzaie, Mehdi

It is nearly half a century past the age of the introduction of the Central Dogma (CD) of molecular biology. This biological axiom has been developed and currently appears to be all the more complex. In this study, we modified CD by adding further species to the CD information flow and mathematically expressed CD within a dynamic framework by using Boolean network based on its present-day and 1965 editions. We show that the enhancement of the Dogma not only now entails a higher level of complexity, but it also shows a higher level of robustness, thus far more consistent with the nature of biological systems. Using this mathematical modeling approach, we put forward a logic-based expression of our conceptual view of molecular biology. Finally, we show that such biological concepts can be converted into dynamic mathematical models using a logic-based approach and thus may be useful as a framework for improving static conceptual models in biology.

A logic-based dynamic modeling approach to explicate the evolution of the central dogma of molecular biology

PubMed Central

Jafari, Mohieddin; Ansari-Pour, Naser; Azimzadeh, Sadegh; Mirzaie, Mehdi

2017-01-01

It is nearly half a century past the age of the introduction of the Central Dogma (CD) of molecular biology. This biological axiom has been developed and currently appears to be all the more complex. In this study, we modified CD by adding further species to the CD information flow and mathematically expressed CD within a dynamic framework by using Boolean network based on its present-day and 1965 editions. We show that the enhancement of the Dogma not only now entails a higher level of complexity, but it also shows a higher level of robustness, thus far more consistent with the nature of biological systems. Using this mathematical modeling approach, we put forward a logic-based expression of our conceptual view of molecular biology. Finally, we show that such biological concepts can be converted into dynamic mathematical models using a logic-based approach and thus may be useful as a framework for improving static conceptual models in biology. PMID:29267315

Imaging molecular dynamics in vivo--from cell biology to animal models.

PubMed

Timpson, Paul; McGhee, Ewan J; Anderson, Kurt I

2011-09-01

Advances in fluorescence microscopy have enabled the study of membrane diffusion, cell adhesion and signal transduction at the molecular level in living cells grown in culture. By contrast, imaging in living organisms has primarily been restricted to the localization and dynamics of cells in tissues. Now, imaging of molecular dynamics is on the cusp of progressing from cell culture to living tissue. This transition has been driven by the understanding that the microenvironment critically determines many developmental and pathological processes. Here, we review recent progress in fluorescent protein imaging in vivo by drawing primarily on cancer-related studies in mice. We emphasize the need for techniques that can be easily combined with genetic models and complement fluorescent protein imaging by providing contextual information about the cellular environment. In this Commentary we will consider differences between in vitro and in vivo experimental design and argue for an approach to in vivo imaging that is built upon the use of intermediate systems, such as 3-D and explant culture models, which offer flexibility and control that is not always available in vivo. Collectively, these methods present a paradigm shift towards the molecular-level investigation of disease and therapy in animal models of disease.

A global "imaging'' view on systems approaches in immunology.

PubMed

Ludewig, Burkhard; Stein, Jens V; Sharpe, James; Cervantes-Barragan, Luisa; Thiel, Volker; Bocharov, Gennady

2012-12-01

The immune system exhibits an enormous complexity. High throughput methods such as the "-omic'' technologies generate vast amounts of data that facilitate dissection of immunological processes at ever finer resolution. Using high-resolution data-driven systems analysis, causal relationships between complex molecular processes and particular immunological phenotypes can be constructed. However, processes in tissues, organs, and the organism itself (so-called higher level processes) also control and regulate the molecular (lower level) processes. Reverse systems engineering approaches, which focus on the examination of the structure, dynamics and control of the immune system, can help to understand the construction principles of the immune system. Such integrative mechanistic models can properly describe, explain, and predict the behavior of the immune system in health and disease by combining both higher and lower level processes. Moving from molecular and cellular levels to a multiscale systems understanding requires the development of methodologies that integrate data from different biological levels into multiscale mechanistic models. In particular, 3D imaging techniques and 4D modeling of the spatiotemporal dynamics of immune processes within lymphoid tissues are central for such integrative approaches. Both dynamic and global organ imaging technologies will be instrumental in facilitating comprehensive multiscale systems immunology analyses as discussed in this review. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Designing an Educative Curriculum Unit for Teaching Molecular Geometry in High School Chemistry

ERIC Educational Resources Information Center

Makarious, Nader N.

2017-01-01

Chemistry is a highly abstract discipline that is taught and learned with the aid of various models. Among the most challenging, yet a fundamental topic in general chemistry at the high school level, is molecular geometry. This study focused on developing exemplary educative curriculum materials pertaining to the topic of molecular geometry. The…

The use of many-body physics and thermodynamics to describe the dynamics of rhythmic generators in sensory cortices engaged in memory and learning.

PubMed

Vitiello, Giuseppe

2015-04-01

The problem of the transition from the molecular and cellular level to the macroscopic level of observed assemblies of myriads of neurons is the subject addressed in this report. The great amount of detailed information available at molecular and cellular level seems not sufficient to account for the high effectiveness and reliability observed in the brain macroscopic functioning. It is suggested that the dissipative many-body model and thermodynamics might offer the dynamical frame underlying the rich phenomenology observed at microscopic and macroscopic level and help in the understanding on how to fill the gap between the bio-molecular and cellular level and the one of brain macroscopic functioning. Copyright © 2014 Elsevier Ltd. All rights reserved.

Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

PubMed

Tvaroška, Igor

2015-02-11

Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Smart Sensing Based on DNA-Metal Interaction Enables a Label-Free and Resettable Security Model of Electrochemical Molecular Keypad Lock.

PubMed

Du, Yan; Han, Xu; Wang, Chenxu; Li, Yunhui; Li, Bingling; Duan, Hongwei

2018-01-26

Recently, molecular keypad locks have received increasing attention. As a new subgroup of smart biosensors, they show great potential for protecting information as a molecular security data processor, rather than merely molecular recognition and quantitation. Herein, label-free electrochemically transduced Ag + and cysteine (Cys) sensors were developed. A molecular keypad lock model with reset function was successfully realized based on the balanced interaction of metal ion with its nucleic acid and chemical ligands. The correct input of "1-2-3" (i.e., "Ag + -Cys-cDNA") is the only password of such molecular keypad lock. Moreover, the resetting process of either correct or wrong input order could be easily made by Cys, buffer, and DI water treatment. Therefore, our system provides an even smarter system of molecular keypad lock, which could inhibit illegal access of unauthorized users, holding great promise in information protection at the molecular level.

Computer Simulation of the Forces Acting on a Submerged Polystyrene Probe as it Approaches the Succinonitrile Melt-Solid Interface

NASA Technical Reports Server (NTRS)

Bune, Andris V.; Kaukler, William; Whitaker, Ann (Technical Monitor)

2001-01-01

A Modeling approach to simulate both mesoscale and microscopic forces acting in a typical AFM experiment is presented. A mesoscale level interaction between the cantilever tip and the sample surface is primarily described by the balance of attractive Van der Waals and repulsive forces. Ultimately, the goal is to measure the forces between a particle and the crystal-melt interface. Two modes of AFM operation are considered in this paper - a stationary and a "tapping" one. The continuous mechanics approach to model tip-surface interaction is presented. At microscopic levels, tip contamination and details of tip-surface interaction are modeled using a molecular dynamics approach for the case of polystyrene - succinonitrile contact. Integration of the mesoscale model with a molecular dynamic model is discussed.

Energetics using the single point IMOMO (integrated molecular orbital+molecular orbital) calculations: Choices of computational levels and model system

NASA Astrophysics Data System (ADS)

Svensson, Mats; Humbel, Stéphane; Morokuma, Keiji

1996-09-01

The integrated MO+MO (IMOMO) method, recently proposed for geometry optimization, is tested for accurate single point calculations. The principle idea of the IMOMO method is to reproduce results of a high level MO calculation for a large ``real'' system by dividing it into a small ``model'' system and the rest and applying different levels of MO theory for the two parts. Test examples are the activation barrier of the SN2 reaction of Cl-+alkyl chlorides, the C=C double bond dissociation of olefins and the energy of reaction for epoxidation of benzene. The effects of basis set and method in the lower level calculation as well as the effects of the choice of model system are investigated in detail. The IMOMO method gives an approximation to the high level MO energetics on the real system, in most cases with very small errors, with a small additional cost over the low level calculation. For instance, when the MP2 (Møller-Plesset second-order perturbation) method is used as the lower level method, the IMOMO method reproduces the results of very high level MO method within 2 kcal/mol, with less than 50% of additional computer time, for the first two test examples. When the HF (Hartree-Fock) method is used as the lower level method, it is less accurate and depends more on the choice of model system, though the improvement over the HF energy is still very significant. Thus the IMOMO single point calculation provides a method for obtaining reliable local energetics such as bond energies and activation barriers for a large molecular system.

Live Cell Imaging of Viscosity in 3D Tumour Cell Models.

PubMed

Shirmanova, Marina V; Shimolina, Lubov' E; Lukina, Maria M; Zagaynova, Elena V; Kuimova, Marina K

2017-01-01

Abnormal levels of viscosity in tissues and cells are known to be associated with disease and malfunction. While methods to measure bulk macroscopic viscosity of bio-tissues are well developed, imaging viscosity at the microscopic scale remains a challenge, especially in vivo. Molecular rotors are small synthetic viscosity-sensitive fluorophores in which fluorescence parameters are strongly correlated to the microviscosity of their immediate environment. Hence, molecular rotors represent a promising instrument for mapping of viscosity in living cells and tissues at the microscopic level. Quantitative measurements of viscosity can be achieved by recording time-resolved fluorescence decays of molecular rotor using fluorescence lifetime imaging microscopy (FLIM), which is also suitable for dynamic viscosity mapping, both in cellulo and in vivo. Among tools of experimental oncology, 3D tumour cultures, or spheroids, are considered a more adequate in vitro model compared to a cellular monolayer, and represent a less labour-intensive and more unified approach compared to animal tumour models. This chapter describes a methodology for microviscosity imaging in tumour spheroids using BODIPY-based molecular rotors and two photon-excited FLIM.

Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection

PubMed Central

Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

2017-01-01

Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung. PMID:28912729

Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

PubMed

Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

2017-01-01

Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

Diamond-like nanoparticles influence on flavonoids transport: molecular modelling

NASA Astrophysics Data System (ADS)

Plastun, Inna L.; Agandeeva, Ksenia E.; Bokarev, Andrey N.; Zenkin, Nikita S.

2017-03-01

Intermolecular interaction of diamond-like nanoparticles and flavonoids is investigated by numerical simulation. Using molecular modelling by the density functional theory method, we analyze hydrogen bonds formation and their influence on IR - spectra and structure of molecular complex which is formed due to interaction between flavonoids and nanodiamonds surrounded with carboxylic groups. Enriched adamantane (1,3,5,7 - adamantanetetracarboxylic acid) is used as an example of diamond-like nanoparticles. Intermolecular forces and structure of hydrogen bonds are investigated. IR - spectra and structure parameters of quercetin - adamantanetetracarboxylic acid molecular complex are obtained by numerical simulation using the Gaussian software complex. Received data coincide well with experimental results. Intermolecular interactions and hydrogen bonding structure in the obtained molecular complex are examined. Possibilities of flavonoids interaction with DNA at the molecular level are also considered.

Self-consistent Non-LTE Model of Infrared Molecular Emissions and Oxygen Dayglows in the Mesosphere and Lower Thermosphere

NASA Technical Reports Server (NTRS)

Feofilov, Artem G.; Yankovsky, Valentine A.; Pesnell, William D.; Kutepov, Alexander A.; Goldberg, Richard A.; Mauilova, Rada O.

2007-01-01

We present the new version of the ALI-ARMS (for Accelerated Lambda Iterations for Atmospheric Radiation and Molecular Spectra) model. The model allows simultaneous self-consistent calculating the non-LTE populations of the electronic-vibrational levels of the O3 and O2 photolysis products and vibrational level populations of CO2, N2,O2, O3, H2O, CO and other molecules with detailed accounting for the variety of the electronic-vibrational, vibrational-vibrational and vibrational-translational energy exchange processes. The model was used as the reference one for modeling the O2 dayglows and infrared molecular emissions for self-consistent diagnostics of the multi-channel space observations of MLT in the SABER experiment It also allows reevaluating the thermalization efficiency of the absorbed solar ultraviolet energy and infrared radiative cooling/heating of MLT by detailed accounting of the electronic-vibrational relaxation of excited photolysis products via the complex chain of collisional energy conversion processes down to the vibrational energy of optically active trace gas molecules.

Characteristics and Levels of Sophistication: An Analysis of Chemistry Students' Ability to Think with Mental Models

ERIC Educational Resources Information Center

Wang, Chia-Yu; Barrow, Lloyd H.

2011-01-01

This study employed a case-study approach to reveal how an ability to think with mental models contributes to differences in students' understanding of molecular geometry and polarity. We were interested in characterizing features and levels of sophistication regarding first-year university chemistry learners' mental modeling behaviors while the…

Molecular Modeling of Water Interfaces: From Molecular Spectroscopy to Thermodynamics.

PubMed

Nagata, Yuki; Ohto, Tatsuhiko; Backus, Ellen H G; Bonn, Mischa

2016-04-28

Understanding aqueous interfaces at the molecular level is not only fundamentally important, but also highly relevant for a variety of disciplines. For instance, electrode-water interfaces are relevant for electrochemistry, as are mineral-water interfaces for geochemistry and air-water interfaces for environmental chemistry; water-lipid interfaces constitute the boundaries of the cell membrane, and are thus relevant for biochemistry. One of the major challenges in these fields is to link macroscopic properties such as interfacial reactivity, solubility, and permeability as well as macroscopic thermodynamic and spectroscopic observables to the structure, structural changes, and dynamics of molecules at these interfaces. Simulations, by themselves, or in conjunction with appropriate experiments, can provide such molecular-level insights into aqueous interfaces. In this contribution, we review the current state-of-the-art of three levels of molecular dynamics (MD) simulation: ab initio, force field, and coarse-grained. We discuss the advantages, the potential, and the limitations of each approach for studying aqueous interfaces, by assessing computations of the sum-frequency generation spectra and surface tension. The comparison of experimental and simulation data provides information on the challenges of future MD simulations, such as improving the force field models and the van der Waals corrections in ab initio MD simulations. Once good agreement between experimental observables and simulation can be established, the simulation can be used to provide insights into the processes at a level of detail that is generally inaccessible to experiments. As an example we discuss the mechanism of the evaporation of water. We finish by presenting an outlook outlining four future challenges for molecular dynamics simulations of aqueous interfacial systems.

Numerical study of influence of molecular diffusion in the Mild combustion regime

NASA Astrophysics Data System (ADS)

Mardani, Amir; Tabejamaat, Sadegh; Ghamari, Mohsen

2010-09-01

In this paper, the importance of molecular diffusion versus turbulent transport in the moderate or intense low-oxygen dilution (Mild) combustion mode has been numerically studied. The experimental conditions of Dally et al. [Proc. Combust. Inst. 29 (2002) 1147-1154] were used for modelling. The EDC model was used to describe the turbulence-chemistry interaction. The DRM-22 reduced mechanism and the GRI 2.11 full mechanism were used to represent the chemical reactions of an H2/methane jet flame. The importance of molecular diffusion for various O2 levels, jet Reynolds numbers and H2 fuel contents was investigated. Results show that the molecular diffusion in Mild combustion cannot be ignored in comparison with the turbulent transport. Also, the method of inclusion of molecular diffusion in combustion modelling has a considerable effect on the accuracy of numerical modelling of Mild combustion. By decreasing the jet Reynolds number, decreasing the oxygen concentration in the airflow or increasing H2 in the fuel mixture, the influence of molecular diffusion on Mild combustion increases.

Studies of chain substitution caused sub-fibril level differences in stiffness and ultrastructure of wildtype and oim/oim collagen fibers using multifrequency-AFM and molecular modeling.

PubMed

Li, Tao; Chang, Shu-Wei; Rodriguez-Florez, Naiara; Buehler, Markus J; Shefelbine, Sandra; Dao, Ming; Zeng, Kaiyang

2016-11-01

Molecular alteration in type I collagen, i.e., substituting the α2 chain with α1 chain in tropocollagen molecule, can cause osteogenesis imperfecta (OI), a brittle bone disease, which can be represented by a mouse model (oim/oim). In this work, we use dual-frequency Atomic Force Microscopy (AFM) and incorporated with molecular modeling to quantify the ultrastructure and stiffness of the individual native collagen fibers from wildtype (+/+) and oim/oim diseased mice humeri. Our work presents direct experimental evidences that the +/+ fibers have highly organized and compact ultrastructure and corresponding ordered stiffness distribution. In contrast, oim/oim fibers have ordered but loosely packed ultrastructure with uncorrelated stiffness distribution, as well as local defects. The molecular model also demonstrates the structural and molecular packing differences between +/+ and oim/oim collagens. The molecular mutation significantly altered sub-fibril structure and mechanical property of collagen fibers. This study can give the new insight for the mechanisms and treatment of the brittle bone disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gas solubility in dilute solutions: A novel molecular thermodynamic perspective

NASA Astrophysics Data System (ADS)

Chialvo, Ariel A.

2018-05-01

We present an explicit molecular-based interpretation of the thermodynamic phase equilibrium underlying gas solubility in liquids, through rigorous links between the microstructure of the dilute systems and the relevant macroscopic quantities that characterize their solution thermodynamics. We apply the formal analysis to unravel and highlight the molecular-level nature of the approximations behind the widely used Krichevsky-Kasarnovsky [J. Am. Chem. Soc. 57, 2168 (1935)] and Krichevsky-Ilinskaya [Acta Physicochim. 20, 327 (1945)] equations for the modeling of gas solubility. Then, we implement a general molecular-based approach to gas solubility and illustrate it by studying Lennard-Jones binary systems whose microstructure and thermodynamic properties were consistently generated via integral equation calculations. Furthermore, guided by the molecular-based analysis, we propose a novel macroscopic modeling approach to gas solubility, emphasize some usually overlook modeling subtleties, and identify novel interdependences among relevant solubility quantities that can be used as either handy modeling constraints or tools for consistency tests.

Gas solubility in dilute solutions: A novel molecular thermodynamic perspective.

PubMed

Chialvo, Ariel A

2018-05-07

We present an explicit molecular-based interpretation of the thermodynamic phase equilibrium underlying gas solubility in liquids, through rigorous links between the microstructure of the dilute systems and the relevant macroscopic quantities that characterize their solution thermodynamics. We apply the formal analysis to unravel and highlight the molecular-level nature of the approximations behind the widely used Krichevsky-Kasarnovsky [J. Am. Chem. Soc. 57, 2168 (1935)] and Krichevsky-Ilinskaya [Acta Physicochim. 20, 327 (1945)] equations for the modeling of gas solubility. Then, we implement a general molecular-based approach to gas solubility and illustrate it by studying Lennard-Jones binary systems whose microstructure and thermodynamic properties were consistently generated via integral equation calculations. Furthermore, guided by the molecular-based analysis, we propose a novel macroscopic modeling approach to gas solubility, emphasize some usually overlook modeling subtleties, and identify novel interdependences among relevant solubility quantities that can be used as either handy modeling constraints or tools for consistency tests.

When the human viral infectome and diseasome networks collide: towards a systems biology platform for the aetiology of human diseases

PubMed Central

2011-01-01

Background Comprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases. New advances in the field are expected from systems-level modelling and integration of the incessant torrent of high-throughput "-omics" data. Results Here, we describe the Human Infectome protein interaction Network, a novel systems virology model of a virtual virus-infected human cell concerning 110 viruses. This in silico model was applied to comprehensively explore the molecular relationships between viruses and their associated diseases. This was done by merging virus-host and host-host physical protein-protein interactomes with the set of genes essential for viral replication and involved in human genetic diseases. This systems-level approach provides strong evidence that viral proteomes target a wide range of functional and inter-connected modules of proteins as well as highly central and bridging proteins within the human interactome. The high centrality of targeted proteins was correlated to their essentiality for viruses' lifecycle, using functional genomic RNAi data. A stealth-attack of viruses on proteins bridging cellular functions was demonstrated by simulation of cellular network perturbations, a property that could be essential in the molecular aetiology of some human diseases. Networking the Human Infectome and Diseasome unravels the connectivity of viruses to a wide range of diseases and profiled molecular basis of Hepatitis C Virus-induced diseases as well as 38 new candidate genetic predisposition factors involved in type 1 diabetes mellitus. Conclusions The Human Infectome and Diseasome Networks described here provide a unique gateway towards the comprehensive modelling and analysis of the systems level properties associated to viral infection as well as candidate genes potentially involved in the molecular aetiology of human diseases. PMID:21255393

Multiscale modeling of a rectifying bipolar nanopore: explicit-water versus implicit-water simulations.

PubMed

Ható, Zoltán; Valiskó, Mónika; Kristóf, Tamás; Gillespie, Dirk; Boda, Dezsö

2017-07-21

In a multiscale modeling approach, we present computer simulation results for a rectifying bipolar nanopore at two modeling levels. In an all-atom model, we use explicit water to simulate ion transport directly with the molecular dynamics technique. In a reduced model, we use implicit water and apply the Local Equilibrium Monte Carlo method together with the Nernst-Planck transport equation. This hybrid method makes the fast calculation of ion transport possible at the price of lost details. We show that the implicit-water model is an appropriate representation of the explicit-water model when we look at the system at the device (i.e., input vs. output) level. The two models produce qualitatively similar behavior of the electrical current for different voltages and model parameters. Looking at the details of concentration and potential profiles, we find profound differences between the two models. These differences, however, do not influence the basic behavior of the model as a device because they do not influence the z-dependence of the concentration profiles which are the main determinants of current. These results then address an old paradox: how do reduced models, whose assumptions should break down in a nanoscale device, predict experimental data? Our simulations show that reduced models can still capture the overall device physics correctly, even though they get some important aspects of the molecular-scale physics quite wrong; reduced models work because they include the physics that is necessary from the point of view of device function. Therefore, reduced models can suffice for general device understanding and device design, but more detailed models might be needed for molecular level understanding.

Molecular-Level Simulations of Shock Generation and Propagation in Soda-Lime Glass

DTIC Science & Technology

2012-08-01

Molecular-Level Simulations of Shock Generation and Propagation in Soda-Lime Glass M. Grujicic, W.C. Bell, B. Pandurangan, B.A. Cheeseman, C ...transparent structures with thickness approaching several inches; (b) relatively low material and manufacturing costs; and ( c ) compositional modifications... c ) models based on explicit crack representation (Ref 15, 16). Since a M. Grujicic, W.C. Bell, and B. Pandurangan, Department of Mec- hanical

Multilevel functional genomics data integration as a tool for understanding physiology: a network biology perspective.

PubMed

Davidsen, Peter K; Turan, Nil; Egginton, Stuart; Falciani, Francesco

2016-02-01

The overall aim of physiological research is to understand how living systems function in an integrative manner. Consequently, the discipline of physiology has since its infancy attempted to link multiple levels of biological organization. Increasingly this has involved mathematical and computational approaches, typically to model a small number of components spanning several levels of biological organization. With the advent of "omics" technologies, which can characterize the molecular state of a cell or tissue (intended as the level of expression and/or activity of its molecular components), the number of molecular components we can quantify has increased exponentially. Paradoxically, the unprecedented amount of experimental data has made it more difficult to derive conceptual models underlying essential mechanisms regulating mammalian physiology. We present an overview of state-of-the-art methods currently used to identifying biological networks underlying genomewide responses. These are based on a data-driven approach that relies on advanced computational methods designed to "learn" biology from observational data. In this review, we illustrate an application of these computational methodologies using a case study integrating an in vivo model representing the transcriptional state of hypoxic skeletal muscle with a clinical study representing muscle wasting in chronic obstructive pulmonary disease patients. The broader application of these approaches to modeling multiple levels of biological data in the context of modern physiology is discussed. Copyright © 2016 the American Physiological Society.

In Vivo Imaging of Immuno-Spin Trapped Radicals With Molecular Magnetic Resonance Imaging in a Diabetic Mouse Model

PubMed Central

Towner, Rheal A.; Smith, Nataliya; Saunders, Debra; Henderson, Michael; Downum, Kristen; Lupu, Florea; Silasi-Mansat, Robert; Ramirez, Dario C.; Gomez-Mejiba, Sandra E.; Bonini, Marcelo G.; Ehrenshaft, Marilyn; Mason, Ronald P.

2012-01-01

Oxidative stress plays a major role in diabetes. In vivo levels of membrane-bound radicals (MBRs) in a streptozotocin-induced diabetic mouse model were uniquely detected by combining molecular magnetic resonance imaging (mMRI) and immunotrapping techniques. An anti-DMPO (5,5-dimethyl-1-pyrroline N-oxide) antibody (Ab) covalently bound to an albumin (BSA)-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin MRI contrast agent (anti-DMPO probe), and mMRI, were used to detect in vivo levels of DMPO-MBR adducts in kidneys, livers, and lungs of diabetic mice, after DMPO administration. Magnetic resonance signal intensities, which increase in the presence of a Gd-based molecular probe, were significantly higher within the livers, kidneys, and lungs of diabetic animals administered the anti-DMPO probe compared with controls. Fluorescence images validated the location of the anti-DMPO probe in excised tissues via conjugation of streptavidin-Cy3, which targeted the probe biotin moiety, and immunohistochemistry was used to validate the presence of DMPO adducts in diabetic mouse livers. This is the first report of noninvasively imaging in vivo levels of MBRs within any disease model. This method can be specifically applied toward diabetes models for in vivo assessment of free radical levels, providing an avenue to more fully understand the role of free radicals in diabetes. PMID:22698922

Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles

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

Oh, Jung-Hwa; Department of human and environmental toxicology, University of Science & Technology, Daejeon 34113; Son, Mi-Young

Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10–200 μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24 h. The results showed that Ag NPs evoked significant toxicity in hESC-derivedmore » NPCs at 24 h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans. - Highlights: • This system served as a suitable model for developmental neurotoxicity testing. • Ag NPs induce the apoptosis in human neural cells by ROS generation. • Genes for development of neurons were dysregulated in response to Ag NPs. • Molecular events during early developmental neurotoxicity were proposed.« less

Genome-wide investigation reveals high evolutionary rates in annual model plants.

PubMed

Yue, Jia-Xing; Li, Jinpeng; Wang, Dan; Araki, Hitoshi; Tian, Dacheng; Yang, Sihai

2010-11-09

Rates of molecular evolution vary widely among species. While significant deviations from molecular clock have been found in many taxa, effects of life histories on molecular evolution are not fully understood. In plants, annual/perennial life history traits have long been suspected to influence the evolutionary rates at the molecular level. To date, however, the number of genes investigated on this subject is limited and the conclusions are mixed. To evaluate the possible heterogeneity in evolutionary rates between annual and perennial plants at the genomic level, we investigated 85 nuclear housekeeping genes, 10 non-housekeeping families, and 34 chloroplast genes using the genomic data from model plants including Arabidopsis thaliana and Medicago truncatula for annuals and grape (Vitis vinifera) and popular (Populus trichocarpa) for perennials. According to the cross-comparisons among the four species, 74-82% of the nuclear genes and 71-97% of the chloroplast genes suggested higher rates of molecular evolution in the two annuals than those in the two perennials. The significant heterogeneity in evolutionary rate between annuals and perennials was consistently found both in nonsynonymous sites and synonymous sites. While a linear correlation of evolutionary rates in orthologous genes between species was observed in nonsynonymous sites, the correlation was weak or invisible in synonymous sites. This tendency was clearer in nuclear genes than in chloroplast genes, in which the overall evolutionary rate was small. The slope of the regression line was consistently lower than unity, further confirming the higher evolutionary rate in annuals at the genomic level. The higher evolutionary rate in annuals than in perennials appears to be a universal phenomenon both in nuclear and chloroplast genomes in the four dicot model plants we investigated. Therefore, such heterogeneity in evolutionary rate should result from factors that have genome-wide influence, most likely those associated with annual/perennial life history. Although we acknowledge current limitations of this kind of study, mainly due to a small sample size available and a distant taxonomic relationship of the model organisms, our results indicate that the genome-wide survey is a promising approach toward further understanding of the mechanism determining the molecular evolutionary rate at the genomic level.

Linking short-term responses to ecologically-relevant outcomes

EPA Pesticide Factsheets

Opportunity to participate in the conduct of collaborative integrative lab, field and modelling efforts to characterize molecular-to-organismal level responses and make quantitative testable predictions of population level outcomes

Computer display and manipulation of biological molecules

NASA Technical Reports Server (NTRS)

Coeckelenbergh, Y.; Macelroy, R. D.; Hart, J.; Rein, R.

1978-01-01

This paper describes a computer model that was designed to investigate the conformation of molecules, macromolecules and subsequent complexes. Utilizing an advanced 3-D dynamic computer display system, the model is sufficiently versatile to accommodate a large variety of molecular input and to generate data for multiple purposes such as visual representation of conformational changes, and calculation of conformation and interaction energy. Molecules can be built on the basis of several levels of information. These include the specification of atomic coordinates and connectivities and the grouping of building blocks and duplicated substructures using symmetry rules found in crystals and polymers such as proteins and nucleic acids. Called AIMS (Ames Interactive Molecular modeling System), the model is now being used to study pre-biotic molecular evolution toward life.

GENE EXPRESSION PATTERNS ASSOCIATED WITH INFERTILITY IN HUMAN AND RODENT MODELS

EPA Science Inventory

Modern genomic technologies such as DNA arrays provide the means to investigate molecular interactions at an unprecedented level, and arrays have been used to carry out gene expression profiling as a means of identifying candidate genes involved in molecular mechanisms underlying...

A Systems Approach to Radiation Carcinogenesis

NASA Astrophysics Data System (ADS)

Hlatky, Lynn

Understanding carcinogenesis risk is complicated by a number of factors, among these the lack of a common platform to integrate and analyze the available data, and the inherently systemsbiologic nature of the problem. We have investigated mechanistic approaches to radiogenic risk estimation that draw on unifying biological principles and incorporate data from multiscale sources. The resultant modeling takes into account that carcinogenesis is a multi-scale phenomenon, critically influenced by determinants not only at the molecular level, but at the cell and tissue-levels as well. To account for cell-level carcinogenesis progression as influenced by inter-tissue signaling, we have developed a dynamic carrying capacity construct that couples the growth of a tumor with the degree of induced vascularization. We have also characterized the molecular responses to radiation incorporating tissue-level angiogenesis implications, and have found striking radiation-quality-dependent responses. The molecular-level events of initiation and promotion are considered in our Two-Stage Logistic model, while incorporating in a rudimentary way the larger-scale growth-limiting role of cell-cell interactions. These and other recent studies undertaken to elaborate radiation-induced carcinogenesis are discussed, in pursuit of a more complete paradigm for understanding radiation induction of cancer and the consequent risk.

Neural Plasticity and Memory: Is Memory Encoded in Hydrogen Bonding Patterns?

PubMed

Amtul, Zareen; Rahman, Atta-Ur

2016-02-01

Current models of memory storage recognize posttranslational modification vital for short-term and mRNA translation for long-lasting information storage. However, at the molecular level things are quite vague. A comprehensive review of the molecular basis of short and long-lasting synaptic plasticity literature leads us to propose that the hydrogen bonding pattern at the molecular level may be a permissive, vital step of memory storage. Therefore, we propose that the pattern of hydrogen bonding network of biomolecules (glycoproteins and/or DNA template, for instance) at the synapse is the critical edifying mechanism essential for short- and long-term memories. A novel aspect of this model is that nonrandom impulsive (or unplanned) synaptic activity functions as a synchronized positive-feedback rehearsal mechanism by revising the configurations of the hydrogen bonding network by tweaking the earlier tailored hydrogen bonds. This process may also maintain the elasticity of the related synapses involved in memory storage, a characteristic needed for such networks to alter intricacy and revise endlessly. The primary purpose of this review is to stimulate the efforts to elaborate the mechanism of neuronal connectivity both at molecular and chemical levels. © The Author(s) 2014.

Simulational nanoengineering: Molecular dynamics implementation of an atomistic Stirling engine.

PubMed

Rapaport, D C

2009-04-01

A nanoscale-sized Stirling engine with an atomistic working fluid has been modeled using molecular dynamics simulation. The design includes heat exchangers based on thermostats, pistons attached to a flywheel under load, and a regenerator. Key aspects of the behavior, including the time-dependent flows, are described. The model is shown to be capable of stable operation while producing net work at a moderate level of efficiency.

Charge Transport Processes in Molecular Junctions

NASA Astrophysics Data System (ADS)

Smith, Christopher Eugene

Molecular electronics (ME) has evolved into a rich area of exploration that combines the fields of chemistry, materials, electronic engineering and computational modeling to explore the physics behind electronic conduction at the molecular level. Through studying charge transport properties of single molecules and nanoscale molecular materials the field has gained the potential to bring about new avenues for the miniaturization of electrical components where quantum phenomena are utilized to achieve solid state molecular device functionality. Molecular junctions are platforms that enable these studies and consist of a single molecule or a small group of molecules directly connected to electrodes. The work presented in this thesis has built upon the current understanding of the mechanisms of charge transport in ordered junctions using self-assembled monolayer (SAM) molecular thin films. Donor and acceptor compounds were synthesized and incorporated into SAMs grown on metal substrates then the transport properties were measured with conducting probe atomic force microscopy (CP-AFM). In addition to experimentally measured current-voltage (I-V) curves, the transport properties were addressed computationally and modeled theoretically. The key objectives of this project were to 1) investigate the impact of molecular structure on hole and electron charge transport, 2) understand the nature of the charge carriers and their structure-transport properties through long (<4 nm) conjugated molecular wires, and 3) quantitatively extract interfacial properties characteristic to macroscopic junctions, such as energy level alignment and molecule-contact electronic coupling from experimental I-V curves. Here, we lay ground work for creating a more complete picture of charge transport in macroscopically ordered molecular junctions of controlled architecture, length and charge carrier. The polaronic nature of hopping transport has been predicted in long, conjugated molecular wires. Using quantum-based calculations, we modeled 'p-type' polaron transport through oligophenylenethiophene (OPTI) wires and assigned transport activation energies to specific modes of nuclear motion. We also show control over 'n-type', LUMO-mediated transport in short ( 2 nm) redox-active perylenediimide (PDI) SAMs bound to contacts through isocyano linkers. By changing the contact work function (φ) and temperature, we were able to verify thermally-assisted LUMO transport. Transition voltage spectroscopy and the single level model was employed to fit the experimental I-V curves and extract the electronic coupling (epsilon) and the EF-LUMO offset (epsilonl). It was found that epsilonl does not change with φ (LUMO pinning), while Gamma changes with both φ and temperature. Further, the PDI SAMs could be reversibly chemically gated to modulate the transport. These results help advance our understanding of transport behavior in semiconducting molecular thin films, and open opportunities to engineer improved electronic functionality into molecular devices.

Bad Behavior: Improving Reproducibility in Behavior Testing.

PubMed

Andrews, Anne M; Cheng, Xinyi; Altieri, Stefanie C; Yang, Hongyan

2018-01-24

Systems neuroscience research is increasingly possible through the use of integrated molecular and circuit-level analyses. These studies depend on the use of animal models and, in many cases, molecular and circuit-level analyses. Associated with genetic, pharmacologic, epigenetic, and other types of environmental manipulations. We illustrate typical pitfalls resulting from poor validation of behavior tests. We describe experimental designs and enumerate controls needed to improve reproducibility in investigating and reporting of behavioral phenotypes.

Modelling the molecular mechanisms of aging

PubMed Central

Mc Auley, Mark T.; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M.; Morgan, Amy E.

2017-01-01

The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field. PMID:28096317

Modeling molecular hydrogen emission in M dwarf exoplanetary systems

NASA Astrophysics Data System (ADS)

Evonosky, William; France, Kevin; Kruczek, Nick E.; Youngblood, Allison; Measurements of the Ultraviolet Spectral Characteristics of Low-mass Exoplanet host Stars (MUSCLES)

2017-01-01

Exoplanets orbiting low-mass stars are prime candidates for atmospheric characterization due to their astronomical abundance and short orbital periods. These planets orbit stars that are often more active than main sequence solar-type stars. They are exposed to differing levels of ultraviolet radiation which can cause traditional “biosignature” gases to be generated abiotically, potentially causing false-positive identifications of life. We modeled the recently discovered molecular hydrogen emission in the ultraviolet spectra (1350 - 1650 Å) as arising from the stellar surface, excited by radiation generated in the upper chromosphere. The model was compared with observed hydrogen emission from the “Measurements of the Ultraviolet Spectral Characteristics of Low-mass Exoplanet host Stars” (MUSCLES) survey by conducting a grid search and implementing a chi-squared minimization routine. We considered only progressions from the [1, 4] and [1, 7] first excited electronic levels. Our modeling procedure varied the atomic hydrogen column density (in the chromosphere) as well as the photospheric molecular hydrogen column density and temperature. The model required as an input a reconstructed intrinsic Lyman α profile which served as the pumping radiation for the molecular hydrogen. We found that an atomic hydrogen column density of log10N(H I) = 14.13 ± 0.16 cm-2 represents a breaking point above which there is not enough Lyman α flux available to excite a significant molecular hydrogen population into the [1, 7] state. We also present H2 temperatures which may suggest that star spots on low mass stars persist longer, and encompass more area than star spots on solar-type stars.

Modeling Molecular Hydrogen Emission in M-Dwarf Exoplanetary Systems

NASA Astrophysics Data System (ADS)

Evonosky, W. R.; France, K.; Kruczek, N.; Youngblood, A.

2016-12-01

Exoplanets orbiting low-mass stars are prime candidates for atmospheric characterization due to their astronomical abundance and short orbital periods. These planets orbit stars that are often more active than main sequence solar-type stars. They are exposed to differing levels of ultraviolet radiation which can cause traditional "biosignature" gases to be generated abiotically, potentially causing false-positive identifications of life. We modeled the recently discovered molecular hydrogen emission in the ultraviolet spectra (1350 - 1650 Å) as arising from the stellar surface, excited by radiation generated in the upper chromosphere. The model was compared with observed hydrogen emission from the "Measurements of the Ultraviolet Spectral Characteristics of Low-mass Exoplanet host Stars" (MUSCLES) survey by conducting a grid search and implementing a chi-squared minimization routine. We considered only progressions from the [1, 4] and [1, 7] first excited electronic levels. Our modeling procedure varied the atomic hydrogen column density (in the chromosphere) as well as the photospheric molecular hydrogen column density and temperature. The model required as an input a reconstructed intrinsic Lyman α profile which served as the pumping radiation for the molecular hydrogen. We found that an atomic hydrogen column density of log10N(H I) = 14.13 ± 0.16 cm-2 represents a breaking point above which there is not enough Lyman α flux available to excite a significant molecular hydrogen population into the [1, 7] state. We also present H2 temperatures which may suggest that star spots on low mass stars persist longer, and encompass more area than star spots on solar-type stars.

A closed-loop multi-level model of glucose homeostasis

PubMed Central

Uluseker, Cansu; Simoni, Giulia; Dauriz, Marco; Matone, Alice

2018-01-01

Background The pathophysiologic processes underlying the regulation of glucose homeostasis are considerably complex at both cellular and systemic level. A comprehensive and structured specification for the several layers of abstraction of glucose metabolism is often elusive, an issue currently solvable with the hierarchical description provided by multi-level models. In this study we propose a multi-level closed-loop model of whole-body glucose homeostasis, coupled with the molecular specifications of the insulin signaling cascade in adipocytes, under the experimental conditions of normal glucose regulation and type 2 diabetes. Methodology/Principal findings The ordinary differential equations of the model, describing the dynamics of glucose and key regulatory hormones and their reciprocal interactions among gut, liver, muscle and adipose tissue, were designed for being embedded in a modular, hierarchical structure. The closed-loop model structure allowed self-sustained simulations to represent an ideal in silico subject that adjusts its own metabolism to the fasting and feeding states, depending on the hormonal context and invariant to circadian fluctuations. The cellular level of the model provided a seamless dynamic description of the molecular mechanisms downstream the insulin receptor in the adipocytes by accounting for variations in the surrounding metabolic context. Conclusions/Significance The combination of a multi-level and closed-loop modeling approach provided a fair dynamic description of the core determinants of glucose homeostasis at both cellular and systemic scales. This model architecture is intrinsically open to incorporate supplementary layers of specifications describing further individual components influencing glucose metabolism. PMID:29420588

Madelung and Hubbard interactions in polaron band model of doped organic semiconductors

PubMed Central

Png, Rui-Qi; Ang, Mervin C.Y.; Teo, Meng-How; Choo, Kim-Kian; Tang, Cindy Guanyu; Belaineh, Dagmawi; Chua, Lay-Lay; Ho, Peter K.H.

2016-01-01

The standard polaron band model of doped organic semiconductors predicts that density-of-states shift into the π–π* gap to give a partially filled polaron band that pins the Fermi level. This picture neglects both Madelung and Hubbard interactions. Here we show using ultrahigh workfunction hole-doped model triarylamine–fluorene copolymers that Hubbard interaction strongly splits the singly-occupied molecular orbital from its empty counterpart, while Madelung (Coulomb) interactions with counter-anions and other carriers markedly shift energies of the frontier orbitals. These interactions lower the singly-occupied molecular orbital band below the valence band edge and give rise to an empty low-lying counterpart band. The Fermi level, and hence workfunction, is determined by conjunction of the bottom edge of this empty band and the top edge of the valence band. Calculations are consistent with the observed Fermi-level downshift with counter-anion size and the observed dependence of workfunction on doping level in the strongly doped regime. PMID:27582355

Penalized differential pathway analysis of integrative oncogenomics studies.

PubMed

van Wieringen, Wessel N; van de Wiel, Mark A

2014-04-01

Through integration of genomic data from multiple sources, we may obtain a more accurate and complete picture of the molecular mechanisms underlying tumorigenesis. We discuss the integration of DNA copy number and mRNA gene expression data from an observational integrative genomics study involving cancer patients. The two molecular levels involved are linked through the central dogma of molecular biology. DNA copy number aberrations abound in the cancer cell. Here we investigate how these aberrations affect gene expression levels within a pathway using observational integrative genomics data of cancer patients. In particular, we aim to identify differential edges between regulatory networks of two groups involving these molecular levels. Motivated by the rate equations, the regulatory mechanism between DNA copy number aberrations and gene expression levels within a pathway is modeled by a simultaneous-equations model, for the one- and two-group case. The latter facilitates the identification of differential interactions between the two groups. Model parameters are estimated by penalized least squares using the lasso (L1) penalty to obtain a sparse pathway topology. Simulations show that the inclusion of DNA copy number data benefits the discovery of gene-gene interactions. In addition, the simulations reveal that cis-effects tend to be over-estimated in a univariate (single gene) analysis. In the application to real data from integrative oncogenomic studies we show that inclusion of prior information on the regulatory network architecture benefits the reproducibility of all edges. Furthermore, analyses of the TP53 and TGFb signaling pathways between ER+ and ER- samples from an integrative genomics breast cancer study identify reproducible differential regulatory patterns that corroborate with existing literature.

Knowledge environments representing molecular entities for the virtual physiological human.

PubMed

Hofmann-Apitius, Martin; Fluck, Juliane; Furlong, Laura; Fornes, Oriol; Kolárik, Corinna; Hanser, Susanne; Boeker, Martin; Schulz, Stefan; Sanz, Ferran; Klinger, Roman; Mevissen, Theo; Gattermayer, Tobias; Oliva, Baldo; Friedrich, Christoph M

2008-09-13

In essence, the virtual physiological human (VPH) is a multiscale representation of human physiology spanning from the molecular level via cellular processes and multicellular organization of tissues to complex organ function. The different scales of the VPH deal with different entities, relationships and processes, and in consequence the models used to describe and simulate biological functions vary significantly. Here, we describe methods and strategies to generate knowledge environments representing molecular entities that can be used for modelling the molecular scale of the VPH. Our strategy to generate knowledge environments representing molecular entities is based on the combination of information extraction from scientific text and the integration of information from biomolecular databases. We introduce @neuLink, a first prototype of an automatically generated, disease-specific knowledge environment combining biomolecular, chemical, genetic and medical information. Finally, we provide a perspective for the future implementation and use of knowledge environments representing molecular entities for the VPH.

Advances in the mechanical modeling of filamentous actin and its cross-linked networks on multiple scales.

PubMed

Unterberger, Michael J; Holzapfel, Gerhard A

2014-11-01

The protein actin is a part of the cytoskeleton and, therefore, responsible for the mechanical properties of the cells. Starting with the single molecule up to the final structure, actin creates a hierarchical structure of several levels exhibiting a remarkable behavior. The hierarchy spans several length scales and limitations in computational power; therefore, there is a call for different mechanical modeling approaches for the different scales. On the molecular level, we may consider each atom in molecular dynamics simulations. Actin forms filaments by combining the molecules into a double helix. In a model, we replace molecular subdomains using coarse-graining methods, allowing the investigation of larger systems of several atoms. These models on the nanoscale inform continuum mechanical models of large filaments, which are based on worm-like chain models for polymers. Assemblies of actin filaments are connected with cross-linker proteins. Models with discrete filaments, so-called Mikado models, allow us to investigate the dependence of the properties of networks on the parameters of the constituents. Microstructurally motivated continuum models of the networks provide insights into larger systems containing cross-linked actin networks. Modeling of such systems helps to gain insight into the processes on such small scales. On the other hand, they call for verification and hence trigger the improvement of established experiments and the development of new methods.

Mathematical analysis of compressive/tensile molecular and nuclear structures

NASA Astrophysics Data System (ADS)

Wang, Dayu

Mathematical analysis in chemistry is a fascinating and critical tool to explain experimental observations. In this dissertation, mathematical methods to present chemical bonding and other structures for many-particle systems are discussed at different levels (molecular, atomic, and nuclear). First, the tetrahedral geometry of single, double, or triple carbon-carbon bonds gives an unsatisfying demonstration of bond lengths, compared to experimental trends. To correct this, Platonic solids and Archimedean solids were evaluated as atoms in covalent carbon or nitrogen bond systems in order to find the best solids for geometric fitting. Pentagonal solids, e.g. the dodecahedron and icosidodecahedron, give the best fit with experimental bond lengths; an ideal pyramidal solid which models covalent bonds was also generated. Second, the macroscopic compression/tension architectural approach was applied to forces at the molecular level, considering atomic interactions as compressive (repulsive) and tensile (attractive) forces. Two particle interactions were considered, followed by a model of the dihydrogen molecule (H2; two protons and two electrons). Dihydrogen was evaluated as two different types of compression/tension structures: a coaxial spring model and a ring model. Using similar methods, covalent diatomic molecules (made up of C, N, O, or F) were evaluated. Finally, the compression/tension model was extended to the nuclear level, based on the observation that nuclei with certain numbers of protons/neutrons (magic numbers) have extra stability compared to other nucleon ratios. A hollow spherical model was developed that combines elements of the classic nuclear shell model and liquid drop model. Nuclear structure and the trend of the "island of stability" for the current and extended periodic table were studied.

Modeling a molecular initiating event to population effects: A case study of aromatase inhibition in fathead minnows

EPA Science Inventory

An adverse outcome pathway (AOP) conceptually links a molecular initiating event with measureable key events at higher levels of biological organization that ultimately result in an adverse outcome. Development of an AOP requires experimental data and scientific expertise to ide...

A molecular genetic model for the function of the Gametophyte Factor locus (ga1) in maize

USDA-ARS?s Scientific Manuscript database

The ga1 locus of maize confers unilateral cross incompatibility, preventing cross pollination between females carrying the incompatible allele and males not carrying a corresponding compatible allele. To characterize this system at the molecular level, we carried out a transcript profiling experime...

Coestimation of recombination, substitution and molecular adaptation rates by approximate Bayesian computation.

PubMed

Lopes, J S; Arenas, M; Posada, D; Beaumont, M A

2014-03-01

The estimation of parameters in molecular evolution may be biased when some processes are not considered. For example, the estimation of selection at the molecular level using codon-substitution models can have an upward bias when recombination is ignored. Here we address the joint estimation of recombination, molecular adaptation and substitution rates from coding sequences using approximate Bayesian computation (ABC). We describe the implementation of a regression-based strategy for choosing subsets of summary statistics for coding data, and show that this approach can accurately infer recombination allowing for intracodon recombination breakpoints, molecular adaptation and codon substitution rates. We demonstrate that our ABC approach can outperform other analytical methods under a variety of evolutionary scenarios. We also show that although the choice of the codon-substitution model is important, our inferences are robust to a moderate degree of model misspecification. In addition, we demonstrate that our approach can accurately choose the evolutionary model that best fits the data, providing an alternative for when the use of full-likelihood methods is impracticable. Finally, we applied our ABC method to co-estimate recombination, substitution and molecular adaptation rates from 24 published human immunodeficiency virus 1 coding data sets.

Exploring Conceptual Frameworks of Models of Atomic Structures and Periodic Variations, Chemical Bonding, and Molecular Shape and Polarity: A Comparison of Undergraduate General Chemistry Students with High and Low Levels of Content Knowledge

ERIC Educational Resources Information Center

Wang, Chia-Yu; Barrow, Lloyd H.

2013-01-01

The purpose of the study was to explore students' conceptual frameworks of models of atomic structure and periodic variations, chemical bonding, and molecular shape and polarity, and how these conceptual frameworks influence their quality of explanations and ability to shift among chemical representations. This study employed a purposeful sampling…

Ordinary differential equations with applications in molecular biology.

PubMed

Ilea, M; Turnea, M; Rotariu, M

2012-01-01

Differential equations are of basic importance in molecular biology mathematics because many biological laws and relations appear mathematically in the form of a differential equation. In this article we presented some applications of mathematical models represented by ordinary differential equations in molecular biology. The vast majority of quantitative models in cell and molecular biology are formulated in terms of ordinary differential equations for the time evolution of concentrations of molecular species. Assuming that the diffusion in the cell is high enough to make the spatial distribution of molecules homogenous, these equations describe systems with many participating molecules of each kind. We propose an original mathematical model with small parameter for biological phospholipid pathway. All the equations system includes small parameter epsilon. The smallness of epsilon is relative to the size of the solution domain. If we reduce the size of the solution region the same small epsilon will result in a different condition number. It is clear that the solution for a smaller region is less difficult. We introduce the mathematical technique known as boundary function method for singular perturbation system. In this system, the small parameter is an asymptotic variable, different from the independent variable. In general, the solutions of such equations exhibit multiscale phenomena. Singularly perturbed problems form a special class of problems containing a small parameter which may tend to zero. Many molecular biology processes can be quantitatively characterized by ordinary differential equations. Mathematical cell biology is a very active and fast growing interdisciplinary area in which mathematical concepts, techniques, and models are applied to a variety of problems in developmental medicine and bioengineering. Among the different modeling approaches, ordinary differential equations (ODE) are particularly important and have led to significant advances. Ordinary differential equations are used to model biological processes on various levels ranging from DNA molecules or biosynthesis phospholipids on the cellular level.

Molecular model for the diffusion of associating telechelic polymer networks

NASA Astrophysics Data System (ADS)

Ramirez, Jorge; Dursch, Thomas; Olsen, Bradley

Understanding the mechanisms of motion and stress relaxation of associating polymers at the molecular level is critical for advanced technological applications such as enhanced oil-recovery, self-healing materials or drug delivery. In associating polymers, the strength and rates of association/dissociation of the reversible physical crosslinks govern the dynamics of the network and therefore all the macroscopic properties, like self-diffusion and rheology. Recently, by means of forced Rayleigh scattering experiments, we have proved that associating polymers of different architectures show super-diffusive behavior when the free motion of single molecular species is slowed down by association/dissociation kinetics. Here we discuss a new molecular picture for unentangled associating telechelic polymers that considers concentration, molecular weight, number of arms of the molecules and equilibrium and rate constants of association/dissociation. The model predicts super-diffusive behavior under the right combination of values of the parameters. We discuss some of the predictions of the model using scaling arguments, show detailed results from Brownian dynamics simulations of the FRS experiments, and attempt to compare the predictions of the model to experimental data.

Interactions of beta-blockers with model lipid membranes: molecular view of the interaction of acebutolol, oxprenolol, and propranolol with phosphatidylcholine vesicles by time-dependent fluorescence shift and molecular dynamics simulations.

PubMed

Först, Gesche; Cwiklik, Lukasz; Jurkiewicz, Piotr; Schubert, Rolf; Hof, Martin

2014-08-01

Since pharmacokinetic and pharmacodynamic activities of drugs are often related to their interactions with biomembranes, it is of high interest to establish an approach for the characterization of these interactions at the molecular level. For the present study, beta-blockers (oxprenolol, propranolol, and acebutolol) were selected due to their well described nonspecific membrane effects (NME). Their interactions with model lipid membranes composed of palmitoyloleoylphosphatidylcholine (POPC) were studied using Time-Dependent Fluorescence Shift (TDFS) and Generalized Polarization (GP) as well as molecular dynamics (MD) simulations. Liposomal vesicles were labeled with fluorescent membrane polarity probes (Laurdan, Prodan, and Dtmac). Increasing beta-blocker concentrations (0-10 mM for acebutolol and oxprenolol, and 0-1.5 mM for propranolol) significantly rigidifies the lipid bilayer at the glycerol and headgroup level, which was detected in the steady-state and in the time-resolved fluorescence data. The effects of propranolol were considerably stronger than those of the two other beta-blockers. The addition of fluorescent probes precisely located at different levels within the lipid bilayer revealed the insertion of the beta-blockers into the POPC bilayer at the glycerol backbone level, which was further confirmed by MD simulations in the case of propranolol. Copyright © 2014 Elsevier B.V. All rights reserved.

Multi-Length Scale-Enriched Continuum-Level Material Model for Kevlar (registered trademark)-Fiber-Reinforced Polymer-Matrix Composites

DTIC Science & Technology

2013-03-01

of coarser-scale materials and structures containing Kevlar fibers (e.g., yarns, fabrics, plies, lamina, and laminates ). Journal of Materials...Multi-Length Scale-Enriched Continuum-Level Material Model for Kevlar -Fiber-Reinforced Polymer-Matrix Composites M. Grujicic, B. Pandurangan, J.S...extensive set of molecular-level computational analyses regarding the role of various microstructural/morphological defects on the Kevlar fiber

Molecular imaging with bioconjugates in mouse models of cancer.

PubMed

Mather, Stephen

2009-04-01

The definition of molecular imaging provided by the Society of Nuclear Medicine is "the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems". This review gives an overview of the technologies available for and the potential benefits from molecular imaging at the preclinical stage. It focuses on the use of imaging probes based on bioconjugates and for reasons of brevity confines itself to discussion of applications in the field of oncology, although molecular imaging can be equally useful in many fields including cardiovascular medicine, neurosciences, infection, and others.

Biological intuition in alignment-free methods: response to Posada.

PubMed

Ragan, Mark A; Chan, Cheong Xin

2013-08-01

A recent editorial in Journal of Molecular Evolution highlights opportunities and challenges facing molecular evolution in the era of next-generation sequencing. Abundant sequence data should allow more-complex models to be fit at higher confidence, making phylogenetic inference more reliable and improving our understanding of evolution at the molecular level. However, concern that approaches based on multiple sequence alignment may be computationally infeasible for large datasets is driving the development of so-called alignment-free methods for sequence comparison and phylogenetic inference. The recent editorial characterized these approaches as model-free, not based on the concept of homology, and lacking in biological intuition. We argue here that alignment-free methods have not abandoned models or homology, and can be biologically intuitive.

Two-bead polarizable water models combined with a two-bead multipole force field (TMFF) for coarse-grained simulation of proteins.

PubMed

Li, Min; Zhang, John Z H

2017-03-08

The development of polarizable water models at coarse-grained (CG) levels is of much importance to CG molecular dynamics simulations of large biomolecular systems. In this work, we combined the newly developed two-bead multipole force field (TMFF) for proteins with the two-bead polarizable water models to carry out CG molecular dynamics simulations for benchmark proteins. In our simulations, two different two-bead polarizable water models are employed, the RTPW model representing five water molecules by Riniker et al. and the LTPW model representing four water molecules. The LTPW model is developed in this study based on the Martini three-bead polarizable water model. Our simulation results showed that the combination of TMFF with the LTPW model significantly stabilizes the protein's native structure in CG simulations, while the use of the RTPW model gives better agreement with all-atom simulations in predicting the residue-level fluctuation dynamics. Overall, the TMFF coupled with the two-bead polarizable water models enables one to perform an efficient and reliable CG dynamics study of the structural and functional properties of large biomolecules.

Top-down models in biology: explanation and control of complex living systems above the molecular level.

PubMed

Pezzulo, Giovanni; Levin, Michael

2016-11-01

It is widely assumed in developmental biology and bioengineering that optimal understanding and control of complex living systems follows from models of molecular events. The success of reductionism has overshadowed attempts at top-down models and control policies in biological systems. However, other fields, including physics, engineering and neuroscience, have successfully used the explanations and models at higher levels of organization, including least-action principles in physics and control-theoretic models in computational neuroscience. Exploiting the dynamic regulation of pattern formation in embryogenesis and regeneration requires new approaches to understand how cells cooperate towards large-scale anatomical goal states. Here, we argue that top-down models of pattern homeostasis serve as proof of principle for extending the current paradigm beyond emergence and molecule-level rules. We define top-down control in a biological context, discuss the examples of how cognitive neuroscience and physics exploit these strategies, and illustrate areas in which they may offer significant advantages as complements to the mainstream paradigm. By targeting system controls at multiple levels of organization and demystifying goal-directed (cybernetic) processes, top-down strategies represent a roadmap for using the deep insights of other fields for transformative advances in regenerative medicine and systems bioengineering. © 2016 The Author(s).

Top-down models in biology: explanation and control of complex living systems above the molecular level

PubMed Central

2016-01-01

It is widely assumed in developmental biology and bioengineering that optimal understanding and control of complex living systems follows from models of molecular events. The success of reductionism has overshadowed attempts at top-down models and control policies in biological systems. However, other fields, including physics, engineering and neuroscience, have successfully used the explanations and models at higher levels of organization, including least-action principles in physics and control-theoretic models in computational neuroscience. Exploiting the dynamic regulation of pattern formation in embryogenesis and regeneration requires new approaches to understand how cells cooperate towards large-scale anatomical goal states. Here, we argue that top-down models of pattern homeostasis serve as proof of principle for extending the current paradigm beyond emergence and molecule-level rules. We define top-down control in a biological context, discuss the examples of how cognitive neuroscience and physics exploit these strategies, and illustrate areas in which they may offer significant advantages as complements to the mainstream paradigm. By targeting system controls at multiple levels of organization and demystifying goal-directed (cybernetic) processes, top-down strategies represent a roadmap for using the deep insights of other fields for transformative advances in regenerative medicine and systems bioengineering. PMID:27807271

Automated building of organometallic complexes from 3D fragments.

PubMed

Foscato, Marco; Venkatraman, Vishwesh; Occhipinti, Giovanni; Alsberg, Bjørn K; Jensen, Vidar R

2014-07-28

A method for the automated construction of three-dimensional (3D) molecular models of organometallic species in design studies is described. Molecular structure fragments derived from crystallographic structures and accurate molecular-level calculations are used as 3D building blocks in the construction of multiple molecular models of analogous compounds. The method allows for precise control of stereochemistry and geometrical features that may otherwise be very challenging, or even impossible, to achieve with commonly available generators of 3D chemical structures. The new method was tested in the construction of three sets of active or metastable organometallic species of catalytic reactions in the homogeneous phase. The performance of the method was compared with those of commonly available methods for automated generation of 3D models, demonstrating higher accuracy of the prepared 3D models in general, and, in particular, a much wider range with respect to the kind of chemical structures that can be built automatically, with capabilities far beyond standard organic and main-group chemistry.

The brain as a system of nested but partially overlapping networks. Heuristic relevance of the model for brain physiology and pathology.

PubMed

Agnati, L F; Guidolin, D; Fuxe, K

2007-01-01

A new model of the brain organization is proposed. The model is based on the assumption that a global molecular network enmeshes the entire central nervous system. Thus, brain extra-cellular and intra-cellular molecular networks are proposed to communicate at the level of special plasma membrane regions (e.g., the lipid rafts) where horizontal molecular networks can represent input/output regions allowing the cell to have informational exchanges with the extracellular environment. Furthermore, some "pervasive signals" such as field potentials, pressure waves and thermal gradients that affect large parts of the brain cellular and molecular networks are discussed. Finally, at least two learning paradigms are analyzed taking into account the possible role of Volume Transmission: the so-called model of "temporal difference learning" and the "Turing B-unorganised machine". The relevance of this new view of brain organization for a deeper understanding of some neurophysiological and neuropathological aspects of its function is briefly discussed.

Linking Adverse Outcome Pathways to Dynamic Energy Budgets: A Conceptual Model

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

Murphy, Cheryl; Nisbet, Roger; Antczak, Philipp

Ecological risk assessment quantifies the likelihood of undesirable impacts of stressors, primarily at high levels of biological organization. Data used to inform ecological risk assessments come primarily from tests on individual organisms or from suborganismal studies, indicating a disconnect between primary data and protection goals. We know how to relate individual responses to population dynamics using individual-based models, and there are emerging ideas on how to make connections to ecosystem services. However, there is no established methodology to connect effects seen at higher levels of biological organization with suborganismal dynamics, despite progress made in identifying Adverse Outcome Pathways (AOPs) thatmore » link molecular initiating events to ecologically relevant key events. This chapter is a product of a working group at the National Center for Mathematical and Biological Synthesis (NIMBioS) that assessed the feasibility of using dynamic energy budget (DEB) models of individual organisms as a “pivot” connecting suborganismal processes to higher level ecological processes. AOP models quantify explicit molecular, cellular or organ-level processes, but do not offer a route to linking sub-organismal damage to adverse effects on individual growth, reproduction, and survival, which can be propagated to the population level through individual-based models. DEB models describe these processes, but use abstract variables with undetermined connections to suborganismal biology. We propose linking DEB and quantitative AOP models by interpreting AOP key events as measures of damage-inducing processes in a DEB model. Here, we present a conceptual model for linking AOPs to DEB models and review existing modeling tools available for both AOP and DEB.« less

Protective effects of molecular hydrogen on steroid-induced osteonecrosis in rabbits via reducing oxidative stress and apoptosis.

PubMed

Li, Jia; Ge, Zhaogang; Fan, Lihong; Wang, Kunzheng

2017-02-02

The objective of this study was to investigate the protective effects of molecular hydrogen, a novel and selective antioxidant, on steroid-induced osteonecrosis (ON) in a rabbit model. Sixty rabbits were randomly divided into two groups (model group and hydrogen group). Osteonecrosis was induced according to an established protocol of steroid-induced ON. Rabbits in the hydrogen group were treated with intraperitoneal injections of molecular hydrogen at 10 ml/kg body weight for seven consecutive days. Plasma levels of total cholesterol, triglycerides, soluble thrombomodulin(sTM), glutathione(GSH) and malondialdehyde(MDA) were measured before and after steroid administration. The presence or absence of ON was examined histopathologically. Oxidative injury and vascular injury were assessed in vivo by immunohistochemical staining of 8-hydoxy-2-deoxyguanosine(8-OHdG) and MDA, and ink artery infusion angiography. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays were performed to measure apoptosis. The incidence of steroid-induced ON was significantly lower in hydrogen group (28.6%) than that in model group (68.0%). No statistically differences were observed on the levels of total cholesterol and triglycerides. Oxidative injury, vascular injury and apoptosis were attenuated in the hydrogen group compared with those in the model group in vivo. These results suggested that molecular hydrogen prevents steroid-induced osteonecrosis in rabbits by suppressing oxidative injury, vascular injury and apoptosis.

An autonomous molecular computer for logical control of gene expression.

PubMed

Benenson, Yaakov; Gil, Binyamin; Ben-Dor, Uri; Adar, Rivka; Shapiro, Ehud

2004-05-27

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.

FlyBase: genes and gene models

PubMed Central

Drysdale, Rachel A.; Crosby, Madeline A.

2005-01-01

FlyBase (http://flybase.org) is the primary repository of genetic and molecular data of the insect family Drosophilidae. For the most extensively studied species, Drosophila melanogaster, a wide range of data are presented in integrated formats. Data types include mutant phenotypes, molecular characterization of mutant alleles and aberrations, cytological maps, wild-type expression patterns, anatomical images, transgenic constructs and insertions, sequence-level gene models and molecular classification of gene product functions. There is a growing body of data for other Drosophila species; this is expected to increase dramatically over the next year, with the completion of draft-quality genomic sequences of an additional 11 Drosphila species. PMID:15608223

Extension of a Kinetic-Theory Approach for Computing Chemical-Reaction Rates to Reactions with Charged Particles

NASA Technical Reports Server (NTRS)

Liechty, Derek S.; Lewis, Mark J.

2010-01-01

Recently introduced molecular-level chemistry models that predict equilibrium and nonequilibrium reaction rates using only kinetic theory and fundamental molecular properties (i.e., no macroscopic reaction rate information) are extended to include reactions involving charged particles and electronic energy levels. The proposed extensions include ionization reactions, exothermic associative ionization reactions, endothermic and exothermic charge exchange reactions, and other exchange reactions involving ionized species. The extensions are shown to agree favorably with the measured Arrhenius rates for near-equilibrium conditions.

Hierarchical approaches for systems modeling in cardiac development.

PubMed

Gould, Russell A; Aboulmouna, Lina M; Varner, Jeffrey D; Butcher, Jonathan T

2013-01-01

Ordered cardiac morphogenesis and function are essential for all vertebrate life. The heart begins as a simple contractile tube, but quickly grows and morphs into a multichambered pumping organ complete with valves, while maintaining regulation of blood flow and nutrient distribution. Though not identical, cardiac morphogenesis shares many molecular and morphological processes across vertebrate species. Quantitative data across multiple time and length scales have been gathered through decades of reductionist single variable analyses. These range from detailed molecular signaling pathways at the cellular levels to cardiac function at the tissue/organ levels. However, none of these components act in true isolation from others, and each, in turn, exhibits short- and long-range effects in both time and space. With the absence of a gene, entire signaling cascades and genetic profiles may be shifted, resulting in complex feedback mechanisms. Also taking into account local microenvironmental changes throughout development, it is apparent that a systems level approach is an essential resource to accelerate information generation concerning the functional relationships across multiple length scales (molecular data vs physiological function) and structural development. In this review, we discuss relevant in vivo and in vitro experimental approaches, compare different computational frameworks for systems modeling, and the latest information about systems modeling of cardiac development. Finally, we conclude with some important future directions for cardiac systems modeling. Copyright © 2013 Wiley Periodicals, Inc.

Corresponding-states behavior of SPC/E-based modified (bent and hybrid) water models

NASA Astrophysics Data System (ADS)

Weiss, Volker C.

2017-02-01

The remarkable and sometimes anomalous properties of water can be traced back at the molecular level to the tetrahedral coordination of molecules due to the ability of a water molecule to form four hydrogen bonds to its neighbors; this feature allows for the formation of a network that greatly influences the thermodynamic behavior. Computer simulations are becoming increasingly important for our understanding of water. Molecular models of water, such as SPC/E, are needed for this purpose, and they have proved to capture many important features of real water. Modifications of the SPC/E model have been proposed, some changing the H-O-H angle (bent models) and others increasing the importance of dispersion interactions (hybrid models), to study the structural features that set water apart from other polar fluids and from simple fluids such as argon. Here, we focus on the properties at liquid-vapor equilibrium and study the coexistence curve, the interfacial tension, and the vapor pressure in a corresponding-states approach. In particular, we calculate Guggenheim's ratio for the reduced apparent enthalpy of vaporization and Guldberg's ratio for the reduced normal boiling point. This analysis offers additional insight from a more macroscopic, thermodynamic perspective and augments that which has already been learned at the molecular level from simulations. In the hybrid models, the relative importance of dispersion interactions is increased, which turns the modified water into a Lennard-Jones-like fluid. Consequently, in a corresponding-states framework, the typical behavior of simple fluids, such as argon, is seen to be approached asymptotically. For the bent models, decreasing the bond angle turns the model essentially into a polar diatomic fluid in which the particles form linear molecular arrangements; as a consequence, characteristic features of the corresponding-states behavior of hydrogen halides emerge.

Testing the Use of Implicit Solvent in the Molecular Dynamics Modelling of DNA Flexibility

NASA Astrophysics Data System (ADS)

Mitchell, J.; Harris, S.

DNA flexibility controls packaging, looping and in some cases sequence specific protein binding. Molecular dynamics simulations carried out with a computationally efficient implicit solvent model are potentially a powerful tool for studying larger DNA molecules than can be currently simulated when water and counterions are represented explicitly. In this work we compare DNA flexibility at the base pair step level modelled using an implicit solvent model to that previously determined from explicit solvent simulations and database analysis. Although much of the sequence dependent behaviour is preserved in implicit solvent, the DNA is considerably more flexible when the approximate model is used. In addition we test the ability of the implicit solvent to model stress induced DNA disruptions by simulating a series of DNA minicircle topoisomers which vary in size and superhelical density. When compared with previously run explicit solvent simulations, we find that while the levels of DNA denaturation are similar using both computational methodologies, the specific structural form of the disruptions is different.

Predictive Models of Liver Cancer

EPA Science Inventory

Predictive models of chemical-induced liver cancer face the challenge of bridging causative molecular mechanisms to adverse clinical outcomes. The latent sequence of intervening events from chemical insult to toxicity are poorly understood because they span multiple levels of bio...

The interface of protein structure, protein biophysics, and molecular evolution

PubMed Central

Liberles, David A; Teichmann, Sarah A; Bahar, Ivet; Bastolla, Ugo; Bloom, Jesse; Bornberg-Bauer, Erich; Colwell, Lucy J; de Koning, A P Jason; Dokholyan, Nikolay V; Echave, Julian; Elofsson, Arne; Gerloff, Dietlind L; Goldstein, Richard A; Grahnen, Johan A; Holder, Mark T; Lakner, Clemens; Lartillot, Nicholas; Lovell, Simon C; Naylor, Gavin; Perica, Tina; Pollock, David D; Pupko, Tal; Regan, Lynne; Roger, Andrew; Rubinstein, Nimrod; Shakhnovich, Eugene; Sjölander, Kimmen; Sunyaev, Shamil; Teufel, Ashley I; Thorne, Jeffrey L; Thornton, Joseph W; Weinreich, Daniel M; Whelan, Simon

2012-01-01

Abstract The interface of protein structural biology, protein biophysics, molecular evolution, and molecular population genetics forms the foundations for a mechanistic understanding of many aspects of protein biochemistry. Current efforts in interdisciplinary protein modeling are in their infancy and the state-of-the art of such models is described. Beyond the relationship between amino acid substitution and static protein structure, protein function, and corresponding organismal fitness, other considerations are also discussed. More complex mutational processes such as insertion and deletion and domain rearrangements and even circular permutations should be evaluated. The role of intrinsically disordered proteins is still controversial, but may be increasingly important to consider. Protein geometry and protein dynamics as a deviation from static considerations of protein structure are also important. Protein expression level is known to be a major determinant of evolutionary rate and several considerations including selection at the mRNA level and the role of interaction specificity are discussed. Lastly, the relationship between modeling and needed high-throughput experimental data as well as experimental examination of protein evolution using ancestral sequence resurrection and in vitro biochemistry are presented, towards an aim of ultimately generating better models for biological inference and prediction. PMID:22528593

MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

PubMed

Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

2011-03-01

Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A Molecular Imaging Data Grid design, implementation, and initial evaluation is presented to demonstrate the secure and novel data grid solution for sharing preclinical molecular imaging data across the wide-area-network (WAN).

Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles.

PubMed

Oh, Jung-Hwa; Son, Mi-Young; Choi, Mi-Sun; Kim, Soojin; Choi, A-Young; Lee, Hyang-Ae; Kim, Ki-Suk; Kim, Janghwan; Song, Chang Woo; Yoon, Seokjoo

2016-05-15

Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10-200μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

Towards a system level understanding of non-model organisms sampled from the environment: a network biology approach.

PubMed

Williams, Tim D; Turan, Nil; Diab, Amer M; Wu, Huifeng; Mackenzie, Carolynn; Bartie, Katie L; Hrydziuszko, Olga; Lyons, Brett P; Stentiford, Grant D; Herbert, John M; Abraham, Joseph K; Katsiadaki, Ioanna; Leaver, Michael J; Taggart, John B; George, Stephen G; Viant, Mark R; Chipman, Kevin J; Falciani, Francesco

2011-08-01

The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations.

Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

PubMed Central

Williams, Tim D.; Turan, Nil; Diab, Amer M.; Wu, Huifeng; Mackenzie, Carolynn; Bartie, Katie L.; Hrydziuszko, Olga; Lyons, Brett P.; Stentiford, Grant D.; Herbert, John M.; Abraham, Joseph K.; Katsiadaki, Ioanna; Leaver, Michael J.; Taggart, John B.; George, Stephen G.; Viant, Mark R.; Chipman, Kevin J.; Falciani, Francesco

2011-01-01

The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations. PMID:21901081

Dielectric properties of organic solvents from non-polarizable molecular dynamics simulation with electronic continuum model and density functional theory.

PubMed

Lee, Sanghun; Park, Sung Soo

2011-11-03

Dielectric constants of electrolytic organic solvents are calculated employing nonpolarizable Molecular Dynamics simulation with Electronic Continuum (MDEC) model and Density Functional Theory. The molecular polarizabilities are obtained by the B3LYP/6-311++G(d,p) level of theory to estimate high-frequency refractive indices while the densities and dipole moment fluctuations are computed using nonpolarizable MD simulations. The dielectric constants reproduced from these procedures are evaluated to provide a reliable approach for estimating the experimental data. An additional feature, two representative solvents which have similar molecular weights but are different dielectric properties, i.e., ethyl methyl carbonate and propylene carbonate, are compared using MD simulations and the distinctly different dielectric behaviors are observed at short times as well as at long times.

Transient Evolutional Dynamics of Quantum-Dot Molecular Phase Coherence for Sensitive Optical Switching

NASA Astrophysics Data System (ADS)

Shen, Jian Qi; Gu, Jing

2018-04-01

Atomic phase coherence (quantum interference) in a multilevel atomic gas exhibits a number of interesting phenomena. Such an atomic quantum coherence effect can be generalized to a quantum-dot molecular dielectric. Two quantum dots form a quantum-dot molecule, which can be described by a three-level Λ-configuration model { |0> ,|1> ,|2> } , i.e., the ground state of the molecule is the lower level |0> and the highly degenerate electronic states in the two quantum dots are the two upper levels |1> ,|2> . The electromagnetic characteristics due to the |0>-|1> transition can be controllably manipulated by a tunable gate voltage (control field) that drives the |2>-|1> transition. When the gate voltage is switched on, the quantum-dot molecular state can evolve from one steady state (i.e., |0>-|1> two-level dressed state) to another steady state (i.e., three-level coherent-population-trapping state). In this process, the electromagnetic characteristics of a quantum-dot molecular dielectric, which is modified by the gate voltage, will also evolve. In this study, the transient evolutional behavior of the susceptibility of a quantum-dot molecular thin film and its reflection spectrum are treated by using the density matrix formulation of the multilevel systems. The present field-tunable and frequency-sensitive electromagnetic characteristics of a quantum-dot molecular thin film, which are sensitive to the applied gate voltage, can be utilized to design optical switching devices.

Vitamin E models . The effect of heteroatom substitution in 2-ethyl-2-methyl chroman and 2-ethyl-2-methyl-6-hydroxychroman

NASA Astrophysics Data System (ADS)

Setiadi, D. H.; Chass, G. A.; Torday, L. L.; Varro, A.; Papp, J. Gy.; Csizmadia, I. G.

2002-09-01

The molecular conformations of shortened molecular models of vitamin E (tocopherol and tocotrienol) and their sulfur and selenium congeners were studied computationally at the DFT level of theory [B3LYP/6-31G(d)]. The sequence of stabilization by the various heteroatoms was found to be the following: O sim Se > S. On the basis of the present structural results it seems that the seleno-congener of vitamin E is a distinct possibility.

Coarse-Grained Molecular Simulation of the Hierarchical Self-Assembly of π-Conjugated Optoelectronic Peptides

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

Mansbach, Rachael A.; Ferguson, Andrew L.

Self-assembled aggregates of peptides containing aromatic groups possess optoelectronic properties that make them attractive targets for the fabrication of biocompatible electronics. Molecular-level understanding of how the microscopic peptide chemistry influences the properties of the aggregates is vital for rational peptide design. We construct a coarse-grained model of Asp-Phe-Ala-Gly-OPV3-Gly-Ala-Phe-Asp (DFAG-OPV3-GAFD) peptides containing OPV3 (distyrylbenzene) π-conjugated cores explicitly parameterized against all-atom calculations and perform molecular dynamics simulations of the self-assembly of hundreds of molecules over hundreds of nanoseconds. We observe a hierarchical assembly mechanism wherein ~2-8 peptides assemble into stacks with aligned aromatic cores that subsequently form elliptical aggregates and ultimately amore » branched network with a fractal dimensionality of ~1.5. The assembly dynamics are well described by a Smoluchowski coagulation process for which we extract rate constants from the molecular simulations to both furnish insight into the microscopic assembly kinetics and extrapolate our aggregation predictions to time and length scales beyond the reach of molecular simulation. Lastly, this study presents new molecular-level understanding of the morphology and dynamics of the spontaneous self-assembly of DFAG-OPV3-GAFD peptides and establishes a systematic protocol to develop coarse-grained models of optoelectronic peptides for the exploration and design of π-conjugated peptides with tunable optoelectronic properties.« less

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

2016-07-21

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

Coarse-Grained Molecular Simulation of the Hierarchical Self-Assembly of π-Conjugated Optoelectronic Peptides

DOE PAGES

Mansbach, Rachael A.; Ferguson, Andrew L.

2017-02-10

Self-assembled aggregates of peptides containing aromatic groups possess optoelectronic properties that make them attractive targets for the fabrication of biocompatible electronics. Molecular-level understanding of how the microscopic peptide chemistry influences the properties of the aggregates is vital for rational peptide design. We construct a coarse-grained model of Asp-Phe-Ala-Gly-OPV3-Gly-Ala-Phe-Asp (DFAG-OPV3-GAFD) peptides containing OPV3 (distyrylbenzene) π-conjugated cores explicitly parameterized against all-atom calculations and perform molecular dynamics simulations of the self-assembly of hundreds of molecules over hundreds of nanoseconds. We observe a hierarchical assembly mechanism wherein ~2-8 peptides assemble into stacks with aligned aromatic cores that subsequently form elliptical aggregates and ultimately amore » branched network with a fractal dimensionality of ~1.5. The assembly dynamics are well described by a Smoluchowski coagulation process for which we extract rate constants from the molecular simulations to both furnish insight into the microscopic assembly kinetics and extrapolate our aggregation predictions to time and length scales beyond the reach of molecular simulation. Lastly, this study presents new molecular-level understanding of the morphology and dynamics of the spontaneous self-assembly of DFAG-OPV3-GAFD peptides and establishes a systematic protocol to develop coarse-grained models of optoelectronic peptides for the exploration and design of π-conjugated peptides with tunable optoelectronic properties.« less

Simple model of a coherent molecular photocell

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

Ernzerhof, Matthias, E-mail: Matthias.Ernzerhof@UMontreal.ca; Bélanger, Marc-André; Mayou, Didier

2016-04-07

Electron transport in molecular electronic devices is often dominated by a coherent mechanism in which the wave function extends from the left contact over the molecule to the right contact. If the device is exposed to light, photon absorption in the molecule might occur, turning the device into a molecular photocell. The photon absorption promotes an electron to higher energy levels and thus modifies the electron transmission probability through the device. A model for such a molecular photocell is presented that minimizes the complexity of the problem while providing a non-trivial description of the device mechanism. In particular, the rolemore » of the molecule in the photocell is investigated. It is described within the Hückel method and the source-sink potential approach [F. Goyer, M. Ernzerhof, and M. Zhuang, J. Chem. Phys. 126, 144104 (2007)] is used to eliminate the contacts in favor of complex-valued potentials. Furthermore, the photons are explicitly incorporated into the model through a second-quantized field. This facilitates the description of the photon absorption process with a stationary state calculation, where eigenvalues and eigenvectors are determined. The model developed is applied to various generic molecular photocells.« less

Molecular structure of dextran sulphate sodium in aqueous environment

NASA Astrophysics Data System (ADS)

Yu, Miao; Every, Hayley A.; Jiskoot, Wim; Witkamp, Geert-Jan; Buijs, Wim

2018-03-01

Here we propose a 3D-molecular structural model for dextran sulphate sodium (DSS) in a neutral aqueous environment based on the results of a molecular modelling study. The DSS structure is dominated by the stereochemistry of the 1,6-linked α-glucose units and the presence of two sulphate groups on each α-glucose unit. The structure of DSS can be best described as a helix with various patterns of di-sulphate substitution on the glucose rings. The presence of a side chain does not alter the 3D-structure of the linear main chain much, but affects the overall spatial dimension of the polymer. The simulated polymers have a diameter similar to or in some cases even larger than model α-hemolysin nano-pores for macromolecule transport in many biological processes, indicating a size-limited translocation through such pores. All results of the molecular modelling study are in line with previously reported experimental data. This study establishes the three-dimensional structure of DSS and summarizes the spatial dimension of the polymer, serving as the basis for a better understanding on the molecular level of DSS-involved electrostatic interaction processes with biological components like proteins and cell pores.

Molecular Modeling of Nucleic Acid Structure: Electrostatics and Solvation

PubMed Central

Bergonzo, Christina; Galindo-Murillo, Rodrigo; Cheatham, Thomas E.

2014-01-01

This unit presents an overview of computer simulation techniques as applied to nucleic acid systems, ranging from simple in vacuo molecular modeling techniques to more complete all-atom molecular dynamics treatments that include an explicit representation of the environment. The third in a series of four units, this unit focuses on critical issues in solvation and the treatment of electrostatics. UNITS 7.5 & 7.8 introduced the modeling of nucleic acid structure at the molecular level. This included a discussion of how to generate an initial model, how to evaluate the utility or reliability of a given model, and ultimately how to manipulate this model to better understand the structure, dynamics, and interactions. Subject to an appropriate representation of the energy, such as a specifically parameterized empirical force field, the techniques of minimization and Monte Carlo simulation, as well as molecular dynamics (MD) methods, were introduced as means to sample conformational space for a better understanding of the relevance of a given model. From this discussion, the major limitations with modeling, in general, were highlighted. These are the difficult issues in sampling conformational space effectively—the multiple minima or conformational sampling problems—and accurately representing the underlying energy of interaction. In order to provide a realistic model of the underlying energetics for nucleic acids in their native environments, it is crucial to include some representation of solvation (by water) and also to properly treat the electrostatic interactions. These are discussed in detail in this unit. PMID:18428877

Molecular modeling of nucleic Acid structure: electrostatics and solvation.

PubMed

Bergonzo, Christina; Galindo-Murillo, Rodrigo; Cheatham, Thomas E

2014-12-19

This unit presents an overview of computer simulation techniques as applied to nucleic acid systems, ranging from simple in vacuo molecular modeling techniques to more complete all-atom molecular dynamics treatments that include an explicit representation of the environment. The third in a series of four units, this unit focuses on critical issues in solvation and the treatment of electrostatics. UNITS 7.5 & 7.8 introduced the modeling of nucleic acid structure at the molecular level. This included a discussion of how to generate an initial model, how to evaluate the utility or reliability of a given model, and ultimately how to manipulate this model to better understand its structure, dynamics, and interactions. Subject to an appropriate representation of the energy, such as a specifically parameterized empirical force field, the techniques of minimization and Monte Carlo simulation, as well as molecular dynamics (MD) methods, were introduced as a way of sampling conformational space for a better understanding of the relevance of a given model. This discussion highlighted the major limitations with modeling in general. When sampling conformational space effectively, difficult issues are encountered, such as multiple minima or conformational sampling problems, and accurately representing the underlying energy of interaction. In order to provide a realistic model of the underlying energetics for nucleic acids in their native environments, it is crucial to include some representation of solvation (by water) and also to properly treat the electrostatic interactions. These subjects are discussed in detail in this unit. Copyright © 2014 John Wiley & Sons, Inc.

Hands on Group Work Paper Model for Teaching DNA Structure, Central Dogma and Recombinant DNA

ERIC Educational Resources Information Center

Altiparmak, Melek; Nakiboglu Tezer, Mahmure

2009-01-01

Understanding life on a molecular level is greatly enhanced when students are given the opportunity to visualize the molecules. Especially understanding DNA structure and function is essential for understanding key concepts of molecular biology such as DNA, central dogma and the manipulation of DNA. Researches have shown that undergraduate…

Spectral characterization and surface complexation modeling of low molecular weight organics on hematite nanoparticles: Role of electrolytes in the binding mechanism

USDA-ARS?s Scientific Manuscript database

Given the ubiquity of organic-metal oxide interfaces in environmental and medical systems, it is incumbent to obtain mechanistic details at the molecular level from experimental procedures that mimic real systems and conditions. We report herein the adsorption pH envelopes (range 9-5) and isotherms...

Growth of beta-MnO2 Films on TiO2(110) by Oxygen-Plasma-Assisted Molecular Beam Epitaxy

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

Chambers, Scott A.; Liang, Yong

Discusses the essential need to understand the heterogeneous chemistry of mineral surfaces at a molecular level for accurate modeling of surface complexion processes in natural environments. Describes the first MBE growth and characterization of ultrathin films of B-MnO2 on TiO2 (110).

Using Molecular Visualization to Explore Protein Structure and Function and Enhance Student Facility with Computational Tools

ERIC Educational Resources Information Center

Terrell, Cassidy R.; Listenberger, Laura L.

2017-01-01

Recognizing that undergraduate students can benefit from analysis of 3D protein structure and function, we have developed a multiweek, inquiry-based molecular visualization project for Biochemistry I students. This project uses a virtual model of cyclooxygenase-1 (COX-1) to guide students through multiple levels of protein structure analysis. The…

Macro and micro analysis of small molecule diffusion in amorphous polymers

NASA Astrophysics Data System (ADS)

Putta, Santosh Krishna

In this study, both macroscopic and microscopic numerical techniques have been explored, to model and understand the diffusion behavior of small molecules in amorphous polymers, which very often do not follow the classical Fickian law. It was attempted to understand the influence of various aspects of the molecular structure of a polymer on its macroscopic diffusion behavior. At the macroscopic level, a hybrid finite-element/finite-difference model is developed to implement the coupled diffusion and deformation constitutive equations. A viscoelasticity theory, combined with time-freevolume superposition is used to model the deformation processes. A freevolume-based model is used to model the diffusion processes. The freevolume in the polymer is used as a coupling factor between the deformation and the diffusion processes. The model is shown to qualitatively describe some of the typical non-Fickian diffusion behavior in polymers. However, it does not directly involve the microstructure of a polymer. Further, some of the input parameters to the model are difficult to obtain experimentally. A numerical microscopic approach is therefore adopted to study the molecular structure of polymers. A molecular mechanics and dynamics technique combined with a modified Rotational Isomeric State (RIS) approach, is followed to generate the molecular structure for two types of polycarbonates, and, two types of polyacrylates, starting only with their chemical structures. A new efficient 3-D algorithm for Delaunay Tessellation is developed, and, then applied to discretize the molecular structure into Delaunay Tetrahedra. By using the dicretized molecular structure, size, shape, and, connectivity of free-spaces for small molecule diffusion in the above mentioned polymers, are then studied in relation to their diffusion properties. The influence of polymer and side chain flexibility, and diffusant-diffusant and diffusant-polymer molecular interactions, is also discussed with respect to the diffusion properties.

Mixed QM/MM molecular electrostatic potentials.

PubMed

Hernández, B; Luque, F J; Orozco, M

2000-05-01

A new method is presented for the calculation of the Molecular Electrostatic Potential (MEP) in large systems. Based on the mixed Quantum Mechanics/Molecular Mechanics (QM/MM) approach, the method assumes both a quantum and classical description for the molecule, and the calculation of the MEP in the space surrounding the molecule is made using this dual treatment. The MEP at points close to the molecule is computed using a full QM formalism, while a pure classical evaluation of the MEP is used for points located at large distances from the molecule. The algorithm allows the user to select the desired level of accuracy in the MEP, so that the definition of the regions where the MEP is computed at the classical or QM levels is adjusted automatically. The potential use of this QM/MM MEP in molecular modeling studies is discussed.

Multi-scale lung modeling.

PubMed

Tawhai, Merryn H; Bates, Jason H T

2011-05-01

Multi-scale modeling of biological systems has recently become fashionable due to the growing power of digital computers as well as to the growing realization that integrative systems behavior is as important to life as is the genome. While it is true that the behavior of a living organism must ultimately be traceable to all its components and their myriad interactions, attempting to codify this in its entirety in a model misses the insights gained from understanding how collections of system components at one level of scale conspire to produce qualitatively different behavior at higher levels. The essence of multi-scale modeling thus lies not in the inclusion of every conceivable biological detail, but rather in the judicious selection of emergent phenomena appropriate to the level of scale being modeled. These principles are exemplified in recent computational models of the lung. Airways responsiveness, for example, is an organ-level manifestation of events that begin at the molecular level within airway smooth muscle cells, yet it is not necessary to invoke all these molecular events to accurately describe the contraction dynamics of a cell, nor is it necessary to invoke all phenomena observable at the level of the cell to account for the changes in overall lung function that occur following methacholine challenge. Similarly, the regulation of pulmonary vascular tone has complex origins within the individual smooth muscle cells that line the blood vessels but, again, many of the fine details of cell behavior average out at the level of the organ to produce an effect on pulmonary vascular pressure that can be described in much simpler terms. The art of multi-scale lung modeling thus reduces not to being limitlessly inclusive, but rather to knowing what biological details to leave out.

Molecular dynamics simulations on discoidal HDL particles suggest a mechanism for rotation in the apo A-I belt model.

PubMed

Klon, Anthony E; Segrest, Jere P; Harvey, Stephen C

2002-12-06

Apolipoprotein A-I (apo A-I) is the major protein component of high-density lipoprotein (HDL) particles. Elevated levels of HDL in the bloodstream have been shown to correlate strongly with a reduced risk factor for atherosclerosis. Molecular dynamics simulations have been carried out on three separate model discoidal high-density lipoprotein particles (HDL) containing two monomers of apo A-I and 160 molecules of palmitoyloleoylphosphatidylcholine (POPC), to a time-scale of 1ns. The starting structures were on the basis of previously published molecular belt models of HDL consisting of the lipid-binding C-terminal domain (residues 44-243) wrapped around the circumference of a discoidal HDL particle. Subtle changes between two of the starting structures resulted in significantly different behavior during the course of the simulation. The results provide support for the hypothesis of Segrest et al. that helical registration in the molecular belt model of apo A-I is modulated by intermolecular salt bridges. In addition, we propose an explanation for the presence of proline punctuation in the molecular belt model, and for the presence of two 11-mer helical repeats interrupting the otherwise regular pattern of 22-mer helical repeats in the lipid-binding domain of apo A-I.

Sketching the Invisible to Predict the Visible: From Drawing to Modeling in Chemistry.

PubMed

Cooper, Melanie M; Stieff, Mike; DeSutter, Dane

2017-10-01

Sketching as a scientific practice goes beyond the simple act of inscribing diagrams onto paper. Scientists produce a wide range of representations through sketching, as it is tightly coupled to model-based reasoning. Chemists in particular make extensive use of sketches to reason about chemical phenomena and to communicate their ideas. However, the chemical sciences have a unique problem in that chemists deal with the unseen world of the atomic-molecular level. Using sketches, chemists strive to develop causal mechanisms that emerge from the structure and behavior of molecular-level entities, to explain observations of the macroscopic visible world. Interpreting these representations and constructing sketches of molecular-level processes is a crucial component of student learning in the modern chemistry classroom. Sketches also serve as an important component of assessment in the chemistry classroom as student sketches give insight into developing mental models, which allows instructors to observe how students are thinking about a process. In this paper we discuss how sketching can be used to promote such model-based reasoning in chemistry and discuss two case studies of curricular projects, CLUE and The Connected Chemistry Curriculum, that have demonstrated a benefit of this approach. We show how sketching activities can be centrally integrated into classroom norms to promote model-based reasoning both with and without component visualizations. Importantly, each of these projects deploys sketching in support of other types of inquiry activities, such as making predictions or depicting models to support a claim; sketching is not an isolated activity but is used as a tool to support model-based reasoning in the discipline. Copyright © 2017 Cognitive Science Society, Inc.

COMPUTATIONAL MODELING OF SIGNALING PATHWAYS MEDIATING CELL CYCLE AND APOPTOTIC RESPONSES TO IONIZING RADIATION MEDIATED DNA DAMAGE

EPA Science Inventory

Demonstrated of the use of a computational systems biology approach to model dose response relationships. Also discussed how the biologically motivated dose response models have only limited reference to the underlying molecular level. Discussed the integration of Computational S...

Exploring Solid-State Structure and Physical Properties: A Molecular and Crystal Model Exercise

ERIC Educational Resources Information Center

Bindel, Thomas H.

2008-01-01

A crystal model laboratory exercise is presented that allows students to examine relations among the microscopic-macroscopic-symbolic levels, using crystalline mineral samples and corresponding crystal models. Students explore the relationship between solid-state structure and crystal form. Other structure-property relationships are explored. The…

A stochastic thermostat algorithm for coarse-grained thermomechanical modeling of large-scale soft matters: Theory and application to microfilaments

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

Li, Tong; Gu, YuanTong, E-mail: yuantong.gu@qut.edu.au

As all-atom molecular dynamics method is limited by its enormous computational cost, various coarse-grained strategies have been developed to extend the length scale of soft matters in the modeling of mechanical behaviors. However, the classical thermostat algorithm in highly coarse-grained molecular dynamics method would underestimate the thermodynamic behaviors of soft matters (e.g. microfilaments in cells), which can weaken the ability of materials to overcome local energy traps in granular modeling. Based on all-atom molecular dynamics modeling of microfilament fragments (G-actin clusters), a new stochastic thermostat algorithm is developed to retain the representation of thermodynamic properties of microfilaments at extra coarse-grainedmore » level. The accuracy of this stochastic thermostat algorithm is validated by all-atom MD simulation. This new stochastic thermostat algorithm provides an efficient way to investigate the thermomechanical properties of large-scale soft matters.« less

Advances and challenges in logical modeling of cell cycle regulation: perspective for multi-scale, integrative yeast cell models

PubMed Central

Todd, Robert G.; van der Zee, Lucas

2016-01-01

Abstract The eukaryotic cell cycle is robustly designed, with interacting molecules organized within a definite topology that ensures temporal precision of its phase transitions. Its underlying dynamics are regulated by molecular switches, for which remarkable insights have been provided by genetic and molecular biology efforts. In a number of cases, this information has been made predictive, through computational models. These models have allowed for the identification of novel molecular mechanisms, later validated experimentally. Logical modeling represents one of the youngest approaches to address cell cycle regulation. We summarize the advances that this type of modeling has achieved to reproduce and predict cell cycle dynamics. Furthermore, we present the challenge that this type of modeling is now ready to tackle: its integration with intracellular networks, and its formalisms, to understand crosstalks underlying systems level properties, ultimate aim of multi-scale models. Specifically, we discuss and illustrate how such an integration may be realized, by integrating a minimal logical model of the cell cycle with a metabolic network. PMID:27993914

Molecular structure of the lecithin ripple phase

NASA Astrophysics Data System (ADS)

de Vries, Alex H.; Yefimov, Serge; Mark, Alan E.; Marrink, Siewert J.

2005-04-01

Molecular dynamics simulations of lecithin lipid bilayers in water as they are cooled from the liquid crystalline phase show the spontaneous formation of rippled bilayers. The ripple consists of two domains of different length and orientation, connected by a kink. The organization of the lipids in one domain of the ripple is found to be that of a splayed gel; in the other domain the lipids are gel-like and fully interdigitated. In the concave part of the kink region between the domains the lipids are disordered. The results are consistent with the experimental information available and provide an atomic-level model that may be tested by further experiments. molecular dynamics simulation | structural model

Synthesis and CV Studies of Dithiol-terminated Metal Terpyridine Complexes

NASA Technical Reports Server (NTRS)

Asano, Sylvia; Fan, Wendy; Ng, Hou-Tee; Han, Jie; Meyyappan, M.

2003-01-01

Transition metal coordination complexes possess unique electronic structures that should be a good model for studying electronic transport behavior at a molecular level. The discrete, multiple redox states, low redox potential and the superb ability to establish contact with other molecular and electronic components by coordination chemistry have made this a subject of investigation for their possible application as active electronic components in molecular devices. We present the synthesis and electrochemical characterization of 4'-thioacetylphenyl-2'2:6',2"-terpyridine iron(II) complex and compare it with a model bis-terpyridine iron(II) complex by cyclic voltammetry. With the use of different working electrodes, the behavior of these complexes show different electron transfer rates.

Theoretical Studies for Dendrimer-Based Drug Delivery.

PubMed

Bello, Martiniano; Fragoso-Vázquez, Jonathan; Correa-Basurto, José

2017-01-01

Numerous theoretical studies have been performed to iteratively optimize the physicochemical properties such as dendrimer size and surface constituents in solution, as well as their molecular recognition properties for drugs, lipid membranes, nucleic acids and proteins, etc. Molecular modeling approaches such as docking and molecular dynamic (MD) simulations have supported experimental efforts by providing important insights into the structural properties of dendrimers in solution and possible binding properties of drugs at the atomic level. We review the utilization of molecular modelling tools to obtain insight into the study and design of dendrimers, with particular importance placed on the improvement of binding properties of dendrimers for their use as drug nanocarriers and to increase the water solubility properties and drug delivery. The modeling studies discussed in this review have provided substantial insight into the physicochemical properties of dendrimers in solution, including solvent pH and counterion distribution, at the atomic level, as well as the elucidation of some of the key interactions in solution of unmodified and modified dendrimers with some drugs of pharmaceutics interest and biological systems such as nucleic acids, proteins and lipid membranes. the described studies illustrate that whether simulations will be run at the all-atom or coarse-grained level, physicochemical conditions such as the type of force field, the treatment of electrostatics effects, counterion distribution, protonation state of dendrimers, and dendrimer concentrations which have been probed to play a crucial role in the structural behavior and binding properties must be prudently incorporated in the simulations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of Material Ion Exchanges on the Mechanical Stiffness Properties and Shear Deformation of Hydrated Cement Material Chemistry Structure C-S-H Jennite -- A Computational Modeling Study

NASA Astrophysics Data System (ADS)

Adebiyi, Babatunde Mattew

Material properties and performance are governed by material molecular chemistry structures and molecular level interactions. Methods to understand relationships between the material properties and performance and their correlation to the molecular level chemistry and morphology, and thus find ways of manipulating and adjusting matters at the atomistic level in order to improve material performance, are required. A computational material modeling methodology is investigated and demonstrated for a key cement hydrated component material chemistry structure of Calcium-Silicate-Hydrate (C-S-H) Jennite in this work. The effect of material ion exchanges on the mechanical stiffness properties and shear deformation behavior of hydrated cement material chemistry structure of Calcium Silicate Hydrate (C-S-H) Jennite was studied. Calcium ions were replaced with Magnesium ions in Jennite structure of the C-S-H gel. Different level of substitution of the ions was used. The traditional Jennite structure was obtained from the American Mineralogist Crystal Structure Database and super cells of the structures were created using a Molecular Dynamics Analyzer and Visualizer Material Studio. Molecular dynamics parameters used in the modeling analysis were determined by carrying out initial dynamic studies. 64 unit cell of C-S-H Jennite was used in material modeling analysis studies based on convergence results obtained from the elastic modulus and total energies. NVT forcite dynamics using COMPASS force field based on 200 ps dynamics time was used to determine mechanical modulus of the traditional C-S-H gel and the Magnesium ion modified structures. NVT Discover dynamics using COMPASS forcefield was used in the material modeling studies to investigate the influence of ionic exchange on the shear deformation of the associated material chemistry structures. A prior established quasi-static deformation method to emulate shear deformation of C-S-H material chemistry structure that is based on a triclinic crystal structure was used, by deforming the triclinic crystal structure at 0.2 degree per time step for 75 steps of deformation. It was observed that there is a decrease in the total energies of the systems as the percentage of magnesium ion increases in the C-S-H Jennite molecular structure systems. Investigation of effect of ion exchange on the elastic modulus shows that the elastic stiffness modulus tends to decrease as the amount of Mg in the systems increases, using either COMPASS or universal force field. On the other hand, shear moduli obtained after deforming the structures computed from the stress-strain curve obtained from material modeling increases as the amount of Mg increases in the system. The present investigations also showed that ultimate shear stress obtained from predicted shear stress---strain also increases with amount of Mg in the chemistry structure. Present study clearly demonstrates that computational material modeling following molecular dynamics analysis methodology is an effective way to predict and understand the effective material chemistry and additive changes on the stiffness and deformation characteristics in cementitious materials, and the results suggest that this method can be extended to other materials.

A molecular dynamics study of polymer/graphene interfacial systems

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

Rissanou, Anastassia N.; Harmandaris, Vagelis

2014-05-15

Graphene based polymer nanocomposites are hybrid materials with a very broad range of technological applications. In this work, we study three hybrid polymer/graphene interfacial systems (polystyrene/graphene, poly(methyl methacrylate)/graphene and polyethylene/graphene) through detailed atomistic molecular dynamics (MD) simulations. Density profiles, structural characteristics and mobility aspects are being examined at the molecular level for all model systems. In addition, we compare the properties of the hybrid systems to the properties of the corresponding bulk ones, as well as to theoretical predictions.

Characterization of the Host Response to Pichinde Virus Infection in the Syrian Golden Hamster by Species-Specific Kinome Analysis*

PubMed Central

Falcinelli, Shane; Gowen, Brian B.; Trost, Brett; Napper, Scott; Kusalik, Anthony; Johnson, Reed F.; Safronetz, David; Prescott, Joseph; Wahl-Jensen, Victoria; Jahrling, Peter B.; Kindrachuk, Jason

2015-01-01

The Syrian golden hamster has been increasingly used to study viral hemorrhagic fever (VHF) pathogenesis and countermeasure efficacy. As VHFs are a global health concern, well-characterized animal models are essential for both the development of therapeutics and vaccines as well as for increasing our understanding of the molecular events that underlie viral pathogenesis. However, the paucity of reagents or platforms that are available for studying hamsters at a molecular level limits the ability to extract biological information from this important animal model. As such, there is a need to develop platforms/technologies for characterizing host responses of hamsters at a molecular level. To this end, we developed hamster-specific kinome peptide arrays to characterize the molecular host response of the Syrian golden hamster. After validating the functionality of the arrays using immune agonists of defined signaling mechanisms (lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α), we characterized the host response in a hamster model of VHF based on Pichinde virus (PICV1) infection by performing temporal kinome analysis of lung tissue. Our analysis revealed key roles for vascular endothelial growth factor (VEGF), interleukin (IL) responses, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and Toll-like receptor (TLR) signaling in the response to PICV infection. These findings were validated through phosphorylation-specific Western blot analysis. Overall, we have demonstrated that hamster-specific kinome arrays are a robust tool for characterizing the species-specific molecular host response in a VHF model. Further, our results provide key insights into the hamster host response to PICV infection and will inform future studies with high-consequence VHF pathogens. PMID:25573744

Molecular Mechanisms and Modeling of Skin Irritation from JP-8

DTIC Science & Technology

2006-03-01

levels of performance than shallow levels of processing ( Craik & Lockhart , 1972). Deeper levels of processing focus on the meaning of...of group processes for decision- making. New York: John Wiley & Sons. Craik , F.I.M., & Lockhart , R.S. (1972). Levels of processing : A framework for...has been demonstrated to result in differential levels of memory performance ( Craik & Lockhart , 1972). If the objective is to store

A Simplified Model of Local Structure in Aqueous Proline Amino Acid Revealed by First-Principles Molecular Dynamics Simulations

PubMed Central

Troitzsch, Raphael Z.; Tulip, Paul R.; Crain, Jason; Martyna, Glenn J.

2008-01-01

Aqueous proline solutions are deceptively simple as they can take on complex roles such as protein chaperones, cryoprotectants, and hydrotropic agents in biological processes. Here, a molecular level picture of proline/water mixtures is developed. Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations of aqueous proline amino acid at the B-LYP level of theory, performed using IBM's Blue Gene/L supercomputer and massively parallel software, reveal hydrogen-bonding propensities that are at odds with the predictions of the CHARMM22 empirical force field but are in better agreement with results of recent neutron diffraction experiments. In general, the CPAIMD (B-LYP) simulations predict a simplified structural model of proline/water mixtures consisting of fewer distinct local motifs. Comparisons of simulation results to experiment are made by direct evaluation of the neutron static structure factor S(Q) from CPAIMD (B-LYP) trajectories as well as to the results of the empirical potential structure refinement reverse Monte Carlo procedure applied to the neutron data. PMID:18790850

A simplified model of local structure in aqueous proline amino acid revealed by first-principles molecular dynamics simulations.

PubMed

Troitzsch, Raphael Z; Tulip, Paul R; Crain, Jason; Martyna, Glenn J

2008-12-01

Aqueous proline solutions are deceptively simple as they can take on complex roles such as protein chaperones, cryoprotectants, and hydrotropic agents in biological processes. Here, a molecular level picture of proline/water mixtures is developed. Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations of aqueous proline amino acid at the B-LYP level of theory, performed using IBM's Blue Gene/L supercomputer and massively parallel software, reveal hydrogen-bonding propensities that are at odds with the predictions of the CHARMM22 empirical force field but are in better agreement with results of recent neutron diffraction experiments. In general, the CPAIMD (B-LYP) simulations predict a simplified structural model of proline/water mixtures consisting of fewer distinct local motifs. Comparisons of simulation results to experiment are made by direct evaluation of the neutron static structure factor S(Q) from CPAIMD (B-LYP) trajectories as well as to the results of the empirical potential structure refinement reverse Monte Carlo procedure applied to the neutron data.

Behavior of sphingomyelin and ceramide in a tear film lipid layer model.

PubMed

Olżyńska, Agnieszka; Cwiklik, Lukasz

2017-03-01

Tear film lipid layer is a complex lipid mixture forming the outermost interface between eye and environment. Its key characteristics, such as surface tension and structural stability, are governed by the presence of polar lipids. The origin of these lipids and exact composition of the mixture are still elusive. We focus on two minor polar lipid components of the tear film lipid later: sphingomyelin and ceramide. By employing coarse grain molecular dynamics in silico simulations accompanied by Langmuir balance experiments we provide molecular-level insight into behavior of these two lipids in a tear film lipid layer model. Sphingomyelin headgroups are significantly exposed at the water-lipids boundary while ceramide molecules are incorporated between other lipids frequently interacting with nonpolar lipids. Even though these two lipids increase surface tension of the film, their molecular-level behavior suggests that they have a stabilizing effect on the tear film lipid layer. Copyright © 2016 Elsevier GmbH. All rights reserved.

Enhanced mechanical properties of graphene/copper nanocomposites using a molecular-level mixing process.

PubMed

Hwang, Jaewon; Yoon, Taeshik; Jin, Sung Hwan; Lee, Jinsup; Kim, Taek-Soo; Hong, Soon Hyung; Jeon, Seokwoo

2013-12-10

RGO flakes are homogeneously dispersed in a Cu matrix through a molecular-level mixing process. This novel fabrication process prevents the agglomeration of the RGO and enhances adhesion between the RGO and the Cu. The yield strength of the 2.5 vol% RGO/Cu nanocomposite is 1.8 times higher than that of pure Cu. The strengthening mechanism of the RGO is investigated by a double cantilever beam test using the graphene/Cu model structure. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure and dynamics of human vimentin intermediate filament dimer and tetramer in explicit and implicit solvent models.

PubMed

Qin, Zhao; Buehler, Markus J

2011-01-01

Intermediate filaments, in addition to microtubules and microfilaments, are one of the three major components of the cytoskeleton in eukaryotic cells, and play an important role in mechanotransduction as well as in providing mechanical stability to cells at large stretch. The molecular structures, mechanical and dynamical properties of the intermediate filament basic building blocks, the dimer and the tetramer, however, have remained elusive due to persistent experimental challenges owing to the large size and fibrillar geometry of this protein. We have recently reported an atomistic-level model of the human vimentin dimer and tetramer, obtained through a bottom-up approach based on structural optimization via molecular simulation based on an implicit solvent model (Qin et al. in PLoS ONE 2009 4(10):e7294, 9). Here we present extensive simulations and structural analyses of the model based on ultra large-scale atomistic-level simulations in an explicit solvent model, with system sizes exceeding 500,000 atoms and simulations carried out at 20 ns time-scales. We report a detailed comparison of the structural and dynamical behavior of this large biomolecular model with implicit and explicit solvent models. Our simulations confirm the stability of the molecular model and provide insight into the dynamical properties of the dimer and tetramer. Specifically, our simulations reveal a heterogeneous distribution of the bending stiffness along the molecular axis with the formation of rather soft and highly flexible hinge-like regions defined by non-alpha-helical linker domains. We report a comparison of Ramachandran maps and the solvent accessible surface area between implicit and explicit solvent models, and compute the persistence length of the dimer and tetramer structure of vimentin intermediate filaments for various subdomains of the protein. Our simulations provide detailed insight into the dynamical properties of the vimentin dimer and tetramer intermediate filament building blocks, which may guide the development of novel coarse-grained models of intermediate filaments, and could also help in understanding assembly mechanisms.

An autonomous molecular computer for logical control of gene expression

PubMed Central

Benenson, Yaakov; Gil, Binyamin; Ben-Dor, Uri; Adar, Rivka; Shapiro, Ehud

2013-01-01

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems1–7. Recently, simple molecular-scale autonomous programmable computers were demonstrated8–15 allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for ‘logical’ control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton12–17; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes18–22 associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug. PMID:15116117

New insights into heat induced structural changes of pectin methylesterase on fluorescence spectroscopy and molecular modeling basis

NASA Astrophysics Data System (ADS)

Nistor, Oana Viorela; Stănciuc, Nicoleta; Aprodu, Iuliana; Botez, Elisabeta

2014-07-01

Heat-induced structural changes of Aspergillus oryzae pectin methylesterase (PME) were studied by means of fluorescence spectroscopy and molecular modeling, whereas the functional enzyme stability was monitored by inactivation studies. The fluorescence spectroscopy experiments were performed at two pH value (4.5 and 7.0). At both pH values, the phase diagrams were linear, indicating the presence of two molecular species induced by thermal treatment. A red shift of 7 nm was observed at neutral pH by increasing temperature up to 60 °C, followed by a blue shift of 4 nm at 70 °C, suggesting significant conformational rearrangements. The quenching experiments using acrylamide and iodide demonstrate a more flexible conformation of enzyme with increasing temperature, especially at neutral pH. The experimental results were complemented with atomic level observations on PME model behavior after performing molecular dynamics simulations at different temperatures. The inactivation kinetics of PME in buffer solutions was fitted using a first-order kinetics model, resulting in activation energy of 241.4 ± 7.51 kJ mol-1.

Communication: Understanding molecular representations in machine learning: The role of uniqueness and target similarity

NASA Astrophysics Data System (ADS)

Huang, Bing; von Lilienfeld, O. Anatole

2016-10-01

The predictive accuracy of Machine Learning (ML) models of molecular properties depends on the choice of the molecular representation. Inspired by the postulates of quantum mechanics, we introduce a hierarchy of representations which meet uniqueness and target similarity criteria. To systematically control target similarity, we simply rely on interatomic many body expansions, as implemented in universal force-fields, including Bonding, Angular (BA), and higher order terms. Addition of higher order contributions systematically increases similarity to the true potential energy and predictive accuracy of the resulting ML models. We report numerical evidence for the performance of BAML models trained on molecular properties pre-calculated at electron-correlated and density functional theory level of theory for thousands of small organic molecules. Properties studied include enthalpies and free energies of atomization, heat capacity, zero-point vibrational energies, dipole-moment, polarizability, HOMO/LUMO energies and gap, ionization potential, electron affinity, and electronic excitations. After training, BAML predicts energies or electronic properties of out-of-sample molecules with unprecedented accuracy and speed.

Therapeutic Approaches for Shankopathies

PubMed Central

Wang, Xiaoming; Bey, Alexandra; Chang, Leeyup; Krystal, Andrew D.; Jiang, Yong-hui

2013-01-01

Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANKs as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function. PMID:23536326

On the widths of Stokes lines in Raman scattering from molecules adsorbed at metal surfaces and in molecular conduction junctions

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

Gao, Yi, E-mail: yig057@ucsd.edu; Galperin, Michael, E-mail: migalperin@ucsd.edu; Nitzan, Abraham, E-mail: nitzan@post.tau.ac.il

Within a generic model we analyze the Stokes linewidth in surface enhanced Raman scattering (SERS) from molecules embedded as bridges in molecular junctions. We identify four main contributions to the off-resonant Stokes signal and show that under zero voltage bias (a situation pertaining also to standard SERS experiments) and at low bias junctions only one of these contributions is pronounced. The linewidth of this component is determined by the molecular vibrational relaxation rate, which is dominated by interactions with the essentially bosonic thermal environment when the relevant molecular electronic energy is far from the metal(s) Fermi energy(ies). It increases whenmore » the molecular electronic level is close to the metal Fermi level so that an additional vibrational relaxation channel due to electron-hole (eh) exciton in the molecule opens. Other contributions to the Raman signal, of considerably broader linewidths, can become important at larger junction bias.« less

A challenge for green chemistry: designing molecules that readily dissolve in carbon dioxide.

PubMed

Beckman, E J

2004-09-07

Carbon dioxide is a green yet feeble solvent whose full potential won't be realized until we develop a more thorough understanding of its solvent behavior at the molecular level. Fortunately, advances in molecular modeling coupled with experiments are rapidly improving our understanding of CO(2)'s behavior, permitting design of new, more sustainable "CO(2)-philes".

Control mechanisms for stochastic biochemical systems via computation of reachable sets.

PubMed

Lakatos, Eszter; Stumpf, Michael P H

2017-08-01

Controlling the behaviour of cells by rationally guiding molecular processes is an overarching aim of much of synthetic biology. Molecular processes, however, are notoriously noisy and frequently nonlinear. We present an approach to studying the impact of control measures on motifs of molecular interactions that addresses the problems faced in many biological systems: stochasticity, parameter uncertainty and nonlinearity. We show that our reachability analysis formalism can describe the potential behaviour of biological (naturally evolved as well as engineered) systems, and provides a set of bounds on their dynamics at the level of population statistics: for example, we can obtain the possible ranges of means and variances of mRNA and protein expression levels, even in the presence of uncertainty about model parameters.

Control mechanisms for stochastic biochemical systems via computation of reachable sets

PubMed Central

Lakatos, Eszter

2017-01-01

Controlling the behaviour of cells by rationally guiding molecular processes is an overarching aim of much of synthetic biology. Molecular processes, however, are notoriously noisy and frequently nonlinear. We present an approach to studying the impact of control measures on motifs of molecular interactions that addresses the problems faced in many biological systems: stochasticity, parameter uncertainty and nonlinearity. We show that our reachability analysis formalism can describe the potential behaviour of biological (naturally evolved as well as engineered) systems, and provides a set of bounds on their dynamics at the level of population statistics: for example, we can obtain the possible ranges of means and variances of mRNA and protein expression levels, even in the presence of uncertainty about model parameters. PMID:28878957

Advances in visual representation of molecular potentials.

PubMed

Du, Qi-Shi; Huang, Ri-Bo; Chou, Kuo-Chen

2010-06-01

The recent advances in visual representations of molecular properties in 3D space are summarized, and their applications in molecular modeling study and rational drug design are introduced. The visual representation methods provide us with detailed insights into protein-ligand interactions, and hence can play a major role in elucidating the structure or reactivity of a biomolecular system. Three newly developed computation and visualization methods for studying the physical and chemical properties of molecules are introduced, including their electrostatic potential, lipophilicity potential and excess chemical potential. The newest application examples of visual representations in structure-based rational drug are presented. The 3D electrostatic potentials, calculated using the empirical method (EM-ESP), in which the classical Coulomb equation and traditional atomic partial changes are discarded, are highly consistent with the results by the higher level quantum chemical method. The 3D lipophilicity potentials, computed by the heuristic molecular lipophilicity potential method based on the principles of quantum mechanics and statistical mechanics, are more accurate and reliable than those by using the traditional empirical methods. The 3D excess chemical potentials, derived by the reference interaction site model-hypernetted chain theory, provide a new tool for computational chemistry and molecular modeling. For structure-based drug design, the visual representations of molecular properties will play a significant role in practical applications. It is anticipated that the new advances in computational chemistry will stimulate the development of molecular modeling methods, further enriching the visual representation techniques for rational drug design, as well as other relevant fields in life science.

Uncertainties in Atomic Data and Their Propagation Through Spectral Models. I.

NASA Technical Reports Server (NTRS)

Bautista, M. A.; Fivet, V.; Quinet, P.; Dunn, J.; Gull, T. R.; Kallman, T. R.; Mendoza, C.

2013-01-01

We present a method for computing uncertainties in spectral models, i.e., level populations, line emissivities, and emission line ratios, based upon the propagation of uncertainties originating from atomic data.We provide analytic expressions, in the form of linear sets of algebraic equations, for the coupled uncertainties among all levels. These equations can be solved efficiently for any set of physical conditions and uncertainties in the atomic data. We illustrate our method applied to spectral models of Oiii and Fe ii and discuss the impact of the uncertainties on atomic systems under different physical conditions. As to intrinsic uncertainties in theoretical atomic data, we propose that these uncertainties can be estimated from the dispersion in the results from various independent calculations. This technique provides excellent results for the uncertainties in A-values of forbidden transitions in [Fe ii]. Key words: atomic data - atomic processes - line: formation - methods: data analysis - molecular data - molecular processes - techniques: spectroscopic

Insights about Striatal Circuit Function and Schizophrenia from a Mouse Model of D2 Receptor Upregulation

PubMed Central

Simpson, Eleanor H.; Kellendonk, Christoph

2016-01-01

The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D2 receptor selectively in the striatum. Here we review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D2 receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients. PMID:27720388

Nanopyroxene Grafting with β-Cyclodextrin Monomer for Wastewater Applications.

PubMed

Nafie, Ghada; Vitale, Gerardo; Carbognani Ortega, Lante; Nassar, Nashaat N

2017-12-06

Emerging nanoparticle technology provides opportunities for environmentally friendly wastewater treatment applications, including those in the large liquid tailings containments in the Alberta oil sands. In this study, we synthesize β-cyclodextrin grafted nanopyroxenes to offer an ecofriendly platform for the selective removal of organic compounds typically present in these types of applications. We carry out computational modeling at the micro level through molecular mechanics and molecular dynamics simulations and laboratory experiments at the macro level to understand the interactions between the synthesized nanomaterials and two-model naphthenic acid molecules (cyclopentanecarboxylic and trans-4-pentylcyclohexanecarboxylic acids) typically existing in tailing ponds. The proof-of-concept computational modeling and experiments demonstrate that monomer grafted nanopyroxene  or nano-AE of the sodium iron-silicate aegirine are found to be promising candidates for the removal of polar organic compounds from wastewater, among other applications. These nano-AE offer new possibilities for treating tailing ponds generated by the oil sands industry.

Evidence from mixed hydrate nucleation for a funnel model of crystallization.

PubMed

Hall, Kyle Wm; Carpendale, Sheelagh; Kusalik, Peter G

2016-10-25

The molecular-level details of crystallization remain unclear for many systems. Previous work has speculated on the phenomenological similarities between molecular crystallization and protein folding. Here we demonstrate that molecular crystallization can involve funnel-shaped potential energy landscapes through a detailed analysis of mixed gas hydrate nucleation, a prototypical multicomponent crystallization process. Through this, we contribute both: (i) a powerful conceptual framework for exploring and rationalizing molecular crystallization, and (ii) an explanation of phenomenological similarities between protein folding and crystallization. Such funnel-shaped potential energy landscapes may be typical of broad classes of molecular ordering processes, and can provide a new perspective for both studying and understanding these processes.

Evidence from mixed hydrate nucleation for a funnel model of crystallization

PubMed Central

Hall, Kyle Wm.; Carpendale, Sheelagh; Kusalik, Peter G.

2016-01-01

The molecular-level details of crystallization remain unclear for many systems. Previous work has speculated on the phenomenological similarities between molecular crystallization and protein folding. Here we demonstrate that molecular crystallization can involve funnel-shaped potential energy landscapes through a detailed analysis of mixed gas hydrate nucleation, a prototypical multicomponent crystallization process. Through this, we contribute both: (i) a powerful conceptual framework for exploring and rationalizing molecular crystallization, and (ii) an explanation of phenomenological similarities between protein folding and crystallization. Such funnel-shaped potential energy landscapes may be typical of broad classes of molecular ordering processes, and can provide a new perspective for both studying and understanding these processes. PMID:27790987

Hierarchical coarse-graining strategy for protein-membrane systems to access mesoscopic scales

PubMed Central

Ayton, Gary S.; Lyman, Edward

2014-01-01

An overall multiscale simulation strategy for large scale coarse-grain simulations of membrane protein systems is presented. The protein is modeled as a heterogeneous elastic network, while the lipids are modeled using the hybrid analytic-systematic (HAS) methodology, where in both cases atomistic level information obtained from molecular dynamics simulation is used to parameterize the model. A feature of this approach is that from the outset liposome length scales are employed in the simulation (i.e., on the order of ½ a million lipids plus protein). A route to develop highly coarse-grained models from molecular-scale information is proposed and results for N-BAR domain protein remodeling of a liposome are presented. PMID:20158037

Ames Culture Chamber System: Enabling Model Organism Research Aboard the international Space Station

NASA Technical Reports Server (NTRS)

Steele, Marianne

2014-01-01

Understanding the genetic, physiological, and behavioral effects of spaceflight on living organisms and elucidating the molecular mechanisms that underlie these effects are high priorities for NASA. Certain organisms, known as model organisms, are widely studied to help researchers better understand how all biological systems function. Small model organisms such as nem-atodes, slime mold, bacteria, green algae, yeast, and moss can be used to study the effects of micro- and reduced gravity at both the cellular and systems level over multiple generations. Many model organisms have sequenced genomes and published data sets on their transcriptomes and proteomes that enable scientific investigations of the molecular mechanisms underlying the adaptations of these organisms to space flight.

From UNIX to PC via X-Windows: Molecular Modeling for the General Chemistry Lab

NASA Astrophysics Data System (ADS)

Pavia, Donald; Wicholas, Mark

1997-04-01

The emphasis of molecular modeling in the undergraduate curriculum has generally been directed toward sophomore organic and higher-level chemistry instruction, especially when UNIX systems are used. When developing plans for incorporating molecular modeling into the curriculum, we decided to also include it in our first-year general chemistry course. Modeling would serve primarily as a visualization tool to augment the general chemistry coverage of bonding and structure. Our first thoughts were rather naive: we would set up a number of workstations and somehow get our general chemistry students, as many as 480 in one academic quarter, directly onto these machines at some time in a 1-2 week period during their weekly 3-hour lab. Further exploration of our options revealed that a better approach was to use PCs as dummy terminals for UNIX workstations. Described below are the hardware and software for this venture and the modeling experiment done by our students in general chemistry.

Amplified emission and lasing in a plasmonic nanolaser with many three-level molecules

NASA Astrophysics Data System (ADS)

Zhang, Yuan; Mølmer, Klaus

2018-01-01

Steady-state plasmonic lasing is studied theoretically for a system consisting of many dye molecules arranged regularly around a gold nanosphere. A three-level model with realistic molecular dissipation is employed to analyze the performance as a function of the pump field amplitude and number of molecules. Few molecules and moderate pumping produce a single narrow emission peak because the excited molecules transfer energy to a single dipole plasmon mode by amplified spontaneous emission. Under strong pumping, the single peak splits into broader and weaker emission peaks because two molecular excited levels interfere with each other through coherent coupling with the pump field and with the dipole plasmon field. A large number of molecules gives rise to a Poisson-like distribution of plasmon number states with a large mean number characteristic of lasing action. These characteristics of lasing, however, deteriorate under strong pumping because of the molecular interference effect.

Integration and scaling of UV-B radiation effects on plants: from molecular interactions to whole plant responses.

PubMed

Suchar, Vasile Alexandru; Robberecht, Ronald

2016-07-01

A process based model integrating the effects of UV-B radiation to molecular level processes and their consequences to whole plant growth and development was developed from key parameters in the published literature. Model simulations showed that UV-B radiation induced changes in plant metabolic and/or photosynthesis rates can result in plant growth inhibitions. The costs of effective epidermal UV-B radiation absorptive compounds did not result in any significant changes in plant growth, but any associated metabolic costs effectively reduced the potential plant biomass. The model showed significant interactions between UV-B radiation effects and temperature and any factor leading to inhibition of photosynthetic production or plant growth during the midday, but the effects were not cumulative for all factors. Vegetative growth were significantly delayed in species that do not exhibit reproductive cycles during a growing season, but vegetative growth and reproductive yield in species completing their life cycle in one growing season did not appear to be delayed more than 2-5 days, probably within the natural variability of the life cycles for many species. This is the first model to integrate the effects of increased UV-B radiation through molecular level processes and their consequences to whole plant growth and development.

Quantum mechanical force fields for condensed phase molecular simulations

NASA Astrophysics Data System (ADS)

Giese, Timothy J.; York, Darrin M.

2017-09-01

Molecular simulations are powerful tools for providing atomic-level details into complex chemical and physical processes that occur in the condensed phase. For strongly interacting systems where quantum many-body effects are known to play an important role, density-functional methods are often used to provide the model with the potential energy used to drive dynamics. These methods, however, suffer from two major drawbacks. First, they are often too computationally intensive to practically apply to large systems over long time scales, limiting their scope of application. Second, there remain challenges for these models to obtain the necessary level of accuracy for weak non-bonded interactions to obtain quantitative accuracy for a wide range of condensed phase properties. Quantum mechanical force fields (QMFFs) provide a potential solution to both of these limitations. In this review, we address recent advances in the development of QMFFs for condensed phase simulations. In particular, we examine the development of QMFF models using both approximate and ab initio density-functional models, the treatment of short-ranged non-bonded and long-ranged electrostatic interactions, and stability issues in molecular dynamics calculations. Example calculations are provided for crystalline systems, liquid water, and ionic liquids. We conclude with a perspective for emerging challenges and future research directions.

Extension of the quantum-kinetic model to lunar and Mars return physics

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

Liechty, D. S.; Lewis, M. J.

The ability to compute rarefied, ionized hypersonic flows is becoming more important as missions such as Earth reentry, landing high-mass payloads on Mars, and the exploration of the outer planets and their satellites are being considered. A recently introduced molecular-level chemistry model, the quantum-kinetic, or Q-K, model that predicts reaction rates for gases in thermal equilibrium and non-equilibrium using only kinetic theory and fundamental molecular properties, is extended in the current work to include electronic energy level transitions and reactions involving charged particles. Like the Q-K procedures for neutral species chemical reactions, these new models are phenomenological procedures that aimmore » to reproduce the reaction/transition rates but do not necessarily capture the exact physics. These engineering models are necessarily efficient due to the requirement to compute billions of simulated collisions in direct simulation Monte Carlo (DSMC) simulations. The new models are shown to generally agree within the spread of reported transition and reaction rates from the literature for near equilibrium conditions.« less

An analytical coarse-graining method which preserves the free energy, structural correlations, and thermodynamic state of polymer melts from the atomistic to the mesoscale.

PubMed

McCarty, J; Clark, A J; Copperman, J; Guenza, M G

2014-05-28

Structural and thermodynamic consistency of coarse-graining models across multiple length scales is essential for the predictive role of multi-scale modeling and molecular dynamic simulations that use mesoscale descriptions. Our approach is a coarse-grained model based on integral equation theory, which can represent polymer chains at variable levels of chemical details. The model is analytical and depends on molecular and thermodynamic parameters of the system under study, as well as on the direct correlation function in the k → 0 limit, c0. A numerical solution to the PRISM integral equations is used to determine c0, by adjusting the value of the effective hard sphere diameter, dHS, to agree with the predicted equation of state. This single quantity parameterizes the coarse-grained potential, which is used to perform mesoscale simulations that are directly compared with atomistic-level simulations of the same system. We test our coarse-graining formalism by comparing structural correlations, isothermal compressibility, equation of state, Helmholtz and Gibbs free energies, and potential energy and entropy using both united atom and coarse-grained descriptions. We find quantitative agreement between the analytical formalism for the thermodynamic properties, and the results of Molecular Dynamics simulations, independent of the chosen level of representation. In the mesoscale description, the potential energy of the soft-particle interaction becomes a free energy in the coarse-grained coordinates which preserves the excess free energy from an ideal gas across all levels of description. The structural consistency between the united-atom and mesoscale descriptions means the relative entropy between descriptions has been minimized without any variational optimization parameters. The approach is general and applicable to any polymeric system in different thermodynamic conditions.

Multistate Landau-Zener models with all levels crossing at one point

DOE PAGES

Li, Fuxiang; Sun, Chen; Chernyak, Vladimir Y.; ...

2017-08-04

Within this paper, we discuss common properties and reasons for integrability in the class of multistate Landau-Zener models with all diabatic levels crossing at one point. Exploring the Stokes phenomenon, we show that each previously solved model has a dual one, whose scattering matrix can be also obtained analytically. For applications, we demonstrate how our results can be used to study conversion of molecular into atomic Bose condensates during passage through the Feshbach resonance, and provide purely algebraic solutions of the bowtie and special cases of the driven Tavis-Cummings model.

Mapping Hydrophobicity on the Protein Molecular Surface at Atom-Level Resolution

PubMed Central

Nicolau Jr., Dan V.; Paszek, Ewa; Fulga, Florin; Nicolau, Dan V.

2014-01-01

A precise representation of the spatial distribution of hydrophobicity, hydrophilicity and charges on the molecular surface of proteins is critical for the understanding of the interaction with small molecules and larger systems. The representation of hydrophobicity is rarely done at atom-level, as this property is generally assigned to residues. A new methodology for the derivation of atomic hydrophobicity from any amino acid-based hydrophobicity scale was used to derive 8 sets of atomic hydrophobicities, one of which was used to generate the molecular surfaces for 35 proteins with convex structures, 5 of which, i.e., lysozyme, ribonuclease, hemoglobin, albumin and IgG, have been analyzed in more detail. Sets of the molecular surfaces of the model proteins have been constructed using spherical probes with increasingly large radii, from 1.4 to 20 Å, followed by the quantification of (i) the surface hydrophobicity; (ii) their respective molecular surface areas, i.e., total, hydrophilic and hydrophobic area; and (iii) their relative densities, i.e., divided by the total molecular area; or specific densities, i.e., divided by property-specific area. Compared with the amino acid-based formalism, the atom-level description reveals molecular surfaces which (i) present an approximately two times more hydrophilic areas; with (ii) less extended, but between 2 to 5 times more intense hydrophilic patches; and (iii) 3 to 20 times more extended hydrophobic areas. The hydrophobic areas are also approximately 2 times more hydrophobicity-intense. This, more pronounced “leopard skin”-like, design of the protein molecular surface has been confirmed by comparing the results for a restricted set of homologous proteins, i.e., hemoglobins diverging by only one residue (Trp37). These results suggest that the representation of hydrophobicity on the protein molecular surfaces at atom-level resolution, coupled with the probing of the molecular surface at different geometric resolutions, can capture processes that are otherwise obscured to the amino acid-based formalism. PMID:25462574

Homology modeling, molecular docking and MD simulation studies to investigate role of cysteine protease from Xanthomonas campestris in degradation of Aβ peptide.

PubMed

Dhanavade, Maruti J; Jalkute, Chidambar B; Barage, Sagar H; Sonawane, Kailas D

2013-12-01

Cysteine protease is known to degrade amyloid beta peptide which is a causative agent of Alzheimer's disease. This cleavage mechanism has not been studied in detail at the atomic level. Hence, a three-dimensional structure of cysteine protease from Xanthomonas campestris was constructed by homology modeling using Geno3D, SWISS-MODEL, and MODELLER 9v7. All the predicted models were analyzed by PROCHECK and PROSA. Three-dimensional model of cysteine protease built by MODELLER 9v7 shows similarity with human cathepsin B crystal structure. This model was then used further for docking and simulation studies. The molecular docking study revealed that Cys17, His87, and Gln88 residues of cysteine protease form an active site pocket similar to human cathepsin B. Then the docked complex was refined by molecular dynamic simulation to confirm its stable behavior over the entire simulation period. The molecular docking and MD simulation studies showed that the sulfhydryl hydrogen atom of Cys17 of cysteine protease interacts with carboxylic oxygen of Lys16 of Aβ peptide indicating the cleavage site. Thus, the cysteine protease model from X. campestris having similarity with human cathepsin B crystal structure may be used as an alternate approach to cleave Aβ peptide a causative agent of Alzheimer's disease. © 2013 Elsevier Ltd. All rights reserved.

Boolean Networks in Inference and Dynamic Modeling of Biological Systems at the Molecular and Physiological Level

NASA Astrophysics Data System (ADS)

Thakar, Juilee; Albert, Réka

The following sections are included: * Introduction * Boolean Network Concepts and History * Extensions of the Classical Boolean Framework * Boolean Inference Methods and Examples in Biology * Dynamic Boolean Models: Examples in Plant Biology, Developmental Biology and Immunology * Conclusions * References

Organization of Lipids in the Tear Film: A Molecular-Level View

PubMed Central

Wizert, Alicja; Iskander, D. Robert; Cwiklik, Lukasz

2014-01-01

Biophysical properties of the tear film lipid layer are studied at the molecular level employing coarse grain molecular dynamics (MD) simulations with a realistic model of the human tear film. In this model, polar lipids are chosen to reflect the current knowledge on the lipidome of the tear film whereas typical Meibomian-origin lipids are included in the thick non-polar lipids subphase. Simulation conditions mimic those experienced by the real human tear film during blinks. Namely, thermodynamic equilibrium simulations at different lateral compressions are performed to model varying surface pressure, and the dynamics of the system during a blink is studied by non-equilibrium MD simulations. Polar lipids separate their non-polar counterparts from water by forming a monomolecular layer whereas the non-polar molecules establish a thick outermost lipid layer. Under lateral compression, the polar layer undulates and a sorting of polar lipids occurs. Moreover, formation of three-dimensional aggregates of polar lipids in both non-polar and water subphases is observed. We suggest that these three-dimensional structures are abundant under dynamic conditions caused by the action of eye lids and that they act as reservoirs of polar lipids, thus increasing stability of the tear film. PMID:24651175

Energy level alignment at hybridized organic-metal interfaces from a GW projection approach

NASA Astrophysics Data System (ADS)

Chen, Yifeng; Tamblyn, Isaac; Quek, Su Ying

Energy level alignments at organic-metal interfaces are of profound importance in numerous (opto)electronic applications. Standard density functional theory (DFT) calculations generally give incorrect energy level alignments and missing long-range polarization effects. Previous efforts to address this problem using the many-electron GW method have focused on physisorbed systems where hybridization effects are insignificant. Here, we use state-of-the-art GW methods to predict the level alignment at the amine-Au interface, where molecular levels do hybridize with metallic states. This non-trivial hybridization implies that DFT result is a poor approximation to the quasiparticle states. However, we find that the self-energy operator is approximately diagonal in the molecular basis, allowing us to use a projection approach to predict the level alignments. Our results indicate that the metallic substrate reduces the HOMO-LUMO gap by 3.5 4.0 eV, depending on the molecular coverage/presence of Au adatoms. Our GW results are further compared with those of a simple image charge model that describes the level alignment in physisorbed systems. Syq and YC acknowledge Grant NRF-NRFF2013-07 and the medium-sized centre program from the National Research Foundation, Singapore.

The chemistry side of AOP: implications for toxicity ...

EPA Pesticide Factsheets

An adverse outcome pathway (AOP) is a structured representation of the biological events that lead to adverse impacts following a molecular initiating event caused by chemical interaction with a macromolecule. AOPs have been proposed to facilitate toxicity extrapolation across species through understanding of species similarity in the sequence of molecular, cellular, organ and organismal level responses. However, AOPs are non-specific regarding the identity of the chemical initiators, and the range of structures for which an AOP is considered applicable has generally been poorly defined. Applicability domain has been widely understood in the field of QSAR as the response and chemical structure space in which the model makes predictions with a given reliability, and has been traditionally applied to define the similarity of query molecules within the training set. Three dimensional (3D) receptor modeling offers an approach to better define the applicability domain for selected AOPs through determination of the chemical space of the molecular initiating event. Universal 3D-QSAR models were developed for acetylcholinesterase inhibitors and estrogen receptor agonists and antagonists using a combination of fingerprint, molecular docking and structure-based pharmacophore approaches. The models were based on the critical molecular interactions within each receptor ligand binding domain, and included the key amino acid residues responsible for high binding affinity. T

Problems of low-parameter equations of state

NASA Astrophysics Data System (ADS)

Petrik, G. G.

2017-11-01

The paper focuses on the system approach to problems of low-parametric equations of state (EOS). It is a continuation of the investigations in the field of substantiated prognosis of properties on two levels, molecular and thermodynamic. Two sets of low-parameter EOS have been considered based on two very simple molecular-level models. The first one consists of EOS of van der Waals type (a modification of van der Waals EOS proposed for spheres). The main problem of these EOS is a weak connection with the micro-level, which raise many uncertainties. The second group of EOS has been derived by the author independently of the ideas of van der Waals based on the model of interacting point centers (IPC). All the parameters of the EOS have a meaning and are associated with the manifestation of attractive and repulsive forces. The relationship between them is found to be the control parameter of the thermodynamic level. In this case, EOS IPC passes into a one-parameter family. It is shown that many EOS of vdW-type can be included in the framework of the PC model. Simultaneously, all their parameters acquire a physical meaning.

Probing the effects of surface hydrophobicity and tether orientation on antibody-antigen binding

NASA Astrophysics Data System (ADS)

Bush, Derek B.; Knotts, Thomas A.

2017-04-01

Antibody microarrays have the potential to revolutionize molecular detection for many applications, but their current use is limited by poor reliability, and efforts to change this have not yielded fruitful results. One difficulty which limits the rational engineering of next-generation devices is that little is known, at the molecular level, about the antibody-antigen binding process near solid surfaces. Atomic-level structural information is scant because typical experimental techniques (X-ray crystallography and NMR) cannot be used to image proteins bound to surfaces. To overcome this limitation, this study uses molecular simulation and an advanced, experimentally validated, coarse-grain, protein-surface model to compare fab-lysozyme binding in bulk solution and when the fab is tethered to hydrophobic and hydrophilic surfaces. The results show that the tether site in the fab, as well as the surface hydrophobicity, significantly impacts the binding process and suggests that the optimal design involves tethering fabs upright on a hydrophilic surface. The results offer an unprecedented, molecular-level picture of the binding process and give hope that the rational design of protein-microarrays is possible.

Molecular adaptation in Rubisco: Discriminating between convergent evolution and positive selection using mechanistic and classical codon models.

PubMed

Parto, Sahar; Lartillot, Nicolas

2018-01-01

Rubisco (Ribulose-1, 5-biphosphate carboxylase/oxygenase) is the most important enzyme on earth, catalyzing the first step of photosynthetic CO2 fixation. So, without it, there would be no storing of the sun's energy in plants. Molecular adaptation of Rubisco to C4 photosynthetic pathway has attracted a lot of attention. C4 plants, which comprise less than 5% of land plants, have evolved more efficient photosynthesis compared to C3 plants. Interestingly, a large number of independent transitions from C3 to C4 phenotype have occurred. Each time, the Rubisco enzyme has been subject to similar changes in selective pressure, thus providing an excellent model for convergent evolution at the molecular level. Molecular adaptation is often identified with positive selection and is typically characterized by an elevated ratio of non-synonymous to synonymous substitution rate (dN/dS). However, convergent adaptation is expected to leave a different molecular signature, taking the form of repeated transitions toward identical or similar amino acids. Here, we used a previously introduced codon-based differential-selection model to detect and quantify consistent patterns of convergent adaptation in Rubisco in eudicots. We further contrasted our results with those obtained by classical codon models based on the estimation of dN/dS. We found that the two classes of models tend to select distinct, although overlapping, sets of positions. This discrepancy in the results illustrates the conceptual difference between these models while emphasizing the need to better discriminate between qualitatively different selective regimes, by using a broader class of codon models than those currently considered in molecular evolutionary studies.

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

Henderson, Michael A.; Lyubinetsky, Igor

The field of heterogeneous photocatalysis has grown considerably in the decades since Fujishima and Honda's ground-breaking publications of photoelectrochemistry on TiO2. Numerous review articles continue to point to both progress made in the use of heterogeneous materials (such as TiO2) to perform photoconversion processes, and the many opportunities and challenges in heterogeneous photocatalysis research such as solar energy conversion and environmental remediation. The past decade has also seen an increase in the use of molecular-level approaches applied to model single crystal surfaces in an effort to obtain new insights into photocatalytic phenomena. In particular, scanning probe techniques (SPM) have enabledmore » researchers to take a ‘nanoscale’ approach to photocatalysis that includes interrogation of the reactivities of specific sites and adsorbates on a model photocatalyst surface. The rutile TiO2(110) surface has become the prototypical oxide single crystal surface for fundamental studies of many interfacial phenomena. In particular, TiO2(110) has become an excellent model surface for probing photochemical and photocatalytic reactions at the molecular level. A variety of experimental approaches have emerged as being ideally suited for studying photochemical reactions on TiO2(110), including desorption-oriented approaches and electronic spectroscopies, but perhaps the most promising techniques for evaluating site-specific properties are those of SPM. In this review, we highlight the growing use of SPM techniques in providing molecular-level insights into surface photochemistry on the model photocatalyst surface of rutile TiO2(110). Our objective is to both illustrate the unique knowledge that scanning probe techniques have already provided the field of photocatalysis, and also to motivate a new generation of effort into the use of such approaches to obtain new insights into the molecular level details of photochemical events occurring at interfaces. Discussion will start with an examination of how scanning probe techniques are being used to characterize the TiO2(110) surface in ways that are relevant to photocatalysis. We will then discuss specific classes of photochemical reaction on TiO2(110) for which SPM has proven indispensible in providing unique molecular-level insights, and conclude with discussion of future areas in which SPM studies may prove valuable to photocatalysis on TiO2. This work was supported by the US Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences. I.L. was partially supported by a Pacific Northwest National Laboratory (PNNL) Chemical Imaging Initiative project. PNNL is a multiprogram national laboratory operated for DOE by Battelle.« less

The Development of Students' Mental Models of Chemical Substances and Processes at the Molecular Level

NASA Astrophysics Data System (ADS)

Dalton, Rebecca Marie

The development of student's mental models of chemical substances and processes at the molecular level was studied in a three-phase project. Animations produced in the VisChem project were used as an integral part of the chemistry instruction to help students develop their mental models. Phase one of the project involved examining the effectiveness of using animations to help first-year university chemistry students develop useful mental models of chemical phenomena. Phase two explored factors affecting the development of student's mental models, analysing results in terms of a proposed model of the perceptual processes involved in interpreting an animation. Phase three involved four case studies that served to confirm and elaborate on the effects of prior knowledge and disembedding ability on student's mental model development, and support the influence of study style on learning outcomes. Recommendations for use of the VisChem animations, based on the above findings, include: considering the prior knowledge of students; focusing attention on relevant features; encouraging a deep approach to learning; using animation to teach visual concepts; presenting ideas visually, verbally and conceptually; establishing 'animation literacy'; minimising cognitive load; using animation as feedback; using student drawings; repeating animations; and discussing 'scientific modelling'.

Probing Silica-Biomolecule Interactions by Solid-State NMR and Molecular Dynamics Simulations.

PubMed

Brückner, Stephan Ingmar; Donets, Sergii; Dianat, Arezoo; Bobeth, Manfred; Gutiérrez, Rafael; Cuniberti, Gianaurelio; Brunner, Eike

2016-11-08

Understanding the molecular interactions between inorganic phases such as silica and organic material is fundamental for chromatographic applications, for tailoring silica-enzyme interactions, and for elucidating the mechanisms of biomineralization. The formation, structure, and properties of the organic/inorganic interface is crucial in this context. Here, we investigate the interaction of selectively 13 C-labeled choline with 29 Si-labeled monosilicic acid/silica at the molecular level. Silica/choline nanocomposites were analyzed by solid-state NMR spectroscopy in combination with extended molecular dynamics (MD) simulations to understand the silica/organic interface. Cross-polarization magic angle spinning (CP MAS)-based NMR experiments like 1 H- 13 C CP-REDOR (rotational-echo double resonance), 1 H- 13 C HETCOR (heteronuclear correlation), and 1 H- 29 Si- 1 H double CP are employed to determine spatial parameters. The measurement of 29 Si- 13 C internuclear distances for selectively 13 C-labeled choline provides an experimental parameter that allows the direct verification of MD simulations. Atomistic modeling using classical MD methodologies is performed using the INTERFACE force field. The modeling results are in excellent agreement with the experimental data and reveal the relevant molecular conformations as well as the nature and interplay of the interactions between the choline cation and the silica surface. Electrostatic interactions and hydrogen bonding are both important and depend strongly on the hydration level as well as the charge state of the silica surface.

'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm Lumbricus rubellus.

PubMed

Bundy, Jacob G; Sidhu, Jasmin K; Rana, Faisal; Spurgeon, David J; Svendsen, Claus; Wren, Jodie F; Stürzenbaum, Stephen R; Morgan, A John; Kille, Peter

2008-06-03

New methods are needed for research into non-model organisms, to monitor the effects of toxic disruption at both the molecular and functional organism level. We exposed earthworms (Lumbricus rubellus Hoffmeister) to sub-lethal levels of copper (10-480 mg/kg soil) for 70 days as a real-world situation, and monitored both molecular (cDNA transcript microarrays and nuclear magnetic resonance-based metabolic profiling: metabolomics) and ecological/functional endpoints (reproduction rate and weight change, which have direct relevance to population-level impacts). Both of the molecular endpoints, metabolomics and transcriptomics, were highly sensitive, with clear copper-induced differences even at levels below those that caused a reduction in reproductive parameters. The microarray and metabolomic data provided evidence that the copper exposure led to a disruption of energy metabolism: transcripts of enzymes from oxidative phosphorylation were significantly over-represented, and increases in transcripts of carbohydrate metabolising enzymes (maltase-glucoamylase, mannosidase) had corresponding decreases in small-molecule metabolites (glucose, mannose). Treating both enzymes and metabolites as functional cohorts led to clear inferences about changes in energetic metabolism (carbohydrate use and oxidative phosphorylation), which would not have been possible by taking a 'biomarker' approach to data analysis. Multiple post-genomic techniques can be combined to provide mechanistic information about the toxic effects of chemical contaminants, even for non-model organisms with few additional mechanistic toxicological data. With 70-day no-observed-effect and lowest-observed-effect concentrations (NOEC and LOEC) of 10 and 40 mg kg-1 for metabolomic and microarray profiles, copper is shown to interfere with energy metabolism in an important soil organism at an ecologically and functionally relevant level.

Exploring unimolecular dissociation kinetics of ethyl dibromide through electronic structure calculations

NASA Astrophysics Data System (ADS)

Gulvi, Nitin R.; Patel, Priyanka; Badani, Purav M.

2018-04-01

Pathway for dissociation of multihalogenated alkyls is observed to be competitive between molecular and atomic elimination products. Factors such as molecular structure, temperature and pressure are known to influence the same. Hence present work is focussed to explore mechanism and kinetics of atomic (Br) and molecular (HBr and Br2) elimination upon pyrolysis of 1,1- and 1,2-ethyl dibromide (EDB). For this purpose, electronic structure calculations were performed at DFT and CCSD(T) level of theory. In addition to concerted mechanism, an alternate energetically efficient isomerisation pathway has been exploited for molecular elimination. Energy calculations are further complimented by detailed kinetic investigation, over wide range of temperature and pressure, using suitable models like Canonical Transition State Theory, Statistical Adiabatic Channel Model and Troe's formalism. Our calculations suggest high branching ratio for dehydrohalogentation reaction, from both isomers of EDB. Fall off curve depicts good agreement between theoretically estimated and experimentally reported values.

Using Denatured Egg White as a Macroscopic Model for Teaching Protein Structure and Introducing Protein Synthesis for High School Students

NASA Astrophysics Data System (ADS)

Correia, Paulo R. M.; Torres, Bayardo B.

2007-12-01

The success of teaching molecular and atomic phenomena depends on the didactical strategy and the media selection adopted, in consideration of the level of abstraction of the subject to be taught and the students' capability to deal with abstract operations. Dale's cone of experience was employed to plan three 50-minute classes to discuss protein denaturation from a chemical point of view. Only low abstraction level activities were selected: (i) two demonstrations showing the denaturation of albumin by heating and by changing the solvent, (ii) the assembly of a macroscopic model representing the protein molecule, and (iii) a role-play for simulating glucagon synthesis. A student-centered approach and collaborative learning were used throughout the classes. The use of macroscopic models is a powerful didactical strategy to represent molecular and atomic events. They can convert microscopic entities into touchable objects, reducing the abstraction level required to discuss chemistry with high school students. Thus, interesting topics involving molecules and their behavior can take place efficiently when mediated by concrete experiences.

Non-invasive molecular imaging for preclinical cancer therapeutic development

PubMed Central

O'Farrell, AC; Shnyder, SD; Marston, G; Coletta, PL; Gill, JH

2013-01-01

Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development. PMID:23488622

Chemically specific coarse-grained models to investigate the structure of biomimetic membranes

DOE PAGES

Kowalik, Ma?gorzata; Schantz, Allen B.; Naqi, Abdullah; ...

2017-11-29

Biomimetic polymer/protein membranes are promising materials for DNA sequencing, sensors, drug delivery and water purification. These self-assembled structures are made from low molecular weight amphiphilic block copolymers (N hydrophobic < 40 for a diblock copolymer), including poly(ethylene oxide)–1,2-polybutadiene (EO–1,2-BD) and poly(ethylene oxide)–poly(ethyl ethylene) (EO–EE). To examine these membranes' nanoscale structure, we developed a coarse-grained molecular dynamics (CG MD) model for EO–1,2-BD and assembled a CG MD model for EO–EE using parameters from two published force fields. We observe that the polymers' hydrophobic core blocks are slightly stretched compared to the random coil configuration seen at higher molecular weights. We alsomore » observe an increase in the interdigitation of the hydrophobic leaflets with increasing molecular weight (consistent with literature). The hydration level of the EO corona (which may influence protein incorporation) is higher for membranes with a larger area/chain, regardless of whether EE or 1,2-BD forms the hydrophobic block. Our results provide a molecular-scale view of membrane packing and hydrophobicity, two important properties for creating polymer–protein biomimetic membranes.« less

Chemically specific coarse-grained models to investigate the structure of biomimetic membranes

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

Kowalik, Ma?gorzata; Schantz, Allen B.; Naqi, Abdullah

Biomimetic polymer/protein membranes are promising materials for DNA sequencing, sensors, drug delivery and water purification. These self-assembled structures are made from low molecular weight amphiphilic block copolymers (N hydrophobic < 40 for a diblock copolymer), including poly(ethylene oxide)–1,2-polybutadiene (EO–1,2-BD) and poly(ethylene oxide)–poly(ethyl ethylene) (EO–EE). To examine these membranes' nanoscale structure, we developed a coarse-grained molecular dynamics (CG MD) model for EO–1,2-BD and assembled a CG MD model for EO–EE using parameters from two published force fields. We observe that the polymers' hydrophobic core blocks are slightly stretched compared to the random coil configuration seen at higher molecular weights. We alsomore » observe an increase in the interdigitation of the hydrophobic leaflets with increasing molecular weight (consistent with literature). The hydration level of the EO corona (which may influence protein incorporation) is higher for membranes with a larger area/chain, regardless of whether EE or 1,2-BD forms the hydrophobic block. Our results provide a molecular-scale view of membrane packing and hydrophobicity, two important properties for creating polymer–protein biomimetic membranes.« less

Molecular recognition of the environment and mechanisms of the origin of species in quantum-like modeling of evolution.

PubMed

Melkikh, Alexey V; Khrennikov, Andrei

2017-11-01

A review of the mechanisms of speciation is performed. The mechanisms of the evolution of species, taking into account the feedback of the state of the environment and mechanisms of the emergence of complexity, are considered. It is shown that these mechanisms, at the molecular level, cannot work steadily in terms of classical mechanics. Quantum mechanisms of changes in the genome, based on the long-range interaction potential between biologically important molecules, are proposed as one of possible explanation. Different variants of interactions of the organism and environment based on molecular recognition and leading to new species origins are considered. Experiments to verify the model are proposed. This bio-physical study is completed by the general operational model of based on quantum information theory. The latter is applied to model of epigenetic evolution. We briefly present the basics of the quantum-like approach to modeling of bio-informational processes. This approach is illustrated by the quantum-like model of epigenetic evolution. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modeling of metal thin film growth: Linking angstrom-scale molecular dynamics results to micron-scale film topographies

NASA Astrophysics Data System (ADS)

Hansen, U.; Rodgers, S.; Jensen, K. F.

2000-07-01

A general method for modeling ionized physical vapor deposition is presented. As an example, the method is applied to growth of an aluminum film in the presence of an ionized argon flux. Molecular dynamics techniques are used to examine the surface adsorption, reflection, and sputter reactions taking place during ionized physical vapor deposition. We predict their relative probabilities and discuss their dependence on energy and incident angle. Subsequently, we combine the information obtained from molecular dynamics with a line of sight transport model in a two-dimensional feature, incorporating all effects of reemission and resputtering. This provides a complete growth rate model that allows inclusion of energy- and angular-dependent reaction rates. Finally, a level-set approach is used to describe the morphology of the growing film. We thus arrive at a computationally highly efficient and accurate scheme to model the growth of thin films. We demonstrate the capabilities of the model predicting the major differences on Al film topographies between conventional and ionized sputter deposition techniques studying thin film growth under ionized physical vapor deposition conditions with different Ar fluxes.

From in silica to in silico: retention thermodynamics at solid-liquid interfaces.

PubMed

El Hage, Krystel; Bemish, Raymond J; Meuwly, Markus

2018-06-28

The dynamics of solvated molecules at the solid/liquid interface is essential for a molecular-level understanding for the solution thermodynamics in reversed phase liquid chromatography (RPLC). The heterogeneous nature of the systems and the competing intermolecular interactions makes solute retention in RPLC a surprisingly challenging problem which benefits greatly from modelling at atomistic resolution. However, the quality of the underlying computational model needs to be sufficiently accurate to provide a realistic description of the energetics and dynamics of systems, especially for solution-phase simulations. Here, the retention thermodynamics and the retention mechanism of a range of benzene-derivatives in C18 stationary-phase chains in contact with water/methanol mixtures is studied using point charge (PC) and multipole (MTP) electrostatic models. The results demonstrate that free energy simulations with a faithful MTP representation of the computational model provide quantitative and molecular level insight into the thermodynamics of adsorption/desorption in chromatographic systems while a conventional PC representation fails in doing so. This provides a rational basis to develop more quantitative and validated models for the optimization of separation systems.

The Drosophila Circadian Pacemaker Circuit: Pas de Deux or Tarantella?

PubMed Central

Sheeba, Vasu; Kaneko, Maki; Sharma, Vijay Kumar; Holmes, Todd C.

2008-01-01

Molecular genetic analysis of the fruit fly Drosophila melanogaster has revolutionized our understanding of the transcription/translation loop mechanisms underlying the circadian molecular oscillator. More recently, Drosophila has been used to understand how different neuronal groups within the circadian pacemaker circuit interact to regulate the overall behavior of the fly in response to daily cyclic environmental cues as well as seasonal changes. Our present understanding of circadian timekeeping at the molecular and circuit level is discussed with a critical evaluation of the strengths and weaknesses of present models. Two models for circadian neural circuits are compared: one that posits that two anatomically distinct oscillators control the synchronization to the two major daily morning and evening transitions, versus a distributed network model that posits that many cell-autonomous oscillators are coordinated in a complex fashion and respond via plastic mechanisms to changes in environmental cues. PMID:18307108

Dynamic, mechanistic, molecular-level modelling of cyanobacteria: Anabaena and nitrogen interaction.

PubMed

Hellweger, Ferdi L; Fredrick, Neil D; McCarthy, Mark J; Gardner, Wayne S; Wilhelm, Steven W; Paerl, Hans W

2016-09-01

Phytoplankton (eutrophication, biogeochemical) models are important tools for ecosystem research and management, but they generally have not been updated to include modern biology. Here, we present a dynamic, mechanistic, molecular-level (i.e. gene, transcript, protein, metabolite) model of Anabaena - nitrogen interaction. The model was developed using the pattern-oriented approach to model definition and parameterization of complex agent-based models. It simulates individual filaments, each with individual cells, each with genes that are expressed to yield transcripts and proteins. Cells metabolize various forms of N, grow and divide, and differentiate heterocysts when fixed N is depleted. The model is informed by observations from 269 laboratory experiments from 55 papers published from 1942 to 2014. Within this database, we identified 331 emerging patterns, and, excluding inconsistencies in observations, the model reproduces 94% of them. To explore a practical application, we used the model to simulate nutrient reduction scenarios for a hypothetical lake. For a 50% N only loading reduction, the model predicts that N fixation increases, but this fixed N does not compensate for the loading reduction, and the chlorophyll a concentration decreases substantially (by 33%). When N is reduced along with P, the model predicts an additional 8% reduction (compared to P only). © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

Illustrating the Molecular Origin of Mechanical Stress in Ductile Deformation of Polymer Glasses.

PubMed

Li, Xiaoxiao; Liu, Jianning; Liu, Zhuonan; Tsige, Mesfin; Wang, Shi-Qing

2018-02-16

New experiments show that tensile stress vanishes shortly after preyield deformation of polymer glasses while tensile stress after postyield deformation stays high and relaxes on much longer time scales, thus hinting at a specific molecular origin of stress in ductile cold drawing: chain tension rather than intersegmental interactions. Molecular dynamics simulation based on a coarse-grained model for polystyrene confirms the conclusion that the chain network plays an essential role, causing the glassy state to yield and to respond with a high level of intrachain retractive stress. This identification sheds light on the future development regarding an improved theoretical account for molecular mechanics of polymer glasses and the molecular design of stronger polymeric materials to enhance their mechanical performance.

Illustrating the Molecular Origin of Mechanical Stress in Ductile Deformation of Polymer Glasses

NASA Astrophysics Data System (ADS)

Li, Xiaoxiao; Liu, Jianning; Liu, Zhuonan; Tsige, Mesfin; Wang, Shi-Qing

2018-02-01

New experiments show that tensile stress vanishes shortly after preyield deformation of polymer glasses while tensile stress after postyield deformation stays high and relaxes on much longer time scales, thus hinting at a specific molecular origin of stress in ductile cold drawing: chain tension rather than intersegmental interactions. Molecular dynamics simulation based on a coarse-grained model for polystyrene confirms the conclusion that the chain network plays an essential role, causing the glassy state to yield and to respond with a high level of intrachain retractive stress. This identification sheds light on the future development regarding an improved theoretical account for molecular mechanics of polymer glasses and the molecular design of stronger polymeric materials to enhance their mechanical performance.

Applications and assessment of QM:QM electronic embedding using generalized asymmetric Mulliken atomic charges.

PubMed

Parandekar, Priya V; Hratchian, Hrant P; Raghavachari, Krishnan

2008-10-14

Hybrid QM:QM (quantum mechanics:quantum mechanics) and QM:MM (quantum mechanics:molecular mechanics) methods are widely used to calculate the electronic structure of large systems where a full quantum mechanical treatment at a desired high level of theory is computationally prohibitive. The ONIOM (our own N-layer integrated molecular orbital molecular mechanics) approximation is one of the more popular hybrid methods, where the total molecular system is divided into multiple layers, each treated at a different level of theory. In a previous publication, we developed a novel QM:QM electronic embedding scheme within the ONIOM framework, where the model system is embedded in the external Mulliken point charges of the surrounding low-level region to account for the polarization of the model system wave function. Therein, we derived and implemented a rigorous expression for the embedding energy as well as analytic gradients that depend on the derivatives of the external Mulliken point charges. In this work, we demonstrate the applicability of our QM:QM method with point charge embedding and assess its accuracy. We study two challenging systems--zinc metalloenzymes and silicon oxide cages--and demonstrate that electronic embedding shows significant improvement over mechanical embedding. We also develop a modified technique for the energy and analytic gradients using a generalized asymmetric Mulliken embedding method involving an unequal splitting of the Mulliken overlap populations to offer improvement in situations where the Mulliken charges may be deficient.

Cumulative atomic multipole moments complement any atomic charge model to obtain more accurate electrostatic properties

NASA Technical Reports Server (NTRS)

Sokalski, W. A.; Shibata, M.; Ornstein, R. L.; Rein, R.

1992-01-01

The quality of several atomic charge models based on different definitions has been analyzed using cumulative atomic multipole moments (CAMM). This formalism can generate higher atomic moments starting from any atomic charges, while preserving the corresponding molecular moments. The atomic charge contribution to the higher molecular moments, as well as to the electrostatic potentials, has been examined for CO and HCN molecules at several different levels of theory. The results clearly show that the electrostatic potential obtained from CAMM expansion is convergent up to R-5 term for all atomic charge models used. This illustrates that higher atomic moments can be used to supplement any atomic charge model to obtain more accurate description of electrostatic properties.

Animation Model to Conceptualize ATP Generation: A Mitochondrial Oxidative Phosphorylation

ERIC Educational Resources Information Center

Jena, Ananta Kumar

2015-01-01

Adenosine triphosphate (ATP) is the molecular unit of intracellular energy and it is the product of oxidative phosphorylation of cellular respiration uses in cellular processes. The study explores the growth of the misconception levels amongst the learners and evaluates the effectiveness of animation model over traditional methods. The data…

Predictive Mechanical Characterization of Macro-Molecular Material Chemistry Structures of Cement Paste at Nano Scale - Two-phase Macro-Molecular Structures of Calcium Silicate Hydrate, Tri-Calcium Silicate, Di-Calcium Silicate and Calcium Hydroxide

NASA Astrophysics Data System (ADS)

Padilla Espinosa, Ingrid Marcela

Concrete is a hierarchical composite material with a random structure over a wide range of length scales. At submicron length scale the main component of concrete is cement paste, formed by the reaction of Portland cement clinkers and water. Cement paste acts as a binding matrix for the other components and is responsible for the strength of concrete. Cement paste microstructure contains voids, hydrated and unhydrated cement phases. The main crystalline phases of unhydrated cement are tri-calcium silicate (C3S) and di-calcium silicate (C2S), and of hydrated cement are calcium silicate hydrate (CSH) and calcium hydroxide (CH). Although efforts have been made to comprehend the chemical and physical nature of cement paste, studies at molecular level have primarily been focused on individual components. Present research focuses on the development of a method to model, at molecular level, and analysis of the two-phase combination of hydrated and unhydrated phases of cement paste as macromolecular systems. Computational molecular modeling could help in understanding the influence of the phase interactions on the material properties, and mechanical performance of cement paste. Present work also strives to create a framework for molecular level models suitable for potential better comparisons with low length scale experimental methods, in which the sizes of the samples involve the mixture of different hydrated and unhydrated crystalline phases of cement paste. Two approaches based on two-phase cement paste macromolecular structures, one involving admixed molecular phases, and the second involving cluster of two molecular phases are investigated. The mechanical properties of two-phase macromolecular systems of cement paste consisting of key hydrated phase CSH and unhydrated phases C3S or C2S, as well as CSH with the second hydrated phase CH were calculated. It was found that these cement paste two-phase macromolecular systems predicted an isotropic material behavior. Also, these systems exhibited a high bulk modulus, compared to the elastic modulus. These results are an indication and concur with the high compression strength of cement paste seen at engineering length scale. In addition, the bulk modulus of two-phase systems consisting of hydrated CSH and unhydrated C3S or C2S was found to increase with higher levels of unhydrated components. The interaction energies of two-phase cement paste molecular structures studied in the present work were calculated, showing that a higher interaction is attained when the two phases are admixed as small components instead of cluster of phases. Finally, the mechanical behavior under shear deformation was predicted by using a quasi-static deformation method and analyzed for a representative two-phase (CSH and C2S) macromolecular structure of cement paste.

Cavity hydration dynamics in cytochrome c oxidase and functional implications

PubMed Central

Son, Chang Yun; Cui, Qiang

2017-01-01

Cytochrome c oxidase (CcO) is a transmembrane protein that uses the free energy of O2 reduction to generate the proton concentration gradient across the membrane. The regulation of competitive proton transfer pathways has been established to be essential to the vectorial transport efficiency of CcO, yet the underlying mechanism at the molecular level remains lacking. Recent studies have highlighted the potential importance of hydration-level change in an internal cavity that connects the proton entrance channel, the site of O2 reduction, and the putative proton exit route. In this work, we use atomistic molecular dynamics simulations to investigate the energetics and timescales associated with the volume fluctuation and hydration-level change in this central cavity. Extensive unrestrained molecular dynamics simulations (accumulatively ∼4 μs) and free energy computations for different chemical states of CcO support a model in which the volume and hydration level of the cavity are regulated by the protonation state of a propionate group of heme a3 and, to a lesser degree, the redox state of heme a and protonation state of Glu286. Markov-state model analysis of ∼2-μs trajectories suggests that hydration-level change occurs on the timescale of 100–200 ns before the proton-loading site is protonated. The computed energetic and kinetic features for the cavity wetting transition suggest that reversible hydration-level change of the cavity can indeed be a key factor that regulates the branching of proton transfer events and therefore contributes to the vectorial efficiency of proton transport. PMID:28973914

Finite Element Analysis of Influence of Axial Position of Center of Rotation of a Cervical Total Disc Replacement on Biomechanical Parameters: Simulated 2-Level Replacement Based on a Validated Model.

PubMed

Li, Yang; Zhang, Zhenjun; Liao, Zhenhua; Mo, Zhongjun; Liu, Weiqiang

2017-10-01

Finite element models have been widely used to predict biomechanical parameters of the cervical spine. Previous studies investigated the influence of position of rotational centers of prostheses on cervical biomechanical parameters after 1-level total disc replacement. The purpose of this study was to explore the effects of axial position of rotational centers of prostheses on cervical biomechanics after 2-level total disc replacement. A validated finite element model of C3-C7 segments and 2 prostheses, including the rotational center located at the superior endplate (SE) and inferior endplate (IE), was developed. Four total disc replacement models were used: 1) IE inserted at C4-C5 disc space and IE inserted at C5-C6 disc space (IE-IE), 2) IE-SE, 3) SE-IE, and 4) SE-SE. All models were subjected to displacement control combined with a 50 N follower load to simulate flexion and extension motions in the sagittal plane. For each case, biomechanical parameters, including predicted moments, range of rotation at each level, facet joint stress, and von Mises stress on the ultra-high-molecular-weight polyethylene core of the prostheses, were calculated. The SE-IE model resulted in significantly lower stress at the cartilage level during extension and at the ultra-high-molecular-weight polyethylene cores when compared with the SE-SE construct and did not generate hypermotion at the C4-C5 level compared with the IE-SE and IE-IE constructs. Based on the present analysis, the SE-IE construct is recommended for treating cervical disease at the C4-C6 level. This study may provide a useful model to inform clinical operations. Copyright © 2017 Elsevier Inc. All rights reserved.

Computational Design of Materials: Planetary Entry to Electric Aircraft and Beyond

NASA Technical Reports Server (NTRS)

Thompson, Alexander; Lawson, John W.

2014-01-01

NASA's projects and missions push the bounds of what is possible. To support the agency's work, materials development must stay on the cutting edge in order to keep pace. Today, researchers at NASA Ames Research Center perform multiscale modeling to aid the development of new materials and provide insight into existing ones. Multiscale modeling enables researchers to determine micro- and macroscale properties by connecting computational methods ranging from the atomic level (density functional theory, molecular dynamics) to the macroscale (finite element method). The output of one level is passed on as input to the next level, creating a powerful predictive model.

Students' understanding of primary and secondary protein structure: drawing secondary protein structure reveals student understanding better than simple recognition of structures.

PubMed

Harle, Marissa; Towns, Marcy H

2013-01-01

The interdisciplinary nature of biochemistry courses requires students to use both chemistry and biology knowledge to understand biochemical concepts. Research that has focused on external representations in biochemistry has uncovered student difficulties in comprehending and interpreting external representations in addition to a fragmented understanding of fundamental biochemistry concepts. This project focuses on students' understanding of primary and secondary protein structure and drawings (representations) of hydrogen-bonding in alpha helices and beta sheets. Analysis demonstrated that students can recognize and identify primary protein structure concepts when given a polypeptide. However, when asked to draw alpha helices and beta sheets and explain the role of hydrogen bonding their drawings students exhibited a fragmented understanding that lacked coherence. Faculty are encouraged to have students draw molecular level representations to make their mental models more explicit, complete, and coherent. This is in contrast to recognition and identification tasks, which do not adequately probe mental models and molecular level understanding. © 2013 by The International Union of Biochemistry and Molecular Biology.

Quasiparticle energies and lifetimes in a metallic chain model of a tunnel junction.

PubMed

Szepieniec, Mark; Yeriskin, Irene; Greer, J C

2013-04-14

As electronics devices scale to sub-10 nm lengths, the distinction between "device" and "electrodes" becomes blurred. Here, we study a simple model of a molecular tunnel junction, consisting of an atomic gold chain partitioned into left and right electrodes, and a central "molecule." Using a complex absorbing potential, we are able to reproduce the single-particle energy levels of the device region including a description of the effects of the semi-infinite electrodes. We then use the method of configuration interaction to explore the effect of correlations on the system's quasiparticle peaks. We find that when excitations on the leads are excluded, the device's highest occupied molecular orbital and lowest unoccupied molecular orbital quasiparticle states when including correlation are bracketed by their respective values in the Hartree-Fock (Koopmans) and ΔSCF approximations. In contrast, when excitations on the leads are included, the bracketing property no longer holds, and both the positions and the lifetimes of the quasiparticle levels change considerably, indicating that the combined effect of coupling and correlation is to alter the quasiparticle spectrum significantly relative to an isolated molecule.

Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin.

PubMed

Sogo, Takayuki; Terahara, Norihiko; Hisanaga, Ayami; Kumamoto, Takuma; Yamashiro, Takaaki; Wu, Shusong; Sakao, Kozue; Hou, De-Xing

2015-01-01

Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin, was isolated from the dried calices of Hibiscus sabdariffa L, which has been used for folk beverages and herbal medicine although the molecular mechanisms are poorly defined. Based on the properties of Dp3-Sam and the information of inflammatory processes, we investigated the anti-inflammatory activity and molecular mechanisms in both cell and animal models in the present study. In the cell model, Dp3-Sam and Delphinidin (Dp) reduced the levels of inflammatory mediators including iNOS, NO, IL-6, MCP-1, and TNF-α induced by LPS. Cellular signaling analysis revealed that Dp3-Sam and Dp downregulated NF-κB pathway and MEK1/2-ERK1/2 signaling. In animal model, Dp3-Sam and Dp reduced the production of IL-6, MCP-1 and TNF-α and attenuated mouse paw edema induced by LPS. Our in vitro and in vivo data demonstrated that Hibiscus Dp3-Sam possessed potential anti-inflammatory properties. © 2015 International Union of Biochemistry and Molecular Biology.

Multiscale Modeling of PEEK Using Reactive Molecular Dynamics Modeling and Micromechanics

NASA Technical Reports Server (NTRS)

Pisani, William A.; Radue, Matthew; Chinkanjanarot, Sorayot; Bednarcyk, Brett A.; Pineda, Evan J.; King, Julia A.; Odegard, Gregory M.

2018-01-01

Polyether ether ketone (PEEK) is a high-performance, semi-crystalline thermoplastic that is used in a wide range of engineering applications, including some structural components of aircraft. The design of new PEEK-based materials requires a precise understanding of the multiscale structure and behavior of semi-crystalline PEEK. Molecular Dynamics (MD) modeling can efficiently predict bulk-level properties of single phase polymers, and micromechanics can be used to homogenize those phases based on the overall polymer microstructure. In this study, MD modeling was used to predict the mechanical properties of the amorphous and crystalline phases of PEEK. The hierarchical microstructure of PEEK, which combines the aforementioned phases, was modeled using a multiscale modeling approach facilitated by NASA's MSGMC. The bulk mechanical properties of semi-crystalline PEEK predicted using MD modeling and MSGMC agree well with vendor data, thus validating the multiscale modeling approach.

Fragment-Based Electronic Structure Approach for Computing Nuclear Magnetic Resonance Chemical Shifts in Molecular Crystals.

PubMed

Hartman, Joshua D; Beran, Gregory J O

2014-11-11

First-principles chemical shielding tensor predictions play a critical role in studying molecular crystal structures using nuclear magnetic resonance. Fragment-based electronic structure methods have dramatically improved the ability to model molecular crystal structures and energetics using high-level electronic structure methods. Here, a many-body expansion fragment approach is applied to the calculation of chemical shielding tensors in molecular crystals. First, the impact of truncating the many-body expansion at different orders and the role of electrostatic embedding are examined on a series of molecular clusters extracted from molecular crystals. Second, the ability of these techniques to assign three polymorphic forms of the drug sulfanilamide to the corresponding experimental (13)C spectra is assessed. This challenging example requires discriminating among spectra whose (13)C chemical shifts differ by only a few parts per million (ppm) across the different polymorphs. Fragment-based PBE0/6-311+G(2d,p) level chemical shielding predictions correctly assign these three polymorphs and reproduce the sulfanilamide experimental (13)C chemical shifts with 1 ppm accuracy. The results demonstrate that fragment approaches are competitive with the widely used gauge-invariant projector augmented wave (GIPAW) periodic density functional theory calculations.

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

NASA Astrophysics Data System (ADS)

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

2006-05-01

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

Construction of specific magnetic resonance imaging/optical dual-modality molecular probe used for imaging angiogenesis of gastric cancer.

PubMed

Yan, Xuejie; Song, Xiaoyan; Wang, Zhenbo

2017-05-01

The purpose of the study was to construct specific magnetic resonance imaging (MRI)/optical dual-modality molecular probe. Tumor-bearing animal models were established. MRI/optical dual-modality molecular probe was construed by coupling polyethylene glycol (PEG)-modified nano-Fe 3 O 4 with specific targeted cyclopeptide GX1 and near-infrared fluorescent dyes Cy5.5. MRI/optical imaging effects of the probe were observed and the feasibility of in vivo double-modality imaging was discussed. It was found that, the double-modality probe was of high stability; tumor signal of the experimental group tended to be weak after injection of the probe, but rose to a level which was close to the previous level after 18 h (p > 0.05). We successively completed the construction of an ideal MRI/optical dual-modality molecular probe. MRI/optical dual-modality molecular probe which can selectively gather in gastric cancer is expected to be a novel probe used for diagnosing gastric cancer in the early stage.

Exploration of target molecules for molecular imaging of inflammatory bowel disease

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

Higashikawa, Kei; Akada, Naoki; Yagi, Katsuharu

2011-07-08

Highlights: {sup {yields}18}F-FDG PET could discriminate each inflamed area of IBD model mice clearly. {sup {yields}18}F-FDG PET could not discriminate the difference of pathogenic mechanism. {yields} Cytokines and cytokine receptors expression was different by pathogenic mechanism. {yields} Cytokines and cytokine receptors would be new target molecules for IBD imaging. -- Abstract: Molecular imaging technology is a powerful tool for the diagnosis of inflammatory bowel disease (IBD) and the efficacy evaluation of various drug therapies for it. However, it is difficult to elucidate directly the relationships between the responsible molecules and IBD using existing probes. Therefore, the development of an alternativemore » probe that is able to elucidate the pathogenic mechanism and provide information on the appropriate guidelines for treatment is earnestly awaited. In this study, we investigated pathognomonic molecules in the intestines of model mice. The accumulation of fluorine-18 fluorodeoxyglucose ({sup 18}F-FDG) in the inflamed area of the intestines of dextran sulfate sodium (DSS)- or indomethacin (IND)-induced IBD model mice was measured by positron emission tomography (PET) and autoradiography to confirm the inflamed area. The results suggested that the inflammation was selectively induced in the colons of mice by the administration of DSS, whereas it was induced mainly in the ilea and the proximal colons of mice by the administration of IND. To explore attractive target molecules for the molecular imaging of IBD, we evaluated the gene expression levels of cytokines and cytokine receptors in the inflamed area of the intestines of both model mice. We found that the expression levels of cytokines and cytokine receptors were significantly increased during the progression of IBD, whereas the expression levels were decreased as the mucosa began to heal. In particular, the expression levels of these molecules had already changed before the symptoms of IBD appeared. In addition, the alterations of cytokine and cytokine receptor expression levels indicated differences in the expression pattern depending on the pathogenic mechanism or the region of inflammation (e.g., TNF-{alpha}). Our results suggest that these cytokines or cytokine receptors participate in the pathogenesis of IBD and are valuable biomarkers for the detection of the different circumstances underlying inflammation by the molecular imaging method. Finally, the development of an imaging probe for our target molecules is expected to improve our understanding of the inflammatory conditions of IBD.« less

Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

PubMed Central

Kiss, Tibor; Jungling, Adel

2017-01-01

ABSTRACT Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. PMID:28067625

Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

PubMed

Maasz, Gabor; Zrinyi, Zita; Reglodi, Dora; Petrovics, Dora; Rivnyak, Adam; Kiss, Tibor; Jungling, Adel; Tamas, Andrea; Pirger, Zsolt

2017-02-01

Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. © 2017. Published by The Company of Biologists Ltd.

Molecular deformation mechanisms of the wood cell wall material.

PubMed

Jin, Kai; Qin, Zhao; Buehler, Markus J

2015-02-01

Wood is a biological material with outstanding mechanical properties resulting from its hierarchical structure across different scales. Although earlier work has shown that the cellular structure of wood is a key factor that renders it excellent mechanical properties at light weight, the mechanical properties of the wood cell wall material itself still needs to be understood comprehensively. The wood cell wall material features a fiber reinforced composite structure, where cellulose fibrils act as stiff fibers, and hemicellulose and lignin molecules act as soft matrix. The angle between the fiber direction and the loading direction has been found to be the key factor controlling the mechanical properties. However, how the interactions between theses constitutive molecules contribute to the overall properties is still unclear, although the shearing between fibers has been proposed as a primary deformation mechanism. Here we report a molecular model of the wood cell wall material with atomistic resolution, used to assess the mechanical behavior under shear loading in order to understand the deformation mechanisms at the molecular level. The model includes an explicit description of cellulose crystals, hemicellulose, as well as lignin molecules arranged in a layered nanocomposite. The results obtained using this model show that the wood cell wall material under shear loading deforms in an elastic and then plastic manner. The plastic regime can be divided into two parts according to the different deformation mechanisms: yielding of the matrix and sliding of matrix along the cellulose surface. Our molecular dynamics study provides insights of the mechanical behavior of wood cell wall material at the molecular level, and paves a way for the multi-scale understanding of the mechanical properties of wood. Copyright © 2014 Elsevier Ltd. All rights reserved.

SOMO–HOMO Level Inversion in Biologically Important Radicals

PubMed Central

2017-01-01

Conventionally, the singly occupied molecular orbital (SOMO) of a radical species is considered to be the highest occupied molecular orbital (HOMO), but this is not the case always. In this study, we considered a number of radicals from smallest diatomic anion radicals such as superoxide anion radical to one-electron oxidized DNA related base radicals that show the SOMO is energetically lower than one or more doubly occupied molecular orbitals (MOs) (SOMO–HOMO level inversion). The electronic configurations are calculated employing the B3LYP/6-31++G** method, with the inclusion of aqueous phase via the integral equation formalism of the polarized continuum model solvation model. From the extensive study of the electronic configurations of radicals produced by one-electron oxidation or reduction of natural-DNA bases, bromine-, sulfur-, selenium-, and aza-substituted DNA bases, as well as 20 diatomic molecules, we highlight the following important findings: (i) SOMO–HOMO level inversion is a common phenomenon in radical species. (ii) The more localized spin density in σ-orbital on a single atom (carbon, nitrogen, oxygen, sulfur, or selenium), the greater the gap between HOMO and SOMO. (iii) In species with SOMO–HOMO level inversion, one-electron oxidation takes place from HOMO not from the SOMO, which produces a molecule in its triplet ground state. Oxidation of aqueous superoxide anion producing triplet molecular oxygen is one example of many. (iv) These results are for conventional radicals and in contrast with those reported for distonic radical anions in which SOMO–HOMO gaps are smaller for more localized radicals and the orbital inversions vanish in water. Our findings yield new insights into the properties of free radical systems. PMID:29240424

Transport Phenomena of Water in Molecular Fluidic Channels

PubMed Central

Vo, Truong Quoc; Kim, BoHung

2016-01-01

In molecular-level fluidic transport, where the discrete characteristics of a molecular system are not negligible (in contrast to a continuum description), the response of the molecular water system might still be similar to the continuum description if the time and ensemble averages satisfy the ergodic hypothesis and the scale of the average is enough to recover the classical thermodynamic properties. However, even in such cases, the continuum description breaks down on the material interfaces. In short, molecular-level liquid flows exhibit substantially different physics from classical fluid transport theories because of (i) the interface/surface force field, (ii) thermal/velocity slip, (iii) the discreteness of fluid molecules at the interface and (iv) local viscosity. Therefore, in this study, we present the result of our investigations using molecular dynamics (MD) simulations with continuum-based energy equations and check the validity and limitations of the continuum hypothesis. Our study shows that when the continuum description is subjected to the proper treatment of the interface effects via modified boundary conditions, the so-called continuum-based modified-analytical solutions, they can adequately predict nanoscale fluid transport phenomena. The findings in this work have broad effects in overcoming current limitations in modeling/predicting the fluid behaviors of molecular fluidic devices. PMID:27650138

Application of Deep Learning in Automated Analysis of Molecular Images in Cancer: A Survey

PubMed Central

Xue, Yong; Chen, Shihui; Liu, Yong

2017-01-01

Molecular imaging enables the visualization and quantitative analysis of the alterations of biological procedures at molecular and/or cellular level, which is of great significance for early detection of cancer. In recent years, deep leaning has been widely used in medical imaging analysis, as it overcomes the limitations of visual assessment and traditional machine learning techniques by extracting hierarchical features with powerful representation capability. Research on cancer molecular images using deep learning techniques is also increasing dynamically. Hence, in this paper, we review the applications of deep learning in molecular imaging in terms of tumor lesion segmentation, tumor classification, and survival prediction. We also outline some future directions in which researchers may develop more powerful deep learning models for better performance in the applications in cancer molecular imaging. PMID:29114182

Modeling Protein Expression and Protein Signaling Pathways

PubMed Central

Telesca, Donatello; Müller, Peter; Kornblau, Steven M.; Suchard, Marc A.; Ji, Yuan

2015-01-01

High-throughput functional proteomic technologies provide a way to quantify the expression of proteins of interest. Statistical inference centers on identifying the activation state of proteins and their patterns of molecular interaction formalized as dependence structure. Inference on dependence structure is particularly important when proteins are selected because they are part of a common molecular pathway. In that case, inference on dependence structure reveals properties of the underlying pathway. We propose a probability model that represents molecular interactions at the level of hidden binary latent variables that can be interpreted as indicators for active versus inactive states of the proteins. The proposed approach exploits available expert knowledge about the target pathway to define an informative prior on the hidden conditional dependence structure. An important feature of this prior is that it provides an instrument to explicitly anchor the model space to a set of interactions of interest, favoring a local search approach to model determination. We apply our model to reverse-phase protein array data from a study on acute myeloid leukemia. Our inference identifies relevant subpathways in relation to the unfolding of the biological process under study. PMID:26246646

Design and Analysis of a Petri Net Model of the Von Hippel-Lindau (VHL) Tumor Suppressor Interaction Network

PubMed Central

Minervini, Giovanni; Panizzoni, Elisabetta; Giollo, Manuel; Masiero, Alessandro; Ferrari, Carlo; Tosatto, Silvio C. E.

2014-01-01

Von Hippel-Lindau (VHL) syndrome is a hereditary condition predisposing to the development of different cancer forms, related to germline inactivation of the homonymous tumor suppressor pVHL. The best characterized function of pVHL is the ubiquitination dependent degradation of Hypoxia Inducible Factor (HIF) via the proteasome. It is also involved in several cellular pathways acting as a molecular hub and interacting with more than 200 different proteins. Molecular details of pVHL plasticity remain in large part unknown. Here, we present a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways. PMID:24886840

Design and analysis of a Petri net model of the Von Hippel-Lindau (VHL) tumor suppressor interaction network.

PubMed

Minervini, Giovanni; Panizzoni, Elisabetta; Giollo, Manuel; Masiero, Alessandro; Ferrari, Carlo; Tosatto, Silvio C E

2014-01-01

Von Hippel-Lindau (VHL) syndrome is a hereditary condition predisposing to the development of different cancer forms, related to germline inactivation of the homonymous tumor suppressor pVHL. The best characterized function of pVHL is the ubiquitination dependent degradation of Hypoxia Inducible Factor (HIF) via the proteasome. It is also involved in several cellular pathways acting as a molecular hub and interacting with more than 200 different proteins. Molecular details of pVHL plasticity remain in large part unknown. Here, we present a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways.

Simulating the Physical World

NASA Astrophysics Data System (ADS)

Berendsen, Herman J. C.

2004-06-01

The simulation of physical systems requires a simplified, hierarchical approach which models each level from the atomistic to the macroscopic scale. From quantum mechanics to fluid dynamics, this book systematically treats the broad scope of computer modeling and simulations, describing the fundamental theory behind each level of approximation. Berendsen evaluates each stage in relation to its applications giving the reader insight into the possibilities and limitations of the models. Practical guidance for applications and sample programs in Python are provided. With a strong emphasis on molecular models in chemistry and biochemistry, this book will be suitable for advanced undergraduate and graduate courses on molecular modeling and simulation within physics, biophysics, physical chemistry and materials science. It will also be a useful reference to all those working in the field. Additional resources for this title including solutions for instructors and programs are available online at www.cambridge.org/9780521835275. The first book to cover the wide range of modeling and simulations, from atomistic to the macroscopic scale, in a systematic fashion Providing a wealth of background material, it does not assume advanced knowledge and is eminently suitable for course use Contains practical examples and sample programs in Python

Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes

PubMed Central

Sharabi, Kfir; Lecuona, Emilia; Helenius, Iiro Taneli; Beitel, Greg J; Sznajder, Jacob Iasha; Gruenbaum, Yosef

2009-01-01

Carbon dioxide (CO2) is an important gaseous molecule that maintains biosphere homeostasis and is an important cellular signalling molecule in all organisms. The transport of CO2 through membranes has fundamental roles in most basic aspects of life in both plants and animals. There is a growing interest in understanding how CO2 is transported into cells, how it is sensed by neurons and other cell types and in understanding the physiological and molecular consequences of elevated CO2 levels (hypercapnia) at the cell and organism levels. Human pulmonary diseases and model organisms such as fungi, C. elegans, Drosophila and mice have been proven to be important in understanding of the mechanisms of CO2 sensing and response. PMID:19863692

Correlation between phosphorylation level of a hippocampal 86kDa protein and extinction of a behaviour in a model of Wernicke-Korsakoff syndrome.

PubMed

Pires, Rita G W; Pereira, Sílvia R C; Carvalho, Fabiana M; Oliveira-Silva, Ieda F; Ferraz, Vany P; Ribeiro, Angela M

2007-06-04

The effects of chronic ethanol and thiamine deficiency, alone or associated, on hippocampal protein phosphorylation profiles ranging in molecular weight from 30 to 250kDa molecular weight, in stimulated (high K(+) concentration) and unstimulated (basal) conditions were investigated. These treatments significantly changed the phosphorylation level of an 86kDa phosphoprotein. Thiamine deficiency, but not chronic ethanol, induced a decrease in a behavioural extinction index, which is significantly correlated to the phosphorylation level of the p86 protein. These data add to and extend previous findings by our laboratory implicating the involvement of hippocampal neurotransmission components in extinction of a behaviour which involves learning of environmental spatial cues.

Analysis of conjugation of chloramphenicol and hemoglobin by fluorescence, circular dichroism and molecular modeling

NASA Astrophysics Data System (ADS)

Ding, Fei; Liu, Wei; Sun, Ye; Yang, Xin-Ling; Sun, Ying; Zhang, Li

2012-01-01

Chloramphenicol is a low cost, broad spectrum, highly active antibiotic, and widely used in the treatment of serious infections, including typhoid fever and other life-threatening infections of the central nervous system and respiratory tract. The purpose of the present study was to examine the conjugation of chloramphenicol with hemoglobin (Hb) and compared with albumin at molecular level, utilizing fluorescence, UV/vis absorption, circular dichroism (CD) as well as molecular modeling. Fluorescence data indicate that drug bind Hb generate quenching via static mechanism, this corroborates UV/vis absorption measurements that the ground state complex formation with an affinity of 10 4 M -1, and the driving forces in the Hb-drug complex are hydrophilic interactions and hydrogen bonds, as derived from computational model. The accurate binding site of drug has been identified from the analysis of fluorescence and molecular modeling, α1β2 interface of Hb was assigned to possess high-affinity for drug, which located at the β-37 Trp nearby. The structural investigation of the complexed Hb by synchronous fluorescence, UV/vis absorption, and CD observations revealed some degree of Hb structure unfolding upon complexation. Based on molecular modeling, we can draw the conclusion that the binding affinity of drug with albumin is superior, compared with Hb. These phenomena can provide salient information on the absorption, distribution, pharmacology, and toxicity of chloramphenicol and other drugs which have analogous configuration with chloramphenicol.

Thinking Like a Wolf, a Sheep, or a Firefly: Learning Biology through Constructing and Testing Computational Theories--An Embodied Modeling Approach

ERIC Educational Resources Information Center

Wilensky, Uri; Reisman, Kenneth

2006-01-01

Biological phenomena can be investigated at multiple levels, from the molecular to the cellular to the organismic to the ecological. In typical biology instruction, these levels have been segregated. Yet, it is by examining the connections between such levels that many phenomena in biology, and complex systems in general, are best explained. We…

Multi-scale genetic dynamic modelling I : an algorithm to compute generators.

PubMed

Kirkilionis, Markus; Janus, Ulrich; Sbano, Luca

2011-09-01

We present a new approach or framework to model dynamic regulatory genetic activity. The framework is using a multi-scale analysis based upon generic assumptions on the relative time scales attached to the different transitions of molecular states defining the genetic system. At micro-level such systems are regulated by the interaction of two kinds of molecular players: macro-molecules like DNA or polymerases, and smaller molecules acting as transcription factors. The proposed genetic model then represents the larger less abundant molecules with a finite discrete state space, for example describing different conformations of these molecules. This is in contrast to the representations of the transcription factors which are-like in classical reaction kinetics-represented by their particle number only. We illustrate the method by considering the genetic activity associated to certain configurations of interacting genes that are fundamental to modelling (synthetic) genetic clocks. A largely unknown question is how different molecular details incorporated via this more realistic modelling approach lead to different macroscopic regulatory genetic models which dynamical behaviour might-in general-be different for different model choices. The theory will be applied to a real synthetic clock in a second accompanying article (Kirkilioniset al., Theory Biosci, 2011).

Molecular Physiology of Root System Architecture in Model Grasses

NASA Astrophysics Data System (ADS)

Hixson, K.; Ahkami, A. H.; Anderton, C.; Veličković, D.; Myers, G. L.; Chrisler, W.; Lindenmaier, R.; Fang, Y.; Yabusaki, S.; Rosnow, J. J.; Farris, Y.; Khan, N. E.; Bernstein, H. C.; Jansson, C.

2017-12-01

Unraveling the molecular and physiological mechanisms involved in responses of Root System Architecture (RSA) to abiotic stresses and shifts in microbiome structure is critical to understand and engineer plant-microbe-soil interactions in the rhizosphere. In this study, accessions of Brachypodium distachyon Bd21 (C3 model grass) and Setaria viridis A10.1 (C4 model grass) were grown in phytotron chambers under current and elevated CO2 levels. Detailed growth stage-based phenotypic analysis revealed different above- and below-ground morphological and physiological responses in C3 and C4 grasses to enhanced CO2 levels. Based on our preliminary results and by screening values of total biomass, water use efficiency, root to shoot ratio, RSA parameters and net assimilation rates, we postulated a three-phase physiological mechanism, i.e. RootPlus, BiomassPlus and YieldPlus phases, for grass growth under elevated CO2 conditions. Moreover, this comprehensive set of morphological and process-based observations are currently in use to develop, test, and calibrate biophysical whole-plant models and in particular to simulate leaf-level photosynthesis at various developmental stages of C3 and C4 using the model BioCro. To further link the observed phenotypic traits at the organismal level to tissue and molecular levels, and to spatially resolve the origin and fate of key metabolites involved in primary carbohydrate metabolism in different root sections, we complement root phenotypic observations with spatial metabolomics data using mass spectrometry imaging (MSI) methods. Focusing on plant-microbe interactions in the rhizosphere, six bacterial strains with plant growth promoting features are currently in use in both gel-based and soil systems to screen root growth and development in Brachypodium. Using confocal microscopy, GFP-tagged bacterial systems are utilized to study the initiation of different root types of RSA, including primary root (PR), coleoptile node axile root (CNR) and leaf node axile root (LNR) during developmental stages of root formation. The root exudates also will be quantified and preliminary data will be used to engineer our microbial consortium to improve plant growth.

Roles of water in protein structure and function studied by molecular liquid theory.

PubMed

Imai, Takashi

2009-01-01

The roles of water in the structure and function of proteins have not been completely elucidated. Although molecular simulation has been widely used for the investigation of protein structure and function, it is not always useful for elucidating the roles of water because the effect of water ranges from atomic to thermodynamic level. The three-dimensional reference interaction site model (3D-RISM) theory, which is a statistical-mechanical theory of molecular liquids, can yield the solvation structure at the atomic level and calculate the thermodynamic quantities from the intermolecular potentials. In the last few years, the author and coworkers have succeeded in applying the 3D-RISM theory to protein aqueous solution systems and demonstrated that the theory is useful for investigating the roles of water. This article reviews some of the recent applications and findings, which are concerned with molecular recognition by protein, protein folding, and the partial molar volume of protein which is related to the pressure effect on protein.

EGF targeted fluorescence molecular tomography as a predictor of PDT outcomes in pancreas cancer models

NASA Astrophysics Data System (ADS)

Samkoe, Kimberley S.; Davis, Scott C.; Srinivasan, Subhadra; Isabelle, Martin E.; O'Hara, Julia; Hasan, Tayyaba; Pogue, Brian W.

2010-02-01

Verteporfin photodynamic therapy (PDT) is a promising adjuvant therapy for pancreas cancer and investigations for its use are currently underway in both orthotopic xenograft mouse models and in human clinical trials. The mouse models have been studied extensively using magnetic resonance (MR) imaging as a measure of surrogate response to verteporfin PDT and it was found that tumor lines with different levels of aggression respond with varying levels to PDT. MR imaging was successful in determining the necrotic volume caused by PDT but there was difficultly in distinguishing inflamed tissues and regions of surviving tumor. In order to understand the molecular changes within the tumor immediately post-PDT we propose the implementation of MR-guided fluorescence molecular tomography (FMT) in conjunction with an exogenously administered fluorescently labeled epidermal growth factor (EGF-IRDye800CW, LI-COR Biosciences). We have previously shown that MR-guided FMT is feasible in the mouse abdomen when multiple regions of fluorescence are considered from contributing internal organs. In this case the highly aggressive AsPC-1 (+EGFR) orthotopic tumor was implanted in SCID mice, interstitial verteporfin PDT (1mg/kg, 20J/cm) was performed when the tumor reached ~60mm3 and both tumor volume and EGF binding were followed with MR-guided FMT.

Multiscale Analysis of Delamination of Carbon Fiber-Epoxy Laminates with Carbon Nanotubes

NASA Technical Reports Server (NTRS)

Riddick, Jaret C.; Frankland, SJV; Gates, TS

2006-01-01

A multi-scale analysis is presented to parametrically describe the Mode I delamination of a carbon fiber/epoxy laminate. In the midplane of the laminate, carbon nanotubes are included for the purposes of selectively enhancing the fracture toughness of the laminate. To analyze carbon fiber epoxy carbon nanotube laminate, the multi-scale methodology presented here links a series of parameterizations taken at various length scales ranging from the atomistic through the micromechanical to the structural level. At the atomistic scale molecular dynamics simulations are performed in conjunction with an equivalent continuum approach to develop constitutive properties for representative volume elements of the molecular structure of components of the laminate. The molecular-level constitutive results are then used in the Mori-Tanaka micromechanics to develop bulk properties for the epoxy-carbon nanotube matrix system. In order to demonstrate a possible application of this multi-scale methodology, a double cantilever beam specimen is modeled. An existing analysis is employed which uses discrete springs to model the fiber bridging affect during delamination propagation. In the absence of empirical data or a damage mechanics model describing the effect of CNTs on fracture toughness, several tractions laws are postulated, linking CNT volume fraction to fiber bridging in a DCB specimen. Results from this demonstration are presented in terms of DCB specimen load-displacement responses.

Effects on DNA Damage and/or Repair Processes as Biological Mechanisms Linking Psychological Stress to Cancer Risk

PubMed Central

Jenkins, Frank J.; Van Houten, Bennett; Bovbjerg, Dana H.

2014-01-01

Considerable research effort in the past several decades has focused on the impact of psychological stress, and stress hormones, on cancer progression. Numerous studies have reported that stress hormone treatment or in vivo stress exposure can enhance the growth of tumor cell lines in vitro, as well as tumors in animal models, and have begun to explore molecular mechanisms. Comparatively little research has focused on the impact of psychological stress and stress hormones on cancer initiation, in part due to inherent methodological challenges, but also because potential underlying biological mechanisms have remained obscure. In this review, we present a testable theoretical model of pathways by which stress may result in cellular transformation and tumorigenesis. This model supports our overarching hypothesis that psychological stress, acting through increased levels of catecholamines and/or cortisol, can increase DNA damage and/or reduce repair mechanisms, resulting in increased risk of DNA mutations leading to carcinogenesis. A better understanding of molecular pathways by which psychological stress can increase the risk of cancer initiation would open new avenues of translational research, bringing together psychologists, neuroscientists, and molecular biologists, potentially resulting in the development of novel approaches for cancer risk reduction at the population level. PMID:24891812

Quantitative ultrasound molecular imaging by modeling the binding kinetics of targeted contrast agent

NASA Astrophysics Data System (ADS)

Turco, Simona; Tardy, Isabelle; Frinking, Peter; Wijkstra, Hessel; Mischi, Massimo

2017-03-01

Ultrasound molecular imaging (USMI) is an emerging technique to monitor diseases at the molecular level by the use of novel targeted ultrasound contrast agents (tUCA). These consist of microbubbles functionalized with targeting ligands with high-affinity for molecular markers of specific disease processes, such as cancer-related angiogenesis. Among the molecular markers of angiogenesis, the vascular endothelial growth factor receptor 2 (VEGFR2) is recognized to play a major role. In response, the clinical-grade tUCA BR55 was recently developed, consisting of VEGFR2-targeting microbubbles which can flow through the entire circulation and accumulate where VEGFR2 is over-expressed, thus causing selective enhancement in areas of active angiogenesis. Discrimination between bound and free microbubbles is crucial to assess cancer angiogenesis. Currently, this is done non-quantitatively by looking at the late enhancement, about 10 min after injection, or by calculation of the differential targeted enhancement, requiring the application of a high-pressure ultrasound (US) burst to destroy all the microbubbles in the acoustic field and isolate the signal coming only from bound microbubbles. In this work, we propose a novel method based on mathematical modeling of the binding kinetics during the tUCA first pass, thus reducing the acquisition time and with no need for a destructive US burst. Fitting time-intensity curves measured with USMI by the proposed model enables the assessment of cancer angiogenesis at both the vascular and molecular levels. This is achieved by estimation of quantitative parameters related to the microvascular architecture and microbubble binding. The proposed method was tested in 11 prostate-tumor bearing rats by performing USMI after injection of BR55, and showed good agreement with current USMI methods. The novel information provided by the proposed method, possibly combined with the current non-quantitative methods, may bring deeper insight into cancer angiogenesis, and thus potentially improve cancer diagnosis and management.

Probing the brain with molecular fMRI.

PubMed

Ghosh, Souparno; Harvey, Peter; Simon, Jacob C; Jasanoff, Alan

2018-06-01

One of the greatest challenges of modern neuroscience is to incorporate our growing knowledge of molecular and cellular-scale physiology into integrated, organismic-scale models of brain function in behavior and cognition. Molecular-level functional magnetic resonance imaging (molecular fMRI) is a new technology that can help bridge these scales by mapping defined microscopic phenomena over large, optically inaccessible regions of the living brain. In this review, we explain how MRI-detectable imaging probes can be used to sensitize noninvasive imaging to mechanistically significant components of neural processing. We discuss how a combination of innovative probe design, advanced imaging methods, and strategies for brain delivery can make molecular fMRI an increasingly successful approach for spatiotemporally resolved studies of diverse neural phenomena, perhaps eventually in people. Copyright © 2018 Elsevier Ltd. All rights reserved.

A molecular topology approach to predicting pesticide pollution of groundwater

USGS Publications Warehouse

Worrall , Fred

2001-01-01

Various models have proposed methods for the discrimination of polluting and nonpolluting compounds on the basis of simple parameters, typically adsorption and degradation constants. However, such attempts are prone to site variability and measurement error to the extent that compounds cannot be reliably classified nor the chemistry of pollution extrapolated from them. Using observations of pesticide occurrence in U.S. groundwater it is possible to show that polluting from nonpolluting compounds can be distinguished purely on the basis of molecular topology. Topological parameters can be derived without measurement error or site-specific variability. A logistic regression model has been developed which explains 97% of the variation in the data, with 86% of the variation being explained by the rule that a compound will be found in groundwater if 6 < 0.55. Where 6χp is the sixth-order molecular path connectivity. One group of compounds cannot be classified by this rule and prediction requires reference to higher order connectivity parameters. The use of molecular approaches for understanding pollution at the molecular level and their application to agrochemical development and risk assessment is discussed.

Cluster model studies of anion and molecular specificities via electrospray ionization photoelectron spectroscopy

DOE PAGES

Wang, Xue -Bin

2017-01-06

Ion specificity, a widely observed macroscopic phenomenon in condensed phases and at interfaces, is essentially a fundamental chemical physical issue. We have been investigating such effects using cluster models in an “atom-by-atom” and “molecule-by-molecule” fashion not possible with condensed-phase methods. We use electrospray ionization (ESI) to generate molecular and ionic clusters to simulate key molecular entities involved in local binding regions, and characterize them employing negative ion photoelectron spectroscopy (NIPES). Inter- and intramolecular interactions and binding configurations are directly obtained as functions of cluster size and composition, providing insightful molecular-level description and characterization over the local active sites that playmore » crucial roles in determining solution chemistry and condensed phase phenomena. Finally, the topics covered in this article are relevant to a wide scope of research fields ranging from ion specific effects in electrolyte solutions, ion selectivity/recognition in normal functioning of life, to molecular specificity in aerosol particle formation, as well as in rational material design and synthesis.« less

Lanthanide and transition metal complexes of bioactive coumarins: molecular modeling and spectroscopic studies.

PubMed

Georgieva, I; Mihaylov, Tz; Trendafilova, N

2014-06-01

The present paper summarizes theoretical and spectroscopic investigations on a series of active coumarins and their lanthanide and transition metal complexes with application in medicine and pharmacy. Molecular modeling as well as IR, Raman, NMR and electronic spectral simulations at different levels of theory were performed to obtain important molecular descriptors: total energy, formation energy, binding energy, stability, conformations, structural parameters, electron density distribution, molecular electrostatic potential, Fukui functions, atomic charges, and reactive indexes. The computations are performed both in gas phase and in solution with consideration of the solvent effect on the molecular structural and energetic parameters. The investigations have shown that the advanced computational methods are reliable for prediction of the metal-coumarin binding mode, electron density distribution, thermodynamic properties as well as the strength and nature of the metal-coumarin interaction (not experimentally accessible) and correctly interpret the experimental spectroscopic data. Known results from biological tests for cytotoxic, antimicrobial, anti-fungal, spasmolytic and anti-HIV activities on the studied metal complexes are reported and discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Incorporation of Predictive Population Modeling into the AOP Famework: A Case Study with White Suckers Exposed to Pulp Effluent

EPA Science Inventory

A need in ecological risk assessment is the ability to create linkages between chemically-induced alterations at molecular and biochemical levels of organization with adverse outcomes in whole organisms and populations. A predictive model was developed to translate changes in th...

Length-scale dependent mechanical properties of Al-Cu eutectic alloy: Molecular dynamics based model and its experimental verification

NASA Astrophysics Data System (ADS)

Tiwary, C. S.; Chakraborty, S.; Mahapatra, D. R.; Chattopadhyay, K.

2014-05-01

This paper attempts to gain an understanding of the effect of lamellar length scale on the mechanical properties of two-phase metal-intermetallic eutectic structure. We first develop a molecular dynamics model for the in-situ grown eutectic interface followed by a model of deformation of Al-Al2Cu lamellar eutectic. Leveraging the insights obtained from the simulation on the behaviour of dislocations at different length scales of the eutectic, we present and explain the experimental results on Al-Al2Cu eutectic with various different lamellar spacing. The physics behind the mechanism is further quantified with help of atomic level energy model for different length scale as well as different strain. An atomic level energy partitioning of the lamellae and the interface regions reveals that the energy of the lamellae core are accumulated more due to dislocations irrespective of the length-scale. Whereas the energy of the interface is accumulated more due to dislocations when the length-scale is smaller, but the trend is reversed when the length-scale is large beyond a critical size of about 80 nm.

Radiative Heat Transfer modelling in a Heavy-Duty Diesel Engine

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

Paul, Chandan; Sircar, Arpan; Ferreyro-Fernandez, Sebastian

Detailed radiation modelling in piston engines has received relatively little attention to date. Recently, it is being revisited in light of current trends towards higher operating pressures and higher levels of exhaust-gas recirculation, both of which enhance molecular gas radiation. Advanced high-efficiency engines also are expected to function closer to the limits of stable operation, where even small perturbations to the energy balance can have a large influence on system behavior. Here several different spectral radiation property models and radiative transfer equation (RTE) solvers have been implemented in an OpenFOAM-based engine CFD code, and simulations have been performed for amore » heavy-duty diesel engine. Differences in computed temperature fields, NO and soot levels, and wall heat transfer rates are shown for different combinations of spectral models and RTE solvers. The relative importance of molecular gas radiation versus soot radiation is examined. And the influence of turbulence-radiation interactions is determined by comparing results obtained using local mean values of composition and temperature to compute radiative emission and absorption with those obtained using a particle-based transported probability density function method.« less

A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective interventions

PubMed Central

Phoenix, Chris

2007-01-01

The relative insensitivity of lifespan to environmental factors constitutes compelling evidence that the physiological decline associated with aging derives primarily from the accumulation of intrinsic molecular and cellular side-effects of metabolism. Here we model that accumulation starting from a biologically based interpretation of the way in which those side-effects interact. We first validate this model by showing that it very accurately reproduces the distribution of ages at death seen in typical populations that are well protected from age-independent causes of death. We then exploit the mechanistic basis of this model to explore the impact on lifespans of interventions that combat aging, with an emphasis on interventions that repair (rather than merely retard) the direct molecular or cellular consequences of metabolism and thus prevent them from accumulating to pathogenic levels. Our results strengthen the case that an indefinite extension of healthy and total life expectancy can be achieved by a plausible rate of progress in the development of such therapies, once a threshold level of efficacy of those therapies has been reached. PMID:19424837

Analyzing the Coordinated Gene Network Underlying Temperature-Dependent Sex Determination in Reptiles

PubMed Central

Shoemaker, Christina M.; Crews, David

2009-01-01

Although gonadogenesis has been extensively studied in vertebrates with genetic sex determination, investigations at the molecular level in nontraditional model organisms with temperature-dependent sex determination are a relatively new area of research. Results show that while the key players of the molecular network underlying gonad development appear to be retained, their functions range from conserved to novel roles. In this review, we summarize experiments investigating candidate molecular players underlying temperature-dependent sex determination. We discuss some of the problems encountered unraveling this network, pose potential solutions, and suggest rewarding future directions of research. PMID:19022389

Molecular evidence of stereo-specific lactoferrin dimers in solution.

PubMed

Persson, Björn A; Lund, Mikael; Forsman, Jan; Chatterton, Dereck E W; Akesson, Torbjörn

2010-10-01

Gathering experimental evidence suggests that bovine as well as human lactoferrin self-associate in aqueous solution. Still, a molecular level explanation is unavailable. Using force field based molecular modeling of the protein-protein interaction free energy we demonstrate (1) that lactoferrin forms highly stereo-specific dimers at neutral pH and (2) that the self-association is driven by a high charge complementarity across the contact surface of the proteins. Our theoretical predictions of dimer formation are verified by electrophoretic mobility and N-terminal sequence analysis on bovine lactoferrin. 2010 Elsevier B.V. All rights reserved.

Molecular Treatment of Nano-Kaolinite Generations.

PubMed

Táborosi, Attila; Szilagyi, Robert K; Zsirka, Balázs; Fónagy, Orsolya; Horváth, Erzsébet; Kristóf, János

2018-06-18

A procedure is developed for defining a compositionally and structurally realistic, atomic-scale description of exfoliated clay nanoparticles from the kaolinite family of phylloaluminosilicates. By use of coordination chemical principles, chemical environments within a nanoparticle can be separated into inner, outer, and peripheral spheres. The edges of the molecular models of nanoparticles were protonated in a validated manner to achieve charge neutrality. Structural optimizations using semiempirical methods (NDDO Hamiltonians and DFTB formalism) and ab initio density functionals with a saturated basis set revealed previously overlooked molecular origins of morphological changes as a result of exfoliation. While the use of semiempirical methods is desirable for the treatment of nanoparticles composed of tens of thousands of atoms, the structural accuracy is rather modest in comparison to DFT methods. We report a comparative survey of our infrared data for untreated crystalline and various exfoliated states of kaolinite and halloysite. Given the limited availability of experimental techniques for providing direct structural information about nano-kaolinite, the vibrational spectra can be considered as an essential tool for validating structural models. The comparison of experimental and calculated stretching and bending frequencies further justified the use of the preferred level of theory. Overall, an optimal molecular model of the defect-free, ideal nano-kaolinite can be composed with respect to stationary structure and curvature of the potential energy surface using the PW91/SVP level of theory with empirical dispersion correction (PW91+D) and polarizable continuum solvation model (PCM) without the need for a scaled quantum chemical force field. This validated theoretical approach is essential in order to follow the formation of exfoliated clays and their surface reactivity that is experimentally unattainable.

A Single-Level Tunnel Model to Account for Electrical Transport through Single Molecule- and Self-Assembled Monolayer-based Junctions

PubMed Central

Garrigues, Alvar R.; Yuan, Li; Wang, Lejia; Mucciolo, Eduardo R.; Thompon, Damien; del Barco, Enrique; Nijhuis, Christian A.

2016-01-01

We present a theoretical analysis aimed at understanding electrical conduction in molecular tunnel junctions. We focus on discussing the validity of coherent versus incoherent theoretical formulations for single-level tunneling to explain experimental results obtained under a wide range of experimental conditions, including measurements in individual molecules connecting the leads of electromigrated single-electron transistors and junctions of self-assembled monolayers (SAM) of molecules sandwiched between two macroscopic contacts. We show that the restriction of transport through a single level in solid state junctions (no solvent) makes coherent and incoherent tunneling formalisms indistinguishable when only one level participates in transport. Similar to Marcus relaxation processes in wet electrochemistry, the thermal broadening of the Fermi distribution describing the electronic occupation energies in the electrodes accounts for the exponential dependence of the tunneling current on temperature. We demonstrate that a single-level tunnel model satisfactorily explains experimental results obtained in three different molecular junctions (both single-molecule and SAM-based) formed by ferrocene-based molecules. Among other things, we use the model to map the electrostatic potential profile in EGaIn-based SAM junctions in which the ferrocene unit is placed at different positions within the molecule, and we find that electrical screening gives rise to a strongly non-linear profile across the junction. PMID:27216489

Advanced imaging techniques for the study of plant growth and development.

PubMed

Sozzani, Rosangela; Busch, Wolfgang; Spalding, Edgar P; Benfey, Philip N

2014-05-01

A variety of imaging methodologies are being used to collect data for quantitative studies of plant growth and development from living plants. Multi-level data, from macroscopic to molecular, and from weeks to seconds, can be acquired. Furthermore, advances in parallelized and automated image acquisition enable the throughput to capture images from large populations of plants under specific growth conditions. Image-processing capabilities allow for 3D or 4D reconstruction of image data and automated quantification of biological features. These advances facilitate the integration of imaging data with genome-wide molecular data to enable systems-level modeling. Copyright © 2013 Elsevier Ltd. All rights reserved.

Energy level alignment at planar organic heterojunctions: influence of contact doping and molecular orientation.

PubMed

Opitz, Andreas

2017-04-05

Planar organic heterojunctions are widely used in photovoltaic cells, light-emitting diodes, and bilayer field-effect transistors. The energy level alignment in the devices plays an important role in obtaining the aspired gap arrangement. Additionally, the π-orbital overlap between the involved molecules defines e.g. the charge-separation efficiency in solar cells due to charge-transfer effects. To account for both aspects, direct/inverse photoemission spectroscopy and near edge x-ray absorption fine structure spectroscopy were used to determine the energy level landscape and the molecular orientation at prototypical planar organic heterojunctions. The combined experimental approach results in a comprehensive model for the electronic and morphological characteristics of the interface between the two investigated molecular semiconductors. Following an introduction on heterojunctions used in devices and on energy levels of organic materials, the energy level alignment of planar organic heterojunctions will be discussed. The observed energy landscape is always determined by the individual arrangement between the energy levels of the molecules and the work function of the electrode. This might result in contact doping due to Fermi level pinning at the electrode for donor/acceptor heterojunctions, which also improves the solar cell efficiency. This pinning behaviour can be observed across an unpinned interlayer and results in charge accumulation at the donor/acceptor interface, depending on the transport levels of the respective organic semiconductors. Moreover, molecular orientation will affect the energy levels because of the anisotropy in ionisation energy and electron affinity and is influenced by the structural compatibility of the involved molecules at the heterojunction. High structural compatibility leads to π-orbital stacking between different molecules at a heterojunction, which is of additional interest for photovoltaic active interfaces and for ground-state charge-transfer.

Perspective: Markov models for long-timescale biomolecular dynamics.

PubMed

Schwantes, C R; McGibbon, R T; Pande, V S

2014-09-07

Molecular dynamics simulations have the potential to provide atomic-level detail and insight to important questions in chemical physics that cannot be observed in typical experiments. However, simply generating a long trajectory is insufficient, as researchers must be able to transform the data in a simulation trajectory into specific scientific insights. Although this analysis step has often been taken for granted, it deserves further attention as large-scale simulations become increasingly routine. In this perspective, we discuss the application of Markov models to the analysis of large-scale biomolecular simulations. We draw attention to recent improvements in the construction of these models as well as several important open issues. In addition, we highlight recent theoretical advances that pave the way for a new generation of models of molecular kinetics.

Beyond precision surgery: Molecularly motivated precision care for gastric cancer.

PubMed

Choi, Y Y; Cheong, J-H

2017-05-01

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the high disease prevalence, gastric cancer research has not gained much attention. Recently, genome-scale technology has made it possible to explore the characteristics of gastric cancer at the molecular level. Accordingly, gastric cancer can be classified into molecular subtypes that convey more detailed information of tumor than histopathological characteristics, and these subtypes are associated with clinical outcomes. Furthermore, this molecular knowledge helps to identify new actionable targets and develop novel therapeutic strategies. To advance the concept of precision patient care in the clinic, patient-derived xenograft (PDX) models have recently been developed. PDX models not only represent histology and genomic features, but also predict responsiveness to investigational drugs in patient tumors. Molecularly curated PDX cohorts will be instrumental in hypothesis generation, biomarker discovery, and drug screening and testing in proof-of-concept preclinical trials for precision therapy. In the era of precision medicine, molecularly tailored therapeutic strategies should be individualized for cancer patients. To improve the overall clinical outcome, a multimodal approach is indispensable for advanced cancer patients. Careful, oncological principle-based surgery, combined with a molecularly guided multidisciplinary approach, will open new horizons in surgical oncology. Copyright © 2017. Published by Elsevier Ltd.

Coarse-Grained Models Reveal Functional Dynamics – II. Molecular Dynamics Simulation at the Coarse-Grained Level – Theories and Biological Applications

PubMed Central

Chng, Choon-Peng; Yang, Lee-Wei

2008-01-01

Molecular dynamics (MD) simulation has remained the most indispensable tool in studying equilibrium/non-equilibrium conformational dynamics since its advent 30 years ago. With advances in spectroscopy accompanying solved biocomplexes in growing sizes, sampling their dynamics that occur at biologically interesting spatial/temporal scales becomes computationally intractable; this motivated the use of coarse-grained (CG) approaches. CG-MD models are used to study folding and conformational transitions in reduced resolution and can employ enlarged time steps due to the absence of some of the fastest motions in the system. The Boltzmann-Inversion technique, heavily used in parameterizing these models, provides a smoothed-out effective potential on which molecular conformation evolves at a faster pace thus stretching simulations into tens of microseconds. As a result, a complete catalytic cycle of HIV-1 protease or the assembly of lipid-protein mixtures could be investigated by CG-MD to gain biological insights. In this review, we survey the theories developed in recent years, which are categorized into Folding-based and Molecular-Mechanics-based. In addition, physical bases in the selection of CG beads/time-step, the choice of effective potentials, representation of solvent, and restoration of molecular representations back to their atomic details are systematically discussed. PMID:19812774

Dynamics and kinetics of reversible homo-molecular dimerization of polycyclic aromatic hydrocarbons

NASA Astrophysics Data System (ADS)

Mao, Qian; Ren, Yihua; Luo, K. H.; van Duin, Adri C. T.

2017-12-01

Physical dimerization of polycyclic aromatic hydrocarbons (PAHs) has been investigated via molecular dynamics (MD) simulation with the ReaxFF reactive force field that is developed to bridge the gap between the quantum mechanism and classical MD. Dynamics and kinetics of homo-molecular PAH collision under different temperatures, impact parameters, and orientations are studied at an atomic level, which is of great value to understand and model the PAH dimerization. In the collision process, the enhancement factors of homo-molecular dimerizations are quantified and found to be larger at lower temperatures or with smaller PAH instead of size independent. Within the capture radius, the lifetime of the formed PAH dimer decreases as the impact parameter increases. Temperature and PAH characteristic dependent forward and reverse rate constants of homo-molecular PAH dimerization are derived from MD simulations, on the basis of which a reversible model is developed. This model can predict the tendency of PAH dimerization as validated by pyrene dimerization experiments [H. Sabbah et al., J. Phys. Chem. Lett. 1(19), 2962 (2010)]. Results from this study indicate that the physical dimerization cannot be an important source under the typical flame temperatures and PAH concentrations, which implies a more significant role played by the chemical route.

Synthesis of model humic substances: a mechanistic study using controllable H/D exchange and Fourier transform ion cyclotron resonance mass spectrometry.

PubMed

Zherebker, Alexander Ya; Airapetyan, David; Konstantinov, Andrey I; Kostyukevich, Yury I; Kononikhin, Alexey S; Popov, Igor A; Zaitsev, Kirill V; Nikolaev, Eugene N; Perminova, Irina V

2015-07-07

The products of the oxidative coupling of phenols are frequently used as synthetic analogues to natural humic substances (HS) for biomedical research. However, their molecular compositions and exact structures remain largely unknown. The objective of this study was to develop a novel approach for the molecular-level analysis of phenolic polymerisates that is capable of inventorying molecular constituents and resolving their distinct structural formulas. For this purpose, we have synthesized the model HS using the oxidative coupling of a specifically designed phenylpropanoic monomer, 3-(4-hydroxy-3-methoxyphenyl)-3-oxopropionic acid, to hydroquinone. We have characterized the synthesized model HS using high resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS), (1)H NMR spectroscopy, and controllable hydrogen/deuterium (H/D) exchange. We succeeded in the molecular inventory of the model HS. The assigned molecular formulas occupied the substantial space of CHO compositions in the Van Krevelen diagram with a maximum density found in the regions of tannins and lignins, resembling those of natural HS. To identify the exact structural formulas of the individual constituents in the model HS, we have applied selective H/D exchange of non-labile backbone protons by a choice of basic or acidic catalytic conditions followed by FTICR MS. The determined formulas allowed us to verify the proposed pathways of hydroxylation and carboxylation in the course of the phenolic coupling and to identify the acetylation of aromatic rings as an important side reaction. We conclude that the proposed analytical approach may be used to identify the molecular carriers of biological activity within the phenolic polymerisates and eventually within natural HS.

Radiomics biomarkers for accurate tumor progression prediction of oropharyngeal cancer

NASA Astrophysics Data System (ADS)

Hadjiiski, Lubomir; Chan, Heang-Ping; Cha, Kenny H.; Srinivasan, Ashok; Wei, Jun; Zhou, Chuan; Prince, Mark; Papagerakis, Silvana

2017-03-01

Accurate tumor progression prediction for oropharyngeal cancers is crucial for identifying patients who would best be treated with optimized treatment and therefore minimize the risk of under- or over-treatment. An objective decision support system that can merge the available radiomics, histopathologic and molecular biomarkers in a predictive model based on statistical outcomes of previous cases and machine learning may assist clinicians in making more accurate assessment of oropharyngeal tumor progression. In this study, we evaluated the feasibility of developing individual and combined predictive models based on quantitative image analysis from radiomics, histopathology and molecular biomarkers for oropharyngeal tumor progression prediction. With IRB approval, 31, 84, and 127 patients with head and neck CT (CT-HN), tumor tissue microarrays (TMAs) and molecular biomarker expressions, respectively, were collected. For 8 of the patients all 3 types of biomarkers were available and they were sequestered in a test set. The CT-HN lesions were automatically segmented using our level sets based method. Morphological, texture and molecular based features were extracted from CT-HN and TMA images, and selected features were merged by a neural network. The classification accuracy was quantified using the area under the ROC curve (AUC). Test AUCs of 0.87, 0.74, and 0.71 were obtained with the individual predictive models based on radiomics, histopathologic, and molecular features, respectively. Combining the radiomics and molecular models increased the test AUC to 0.90. Combining all 3 models increased the test AUC further to 0.94. This preliminary study demonstrates that the individual domains of biomarkers are useful and the integrated multi-domain approach is most promising for tumor progression prediction.

The Role of Molecular Motors in the Mechanics of Active Gels and the Effects of Inertia, Hydrodynamic Interaction and Compressibility in Passive Microrheology

DTIC Science & Technology

2014-07-01

to use the two-point microrheology technique 88 to measure the complex compressibility of biopolymers and cell components such as F-actin and...loads [23, 115]. Several works have used a continuum-mechanics level of description to model self- organization [64, 2] and rheology [79, 12, 33] of...morphogenesis [94]. Several works have used a continuum-mechanics level of description to model self- organization [64, 2] and rheology [79, 12, 33] of

Multiscale Modelling for investigating single molecule effects on the mechanics of actin filaments

NASA Astrophysics Data System (ADS)

A, Deriu Marco; C, Bidone Tamara; Laura, Carbone; Cristina, Bignardi; M, Montevecchi Franco; Umberto, Morbiducci

2011-12-01

This work presents a preliminary multiscale computational investigation of the effects of nucleotides and cations on the mechanics of actin filaments (F-actin). At the molecular level, Molecular Dynamics (MD) simulations are employed to characterize the rearrangements of the actin monomers (G-actin) in terms of secondary structures evolution in physiological conditions. At the mesoscale level, a coarse grain (CG) procedure is adopted where each monomer is represented by means of Elastic Network Modeling (ENM) technique. At the macroscale level, actin filaments up to hundreds of nanometers are assumed as isotropic and elastic beams and characterized via Rotation Translation Block (RTB) analysis. F-actin bound to adenosine triphosphate (ATP) shows a persistence length around 5 μm, while actin filaments bound to adenosine diphosphate (ADP) have a persistence length of about 3 μm. With magnesium bound to the high affinity binding site of G-actin, the persistence length of F-actin decreases to about 2 μm only in the ADP-bound form of the filament, while the same ion has no effects, in terms of stiffness variation, on the ATP-bound form of F-actin. The molecular mechanisms behind these changes in flexibility are herein elucidated. Thus, this study allows to analyze how the local binding of cations and nucleotides on G-actin induce molecular rearrangements that transmit to the overall F-actin, characterizing shifts of mechanical properties, that can be related with physiological and pathological cellular phenomena, as cell migration and spreading. Further, this study provides the basis for upcoming investigating of network and cellular remodelling at higher length scales.

Theory of wavelet-based coarse-graining hierarchies for molecular dynamics.

PubMed

Rinderspacher, Berend Christopher; Bardhan, Jaydeep P; Ismail, Ahmed E

2017-07-01

We present a multiresolution approach to compressing the degrees of freedom and potentials associated with molecular dynamics, such as the bond potentials. The approach suggests a systematic way to accelerate large-scale molecular simulations with more than two levels of coarse graining, particularly applications of polymeric materials. In particular, we derive explicit models for (arbitrarily large) linear (homo)polymers and iterative methods to compute large-scale wavelet decompositions from fragment solutions. This approach does not require explicit preparation of atomistic-to-coarse-grained mappings, but instead uses the theory of diffusion wavelets for graph Laplacians to develop system-specific mappings. Our methodology leads to a hierarchy of system-specific coarse-grained degrees of freedom that provides a conceptually clear and mathematically rigorous framework for modeling chemical systems at relevant model scales. The approach is capable of automatically generating as many coarse-grained model scales as necessary, that is, to go beyond the two scales in conventional coarse-grained strategies; furthermore, the wavelet-based coarse-grained models explicitly link time and length scales. Furthermore, a straightforward method for the reintroduction of omitted degrees of freedom is presented, which plays a major role in maintaining model fidelity in long-time simulations and in capturing emergent behaviors.

A parametric study of surface roughness and bonding mechanisms of aluminum alloys with epoxies: a molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Timilsina, Rajendra; Termaath, Stephanie

The marine environment is highly aggressive towards most materials. However, aluminium-magnesium alloys (Al-Mg, specifically, 5xxx series) have exceptionally long service life in such aggressive marine environments. For instance, an Al-Mg alloy, AA5083, is extensively used in naval structures because of its good mechanical strength, formability, seawater corrosion resistance and weldability. However, bonding mechanisms of these alloys with epoxies in a rough surface environment are not fully understood yet. It requires a rigorous investigation at molecular or atomic levels. We performed a molecular dynamics simulation to study an adherend surface preparation and surface bonding mechanisms of Al-Mg alloy (AA5083) with different epoxies by developing several computer models. Various distributions of surface roughness are introduced in the models and performed molecular dynamics simulations. Formation of a beta phase (Al3Mg2) , microstructures, bonding energies at the interface, bonding strengths and durability are investigated. Office of Naval Research.

Water models based on a single potential energy surface and different molecular degrees of freedom

NASA Astrophysics Data System (ADS)

Saint-Martin, Humberto; Hernández-Cobos, Jorge; Ortega-Blake, Iván

2005-06-01

Up to now it has not been possible to neatly assess whether a deficient performance of a model is due to poor parametrization of the force field or the lack of inclusion of enough molecular properties. This work compares several molecular models in the framework of the same force field, which was designed to include many-body nonadditive effects: (a) a polarizable and flexible molecule with constraints that account for the quantal nature of the vibration [B. Hess, H. Saint-Martin, and H. J. C. Berendsen, J. Chem. Phys. 116, 9602 (2002), H. Saint-Martin, B. Hess, and H. J. C. Berendsen, J. Chem. Phys. 120, 11133 (2004)], (b) a polarizable and classically flexible molecule [H. Saint-Martin, J. Hernández-Cobos, M. I. Bernal-Uruchurtu, I. Ortega-Blake, and H. J. C. Berendsen, J. Chem. Phys. 113, 10899 (2000)], (c) a polarizable and rigid molecule, and finally (d) a nonpolarizable and rigid molecule. The goal is to determine how significant the different molecular properties are. The results indicate that all factors—nonadditivity, polarizability, and intramolecular flexibility—are important. Still, approximations can be made in order to diminish the computational cost of the simulations with a small decrease in the accuracy of the predictions, provided that those approximations are counterbalanced by the proper inclusion of an effective molecular property, that is, an average molecular geometry or an average dipole. Hence instead of building an effective force field by parametrizing it in order to reproduce the properties of a specific phase, a building approach is proposed that is based on adequately restricting the molecular flexibility and/or polarizability of a model potential fitted to unimolecular properties, pair interactions, and many-body nonadditive contributions. In this manner, the same parental model can be used to simulate the same substance under a wide range of thermodynamic conditions. An additional advantage of this approach is that, as the force field improves by the quality of the molecular calculations, all levels of modeling can be improved.

Bias effects on the electronic spectrum of a molecular bridge

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

Phillips, Heidi; Prociuk, Alexander; Dunietz, Barry D

2011-01-01

In this paper the effect of bias and geometric symmetry breaking on the electronic spectrum of a model molecular system is studied. Geometric symmetry breaking can either enhance the dissipative effect of the bias, where spectral peaks are disabled, or enable new excitations that are absent under zero bias conditions. The spectralanalysis is performed on a simple model system by solving for the electronic response to an instantaneously impulsive perturbation in the dipole approximation. The dynamical response is extracted from the electronic equations of motion as expressed by the Keldysh formalism. This expression provides for the accurate treatment of themore » electronic structure of a bulk-coupled system at the chosen model Hamiltonian electronic structure level.« less

The Impact of the Tree Prior on Molecular Dating of Data Sets Containing a Mixture of Inter- and Intraspecies Sampling.

PubMed

Ritchie, Andrew M; Lo, Nathan; Ho, Simon Y W

2017-05-01

In Bayesian phylogenetic analyses of genetic data, prior probability distributions need to be specified for the model parameters, including the tree. When Bayesian methods are used for molecular dating, available tree priors include those designed for species-level data, such as the pure-birth and birth-death priors, and coalescent-based priors designed for population-level data. However, molecular dating methods are frequently applied to data sets that include multiple individuals across multiple species. Such data sets violate the assumptions of both the speciation and coalescent-based tree priors, making it unclear which should be chosen and whether this choice can affect the estimation of node times. To investigate this problem, we used a simulation approach to produce data sets with different proportions of within- and between-species sampling under the multispecies coalescent model. These data sets were then analyzed under pure-birth, birth-death, constant-size coalescent, and skyline coalescent tree priors. We also explored the ability of Bayesian model testing to select the best-performing priors. We confirmed the applicability of our results to empirical data sets from cetaceans, phocids, and coregonid whitefish. Estimates of node times were generally robust to the choice of tree prior, but some combinations of tree priors and sampling schemes led to large differences in the age estimates. In particular, the pure-birth tree prior frequently led to inaccurate estimates for data sets containing a mixture of inter- and intraspecific sampling, whereas the birth-death and skyline coalescent priors produced stable results across all scenarios. Model testing provided an adequate means of rejecting inappropriate tree priors. Our results suggest that tree priors do not strongly affect Bayesian molecular dating results in most cases, even when severely misspecified. However, the choice of tree prior can be significant for the accuracy of dating results in the case of data sets with mixed inter- and intraspecies sampling. [Bayesian phylogenetic methods; model testing; molecular dating; node time; tree prior.]. © The authors 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

Evaluation of synthetic linear motor-molecule actuation energetics

PubMed Central

Brough, Branden; Northrop, Brian H.; Schmidt, Jacob J.; Tseng, Hsian-Rong; Houk, Kendall N.; Stoddart, J. Fraser; Ho, Chih-Ming

2006-01-01

By applying atomic force microscope (AFM)-based force spectroscopy together with computational modeling in the form of molecular force-field simulations, we have determined quantitatively the actuation energetics of a synthetic motor-molecule. This multidisciplinary approach was performed on specifically designed, bistable, redox-controllable [2]rotaxanes to probe the steric and electrostatic interactions that dictate their mechanical switching at the single-molecule level. The fusion of experimental force spectroscopy and theoretical computational modeling has revealed that the repulsive electrostatic interaction, which is responsible for the molecular actuation, is as high as 65 kcal·mol−1, a result that is supported by ab initio calculations. PMID:16735470

Quantum mechanics/molecular mechanics modeling of photoelectron spectra: the carbon 1s core-electron binding energies of ethanol-water solutions.

PubMed

Löytynoja, T; Niskanen, J; Jänkälä, K; Vahtras, O; Rinkevicius, Z; Ågren, H

2014-11-20

Using ethanol-water solutions as illustration, we demonstrate the capability of the hybrid quantum mechanics/molecular mechanics (QM/MM) paradigm to simulate core photoelectron spectroscopy: the binding energies and the chemical shifts. An integrated approach with QM/MM binding energy calculations coupled to preceding molecular dynamics sampling is adopted to generate binding energies averaged over the solute-solvent configurations available at a particular temperature and pressure and thus allowing for a statistical assessment with confidence levels for the final binding energies. The results are analyzed in terms of the contributions in the molecular mechanics model-electrostatic, polarization, and van der Waals-with atom or bond granulation of the corresponding MM charge and polarizability force-fields. The role of extramolecular charge transfer screening of the core-hole and explicit hydrogen bonding is studied by extending the QM core to cover the first solvation shell. The results are compared to those obtained from pure electrostatic and polarizable continuum models. Particularly, the dependence of the carbon 1s binding energies with respect to the ethanol concentration is studied. Our results indicate that QM/MM can be used as an all-encompassing model to study photoelectron binding energies and chemical shifts in solvent environments.

Magnetomotive Molecular Nanoprobes

PubMed Central

John, Renu; Boppart, Stephen A.

2012-01-01

Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogen-induced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications. PMID:21517766

Computer simulation of surface and film processes

NASA Technical Reports Server (NTRS)

Tiller, W. A.; Halicioglu, M. T.

1984-01-01

All the investigations which were performed employed in one way or another a computer simulation technique based on atomistic level considerations. In general, three types of simulation methods were used for modeling systems with discrete particles that interact via well defined potential functions: molecular dynamics (a general method for solving the classical equations of motion of a model system); Monte Carlo (the use of Markov chain ensemble averaging technique to model equilibrium properties of a system); and molecular statics (provides properties of a system at T = 0 K). The effects of three-body forces on the vibrational frequencies of triatomic cluster were investigated. The multilayer relaxation phenomena for low index planes of an fcc crystal was analyzed also as a function of the three-body interactions. Various surface properties for Si and SiC system were calculated. Results obtained from static simulation calculations for slip formation were presented. The more elaborate molecular dynamics calculations on the propagation of cracks in two-dimensional systems were outlined.

Modeling of substrate and inhibitor binding to phospholipase A2.

PubMed

Sessions, R B; Dauber-Osguthorpe, P; Campbell, M M; Osguthorpe, D J

1992-09-01

Molecular graphics and molecular mechanics techniques have been used to study the mode of ligand binding and mechanism of action of the enzyme phospholipase A2. A substrate-enzyme complex was constructed based on the crystal structure of the apoenzyme. The complex was minimized to relieve initial strain, and the structural and energetic features of the resultant complex analyzed in detail, at the molecular and residue level. The minimized complex was then used as a basis for examining the action of the enzyme on modified substrates, binding of inhibitors to the enzyme, and possible reaction intermediate complexes. The model is compatible with the suggested mechanism of hydrolysis and with experimental data about stereoselectivity, efficiency of hydrolysis of modified substrates, and inhibitor potency. In conclusion, the model can be used as a tool in evaluating new ligands as possible substrates and in the rational design of inhibitors, for the therapeutic treatment of diseases such as rheumatoid arthritis, atherosclerosis, and asthma.

Predicting unfolding thermodynamics and stable intermediates for alanine-rich helical peptides with the aid of coarse-grained molecular simulation.

PubMed

Calero-Rubio, Cesar; Paik, Bradford; Jia, Xinqiao; Kiick, Kristi L; Roberts, Christopher J

2016-10-01

This report focuses on the molecular-level processes and thermodynamics of unfolding of a series of helical peptides using a coarse-grained (CG) molecular model. The CG model was refined to capture thermodynamics and structural changes as a function of temperature for a set of published peptide sequences. Circular dichroism spectroscopy (CD) was used to experimentally monitor the temperature-dependent conformational changes and stability of published peptides and new sequences introduced here. The model predictions were quantitatively or semi-quantitatively accurate in all cases. The simulations and CD results showed that, as expected, in most cases the unfolding of helical peptides is well described by a simply 2-state model, and conformational stability increased with increased length of the helices. A notable exception in a 19-residue helix was when two Ala residues were each replaced with Phe. This stabilized a partly unfolded intermediate state via hydrophobic contacts, and also promoted aggregates at higher peptide concentrations. Copyright © 2016 Elsevier B.V. All rights reserved.

Transferability of polarizable models for ion-water electrostatic interaction

NASA Astrophysics Data System (ADS)

Masia, Marco

2009-06-01

Studies of ion-water systems at condensed phase and at interfaces have pointed out that molecular and ionic polarization plays an important role for many phenomena ranging from hydrogen bond dynamics to water interfaces' structure. Classical and ab initio Molecular Dynamics simulations reveal that induced dipole moments at interfaces (e.g. air-water and water-protein) are usually high, hinting that polarizable models to be implemented in classical force fields should be very accurate in reproducing the electrostatic properties of the system. In this paper the electrostatic properties of three classical polarizable models for ion-water interaction are compared with ab initio results both at gas and condensed phase. For Li+- water and Cl--water dimers the reproducibility of total dipole moments obtained with high level quantum chemical calculations is studied; for the same ions in liquid water, Car-Parrinello Molecular Dynamics simulations are used to compute the time evolution of ionic and molecular dipole moments, which are compared with the classical models. The PD2-H2O model developed by the author and coworkers [Masia et al. J. Chem. Phys. 2004, 121, 7362] together with the gaussian intermolecular damping for ion-water interaction [Masia et al. J. Chem. Phys. 2005, 123, 164505] showed to be the fittest in reproducing the ab initio results from gas to condensed phase, allowing for force field transferability.

Nonholonomic Hamiltonian Method for Molecular Dynamics Simulations of Reacting Shocks

NASA Astrophysics Data System (ADS)

Fahrenthold, Eric; Bass, Joseph

2015-06-01

Conventional molecular dynamics simulations of reacting shocks employ a holonomic Hamiltonian formulation: the breaking and forming of covalent bonds is described by potential functions. In general these potential functions: (a) are algebraically complex, (b) must satisfy strict smoothness requirements, and (c) contain many fitted parameters. In recent research the authors have developed a new noholonomic formulation of reacting molecular dynamics. In this formulation bond orders are determined by rate equations and the bonding-debonding process need not be described by differentiable functions. This simplifies the representation of complex chemistry and reduces the number of fitted model parameters. Example applications of the method show molecular level shock to detonation simulations in nitromethane and RDX. Research supported by the Defense Threat Reduction Agency.

Manipulation of individual hyperfine states in cold trapped molecular ions and application to HD+ frequency metrology.

PubMed

Bressel, U; Borodin, A; Shen, J; Hansen, M; Ernsting, I; Schiller, S

2012-05-04

Advanced techniques for manipulation of internal states, standard in atomic physics, are demonstrated for a charged molecular species for the first time. We address individual hyperfine states of rovibrational levels of a diatomic ion by optical excitation of individual hyperfine transitions, and achieve controlled transfer of population into a selected hyperfine state. We use molecular hydrogen ions (HD+) as a model system and employ a novel frequency-comb-based, continuous-wave 5  μm laser spectrometer. The achieved spectral resolution is the highest obtained so far in the optical domain on a molecular ion species. As a consequence, we are also able to perform the most precise test yet of the ab initio theory of a molecule.

An Insilico Design of Nanoclay Based Nanocomposites and Scaffolds in Bone Tissue Engineering

NASA Astrophysics Data System (ADS)

Sharma, Anurag

A multiscale in silico approach to design polymer nanocomposites and scaffolds for bone tissue engineering applications is described in this study. This study focuses on the role of biomaterials design and selection, structural integrity and mechanical properties evolution during degradation and tissue regeneration in the successful design of polymer nanocomposite scaffolds. Polymer nanocomposite scaffolds are synthesized using aminoacid modified montmorillonite nanoclay with biomineralized hydroxyapatite and polycaprolactone (PCL/in situ HAPclay). Representative molecular models of polymer nanocomposite system are systematically developed using molecular dynamics (MD) technique and successfully validated using material characterization techniques. The constant force steered molecular dynamics (fSMD) simulation results indicate a two-phase nanomechanical behavior of the polymer nanocomposite. The MD and fSMD simulations results provide quantitative contributions of molecular interactions between different constituents of representative models and their effect on nanomechanical responses of nanoclay based polymer nanocomposite system. A finite element (FE) model of PCL/in situ HAPclay scaffold is built using micro-computed tomography images and bridging the nanomechanical properties obtained from fSMD simulations into the FE model. A new reduction factor, K is introduced into modeling results to consider the effect of wall porosity of the polymer scaffold. The effect of accelerated degradation under alkaline conditions and human osteoblast cells culture on the evolution of mechanical properties of scaffolds are studied and the damage mechanics based analytical models are developed. Finally, the novel multiscale models are developed that incorporate the complex molecular and microstructural properties, mechanical properties at nanoscale and structural levels and mechanical properties evolution during degradation and tissue formation in the polymer nanocomposite scaffold. Overall, this study provides a leap into methodologies for in silico design of biomaterials for bone tissue engineering applications. Furthermore, as a part of this work, a molecular dynamics study of rice DNA in the presence of single walled carbon nanotube is carried out to understand the role played by molecular interactions in the conformation changes of rice DNA. The simulations results showed wrapping of DNA onto SWCNT, breaking and forming of hydrogen bonds due to unzipping of Watson-Crick (WC) nucleobase pairs and forming of new non-WC nucleobase pairs in DNA.

Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice.

PubMed

Shen, Hai-Ying; He, Jin-Cai; Wang, Yumei; Huang, Qing-Yuan; Chen, Jiang-Fan

2005-12-02

As key molecular chaperone proteins, heat shock proteins (HSPs) represent an important cellular protective mechanism against neuronal cell death in various models of neurological disorders. In this study, we investigated the effect as well as the molecular mechanism of geldanamycin (GA), an inhibitor of Hsp90, on 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a mouse model of Parkinson disease. Neurochemical analysis showed that pretreatment with GA (via intracerebral ventricular injection 24 h prior to MPTP treatment) increased residual dopamine content and tyrosine hydroxylase immunoreactivity in the striatum 24 h after MPTP treatment. To dissect out the molecular mechanism underlying this neuroprotection, we showed that the GA-mediated protection against MPTP was associated with a reduction of cytosolic Hsp90 and an increase in Hsp70, with no significant changes in Hsp40 and Hsp25 levels. Furthermore, in parallel with the induction of Hsp70, striatal nuclear HSF1 levels and HSF1 binding to heat shock element sites in the Hsp70 promoter were significantly enhanced by the GA pretreatment. Together these results suggested that the molecular cascade leading to the induction of Hsp70 is critical to the neuroprotection afforded by GA against MPTP-induced neurotoxicity in the brain and that pharmacological inhibition of Hsp90 may represent a potential therapeutic strategy for Parkinson disease.

Quantum chemical characterization of N-(2-hydroxybenzylidene)acetohydrazide (HBAH): a detailed vibrational and NLO analysis.

PubMed

Tamer, Ömer; Avcı, Davut; Atalay, Yusuf

2014-01-03

The molecular modeling of N-(2-hydroxybenzylidene)acetohydrazide (HBAH) was carried out using B3LYP, CAMB3LYP and PBE1PBE levels of density functional theory (DFT). The molecular structure of HBAH was solved by means of IR, NMR and UV-vis spectroscopies. In order to find the stable conformers, conformational analysis was performed based on B3LYP level. A detailed vibrational analysis was made on the basis of potential energy distribution (PED). HOMO and LUMO energies were calculated, and the obtained energies displayed that charge transfer occurs in HBAH. NLO analysis indicated that HBAH can be used as an effective NLO material. NBO analysis also proved that charge transfer, conjugative interactions and intramolecular hydrogen bonding interactions occur through HBAH. Additionally, major contributions from molecular orbitals to the electronic transitions were investigated theoretically. Copyright © 2013 Elsevier B.V. All rights reserved.

Molecular coordination of Staphylococcus aureus cell division

PubMed Central

Cotterell, Bryony E; Walther, Christa G; Fenn, Samuel J; Grein, Fabian; Wollman, Adam JM; Leake, Mark C; Olivier, Nicolas; Cadby, Ashley; Mesnage, Stéphane; Jones, Simon

2018-01-01

The bacterial cell wall is essential for viability, but despite its ability to withstand internal turgor must remain dynamic to permit growth and division. Peptidoglycan is the major cell wall structural polymer, whose synthesis requires multiple interacting components. The human pathogen Staphylococcus aureus is a prolate spheroid that divides in three orthogonal planes. Here, we have integrated cellular morphology during division with molecular level resolution imaging of peptidoglycan synthesis and the components responsible. Synthesis occurs across the developing septal surface in a diffuse pattern, a necessity of the observed septal geometry, that is matched by variegated division component distribution. Synthesis continues after septal annulus completion, where the core division component FtsZ remains. The novel molecular level information requires re-evaluation of the growth and division processes leading to a new conceptual model, whereby the cell cycle is expedited by a set of functionally connected but not regularly distributed components. PMID:29465397

Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations.

PubMed

Gupta, Jasmine; Nunes, Cletus; Vyas, Shyam; Jonnalagadda, Sriramakamal

2011-03-10

The objectives of this study were (i) to develop a computational model based on molecular dynamics technique to predict the miscibility of indomethacin in carriers (polyethylene oxide, glucose, and sucrose) and (ii) to experimentally verify the in silico predictions by characterizing the drug-carrier mixtures using thermoanalytical techniques. Molecular dynamics (MD) simulations were performed using the COMPASS force field, and the cohesive energy density and the solubility parameters were determined for the model compounds. The magnitude of difference in the solubility parameters of drug and carrier is indicative of their miscibility. The MD simulations predicted indomethacin to be miscible with polyethylene oxide and to be borderline miscible with sucrose and immiscible with glucose. The solubility parameter values obtained using the MD simulations values were in reasonable agreement with those calculated using group contribution methods. Differential scanning calorimetry showed melting point depression of polyethylene oxide with increasing levels of indomethacin accompanied by peak broadening, confirming miscibility. In contrast, thermal analysis of blends of indomethacin with sucrose and glucose verified general immiscibility. The findings demonstrate that molecular modeling is a powerful technique for determining the solubility parameters and predicting miscibility of pharmaceutical compounds. © 2011 American Chemical Society

Protonation free energy levels in complex molecular systems.

PubMed

Antosiewicz, Jan M

2008-04-01

All proteins, nucleic acids, and other biomolecules contain residues capable of exchanging protons with their environment. These proton transfer phenomena lead to pH sensitivity of many molecular processes underlying biological phenomena. In the course of biological evolution, Nature has invented some mechanisms to use pH gradients to regulate biomolecular processes inside cells or in interstitial fluids. Therefore, an ability to model protonation equilibria in molecular systems accurately would be of enormous value for our understanding of biological processes and for possible rational influence on them, like in developing pH dependent drugs to treat particular diseases. This work presents a derivation, by thermodynamic and statistical mechanical methods, of an expression for the free energy of a complex molecular system at arbitrary ionization state of its titratable residues. This constitutes one of the elements of modeling protonation equilibria. Starting from a consideration of a simple acid-base equilibrium of a model compound with a single tritratable group, we arrive at an expression which is of general validity for complex systems. The only approximation used in this derivation is the postulating that the interaction energy between any pair of titratable sites does not depend on the protonation states of all the remaining ionizable groups.

Molecular modeling of field-driven ion emission from ionic liquids

NASA Astrophysics Data System (ADS)

Zhang, Fei; He, Yadong; Qiao, Rui

2017-11-01

Traditionally, operating electrosprays in the purely ionic mode is challenging, but recent experiments confirmed that such operation can be achieved using room-temperature ionic liquids as working electrolytes. Such electrosprays have shown promise in applications including chemical analysis, nanomanufacturing, and space propulsion. The mechanistic and quantitative understanding of such electrosprays at the molecular level, however, remain limited at present. In this work, we simulated ion emission from EMIM-PF6 ionic liquid films using the molecular dynamics method. We show that, when the surface electric field is smaller than 1.5V/nm, the ion emission current predicted using coarse-grained ionic liquid model observes the classical scaling law by J. V. Iribarne and B. A. Thomson, i.e., ln(Je/ σ) En1/2. These simulations, however, cannot capture the co-emission of cations and anions from ionic liquid surface observed in some experiments. Such co-emission was successfully captured when united-atom models were adopted for the ionic liquids. By examining the co-emission events with picosecond, sub-angstrom resolution, we clarified the origins of the co-emission phenomenon and delineate the molecular events leading to ion emission.

Modelling the interactions between animal venom peptides and membrane proteins.

PubMed

Hung, Andrew; Kuyucak, Serdar; Schroeder, Christina I; Kaas, Quentin

2017-12-01

The active components of animal venoms are mostly peptide toxins, which typically target ion channels and receptors of both the central and peripheral nervous system, interfering with action potential conduction and/or synaptic transmission. The high degree of sequence conservation of their molecular targets makes a range of these toxins active at human receptors. The high selectivity and potency displayed by some of these toxins have prompted their use as pharmacological tools as well as drugs or drug leads. Molecular modelling has played an essential role in increasing our molecular-level understanding of the activity and specificity of animal toxins, as well as engineering them for biotechnological and pharmaceutical applications. This review focuses on the biological insights gained from computational and experimental studies of animal venom toxins interacting with membranes and ion channels. A host of recent X-ray crystallography and electron-microscopy structures of the toxin targets has contributed to a dramatic increase in the accuracy of the molecular models of toxin binding modes greatly advancing this exciting field of study. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular mechanisms of temperature adaptation

PubMed Central

Bagriantsev, Sviatoslav N; Gracheva, Elena O

2015-01-01

Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a ‘choir’ of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID:25433072

Molecular perspective on diazonium adsorption for controllable functionalization of single-walled carbon nanotubes in aqueous surfactant solutions.

PubMed

Lin, Shangchao; Hilmer, Andrew J; Mendenhall, Jonathan D; Strano, Michael S; Blankschtein, Daniel

2012-05-16

Functionalization of single-walled carbon nanotubes (SWCNTs) using diazonium salts allows modification of their optical and electronic properties for a variety of applications, ranging from drug-delivery vehicles to molecular sensors. However, control of the functionalization process remains a challenge, requiring molecular-level understanding of the adsorption of diazonium ions onto heterogeneous, charge-mobile SWCNT surfaces, which are typically decorated with surfactants. In this paper, we combine molecular dynamics (MD) simulations, experiments, and equilibrium reaction modeling to understand and model the extent of diazonium functionalization of SWCNTs coated with various surfactants (sodium cholate, sodium dodecyl sulfate, and cetyl trimethylammonium bromide). We show that the free energy of diazonium adsorption, determined using simulations, can be used to rank surfactants in terms of the extent of functionalization attained following their adsorption on the nanotube surface. The difference in binding affinities between linear and rigid surfactants is attributed to the synergistic binding of the diazonium ion to the local "hot/cold spots" formed by the charged surfactant heads. A combined simulation-modeling framework is developed to provide guidance for controlling the various sensitive experimental conditions needed to achieve the desired extent of SWCNT functionalization.

Molecular nano-arches on silicon

NASA Astrophysics Data System (ADS)

Dobrin, S.

2007-08-01

The formation of molecular nano-arches on the Si(1 1 1)-7 × 7 surface was modeled using density functional theory (DFT). It has been suggested, based on the calculations, that the arches are formed by molecular dimers of chlorobenzene at near-monolayer coverages. Molecules of the dimer are covalently bound to two silicon adatoms and to each other thereby forming a molecular arch on the surface. The structure of the molecular dimer was calculated at the B3LYP/6-31G(d) level of theory. The dimers were found to be stable at room temperature, and to form a near-monolayer coverage, which has been observed in the experiment [X.H. Chen, Q. Kong, J.C. Polanyi, D. Rogers, S. So, Surf. Sci. 340 (1995) 224; Y. Cao, J.F. Deng, G.Q. Xu, J. Chem. Phys. 112 (2000) 4759].

Rates of molecular evolution in tree ferns are associated with body size, environmental temperature, and biological productivity.

PubMed

Barrera-Redondo, Josué; Ramírez-Barahona, Santiago; Eguiarte, Luis E

2018-05-01

Variation in rates of molecular evolution (heterotachy) is a common phenomenon among plants. Although multiple theoretical models have been proposed, fundamental questions remain regarding the combined effects of ecological and morphological traits on rate heterogeneity. Here, we used tree ferns to explore the correlation between rates of molecular evolution in chloroplast DNA sequences and several morphological and environmental factors within a Bayesian framework. We revealed direct and indirect effects of body size, biological productivity, and temperature on substitution rates, where smaller tree ferns living in warmer and less productive environments tend to have faster rates of molecular evolution. In addition, we found that variation in the ratio of nonsynonymous to synonymous substitution rates (dN/dS) in the chloroplast rbcL gene was significantly correlated with ecological and morphological variables. Heterotachy in tree ferns may be influenced by effective population size associated with variation in body size and productivity. Macroevolutionary hypotheses should go beyond explaining heterotachy in terms of mutation rates and instead, should integrate population-level factors to better understand the processes affecting the tempo of evolution at the molecular level. © 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.

Quantum probability ranking principle for ligand-based virtual screening.

PubMed

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Quantum probability ranking principle for ligand-based virtual screening

NASA Astrophysics Data System (ADS)

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Addressing Loss of Efficiency Due to Misclassification Error in Enriched Clinical Trials for the Evaluation of Targeted Therapies Based on the Cox Proportional Hazards Model.

PubMed

Tsai, Chen-An; Lee, Kuan-Ting; Liu, Jen-Pei

2016-01-01

A key feature of precision medicine is that it takes individual variability at the genetic or molecular level into account in determining the best treatment for patients diagnosed with diseases detected by recently developed novel biotechnologies. The enrichment design is an efficient design that enrolls only the patients testing positive for specific molecular targets and randomly assigns them for the targeted treatment or the concurrent control. However there is no diagnostic device with perfect accuracy and precision for detecting molecular targets. In particular, the positive predictive value (PPV) can be quite low for rare diseases with low prevalence. Under the enrichment design, some patients testing positive for specific molecular targets may not have the molecular targets. The efficacy of the targeted therapy may be underestimated in the patients that actually do have the molecular targets. To address the loss of efficiency due to misclassification error, we apply the discrete mixture modeling for time-to-event data proposed by Eng and Hanlon [8] to develop an inferential procedure, based on the Cox proportional hazard model, for treatment effects of the targeted treatment effect for the true-positive patients with the molecular targets. Our proposed procedure incorporates both inaccuracy of diagnostic devices and uncertainty of estimated accuracy measures. We employed the expectation-maximization algorithm in conjunction with the bootstrap technique for estimation of the hazard ratio and its estimated variance. We report the results of simulation studies which empirically investigated the performance of the proposed method. Our proposed method is illustrated by a numerical example.

Molecular docking and dynamics simulation analyses unraveling the differential enzymatic catalysis by plant and fungal laccases with respect to lignin biosynthesis and degradation.

PubMed

Awasthi, Manika; Jaiswal, Nivedita; Singh, Swati; Pandey, Veda P; Dwivedi, Upendra N

2015-09-01

Laccase, widely distributed in bacteria, fungi, and plants, catalyzes the oxidation of wide range of compounds. With regards to one of the important physiological functions, plant laccases are considered to catalyze lignin biosynthesis while fungal laccases are considered for lignin degradation. The present study was undertaken to explain this dual function of laccases using in-silico molecular docking and dynamics simulation approaches. Modeling and superimposition analyses of one each representative of plant and fungal laccases, namely, Populus trichocarpa and Trametes versicolor, respectively, revealed low level of similarity in the folding of two laccases at 3D levels. Docking analyses revealed significantly higher binding efficiency for lignin model compounds, in proportion to their size, for fungal laccase as compared to that of plant laccase. Residues interacting with the model compounds at the respective enzyme active sites were found to be in conformity with their role in lignin biosynthesis and degradation. Molecular dynamics simulation analyses for the stability of docked complexes of plant and fungal laccases with lignin model compounds revealed that tetrameric lignin model compound remains attached to the active site of fungal laccase throughout the simulation period, while it protrudes outwards from the active site of plant laccase. Stability of these complexes was further analyzed on the basis of binding energy which revealed significantly higher stability of fungal laccase with tetrameric compound than that of plant. The overall data suggested a situation favorable for the degradation of lignin polymer by fungal laccase while its synthesis by plant laccase.

The First Molecular Phylogeny of Strepsiptera (Insecta) Reveals an Early Burst of Molecular Evolution Correlated with the Transition to Endoparasitism

PubMed Central

McMahon, Dino P.; Hayward, Alexander; Kathirithamby, Jeyaraney

2011-01-01

A comprehensive model of evolution requires an understanding of the relationship between selection at the molecular and phenotypic level. We investigate this in Strepsiptera, an order of endoparasitic insects whose evolutionary biology is poorly studied. We present the first molecular phylogeny of Strepsiptera, and use this as a framework to investigate the association between parasitism and molecular evolution. We find evidence of a significant burst in the rate of molecular evolution in the early history of Strepsiptera. The evolution of morphological traits linked to parasitism is significantly correlated with the pattern in molecular rate. The correlated burst in genotypic-phenotypic evolution precedes the main phase of strepsipteran diversification, which is characterised by the return to a low and even molecular rate, and a period of relative morphological stability. These findings suggest that the transition to endoparasitism led to relaxation of selective constraint in the strepsipteran genome. Our results indicate that a parasitic lifestyle can affect the rate of molecular evolution, although other causal life-history traits correlated with parasitism may also play an important role. PMID:21738621

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice.

PubMed

Jorge-Torres, Olga C; Szczesna, Karolina; Roa, Laura; Casal, Carme; Gonzalez-Somermeyer, Louisa; Soler, Marta; Velasco, Cecilia D; Martínez-San Segundo, Pablo; Petazzi, Paolo; Sáez, Mauricio A; Delgado-Morales, Raúl; Fourcade, Stephane; Pujol, Aurora; Huertas, Dori; Llobet, Artur; Guil, Sonia; Esteller, Manel

2018-05-08

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6.

PubMed

Tsai, Yuan-Chin; Chen, Wei-Yu; Siu, Man Kit; Tsai, Hong-Yuan; Yin, Juan Juan; Huang, Jiaoti; Liu, Yen-Nien

2017-01-01

It has been suggested that ETV6 serves as a tumor suppressor; however, its molecular regulation and cellular functions remain unclear. We used prostate cancer as a model system and demonstrated a molecular mechanism in which ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA-96 (miR-96)-mediated downregulation. In addition, EGFR acts as a transcriptional coactivator that binds to the promoter of primary miR-96 and transcriptionally regulates miR-96 levels. We analyzed two sets of clinical prostate cancer samples, confirmed association patterns that were consistent with the EGFR-miR-96-ETV6 signaling model and demonstrated that the reduced ETV6 levels were associated with malignant prostate cancer. Based on results derived from multiple approaches, we identified the biological functions of ETV6 as a tumor suppressor that inhibits proliferation and metastasis in prostate cancer. We present a molecular mechanism in which EGFR activation leads to the induction of miR-96 expression and suppression of ETV6, which contributes to prostate cancer progression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Neural network approach to quantum-chemistry data: accurate prediction of density functional theory energies.

PubMed

Balabin, Roman M; Lomakina, Ekaterina I

2009-08-21

Artificial neural network (ANN) approach has been applied to estimate the density functional theory (DFT) energy with large basis set using lower-level energy values and molecular descriptors. A total of 208 different molecules were used for the ANN training, cross validation, and testing by applying BLYP, B3LYP, and BMK density functionals. Hartree-Fock results were reported for comparison. Furthermore, constitutional molecular descriptor (CD) and quantum-chemical molecular descriptor (QD) were used for building the calibration model. The neural network structure optimization, leading to four to five hidden neurons, was also carried out. The usage of several low-level energy values was found to greatly reduce the prediction error. An expected error, mean absolute deviation, for ANN approximation to DFT energies was 0.6+/-0.2 kcal mol(-1). In addition, the comparison of the different density functionals with the basis sets and the comparison of multiple linear regression results were also provided. The CDs were found to overcome limitation of the QD. Furthermore, the effective ANN model for DFT/6-311G(3df,3pd) and DFT/6-311G(2df,2pd) energy estimation was developed, and the benchmark results were provided.

REVIEWS OF TOPICAL PROBLEMS: Physical aspects of cryobiology

NASA Astrophysics Data System (ADS)

Zhmakin, A. I.

2008-03-01

Physical phenomena during biological freezing and thawing processes at the molecular, cellular, tissue, and organ levels are examined. The basics of cryosurgery and cryopreservation of cells and tissues are presented. Existing cryobiological models, including numerical ones, are reviewed.

A Qualitative Investigation of Undergraduate Chemistry Students' Macroscopic Interpretations of the Submicroscopic Structure of Molecules.

ERIC Educational Resources Information Center

Nicoll, Gayle

2003-01-01

Reports research that investigates the encoding that students use to develop molecular models at the undergraduate level. Focuses on the translation between symbolic and subatomic representations of molecules. (Contains 31 references.) (DDR)

Computing molecular fluctuations in biochemical reaction systems based on a mechanistic, statistical theory of irreversible processes.

PubMed

Kulasiri, Don

2011-01-01

We discuss the quantification of molecular fluctuations in the biochemical reaction systems within the context of intracellular processes associated with gene expression. We take the molecular reactions pertaining to circadian rhythms to develop models of molecular fluctuations in this chapter. There are a significant number of studies on stochastic fluctuations in intracellular genetic regulatory networks based on single cell-level experiments. In order to understand the fluctuations associated with the gene expression in circadian rhythm networks, it is important to model the interactions of transcriptional factors with the E-boxes in the promoter regions of some of the genes. The pertinent aspects of a near-equilibrium theory that would integrate the thermodynamical and particle dynamic characteristics of intracellular molecular fluctuations would be discussed, and the theory is extended by using the theory of stochastic differential equations. We then model the fluctuations associated with the promoter regions using general mathematical settings. We implemented ubiquitous Gillespie's algorithms, which are used to simulate stochasticity in biochemical networks, for each of the motifs. Both the theory and the Gillespie's algorithms gave the same results in terms of the time evolution of means and variances of molecular numbers. As biochemical reactions occur far away from equilibrium-hence the use of the Gillespie algorithm-these results suggest that the near-equilibrium theory should be a good approximation for some of the biochemical reactions. © 2011 Elsevier Inc. All rights reserved.

Reasoning Using Particulate Nature of Matter: An Example of a Sociochemical Norm in a University-Level Physical Chemistry Class

ERIC Educational Resources Information Center

Becker, Nicole; Rasmussen, Chris; Sweeney, George; Wawro, Megan; Towns, Marcy; Cole, Renee

2013-01-01

In college level chemistry courses, reasoning using molecular and particulate descriptions of matter becomes central to understanding physical and chemical properties. In this study, we used a qualitative approach to analyzing classroom discourse derived from Toulmin's model of argumentation in order to describe the ways in which students develop…

Combining measurements to estimate properties and characterization extent of complex biochemical mixtures; applications to Heparan Sulfate

PubMed Central

Pradines, Joël R.; Beccati, Daniela; Lech, Miroslaw; Ozug, Jennifer; Farutin, Victor; Huang, Yongqing; Gunay, Nur Sibel; Capila, Ishan

2016-01-01

Complex mixtures of molecular species, such as glycoproteins and glycosaminoglycans, have important biological and therapeutic functions. Characterization of these mixtures with analytical chemistry measurements is an important step when developing generic drugs such as biosimilars. Recent developments have focused on analytical methods and statistical approaches to test similarity between mixtures. The question of how much uncertainty on mixture composition is reduced by combining several measurements still remains mostly unexplored. Mathematical frameworks to combine measurements, estimate mixture properties, and quantify remaining uncertainty, i.e. a characterization extent, are introduced here. Constrained optimization and mathematical modeling are applied to a set of twenty-three experimental measurements on heparan sulfate, a mixture of linear chains of disaccharides having different levels of sulfation. While this mixture has potentially over two million molecular species, mathematical modeling and the small set of measurements establish the existence of nonhomogeneity of sulfate level along chains and the presence of abundant sulfate repeats. Constrained optimization yields not only estimations of sulfate repeats and sulfate level at each position in the chains but also bounds on these levels, thereby estimating the extent of characterization of the sulfation pattern which is achieved by the set of measurements. PMID:27112127

Combining measurements to estimate properties and characterization extent of complex biochemical mixtures; applications to Heparan Sulfate.

PubMed

Pradines, Joël R; Beccati, Daniela; Lech, Miroslaw; Ozug, Jennifer; Farutin, Victor; Huang, Yongqing; Gunay, Nur Sibel; Capila, Ishan

2016-04-26

Complex mixtures of molecular species, such as glycoproteins and glycosaminoglycans, have important biological and therapeutic functions. Characterization of these mixtures with analytical chemistry measurements is an important step when developing generic drugs such as biosimilars. Recent developments have focused on analytical methods and statistical approaches to test similarity between mixtures. The question of how much uncertainty on mixture composition is reduced by combining several measurements still remains mostly unexplored. Mathematical frameworks to combine measurements, estimate mixture properties, and quantify remaining uncertainty, i.e. a characterization extent, are introduced here. Constrained optimization and mathematical modeling are applied to a set of twenty-three experimental measurements on heparan sulfate, a mixture of linear chains of disaccharides having different levels of sulfation. While this mixture has potentially over two million molecular species, mathematical modeling and the small set of measurements establish the existence of nonhomogeneity of sulfate level along chains and the presence of abundant sulfate repeats. Constrained optimization yields not only estimations of sulfate repeats and sulfate level at each position in the chains but also bounds on these levels, thereby estimating the extent of characterization of the sulfation pattern which is achieved by the set of measurements.

Combining measurements to estimate properties and characterization extent of complex biochemical mixtures; applications to Heparan Sulfate

NASA Astrophysics Data System (ADS)

Pradines, Joël R.; Beccati, Daniela; Lech, Miroslaw; Ozug, Jennifer; Farutin, Victor; Huang, Yongqing; Gunay, Nur Sibel; Capila, Ishan

2016-04-01

Complex mixtures of molecular species, such as glycoproteins and glycosaminoglycans, have important biological and therapeutic functions. Characterization of these mixtures with analytical chemistry measurements is an important step when developing generic drugs such as biosimilars. Recent developments have focused on analytical methods and statistical approaches to test similarity between mixtures. The question of how much uncertainty on mixture composition is reduced by combining several measurements still remains mostly unexplored. Mathematical frameworks to combine measurements, estimate mixture properties, and quantify remaining uncertainty, i.e. a characterization extent, are introduced here. Constrained optimization and mathematical modeling are applied to a set of twenty-three experimental measurements on heparan sulfate, a mixture of linear chains of disaccharides having different levels of sulfation. While this mixture has potentially over two million molecular species, mathematical modeling and the small set of measurements establish the existence of nonhomogeneity of sulfate level along chains and the presence of abundant sulfate repeats. Constrained optimization yields not only estimations of sulfate repeats and sulfate level at each position in the chains but also bounds on these levels, thereby estimating the extent of characterization of the sulfation pattern which is achieved by the set of measurements.

An Efficient Variable Screening Method for Effective Surrogate Models for Reliability-Based Design Optimization

DTIC Science & Technology

2014-04-01

surrogate model generation is difficult for high -dimensional problems, due to the curse of dimensionality. Variable screening methods have been...a variable screening model was developed for the quasi-molecular treatment of ion-atom collision [16]. In engineering, a confidence interval of...for high -level radioactive waste [18]. Moreover, the design sensitivity method can be extended to the variable screening method because vital

Model systems for single molecule polymer dynamics

PubMed Central

Latinwo, Folarin

2012-01-01

Double stranded DNA (dsDNA) has long served as a model system for single molecule polymer dynamics. However, dsDNA is a semiflexible polymer, and the structural rigidity of the DNA double helix gives rise to local molecular properties and chain dynamics that differ from flexible chains, including synthetic organic polymers. Recently, we developed single stranded DNA (ssDNA) as a new model system for single molecule studies of flexible polymer chains. In this work, we discuss model polymer systems in the context of “ideal” and “real” chain behavior considering thermal blobs, tension blobs, hydrodynamic drag and force–extension relations. In addition, we present monomer aspect ratio as a key parameter describing chain conformation and dynamics, and we derive dynamical scaling relations in terms of this molecular-level parameter. We show that asymmetric Kuhn segments can suppress monomer–monomer interactions, thereby altering global chain dynamics. Finally, we discuss ssDNA in the context of a new model system for single molecule polymer dynamics. Overall, we anticipate that future single polymer studies of flexible chains will reveal new insight into the dynamic behavior of “real” polymers, which will highlight the importance of molecular individualism and the prevalence of non-linear phenomena. PMID:22956980

Ambiguities in the identification of giant molecular cloud complexes from longitude-velocity diagrams

NASA Technical Reports Server (NTRS)

Adler, David S.; Roberts, William W., Jr.

1992-01-01

Techniques which use longitude-velocity diagrams to identify molecular cloud complexes in the disk of the Galaxy are investigated by means of model Galactic disks generated from N-body cloud-particle simulations. A procedure similar to the method used to reduce the low-level emission in Galactic l-v diagrams is employed to isolate complexes of emission in the model l-v diagram (LVCs) from the 'background'clouds. The LVCs produced in this manner yield a size-line-width relationship with a slope of 0.58 and a mass spectrum with a slope of 1.55, consistent with Galactic observations. It is demonstrated that associations identified as LVCs are often chance superpositions of clouds spread out along the line of sight in the disk of the model system. This indicates that the l-v diagram cannot be used to unambiguously determine the location of molecular cloud complexes in the model Galactic disk. The modeling results also indicate that the existence of a size-line-width relationship is not a reliable indicator of the physical nature of cloud complexes, in particular, whether the complexes are gravitationally bound objects.

Applying ecological models to communities of genetic elements: the case of neutral theory.

PubMed

Linquist, Stefan; Cottenie, Karl; Elliott, Tyler A; Saylor, Brent; Kremer, Stefan C; Gregory, T Ryan

2015-07-01

A promising recent development in molecular biology involves viewing the genome as a mini-ecosystem, where genetic elements are compared to organisms and the surrounding cellular and genomic structures are regarded as the local environment. Here, we critically evaluate the prospects of ecological neutral theory (ENT), a popular model in ecology, as it applies at the genomic level. This assessment requires an overview of the controversy surrounding neutral models in community ecology. In particular, we discuss the limitations of using ENT both as an explanation of community dynamics and as a null hypothesis. We then analyse a case study in which ENT has been applied to genomic data. Our central finding is that genetic elements do not conform to the requirements of ENT once its assumptions and limitations are made explicit. We further compare this genome-level application of ENT to two other, more familiar approaches in genomics that rely on neutral mechanisms: Kimura's molecular neutral theory and Lynch's mutational-hazard model. Interestingly, this comparison reveals that there are two distinct concepts of neutrality associated with these models, which we dub 'fitness neutrality' and 'competitive neutrality'. This distinction helps to clarify the various roles for neutral models in genomics, for example in explaining the evolution of genome size. © 2015 John Wiley & Sons Ltd.

Molecular view modeling of atmospheric organic particulate matter: Incorporating molecular structure and co-condensation of water

NASA Astrophysics Data System (ADS)

Pankow, James F.; Marks, Marguerite C.; Barsanti, Kelley C.; Mahmud, Abdullah; Asher, William E.; Li, Jingyi; Ying, Qi; Jathar, Shantanu H.; Kleeman, Michael J.

2015-12-01

Most urban and regional models used to predict levels of organic particulate matter (OPM) are based on fundamental equations for gas/particle partitioning, but make the highly simplifying, anonymized-view (AV) assumptions that OPM levels are not affected by either: a) the molecular characteristics of the condensing organic compounds (other than simple volatility); or b) co-condensation of water as driven by non-zero relative humidity (RH) values. The simplifying assumptions have allowed parameterized chamber results for formation of secondary organic aerosol (SOA) (e.g., ;two-product; (2p) coefficients) to be incorporated in chemical transport models. However, a return towards a less simplistic (and more computationally demanding) molecular view (MV) is needed that acknowledges that atmospheric OPM is a mixture of organic compounds with differing polarities, water, and in some cases dissolved salts. The higher computational cost of MV modeling results from a need for iterative calculations of the composition-dependent gas/particle partition coefficient values. MV modeling of OPM that considered water uptake (but not dissolved salts) was carried out for the southeast United States for the period August 29 through September 7, 2006. Three model variants were used at three universities: CMAQ-RH-2p (at PSU), UCD/CIT-RH-2p (at UCD), and CMAQ-RH-MCM (at TAMU). With the first two, MV structural characteristics (carbon number and numbers of functional groups) were assigned to each of the 2p products used in CMAQv.4.7.1 such that resulting predicted Kp,i values matched those in CMAQv.4.7.1. When water uptake was allowed, most runs assumed that uptake occurred only into the SOA portion, and imposed immiscibility of SOA with primary organic aerosol (POA). (POA is often viewed as rather non-polar, while SOA is commonly viewed as moderately-to-rather polar. Some runs with UCD/CIT-RH-2p were used to investigate the effects of POA/SOA miscibility.) CMAQ-RH-MCM used MCM to generate oxidation products, and assumed miscibility of SOA and POA. In a ∼500 km wide band from Louisiana through to at least North Carolina, CMAQ-RH-2p and UCD/CIT-RH-2p predicted that water uptake can increase SOA levels by as much as 50-100% (from a range of ∼1-2 μg m-3 to a range of ∼1-4 μg m-3). CMAQ-RH-MCM predicted much lower effects of water uptake on SOA levels (<10% increase). The results from CMAQ-RH-2p and UCD/CIT-RH-2p are considered more reflective of reality. In the Alabama/Georgia hotspot, both CMAQ-RH-2p and UCD/CIT-RH-2p predicted aerosol water levels that are up to nearly half the predicted SOA levels, namely ∼0.5-2 μg m-3. Such water levels in SOA will affect particle optical properties, viscosity, gas/particle partitioning times, and rates of hydrolysis and water elimination reactions.

Nucleotide Interdependency in Transcription Factor Binding Sites in the Drosophila Genome.

PubMed

Dresch, Jacqueline M; Zellers, Rowan G; Bork, Daniel K; Drewell, Robert A

2016-01-01

A long-standing objective in modern biology is to characterize the molecular components that drive the development of an organism. At the heart of eukaryotic development lies gene regulation. On the molecular level, much of the research in this field has focused on the binding of transcription factors (TFs) to regulatory regions in the genome known as cis-regulatory modules (CRMs). However, relatively little is known about the sequence-specific binding preferences of many TFs, especially with respect to the possible interdependencies between the nucleotides that make up binding sites. A particular limitation of many existing algorithms that aim to predict binding site sequences is that they do not allow for dependencies between nonadjacent nucleotides. In this study, we use a recently developed computational algorithm, MARZ, to compare binding site sequences using 32 distinct models in a systematic and unbiased approach to explore nucleotide dependencies within binding sites for 15 distinct TFs known to be critical to Drosophila development. Our results indicate that many of these proteins have varying levels of nucleotide interdependencies within their DNA recognition sequences, and that, in some cases, models that account for these dependencies greatly outperform traditional models that are used to predict binding sites. We also directly compare the ability of different models to identify the known KRUPPEL TF binding sites in CRMs and demonstrate that a more complex model that accounts for nucleotide interdependencies performs better when compared with simple models. This ability to identify TFs with critical nucleotide interdependencies in their binding sites will lead to a deeper understanding of how these molecular characteristics contribute to the architecture of CRMs and the precise regulation of transcription during organismal development.

Nucleotide Interdependency in Transcription Factor Binding Sites in the Drosophila Genome

PubMed Central

Dresch, Jacqueline M.; Zellers, Rowan G.; Bork, Daniel K.; Drewell, Robert A.

2016-01-01

A long-standing objective in modern biology is to characterize the molecular components that drive the development of an organism. At the heart of eukaryotic development lies gene regulation. On the molecular level, much of the research in this field has focused on the binding of transcription factors (TFs) to regulatory regions in the genome known as cis-regulatory modules (CRMs). However, relatively little is known about the sequence-specific binding preferences of many TFs, especially with respect to the possible interdependencies between the nucleotides that make up binding sites. A particular limitation of many existing algorithms that aim to predict binding site sequences is that they do not allow for dependencies between nonadjacent nucleotides. In this study, we use a recently developed computational algorithm, MARZ, to compare binding site sequences using 32 distinct models in a systematic and unbiased approach to explore nucleotide dependencies within binding sites for 15 distinct TFs known to be critical to Drosophila development. Our results indicate that many of these proteins have varying levels of nucleotide interdependencies within their DNA recognition sequences, and that, in some cases, models that account for these dependencies greatly outperform traditional models that are used to predict binding sites. We also directly compare the ability of different models to identify the known KRUPPEL TF binding sites in CRMs and demonstrate that a more complex model that accounts for nucleotide interdependencies performs better when compared with simple models. This ability to identify TFs with critical nucleotide interdependencies in their binding sites will lead to a deeper understanding of how these molecular characteristics contribute to the architecture of CRMs and the precise regulation of transcription during organismal development. PMID:27330274

Understanding the atomic-level Green-Kubo stress correlation function for a liquid through phonons in a model crystal

NASA Astrophysics Data System (ADS)

Levashov, V. A.

2014-11-01

In order to gain insight into the connection between the vibrational dynamics and the atomic-level Green-Kubo stress correlation function in liquids, we consider this connection in a model crystal instead. Of course, vibrational dynamics in liquids and crystals are quite different and it is not expected that the results obtained on a model crystal should be valid for liquids. However, these considerations provide a benchmark to which the results of the previous molecular dynamics simulations can be compared. Thus, assuming that vibrations are plane waves, we derive analytical expressions for the atomic-level stress correlation functions in the classical limit and analyze them. These results provide, in particular, a recipe for analysis of the atomic-level stress correlation functions in Fourier space and extraction of the wave-vector and frequency-dependent information. We also evaluate the energies of the atomic-level stresses. The energies obtained are significantly smaller than the energies previously determined in molecular dynamics simulations of several model liquids. This result suggests that the average energies of the atomic-level stresses in liquids and glasses are largely determined by the structural disorder. We discuss this result in the context of equipartition of the atomic-level stress energies. Analysis of the previously published data suggests that it is possible to speak about configurational and vibrational contributions to the average energies of the atomic-level stresses in a glass state. However, this separation in a liquid state is problematic. We also introduce and briefly consider the atomic-level transverse current correlation function. Finally, we address the broadening of the peaks in the pair distribution function with increase of distance. We find that the peaks' broadening (by ≈40 % ) occurs due to the transverse vibrational modes, while contribution from the longitudinal modes does not change with distance.

Systems Epidemiology: What’s in a Name?

PubMed Central

Dammann, O.; Gray, P.; Gressens, P.; Wolkenhauer, O.; Leviton, A.

2014-01-01

Systems biology is an interdisciplinary effort to integrate molecular, cellular, tissue, organ, and organism levels of function into computational models that facilitate the identification of general principles. Systems medicine adds a disease focus. Systems epidemiology adds yet another level consisting of antecedents that might contribute to the disease process in populations. In etiologic and prevention research, systems-type thinking about multiple levels of causation will allow epidemiologists to identify contributors to disease at multiple levels as well as their interactions. In public health, systems epidemiology will contribute to the improvement of syndromic surveillance methods. We encourage the creation of computational simulation models that integrate information about disease etiology, pathogenetic data, and the expertise of investigators from different disciplines. PMID:25598870

Exploratory factor analysis of pathway copy number data with an application towards the integration with gene expression data.

PubMed

van Wieringen, Wessel N; van de Wiel, Mark A

2011-05-01

Realizing that genes often operate together, studies into the molecular biology of cancer shift focus from individual genes to pathways. In order to understand the regulatory mechanisms of a pathway, one must study its genes at all molecular levels. To facilitate such study at the genomic level, we developed exploratory factor analysis for the characterization of the variability of a pathway's copy number data. A latent variable model that describes the call probability data of a pathway is introduced and fitted with an EM algorithm. In two breast cancer data sets, it is shown that the first two latent variables of GO nodes, which inherit a clear interpretation from the call probabilities, are often related to the proportion of aberrations and a contrast of the probabilities of a loss and of a gain. Linking the latent variables to the node's gene expression data suggests that they capture the "global" effect of genomic aberrations on these transcript levels. In all, the proposed method provides an possibly insightful characterization of pathway copy number data, which may be fruitfully exploited to study the interaction between the pathway's DNA copy number aberrations and data from other molecular levels like gene expression.

Simulation tools for particle-based reaction-diffusion dynamics in continuous space

PubMed Central

2014-01-01

Particle-based reaction-diffusion algorithms facilitate the modeling of the diffusional motion of individual molecules and the reactions between them in cellular environments. A physically realistic model, depending on the system at hand and the questions asked, would require different levels of modeling detail such as particle diffusion, geometrical confinement, particle volume exclusion or particle-particle interaction potentials. Higher levels of detail usually correspond to increased number of parameters and higher computational cost. Certain systems however, require these investments to be modeled adequately. Here we present a review on the current field of particle-based reaction-diffusion software packages operating on continuous space. Four nested levels of modeling detail are identified that capture incrementing amount of detail. Their applicability to different biological questions is discussed, arching from straight diffusion simulations to sophisticated and expensive models that bridge towards coarse grained molecular dynamics. PMID:25737778

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

Wykes, M., E-mail: mikewykes@gmail.com; Parambil, R.; Gierschner, J.

Here, we present a general approach to treating vibronic coupling in molecular crystals based on atomistic simulations of large clusters. Such clusters comprise model aggregates treated at the quantum chemical level embedded within a realistic environment treated at the molecular mechanics level. As we calculate ground and excited state equilibrium geometries and vibrational modes of model aggregates, our approach is able to capture effects arising from coupling to intermolecular degrees of freedom, absent from existing models relying on geometries and normal modes of single molecules. Using the geometries and vibrational modes of clusters, we are able to simulate the fluorescencemore » spectra of aggregates for which the lowest excited state bears negligible oscillator strength (as is the case, e.g., ideal H-aggregates) by including both Franck-Condon (FC) and Herzberg-Teller (HT) vibronic transitions. The latter terms allow the adiabatic excited state of the cluster to couple with vibrations in a perturbative fashion via derivatives of the transition dipole moment along nuclear coordinates. While vibronic coupling simulations employing FC and HT terms are well established for single-molecules, to our knowledge this is the first time they are applied to molecular aggregates. Here, we apply this approach to the simulation of the low-temperature fluorescence spectrum of para-distyrylbenzene single-crystal H-aggregates and draw comparisons with coarse-grained Frenkel-Holstein approaches previously extensively applied to such systems.« less

Final Technical Report

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

W. C. Griffith

In this project we provide an example of how to develop multi-tiered models to go across levels of biological organization to provide a framework for relating results of studies of low doses of ionizing radiation. This framework allows us to better understand how to extrapolate laboratory results to policy decisions, and to identify future studies that will increase confidence in policy decisions. In our application of the conceptual Model we were able to move across multiple levels of biological assessment for rodents going from molecular to organism level for in vitro and in vivo endpoints and to relate these tomore » human in vivo organism level effects. We used the rich literature on the effects of ionizing radiation on the developing brain in our models. The focus of this report is on disrupted neuronal migration due to radiation exposure and the structural and functional implications of these early biological effects. The cellular mechanisms resulting in pathogenesis are most likely due to a combination of the three mechanisms mentioned. For the purposes of a computational model, quantitative studies of low dose radiation effects on migration of neuronal progenitor cells in the cerebral mantle of experimental animals were used. In this project we were able to show now results from studies of low doses of radiation can be used in a multidimensional framework to construct linked models of neurodevelopment using molecular, cellular, tissue, and organ level studies conducted both in vitro and in vivo in rodents. These models could also be linked to behavioral endpoints in rodents which can be compared to available results in humans. The available data supported modeling to 10 cGy with limited data available at 5 cGy. We observed gradual but non-linear changes as the doses decreased. For neurodevelopment it appears that the slope of the dose response decreases from 25 cGy to 10 cGy. Future studies of neurodevelopment should be able to better define the dose response in this range.« less

A Molecular atlas of Xenopus respiratory system development.

PubMed

Rankin, Scott A; Thi Tran, Hong; Wlizla, Marcin; Mancini, Pamela; Shifley, Emily T; Bloor, Sean D; Han, Lu; Vleminckx, Kris; Wert, Susan E; Zorn, Aaron M

2015-01-01

Respiratory system development is regulated by a complex series of endoderm-mesoderm interactions that are not fully understood. Recently Xenopus has emerged as an alternative model to investigate early respiratory system development, but the extent to which the morphogenesis and molecular pathways involved are conserved between Xenopus and mammals has not been systematically documented. In this study, we provide a histological and molecular atlas of Xenopus respiratory system development, focusing on Nkx2.1+ respiratory cell fate specification in the developing foregut. We document the expression patterns of Wnt/β-catenin, fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) signaling components in the foregut and show that the molecular mechanisms of respiratory lineage induction are remarkably conserved between Xenopus and mice. Finally, using several functional experiments we refine the epistatic relationships among FGF, Wnt, and BMP signaling in early Xenopus respiratory system development. We demonstrate that Xenopus trachea and lung development, before metamorphosis, is comparable at the cellular and molecular levels to embryonic stages of mouse respiratory system development between embryonic days 8.5 and 10.5. This molecular atlas provides a fundamental starting point for further studies using Xenopus as a model to define the conserved genetic programs controlling early respiratory system development. © 2014 Wiley Periodicals, Inc.

A pharma perspective on the systems medicine and pharmacology of inflammation.

PubMed

Lahoz-Beneytez, Julio; Schnizler, Katrin; Eissing, Thomas

2015-02-01

Biological systems are complex and comprehend multiple scales of organisation. Hence, holistic approaches are necessary to capture the behaviour of these entities from the molecular and cellular to the whole organism level. This also applies to the understanding and treatment of different diseases. Traditional systems biology has been successful in describing different biological phenomena at the cellular level, but it still lacks of a holistic description of the multi-scale interactions within the body. The importance of the physiological context is of particular interest in inflammation. Regulatory agencies have urged the scientific community to increase the translational power of bio-medical research and it has been recognised that modelling and simulation could be a path to follow. Interestingly, in pharma R&D, modelling and simulation has been employed since a long time ago. Systems pharmacology, and particularly physiologically based pharmacokinetic/pharmacodynamic models, serve as a suitable framework to integrate the available and emerging knowledge at different levels of the drug development process. Systems medicine and pharmacology of inflammation will potentially benefit from this framework in order to better understand inflammatory diseases and to help to transfer the vast knowledge on the molecular and cellular level into a more physiological context. Ultimately, this may lead to reliable predictions of clinical outcomes such as disease progression or treatment efficacy, contributing thereby to a better care of patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Ciona intestinalis: chordate development made simple.

PubMed

Passamaneck, Yale J; Di Gregorio, Anna

2005-05-01

Thanks to their transparent and rapidly developing mosaic embryos, ascidians (or sea squirts) have been a model system for embryological studies for over a century. Recently, ascidians have entered the postgenomic era, with the sequencing of the Ciona intestinalis genome and the accumulation of molecular resources that rival those available for fruit flies and mice. One strength of ascidians as a model system is their close similarity to vertebrates. Literature reporting molecular homologies between vertebrate and ascidian tissues has flourished over the past 15 years, since the first ascidian genes were cloned. However, it should not be forgotten that ascidians diverged from the lineage leading to vertebrates over 500 million years ago. Here, we review the main similarities and differences so far identified, at the molecular level, between ascidian and vertebrate tissues and discuss the evolution of the compact ascidian genome. Copyright 2005 Wiley-Liss, Inc.

Molecular design and MD simulations of epitaxial superlattice of self-assembling ternary lipid bilayers

NASA Astrophysics Data System (ADS)

Chou, George; Vaughn, Mark; Cheng, K.

2011-10-01

Multicomponent lipid bilayers represent an important model system for studying cell membranes. At present, an ordered multicomponent phospholipid/cholesterol bilayer system involving charged lipid is still not available. Using a lipid superlattice (SL) model, a 13 x 15 x 15 nm^3 ternary phosphatidylcholine/phosphatidylserine/cholesterol bilayer system in water with simultaneous headgroup SL and acyl chain SL at different depths, or epitaxial SL, of the bilayer has been designed with atomistic detail. The arrangements of this epitaxial SL system were optimized by only two molecular parameters, lattice space and rotational angle of the lipids. Using atomistic MD simulations, we demonstrated the stability of the ordered structures for more than 100 ns. A positional restrained system was also used as a control. This system will provide new insights into understanding the nanodomain structures of cell membranes at the molecular level.

Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice.

PubMed

Couch, Yvonne; Trofimov, Alexander; Markova, Natalyia; Nikolenko, Vladimir; Steinbusch, Harry W; Chekhonin, Vladimir; Schroeter, Careen; Lesch, Klaus-Peter; Anthony, Daniel C; Strekalova, Tatyana

2016-05-16

Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours.

Molecular identification of organic compounds in atmospheric complex mixtures and relationship to atmospheric chemistry and sources.

PubMed

Mazurek, Monica A

2002-12-01

This article describes a chemical characterization approach for complex organic compound mixtures associated with fine atmospheric particles of diameters less than 2.5 m (PM2.5). It relates molecular- and bulk-level chemical characteristics of the complex mixture to atmospheric chemistry and to emission sources. Overall, the analytical approach describes the organic complex mixtures in terms of a chemical mass balance (CMB). Here, the complex mixture is related to a bulk elemental measurement (total carbon) and is broken down systematically into functional groups and molecular compositions. The CMB and molecular-level information can be used to understand the sources of the atmospheric fine particles through conversion of chromatographic data and by incorporation into receptor-based CMB models. Once described and quantified within a mass balance framework, the chemical profiles for aerosol organic matter can be applied to existing air quality issues. Examples include understanding health effects of PM2.5 and defining and controlling key sources of anthropogenic fine particles. Overall, the organic aerosol compositional data provide chemical information needed for effective PM2.5 management.

Optical Lattice Clocks with Weakly Bound Molecules.

PubMed

Borkowski, Mateusz

2018-02-23

Optical molecular clocks promise unparalleled sensitivity to the temporal variation of the electron-to-proton mass ratio and insight into possible new physics beyond the standard model. We propose to realize a molecular clock with bosonic ^{174}Yb_{2} molecules, where the forbidden ^{1}S_{0}→^{3}P_{0} clock transition would be induced magnetically. The use of a bosonic species avoids possible complications due to the hyperfine structure present in fermionic species. While direct clock line photoassociation would be challenging, weakly bound ground state molecules could be produced by stimulated Raman adiabatic passage and used instead. The recent scattering measurements [L. Franchi, et al. New J. Phys. 19, 103037 (2017)NJOPFM1367-263010.1088/1367-2630/aa8fb4] enable us to determine the positions of target ^{1}S_{0}+^{3}P_{0} vibrational levels and calculate the Franck-Condon factors for clock transitions between ground and excited molecular states. The resulting magnetically induced Rabi frequencies are similar to those for atoms hinting that an experimental realization is feasible. A successful observation could pave the way towards Hz-level molecular spectroscopy.

Molecular Dynamics Simulations of Voltage-Gated Cation Channels: Insights on Voltage-Sensor Domain Function and Modulation

PubMed Central

Delemotte, Lucie; Klein, Michael L.; Tarek, Mounir

2012-01-01

Since their discovery in the 1950s, the structure and function of voltage-gated cation channels (VGCC) has been largely understood thanks to results stemming from electrophysiology, pharmacology, spectroscopy, and structural biology. Over the past decade, computational methods such as molecular dynamics (MD) simulations have also contributed, providing molecular level information that can be tested against experimental results, thereby allowing the validation of the models and protocols. Importantly, MD can shed light on elements of VGCC function that cannot be easily accessed through “classical” experiments. Here, we review the results of recent MD simulations addressing key questions that pertain to the function and modulation of the VGCC’s voltage-sensor domain (VSD) highlighting: (1) the movement of the S4-helix basic residues during channel activation, articulating how the electrical driving force acts upon them; (2) the nature of the VSD intermediate states on transitioning between open and closed states of the VGCC; and (3) the molecular level effects on the VSD arising from mutations of specific S4 positively charged residues involved in certain genetic diseases. PMID:22654756

Optical Lattice Clocks with Weakly Bound Molecules

NASA Astrophysics Data System (ADS)

Borkowski, Mateusz

2018-02-01

Optical molecular clocks promise unparalleled sensitivity to the temporal variation of the electron-to-proton mass ratio and insight into possible new physics beyond the standard model. We propose to realize a molecular clock with bosonic 174Yb2 molecules, where the forbidden 1S0 →3P0 clock transition would be induced magnetically. The use of a bosonic species avoids possible complications due to the hyperfine structure present in fermionic species. While direct clock line photoassociation would be challenging, weakly bound ground state molecules could be produced by stimulated Raman adiabatic passage and used instead. The recent scattering measurements [L. Franchi, et al. New J. Phys. 19, 103037 (2017), 10.1088/1367-2630/aa8fb4] enable us to determine the positions of target 1S0 +3P0 vibrational levels and calculate the Franck-Condon factors for clock transitions between ground and excited molecular states. The resulting magnetically induced Rabi frequencies are similar to those for atoms hinting that an experimental realization is feasible. A successful observation could pave the way towards Hz-level molecular spectroscopy.

Human Xq28 inversion polymorphism: From sex linkage to Genomics--A genetic mother lode.

PubMed

Kirby, Cait S; Kolber, Natalie; Salih Almohaidi, Asmaa M; Bierwert, Lou Ann; Saunders, Lori; Williams, Steven; Merritt, Robert

2016-01-01

An inversion polymorphism of the filamin and emerin genes at the tip of the long arm of the human X-chromosome serves as the basis of an investigative laboratory in which students learn something new about their own genomes. Long, nearly identical inverted repeats flanking the filamin and emerin genes illustrate how repetitive elements can lead to alterations in genome structure (inversions) through nonallelic homologous recombination. The near identity of the inverted repeats is an example of concerted evolution through gene conversion. While the laboratory in its entirety is designed for college level genetics courses, portions of the laboratory are appropriate for courses at other levels. Because the polymorphism is on the X-chromosome, the laboratory can be used in introductory biology courses to enhance understanding of sex-linkage and to test for Hardy-Weinberg equilibrium in females. More advanced topics, such as chromosome interference, the molecular model for recombination, and inversion heterozygosity suppression of recombination can be explored in upper-level genetics and evolution courses. DNA isolation, restriction digests, ligation, long PCR, and iPCR provide experience with techniques in molecular biology. This investigative laboratory weaves together topics stretching from molecular genetics to cytogenetics and sex-linkage, population genetics and evolutionary genetics. © 2016 The International Union of Biochemistry and Molecular Biology.

Coupling of lipid membrane elasticity and in-plane dynamics

NASA Astrophysics Data System (ADS)

Tsang, Kuan-Yu; Lai, Yei-Chen; Chiang, Yun-Wei; Chen, Yi-Fan

2017-07-01

Biomembranes exhibit liquid and solid features concomitantly with their in-plane fluidity and elasticity tightly regulated by cells. Here, we present experimental evidence supporting the existence of the dynamics-elasticity correlations for lipid membranes and propose a mechanism involving molecular packing densities to explain them. This paper thereby unifies, at the molecular level, the aspects of the continuum mechanics long used to model the two membrane features. This ultimately may elucidate the universal physical principles governing the cellular phenomena involving biomembranes.

Breakdown parameter for kinetic modeling of multiscale gas flows.

PubMed

Meng, Jianping; Dongari, Nishanth; Reese, Jason M; Zhang, Yonghao

2014-06-01

Multiscale methods built purely on the kinetic theory of gases provide information about the molecular velocity distribution function. It is therefore both important and feasible to establish new breakdown parameters for assessing the appropriateness of a fluid description at the continuum level by utilizing kinetic information rather than macroscopic flow quantities alone. We propose a new kinetic criterion to indirectly assess the errors introduced by a continuum-level description of the gas flow. The analysis, which includes numerical demonstrations, focuses on the validity of the Navier-Stokes-Fourier equations and corresponding kinetic models and reveals that the new criterion can consistently indicate the validity of continuum-level modeling in both low-speed and high-speed flows at different Knudsen numbers.

Multiscale Investigation of the Depth-Dependent Mechanical Anisotropy of the Human Corneal Stroma

PubMed Central

Labate, Cristina; Lombardo, Marco; De Santo, Maria P.; Dias, Janice; Ziebarth, Noel M.; Lombardo, Giuseppe

2015-01-01

Purpose. To investigate the depth-dependent mechanical anisotropy of the human corneal stroma at the tissue (stroma) and molecular (collagen) level by using atomic force microscopy (AFM). Methods. Eleven human donor corneas were dissected at different stromal depths by using a microkeratome. Mechanical measurements were performed in 15% dextran on the surface of the exposed stroma of each sample by using a custom-built AFM in force spectroscopy mode using both microspherical (38-μm diameter) and nanoconical (10-nm radius of curvature) indenters at 2-μm/s and 15-μm/s indentation rates. Young's modulus was determined by fitting force curve data using the Hertz and Hertz-Sneddon models for a spherical and a conical indenter, respectively. The depth-dependent anisotropy of stromal elasticity was correlated with images of the corneal stroma acquired by two-photon microscopy. Results. The force curves were obtained at stromal depths ranging from 59 to 218 μm. At the tissue level, Young's modulus (ES) showed a steep decrease at approximately 140-μm stromal depth (from 0.8 MPa to 0.3 MPa; P = 0.03) and then was stable in the posterior stroma. At the molecular level, Young's modulus (EC) was significantly greater than at the tissue level; EC decreased nonlinearly with increasing stromal depth from 3.9 to 2.6 MPa (P = 0.04). The variation of microstructure through the thickness correlated highly with a nonconstant profile of the mechanical properties in the stroma. Conclusions. The corneal stroma exhibits unique anisotropic elastic behavior at the tissue and molecular levels. This knowledge may benefit modeling of corneal behavior and help in the development of biomimetic materials. PMID:26098472

Superluminescence from an optically pumped molecular tunneling junction by injection of plasmon induced hot electrons

PubMed Central

Braun, Kai; Wang, Xiao; Kern, Andreas M; Adler, Hilmar; Peisert, Heiko; Chassé, Thomas; Zhang, Dai

2015-01-01

Summary Here, we demonstrate a bias-driven superluminescent point light-source based on an optically pumped molecular junction (gold substrate/self-assembled molecular monolayer/gold tip) of a scanning tunneling microscope, operating at ambient conditions and providing almost three orders of magnitude higher electron-to-photon conversion efficiency than electroluminescence induced by inelastic tunneling without optical pumping. A positive, steadily increasing bias voltage induces a step-like rise of the Stokes shifted optical signal emitted from the junction. This emission is strongly attenuated by reversing the applied bias voltage. At high bias voltage, the emission intensity depends non-linearly on the optical pump power. The enhanced emission can be modelled by rate equations taking into account hole injection from the tip (anode) into the highest occupied orbital of the closest substrate-bound molecule (lower level) and radiative recombination with an electron from above the Fermi level (upper level), hence feeding photons back by stimulated emission resonant with the gap mode. The system reflects many essential features of a superluminescent light emitting diode. PMID:26171286

Decreased hepatic contents of coenzyme A molecular species in mice after subchronic mild social defeat stress.

PubMed

Kubota, Yoshifumi; Goto, Tatsuhiko; Hagiya, Yuki; Chohnan, Shigeru; Toyoda, Atsushi

2016-01-01

Social stress may precipitate psychiatric disorders such as depression, which is related to the occurrence of the metabolic syndrome, including obesity and type 2 diabetes. We have evaluated the effects of social stress on central and peripheral metabolism using a model of depression in mice. In the present study, we focused on coenzyme A (CoA) molecular species [i.e. non-esterified CoA (CoASH), acetyl-CoA and malonyl-CoA] which play important roles in numerous metabolic pathways, and we analyzed changes in expression of these molecules in the hypothalamus and liver of adult male mice (C57BL/6J) subjected to 10 days of subchronic mild social defeat stress (sCSDS) with ICR mice as aggressors. Mice (n = 12) exposed to showed hyperphagia- and polydipsia-like symptoms and increased body weight gain compared with control mice which were not affected by exposure to ICR mice (n = 12). To elucidate the underlying metabolic features in the sCSDS model, acetyl-CoA, malonyl-CoA and CoASH tissue levels were analyzed using the acyl-CoA cycling method. The levels of hypothalamic malonyl-CoA, which decreases feeding behavior, were not influenced by sCSDS. However, sCSDS reduced levels of acetyl-CoA, malonyl-CoA and total CoA (sum of the three CoA molecular species) in the liver. Hence, hyperphagia-like symptoms in sCSDS mice evidently occurred independently of hypothalamic malonyl-CoA, but might consequently lead to down-regulation of hepatic CoA via altered expression of nudix hydrolase 7. Future studies should investigate the molecular mechanism(s) underlying the down-regulation of liver CoA pools in sCSDS mice.

Investigating the properties and interaction mechanism of nano-silica in polyvinyl alcohol/polyacrylamide blends at an atomic level.

PubMed

Wei, Qinghua; Wang, Yanen; Wang, Shuzhi; Zhang, Yingfeng; Chen, Xiongbiao

2017-11-01

The nano-silica can be incorporated into polymers for improved mechanical properties. Notably, the interaction between nano-silica and polymer is of a microscopic phenomenon and thus, hard to observe and study by using experimental methods. Based on molecular dynamics, this paper presents a study on the properties and the interaction mechanism of nano-silica in the polyvinyl alcohol (PVA)/polyacrylamide (PAM) blends at an atomic level. Specifically, six blends of PVA/PAM with varying concentrations of nano-silica (0-13wt%) and two interfacial interaction models of polymers on the silica surface were designed and analyzed at an atomic level in terms of concentration profile, mechanical properties, fractional free volume (FFV), dynamic properties of polymers and X-ray diffraction patterns. The concentration profile results and micromorphologies of equilibrium models suggest PAM molecular chains are easier to be adsorbed on the silica surface than PVA molecular chains in blends. The incorporation of nano-silica into the PVA/PAM blends can increase the blend mechanical properties, densities, and semicrystalline character. Meanwhile, the FFV and the mobility of polymer chain decrease with the silica concentration, which agrees with the results of mechanical properties, densities, and semicrystalline character. Our results also illustrate that an analysis of binding energies and pair correlation functions (PCF) allows for the discovery of the interaction mechanism of nano-silica in PVA/PAM blends; and that hydrogen bond interactions between polar functional groups of polymer molecular chains and the hydroxyl groups of the silica surface are involved in adsorption of the polymers on the silica surface, thus affecting the interaction mechanism of nano-silica in PVA/PAM blend systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

A cascaded QSAR model for efficient prediction of overall power conversion efficiency of all-organic dye-sensitized solar cells.

PubMed

Li, Hongzhi; Zhong, Ziyan; Li, Lin; Gao, Rui; Cui, Jingxia; Gao, Ting; Hu, Li Hong; Lu, Yinghua; Su, Zhong-Min; Li, Hui

2015-05-30

A cascaded model is proposed to establish the quantitative structure-activity relationship (QSAR) between the overall power conversion efficiency (PCE) and quantum chemical molecular descriptors of all-organic dye sensitizers. The cascaded model is a two-level network in which the outputs of the first level (JSC, VOC, and FF) are the inputs of the second level, and the ultimate end-point is the overall PCE of dye-sensitized solar cells (DSSCs). The model combines quantum chemical methods and machine learning methods, further including quantum chemical calculations, data division, feature selection, regression, and validation steps. To improve the efficiency of the model and reduce the redundancy and noise of the molecular descriptors, six feature selection methods (multiple linear regression, genetic algorithms, mean impact value, forward selection, backward elimination, and +n-m algorithm) are used with the support vector machine. The best established cascaded model predicts the PCE values of DSSCs with a MAE of 0.57 (%), which is about 10% of the mean value PCE (5.62%). The validation parameters according to the OECD principles are R(2) (0.75), Q(2) (0.77), and Qcv2 (0.76), which demonstrate the great goodness-of-fit, predictivity, and robustness of the model. Additionally, the applicability domain of the cascaded QSAR model is defined for further application. This study demonstrates that the established cascaded model is able to effectively predict the PCE for organic dye sensitizers with very low cost and relatively high accuracy, providing a useful tool for the design of dye sensitizers with high PCE. © 2015 Wiley Periodicals, Inc.

A multiscale simulation technique for molecular electronics: design of a directed self-assembled molecular n-bit shift register memory device.

PubMed

Lambropoulos, Nicholas A; Reimers, Jeffrey R; Crossley, Maxwell J; Hush, Noel S; Silverbrook, Kia

2013-12-20

A general method useful in molecular electronics design is developed that integrates modelling on the nano-scale (using quantum-chemical software) and on the micro-scale (using finite-element methods). It is applied to the design of an n-bit shift register memory that could conceivably be built using accessible technologies. To achieve this, the entire complex structure of the device would be built to atomic precision using feedback-controlled lithography to provide atomic-level control of silicon devices, controlled wet-chemical synthesis of molecular insulating pillars above the silicon, and controlled wet-chemical self-assembly of modular molecular devices to these pillars that connect to external metal electrodes (leads). The shift register consists of n connected cells that read data from an input electrode, pass it sequentially between the cells under the control of two external clock electrodes, and deliver it finally to an output device. The proposed cells are trimeric oligoporphyrin units whose internal states are manipulated to provide functionality, covalently connected to other cells via dipeptide linkages. Signals from the clock electrodes are conveyed by oligoporphyrin molecular wires, and μ-oxo porphyrin insulating columns are used as the supporting pillars. The developed multiscale modelling technique is applied to determine the characteristics of this molecular device, with in particular utilization of the inverted region for molecular electron-transfer processes shown to facilitate latching and control using exceptionally low energy costs per logic operation compared to standard CMOS shift register technology.

A multiscale simulation technique for molecular electronics: design of a directed self-assembled molecular n-bit shift register memory device

NASA Astrophysics Data System (ADS)

Lambropoulos, Nicholas A.; Reimers, Jeffrey R.; Crossley, Maxwell J.; Hush, Noel S.; Silverbrook, Kia

2013-12-01

A general method useful in molecular electronics design is developed that integrates modelling on the nano-scale (using quantum-chemical software) and on the micro-scale (using finite-element methods). It is applied to the design of an n-bit shift register memory that could conceivably be built using accessible technologies. To achieve this, the entire complex structure of the device would be built to atomic precision using feedback-controlled lithography to provide atomic-level control of silicon devices, controlled wet-chemical synthesis of molecular insulating pillars above the silicon, and controlled wet-chemical self-assembly of modular molecular devices to these pillars that connect to external metal electrodes (leads). The shift register consists of n connected cells that read data from an input electrode, pass it sequentially between the cells under the control of two external clock electrodes, and deliver it finally to an output device. The proposed cells are trimeric oligoporphyrin units whose internal states are manipulated to provide functionality, covalently connected to other cells via dipeptide linkages. Signals from the clock electrodes are conveyed by oligoporphyrin molecular wires, and μ-oxo porphyrin insulating columns are used as the supporting pillars. The developed multiscale modelling technique is applied to determine the characteristics of this molecular device, with in particular utilization of the inverted region for molecular electron-transfer processes shown to facilitate latching and control using exceptionally low energy costs per logic operation compared to standard CMOS shift register technology.

Length-scale dependent mechanical properties of Al-Cu eutectic alloy: Molecular dynamics based model and its experimental verification

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

Tiwary, C. S., E-mail: cst.iisc@gmail.com; Chattopadhyay, K.; Chakraborty, S.

2014-05-28

This paper attempts to gain an understanding of the effect of lamellar length scale on the mechanical properties of two-phase metal-intermetallic eutectic structure. We first develop a molecular dynamics model for the in-situ grown eutectic interface followed by a model of deformation of Al-Al{sub 2}Cu lamellar eutectic. Leveraging the insights obtained from the simulation on the behaviour of dislocations at different length scales of the eutectic, we present and explain the experimental results on Al-Al{sub 2}Cu eutectic with various different lamellar spacing. The physics behind the mechanism is further quantified with help of atomic level energy model for different lengthmore » scale as well as different strain. An atomic level energy partitioning of the lamellae and the interface regions reveals that the energy of the lamellae core are accumulated more due to dislocations irrespective of the length-scale. Whereas the energy of the interface is accumulated more due to dislocations when the length-scale is smaller, but the trend is reversed when the length-scale is large beyond a critical size of about 80 nm.« less

Modeling Radiative Heat Transfer and Turbulence-Radiation Interactions in Engines

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

Paul, Chandan; Sircar, Arpan; Ferreyro-Fernandez, Sebastian

Detailed radiation modelling in piston engines has received relatively little attention to date. Recently, it is being revisited in light of current trends towards higher operating pressures and higher levels of exhaust-gas recirculation, both of which enhance molecular gas radiation. Advanced high-efficiency engines also are expected to function closer to the limits of stable operation, where even small perturbations to the energy balance can have a large influence on system behavior. Here several different spectral radiation property models and radiative transfer equation (RTE) solvers have been implemented in an OpenFOAM-based engine CFD code, and simulations have been performed for amore » full-load (peak pressure ~200 bar) heavy-duty diesel engine. Differences in computed temperature fields, NO and soot levels, and wall heat transfer rates are shown for different combinations of spectral models and RTE solvers. The relative importance of molecular gas radiation versus soot radiation is examined. And the influence of turbulence-radiation interactions is determined by comparing results obtained using local mean values of composition and temperature to compute radiative emission and absorption with those obtained using a particle-based transported probability density function method.« less

Level-Set Variational Implicit-Solvent Modeling of Biomolecules with the Coulomb-Field Approximation

PubMed Central

2011-01-01

Central in the variational implicit-solvent model (VISM) [Dzubiella, Swanson, and McCammon Phys. Rev. Lett.2006, 96, 087802 and J. Chem. Phys.2006, 124, 084905] of molecular solvation is a mean-field free-energy functional of all possible solute–solvent interfaces or dielectric boundaries. Such a functional can be minimized numerically by a level-set method to determine stable equilibrium conformations and solvation free energies. Applications to nonpolar systems have shown that the level-set VISM is efficient and leads to qualitatively and often quantitatively correct results. In particular, it is capable of capturing capillary evaporation in hydrophobic confinement and corresponding multiple equilibrium states as found in molecular dynamics (MD) simulations. In this work, we introduce into the VISM the Coulomb-field approximation of the electrostatic free energy. Such an approximation is a volume integral over an arbitrary shaped solvent region, requiring no solutions to any partial differential equations. With this approximation, we obtain the effective boundary force and use it as the “normal velocity” in the level-set relaxation. We test the new approach by calculating solvation free energies and potentials of mean force for small and large molecules, including the two-domain protein BphC. Our results reveal the importance of coupling polar and nonpolar interactions in the underlying molecular systems. In particular, dehydration near the domain interface of BphC subunits is found to be highly sensitive to local electrostatic potentials as seen in previous MD simulations. This is a first step toward capturing the complex protein dehydration process by an implicit-solvent approach. PMID:22346739

Understanding Molecular Conduction: Old Wine in a New Bottle?

NASA Astrophysics Data System (ADS)

Ghosh, Avik

2007-03-01

Molecules provide an opportunity to test our understanding of fundamental non-equilibrium transport processes, as well as explore new device possibilities. We have developed a unified approach to nanoscale conduction, coupling bandstructure and electrostatics of the channel and contacts with a quantum kinetic theory of current flow. This allows us to describe molecular conduction at various levels of detail, -- from quantum corrected compact models, to semi-empirical models for quick physical insights, and `first-principles' calculations of current-voltage (I-V) characteristics with no adjustable parameters. Using this suite of tools, we can quantitatively explain various experimental I-Vs, including complex reconstructed silicon substrates. We find that conduction in most molecules is contact dominated, and limited by fundamental electrostatic and thermodynamic restrictions quite analogous to those faced by the silicon industry, barring a few interesting exceptions. The distinction between molecular and silicon electronics must therefore be probed at a more fundamental level. Ultra-short molecules are unique in that they possess large Coulomb energies as well as anomalous vibronic couplings with current flow -- in other words, strong non-equilibrium electron-electron and electron-phonon correlations. These effects yield prominent experimental signatures, but require a completely different modeling approach -- in fact, popular approaches to include correlation typically do not work for non-equilibrium. Molecules exhibit rich physics, including the ability to function both as weakly interacting current conduits (quantum wires) as well as strongly correlated charge storage centers (quantum dots). Theoretical treatment of the intermediate coupling regime is particularly challenging, with a large `fine structure constant' for transport that negates orthodox theories of Coulomb Blockade and phonon-assisted tunneling. It is in this regime that the scientific and technological merits of molecular conductors may need to be explored. For instance, the tunable quantum coupling of current flow in silicon transistors with engineered molecular scatterers could lead to devices that operate on completely novel principles.

Molecular dynamics simulations on networks of heparin and collagen.

PubMed

Kulke, Martin; Geist, Norman; Friedrichs, Wenke; Langel, Walter

2017-06-01

Synthetic scaffolds containing collagen (Type I) are of increasing interest for bone tissue engineering, especially for highly porous biomaterials in combination with glycosaminoglycans. In experiments the integration of heparin during the fibrillogenesis resulted in different types of collagen fibrils, but models for this aggregation on a molecular scale were only tentative. We conducted molecular dynamic simulations investigating the binding of heparin to collagen and the influence of the telopeptides during collagen aggregation. This aims at explaining experimental findings on a molecular level. Novel structures for N- and C-telopeptides were developed with the TIGER2 replica exchange algorithm and dihedral principle component analysis. We present an extended statistical analysis of the mainly electrostatic interaction between heparin and collagen and identify several binding sites. Finally, we propose a molecular mechanism for the influence of glycosaminoglycans on the morphology of collagen fibrils. Proteins 2017; 85:1119-1130. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Kinetic Theory and Simulation of Single-Channel Water Transport

NASA Astrophysics Data System (ADS)

Tajkhorshid, Emad; Zhu, Fangqiang; Schulten, Klaus

Water translocation between various compartments of a system is a fundamental process in biology of all living cells and in a wide variety of technological problems. The process is of interest in different fields of physiology, physical chemistry, and physics, and many scientists have tried to describe the process through physical models. Owing to advances in computer simulation of molecular processes at an atomic level, water transport has been studied in a variety of molecular systems ranging from biological water channels to artificial nanotubes. While simulations have successfully described various kinetic aspects of water transport, offering a simple, unified model to describe trans-channel translocation of water turned out to be a nontrivial task.

Unraveling the benzocaine-receptor interaction at molecular level using mass-resolved spectroscopy.

PubMed

Aguado, Edurne; León, Iker; Millán, Judith; Cocinero, Emilio J; Jaeqx, Sander; Rijs, Anouk M; Lesarri, Alberto; Fernández, José A

2013-10-31

The benzocaine-toluene cluster has been used as a model system to mimic the interaction between the local anesthetic benzocaine and the phenylalanine residue in Na(+) channels. The cluster was generated in a supersonic expansion of benzocaine and toluene in helium. Using a combination of mass-resolved laser-based experimental techniques and computational methods, the complex was fully characterized, finding four conformational isomers in which the molecules are bound through N-H···π and π···π weak hydrogen bonds. The structures of the detected isomers closely resemble those predicted for benzocaine in the inner pore of the ion channels, giving experimental support to previously reported molecular chemistry models.

From Occasional Choices to Inevitable Musts: A Computational Model of Nicotine Addiction

PubMed Central

Metin, Selin; Sengor, N. Serap

2012-01-01

Although, there are considerable works on the neural mechanisms of reward-based learning and decision making, and most of them mention that addiction can be explained by malfunctioning in these cognitive processes, there are very few computational models. This paper focuses on nicotine addiction, and a computational model for nicotine addiction is proposed based on the neurophysiological basis of addiction. The model compromises different levels ranging from molecular basis to systems level, and it demonstrates three different possible behavioral patterns which are addict, nonaddict, and indecisive. The dynamical behavior of the proposed model is investigated with tools used in analyzing nonlinear dynamical systems, and the relation between the behavioral patterns and the dynamics of the system is discussed. PMID:23251144

A point of view: quantitative and qualitative imbalance in disease pathogenesis; pulmonary surfactant protein A genetic variants as a model.

PubMed

Floros, J; Wang, G

2001-05-01

The high degree of similarity at the molecular level, between humans and other species, has provided the rationale for the use of a variety of species as model systems in research, resulting in enormous advances in biological sciences and medicine. In contrast, the individual variability observed among humans, for example, in external physique, organ functionality and others, is accounted for, by only a fraction of 1% of differences at the DNA level. These small differences, which are essential for understanding disease pathogenesis, have posed enormous challenges in medicine, as we try to understand why patients may respond differently to drugs or why one patient has complications and another does not. Differences in outcome are most likely the result of interactions among genetic components themselves and/or the environment at the molecular, cellular, organ, or organismal level, or the macroenvironment. In this paper: (1) we consider some issues for multifactorial disease pathogenesis; (2) we provide a review of human SP-A and how the knowledge gained and the characteristics of the hSP-A system may serve as a model in the study of disease with multifactorial etiology; and (3) we describe examples where hSP-A has been used in the study of disease.

Sleep and Behavior in Cross-Fostering Rats: Developmental and Sex Aspects.

PubMed

Santangeli, Olena; Lehtikuja, Henna; Palomäki, Eeva; Wigren, Henna-Kaisa; Paunio, Tiina; Porkka-Heiskanen, Tarja

2016-12-01

Adverse early-life events induce behavioral psychopathologies and sleep changes in adulthood. In order to understand the molecular level mechanisms by which the maltreatment modifies sleep, valid animal models are needed. Changing pups between mothers at early age (cross-fostering) may satisfyingly model adverse events in human childhood. Cross-fostering (CF) was used to model mild early-life stress in male and female Wistar rats. Behavior and BDNF gene expression in the basal forebrain (BF), cortex, and hypothalamus were assessed during adolescence and adulthood. Spontaneous sleep, sleep homeostasis, and BF extracellular adenosine levels were assessed in adulthood. CF rats demonstrated increased number of REM sleep onsets in light and dark periods of the day. Total REM and NREM sleep duration was also increased during the light period. While sleep homeostasis was not severely affected, basal level of adenosine in the BF of both male and female CF rats was lower than in controls. CF did not lead to considerable changes in behavior. Even when the consequences of adverse early-life events are not observed in tests for anxiety and depression, they leave a molecular mark in the brain, which can act as a vulnerability factor for psychopathologies in later life. Sleep is a sensitive indicator for even mild early-life stress. © 2016 Associated Professional Sleep Societies, LLC.

Molecular structure, mechanical behavior and failure mechanism of the C-terminal cross-link domain in type I collagen.

PubMed

Uzel, Sebastien G M; Buehler, Markus J

2011-02-01

Collagen is a key constituent in structural materials found in biology, including bone, tendon, skin and blood vessels. Here we report a first molecular level model of an entire overlap region of a C-terminal cross-linked type I collagen assembly and carry out a nanomechanical characterization based on large-scale molecular dynamics simulation in explicit water solvent. Our results show that the deformation mechanism and strength of the structure are greatly affected by the presence of the cross-link, and by the specific loading condition of how the stretching is applied. We find that the presence of a cross-link results in greater strength during deformation as complete intermolecular slip is prevented, and thereby particularly affects larger deformation levels. Conversely, the lack of a cross-link results in the onset of intermolecular sliding during deformation and as a result an overall weaker structure is obtained. Through a detailed analysis of the distribution of deformation by calculating the molecular strain we show that the location of largest strains does not occur around the covalent bonding region, but is found in regions further away from this location. The insight developed from understanding collagenous materials from a fundamental molecular level upwards could play a role in advancing our understanding of physiological and disease states of connective tissues, and also enable the development of new scaffolding material for applications in regenerative medicine and biologically inspired materials. Copyright © 2011. Elsevier Ltd. All rights reserved.

Molecular- and Domain-level Microstructure-dependent Material Model for Nano-segregated Polyurea

DTIC Science & Technology

2013-04-15

material subroutine VUMAT of ABAQUS /Explicit (Dassault Systems, 2010), a commercial finite element code. This subroutine is called by the ABAQUS solver...rate of change of the local internal thermal energy is equal to the corresponding rate of dissipative work. Critical assessment of this model identified...The model also takes into account the plastic expansion or contraction of voids and therefore the stresses are appropriately modified to account for

Computational Modeling of Multi-Scale Material Features in Cement Paste - An Overview

DTIC Science & Technology

2015-05-25

and concrete ; though commonly used are one of the most complex in terms of material morphology and structure than most materials, for example...across the multiple scales are required. In this paper, recent work from our research group on the nano to continuum level modeling of cementitious...of our research work consisting of, • Molecular Dynamics (MD) modeling for the nano scale features of the cementitious material chemistry. • Micro

Modular Electron Donor Group Tuning Of Frontier Energy Levels In Diarylaminofluorenone Push-Pull Molecules

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

Homnick, Paul J.; Lahti, P. M.

2012-01-01

Push–pull organic molecules composed of electron donor diarylamines at the 2- and 2,7-positions of fluorenone exhibit intramolecular charge-transfer behaviour in static absorption and emission spectra. Electrochemical and spectral data combined in a modular electronic analysis model show how the donor HOMO and acceptor LUMO act as major determinants of the frontier molecular orbital energy levels.

Challenges and Advances for Genetic Engineering of Non-model Bacteria and Uses in Consolidated Bioprocessing

PubMed Central

Yan, Qiang; Fong, Stephen S.

2017-01-01

Metabolic diversity in microorganisms can provide the basis for creating novel biochemical products. However, most metabolic engineering projects utilize a handful of established model organisms and thus, a challenge for harnessing the potential of novel microbial functions is the ability to either heterologously express novel genes or directly utilize non-model organisms. Genetic manipulation of non-model microorganisms is still challenging due to organism-specific nuances that hinder universal molecular genetic tools and translatable knowledge of intracellular biochemical pathways and regulatory mechanisms. However, in the past several years, unprecedented progress has been made in synthetic biology, molecular genetics tools development, applications of omics data techniques, and computational tools that can aid in developing non-model hosts in a systematic manner. In this review, we focus on concerns and approaches related to working with non-model microorganisms including developing molecular genetics tools such as shuttle vectors, selectable markers, and expression systems. In addition, we will discuss: (1) current techniques in controlling gene expression (transcriptional/translational level), (2) advances in site-specific genome engineering tools [homologous recombination (HR) and clustered regularly interspaced short palindromic repeats (CRISPR)], and (3) advances in genome-scale metabolic models (GSMMs) in guiding design of non-model species. Application of these principles to metabolic engineering strategies for consolidated bioprocessing (CBP) will be discussed along with some brief comments on foreseeable future prospects. PMID:29123506

DSMC Simulation and Experimental Validation of Shock Interaction in Hypersonic Low Density Flow

PubMed Central

2014-01-01

Direct simulation Monte Carlo (DSMC) of shock interaction in hypersonic low density flow is developed. Three collision molecular models, including hard sphere (HS), variable hard sphere (VHS), and variable soft sphere (VSS), are employed in the DSMC study. The simulations of double-cone and Edney's type IV hypersonic shock interactions in low density flow are performed. Comparisons between DSMC and experimental data are conducted. Investigation of the double-cone hypersonic flow shows that three collision molecular models can predict the trend of pressure coefficient and the Stanton number. HS model shows the best agreement between DSMC simulation and experiment among three collision molecular models. Also, it shows that the agreement between DSMC and experiment is generally good for HS and VHS models in Edney's type IV shock interaction. However, it fails in the VSS model. Both double-cone and Edney's type IV shock interaction simulations show that the DSMC errors depend on the Knudsen number and the models employed for intermolecular interaction. With the increase in the Knudsen number, the DSMC error is decreased. The error is the smallest in HS compared with those in the VHS and VSS models. When the Knudsen number is in the level of 10−4, the DSMC errors, for pressure coefficient, the Stanton number, and the scale of interaction region, are controlled within 10%. PMID:24672360

Predicting Biological Information Flow in a Model Oxygen Minimum Zone

NASA Astrophysics Data System (ADS)

Louca, S.; Hawley, A. K.; Katsev, S.; Beltran, M. T.; Bhatia, M. P.; Michiels, C.; Capelle, D.; Lavik, G.; Doebeli, M.; Crowe, S.; Hallam, S. J.

2016-02-01

Microbial activity drives marine biochemical fluxes and nutrient cycling at global scales. Geochemical measurements as well as molecular techniques such as metagenomics, metatranscriptomics and metaproteomics provide great insight into microbial activity. However, an integration of molecular and geochemical data into mechanistic biogeochemical models is still lacking. Recent work suggests that microbial metabolic pathways are, at the ecosystem level, strongly shaped by stoichiometric and energetic constraints. Hence, models rooted in fluxes of matter and energy may yield a holistic understanding of biogeochemistry. Furthermore, such pathway-centric models would allow a direct consolidation with meta'omic data. Here we present a pathway-centric biogeochemical model for the seasonal oxygen minimum zone in Saanich Inlet, a fjord off the coast of Vancouver Island. The model considers key dissimilatory nitrogen and sulfur fluxes, as well as the population dynamics of the genes that mediate them. By assuming a direct translation of biocatalyzed energy fluxes to biosynthesis rates, we make predictions about the distribution and activity of the corresponding genes. A comparison of the model to molecular measurements indicates that the model explains observed DNA, RNA, protein and cell depth profiles. This suggests that microbial activity in marine ecosystems such as oxygen minimum zones is well described by DNA abundance, which, in conjunction with geochemical constraints, determines pathway expression and process rates. Our work further demonstrates how meta'omic data can be mechanistically linked to environmental redox conditions and biogeochemical processes.

Soy protein diet inhibits zymosan induced monocyte migration

USDA-ARS?s Scientific Manuscript database

Atherosclerosis has been recognized as a chronic inflammatory disease. Recently, we showed reduced atherosclerotic lesions in a hyperlipidemic mouse model fed isoflavone-free soy protein diet (SPI) compared to casein (CAS)-fed mice, despite unchanged serum lipid levels. However, the molecular mechan...

Effects of temperature-dependent molecular absorption coefficients on the thermal infrared remote sensing of the earth surface

NASA Technical Reports Server (NTRS)

Wan, Zhengming; Dozier, Jeff

1992-01-01

The effect of temperature-dependent molecular absorption coefficients on thermal infrared spectral signatures measured from satellite sensors is investigated by comparing results from the atmospheric transmission and radiance codes LOWTRAN and MODTRAN and the accurate multiple scattering radiative transfer model ATRAD for different atmospheric profiles. The sensors considered include the operational NOAA AVHRR and two research instruments planned for NASA's Earth Observing System (EOS): MODIS-N (Moderate Resolution Imaging Spectrometer-Nadir-Mode) and ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer). The difference in band transmittance is as large as 6 percent for some thermal bands within atmospheric windows and more than 30 percent near the edges of these atmospheric windows. The effect of temperature-dependent molecular absorption coefficients on satellite measurements of sea-surface temperature can exceed 0.6 K. Quantitative comparison and factor analysis indicate that more accurate measurements of molecular absorption coefficients and better radiative transfer simulation methods are needed to achieve SST accuracy of 0.3 K, as required for global numerical models of climate, and to develop land-surface temperature algorithms at the 1-K accuracy level.

Neurobiological Mechanisms for the Regulation of Mammalian Sleep-Wake Behavior: Reinterpretation of Historical Evidence and Inclusion of Contemporary Cellular and Molecular Evidence

PubMed Central

Datta, Subimal; MacLean, Robert Ross

2007-01-01

At its most basic level, the function of mammalian sleep can be described as a restorative process of the brain and body; recently, however, progressive research has revealed a host of vital functions to which sleep is essential. Although many excellent reviews on sleep behavior have been published, none have incorporated contemporary studies examining the molecular mechanisms that govern the various stages of sleep. Utilizing a holistic approach, this review is focused on the basic mechanisms involved in the transition from wakefulness, initiation of sleep and the subsequent generation of slow-wave sleep and rapid eye movement (REM) sleep. Additionally, using recent molecular studies and experimental evidence that provides a direct link to sleep as a behavior, we have developed a new model, the Cellular-Molecular-Network model, explaining the mechanisms responsible for regulating REM sleep. By analyzing the fundamental neurobiological mechanisms responsible for the generation and maintenance of sleep-wake behavior in mammals, we intend to provide a broader understanding of our present knowledge in the field of sleep research. PMID:17445891

Molecular C dynamics downstream: the biochemical decomposition sequence and its impact on soil organic matter structure and function.

PubMed

Grandy, A Stuart; Neff, Jason C

2008-10-15

Advances in spectroscopic and other chemical methods have greatly enhanced our ability to characterize soil organic matter chemistry. As a result, the molecular characteristics of soil C are now known for a range of ecosystems, soil types, and management intensities. Placing this knowledge into a broader ecological and management context is difficult, however, and remains one of the fundamental challenges of soil organic matter research. Here we present a conceptual model of molecular soil C dynamics to stimulate inter-disciplinary research into the ecological implications of molecular C turnover and its management- and process-level controls. Our model describes three properties of soil C dynamics: 1) soil size fractions have unique molecular patterns that reflect varying degrees of biological and physical control over decomposition; 2) there is a common decomposition sequence independent of plant inputs or other ecosystem properties; and 3) molecular decomposition sequences, although consistent, are not uniform and can be altered by processes that accelerate or slow the microbial transformation of specific molecules. The consequences of this model include several key points. First, lignin presents a constraint to decomposition of plant litter and particulate C (>53 microm) but exerts little influence on more stable mineral-associated soil fractions <53 microm. Second, carbon stabilized onto mineral fractions has a distinct composition related more to microbially processed organic matter than to plant-related compounds. Third, disturbances, such as N fertilization and tillage, which alter decomposition rates, can have "downstream effects"; that is, a disturbance that directly alters the molecular dynamics of particulate C may have a series of indirect effects on C stabilization in silt and clay fractions.

Complete protein-protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling

NASA Astrophysics Data System (ADS)

Plattner, Nuria; Doerr, Stefan; de Fabritiis, Gianni; Noé, Frank

2017-10-01

Protein-protein association is fundamental to many life processes. However, a microscopic model describing the structures and kinetics during association and dissociation is lacking on account of the long lifetimes of associated states, which have prevented efficient sampling by direct molecular dynamics (MD) simulations. Here we demonstrate protein-protein association and dissociation in atomistic resolution for the ribonuclease barnase and its inhibitor barstar by combining adaptive high-throughput MD simulations and hidden Markov modelling. The model reveals experimentally consistent intermediate structures, energetics and kinetics on timescales from microseconds to hours. A variety of flexibly attached intermediates and misbound states funnel down to a transition state and a native basin consisting of the loosely bound near-native state and the tightly bound crystallographic state. These results offer a deeper level of insight into macromolecular recognition and our approach opens the door for understanding and manipulating a wide range of macromolecular association processes.

Scanning number and brightness yields absolute protein concentrations in live cells: a crucial parameter controlling functional bio-molecular interaction networks.

PubMed

Papini, Christina; Royer, Catherine A

2018-02-01

Biological function results from properly timed bio-molecular interactions that transduce external or internal signals, resulting in any number of cellular fates, including triggering of cell-state transitions (division, differentiation, transformation, apoptosis), metabolic homeostasis and adjustment to changing physical or nutritional environments, amongst many more. These bio-molecular interactions can be modulated by chemical modifications of proteins, nucleic acids, lipids and other small molecules. They can result in bio-molecular transport from one cellular compartment to the other and often trigger specific enzyme activities involved in bio-molecular synthesis, modification or degradation. Clearly, a mechanistic understanding of any given high level biological function requires a quantitative characterization of the principal bio-molecular interactions involved and how these may change dynamically. Such information can be obtained using fluctation analysis, in particular scanning number and brightness, and used to build and test mechanistic models of the functional network to define which characteristics are the most important for its regulation.

A Model for Atomic and Molecular Interstellar Gas: The Meudon PDR Code

NASA Astrophysics Data System (ADS)

Le Petit, Franck; Nehmé, Cyrine; Le Bourlot, Jacques; Roueff, Evelyne

2006-06-01

We present the revised ``Meudon'' model of photon-dominated region (PDR) code, available on the Web under the GNU Public License. General organization of the code is described down to a level that should allow most observers to use it as an interpretation tool with minimal help from our part. Two grids of models, one for low-excitation diffuse clouds and one for dense highly illuminated clouds, are discussed, and some new results on PDR modelization highlighted.

A hierarchical dislocation-grain boundary interaction model based on 3D discrete dislocation dynamics and molecular dynamics

NASA Astrophysics Data System (ADS)

Gao, Yuan; Zhuang, Zhuo; You, XiaoChuan

2011-04-01

We develop a new hierarchical dislocation-grain boundary (GB) interaction model to predict the mechanical behavior of polycrystalline metals at micro and submicro scales by coupling 3D Discrete Dislocation Dynamics (DDD) simulation with the Molecular Dynamics (MD) simulation. At the microscales, the DDD simulations are responsible for capturing the evolution of dislocation structures; at the nanoscales, the MD simulations are responsible for obtaining the GB energy and ISF energy which are then transferred hierarchically to the DDD level. In the present model, four kinds of dislocation-GB interactions, i.e. transmission, absorption, re-emission and reflection, are all considered. By this methodology, the compression of a Cu micro-sized bi-crystal pillar is studied. We investigate the characteristic mechanical behavior of the bi-crystal compared with that of the single-crystal. Moreover, the comparison between the present penetrable model of GB and the conventional impenetrable model also shows the accuracy and efficiency of the present model.

Markov State Models of gene regulatory networks.

PubMed

Chu, Brian K; Tse, Margaret J; Sato, Royce R; Read, Elizabeth L

2017-02-06

Gene regulatory networks with dynamics characterized by multiple stable states underlie cell fate-decisions. Quantitative models that can link molecular-level knowledge of gene regulation to a global understanding of network dynamics have the potential to guide cell-reprogramming strategies. Networks are often modeled by the stochastic Chemical Master Equation, but methods for systematic identification of key properties of the global dynamics are currently lacking. The method identifies the number, phenotypes, and lifetimes of long-lived states for a set of common gene regulatory network models. Application of transition path theory to the constructed Markov State Model decomposes global dynamics into a set of dominant transition paths and associated relative probabilities for stochastic state-switching. In this proof-of-concept study, we found that the Markov State Model provides a general framework for analyzing and visualizing stochastic multistability and state-transitions in gene networks. Our results suggest that this framework-adopted from the field of atomistic Molecular Dynamics-can be a useful tool for quantitative Systems Biology at the network scale.

Effects of non-ablative fractional erbium glass laser treatment on gene regulation in human three-dimensional skin models.

PubMed

Amann, Philipp M; Marquardt, Yvonne; Steiner, Timm; Hölzle, Frank; Skazik-Voogt, Claudia; Heise, Ruth; Baron, Jens M

2016-04-01

Clinical experiences with non-ablative fractional erbium glass laser therapy have demonstrated promising results for dermal remodelling and for the indications of striae, surgical scars and acne scars. So far, molecular effects on human skin following treatment with these laser systems have not been elucidated. Our aim was to investigate laser-induced effects on skin morphology and to analyse molecular effects on gene regulation. Therefore, human three-dimensional (3D) organotypic skin models were irradiated with non-ablative fractional erbium glass laser systems enabling qRT-PCR, microarray and histological studies at same and different time points. A decreased mRNA expression of matrix metalloproteinases (MMPs) 3 and 9 was observed 3 days after treatment. MMP3 also remained downregulated on protein level, whereas the expression of other MMPs like MMP9 was recovered or even upregulated 5 days after irradiation. Inflammatory gene regulatory responses measured by the expression of chemokine (C-X-C motif) ligands (CXCL1, 2, 5, 6) and interleukin expression (IL8) were predominantly reduced. Epidermal differentiation markers such as loricrin, filaggrin-1 and filaggrin-2 were upregulated by both tested laser optics, indicating a potential epidermal involvement. These effects were also shown on protein level in the immunofluorescence analysis. This novel standardised laser-treated human 3D skin model proves useful for monitoring time-dependent ex vivo effects of various laser systems on gene expression and human skin morphology. Our study reveals erbium glass laser-induced regulations of MMP and interleukin expression. We speculate that these alterations on gene expression level could play a role for dermal remodelling, anti-inflammatory effects and increased epidermal differentiation. Our finding may have implications for further understanding of the molecular mechanism of erbium glass laser-induced effects on human skin.

Structural Insights into the Atomistic Mechanisms of Action of Small Molecule Inhibitors Targeting the KCa3.1 Channel Pore

PubMed Central

Nguyen, Hai M.; Singh, Vikrant; Pressly, Brandon; Jenkins, David Paul

2017-01-01

The intermediate-conductance Ca2+-activated K+ channel (KCa3.1) constitutes an attractive pharmacological target for immunosuppression, fibroproliferative disorders, atherosclerosis, and stroke. However, there currently is no available crystal structure of this medically relevant channel that could be used for structure-assisted drug design. Using the Rosetta molecular modeling suite we generated a molecular model of the KCa3.1 pore and tested the model by first confirming previously mapped binding sites and visualizing the mechanism of TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole), senicapoc (2,2-bis-(4-fluorophenyl)-2-phenylacetamide), and NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) inhibition at the atomistic level. All three compounds block ion conduction directly by fully or partially occupying the site that would normally be occupied by K+ before it enters the selectivity filter. We then challenged the model to predict the receptor sites and mechanisms of action of the dihydropyridine nifedipine and an isosteric 4-phenyl-pyran. Rosetta predicted receptor sites for nifedipine in the fenestration region and for the 4-phenyl-pyran in the pore lumen, which could both be confirmed by site-directed mutagenesis and electrophysiology. While nifedipine is thus not a pore blocker and might be stabilizing the channel in a nonconducting conformation or interfere with gating, the 4-phenyl-pyran was found to be a classical pore blocker that directly inhibits ion conduction similar to the triarylmethanes TRAM-34 and senicapoc. The Rosetta KCa3.1 pore model explains the mechanism of action of several KCa3.1 blockers at the molecular level and could be used for structure-assisted drug design. PMID:28126850

Characterization of Gravity Regulated Osteoprotegerin Expression in Fish Models

NASA Astrophysics Data System (ADS)

Renn, J.; Nourizadeh-Lillabadi, R.; Alestrom, P.; Seibt, D.; Goerlich, R.; Schartl, M.; Winkler, C.

Human osteoprotegerin (opg) is a secreted protein of 401 amino acids that acts as a decoy receptor for RANKL (receptor activator of NFB ligand). Opg prevents binding of RANKL to its receptor, which is present on osteoclasts and their precursors. Thereby, opg blocks the formation, differentiation and activation of osteoclasts and stimulates apoptosis of mature osteoclasts. As a consequence, opg regulates the degree of bone resorption in order to keep a constant bone mass under normal gravity conditions. Recently, clinorotation experiments using mammalian cell cultures have shown that the opg gene is down-regulated in simulated microgravity at the transcriptional level (Kanematsu et al., Bone 30, 2002). We have identified opg genes in the fish models Medaka and zebrafish to study gravity regulation of opg expression in these models at the organismal level. In Medaka embryos, opg expression starts at stages when first skeletal elements are already detectable. Putative consensus binding sites for transcription factors were identified in the promoter region of the Medaka opg gene indicating possible evolutionary conservation of gene regulatory mechanisms between fish and mammals. To analyze, whether model fish species are suitable tools to study microgravity induced changes at the molecular level in vivo, we investigated regulation of fish opg genes as a consequence of altered gravity. For this, we performed centrifugation and clinorotation experiments, subjecting fish larvae to hypergravity and simulated microgravity, and analyzed expression profiles of skeletal genes by real-time PCR. Our data represent the first experiments using whole animal model organisms to study gravity induced alteration of skeletal factors at the molecular level. Acknowledgement: This work is supported by the German Aerospace Center (DLR) (50 WB 0152) and the European Space Agency (AO-LS-99-MAP-LSS-003).

Probing amyloid protein aggregation with optical superresolution methods: from the test tube to models of disease

PubMed Central

Kaminski, Clemens F.; Kaminski Schierle, Gabriele S.

2016-01-01

Abstract. The misfolding and self-assembly of intrinsically disordered proteins into insoluble amyloid structures are central to many neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Optical imaging of this self-assembly process in vitro and in cells is revolutionizing our understanding of the molecular mechanisms behind these devastating conditions. In contrast to conventional biophysical methods, optical imaging and, in particular, optical superresolution imaging, permits the dynamic investigation of the molecular self-assembly process in vitro and in cells, at molecular-level resolution. In this article, current state-of-the-art imaging methods are reviewed and discussed in the context of research into neurodegeneration. PMID:27413767

Molecular diagnosis and precision medicine in allergy management.

PubMed

Riccio, Anna Maria; De Ferrari, Laura; Chiappori, Alessandra; Ledda, Sabina; Passalacqua, Giovanni; Melioli, Giovanni; Canonica, Giorgio Walter

2016-11-01

Precision medicine (PM) can be defined as a structural model aimed at customizing healthcare, with medical decisions/products tailored on an individual patient at a highly detailed level. In this sense, allergy diagnostics based on molecular allergen components allows to accurately define the patient's IgE repertoire. The availability of highly specialized singleplexed and multiplexed platforms support allergists with an advanced diagnostic armamentarium. The therapeutic intervention, driven by the standard diagnostic approach, but further supported by these innovative tools may result, for instance, in a more appropriate prescription of allergen immunotherapy (AIT). Also, the phenotyping of patients, which may have relevant effects on the treatment strategy, could be take advantage by the molecular allergy diagnosis.

Lotus Dust Mitigation Coating and Molecular Adsorber Coating

NASA Technical Reports Server (NTRS)

O'Connor, Kenneth M.; Abraham, Nithin S.

2015-01-01

NASA Goddard Space Flight Center has developed two unique coating formulations that will keep surfaces clean and sanitary and contain contaminants.The Lotus Dust Mitigation Coating, modeled after the self-cleaning, water-repellant lotus leaf, disallows buildup of dust, dirt, water, and more on surfaces. This coating, has been successfully tested on painted, aluminum, glass, silica, and some composite surfaces, could aid in keeping medical assets clean.The Molecular Adsorber Coating is a zeolite-based, sprayable molecular adsorber coating, designed to prevent outgassing in materials in vacuums. The coating works well to adsorb volatiles and contaminates in manufacturing and processing, such as in pharmaceutical production. The addition of a biocide would also aid in controlling bacteria levels.

Gravity and neuronal adaptation, in vitro and in vivo-from neuronal cells up to neuromuscular responses: a first model.

PubMed

Kohn, Florian P M; Ritzmann, Ramona

2018-03-01

For decades it has been shown that acute changes in gravity have an effect on neuronal systems of human and animals on different levels, from the molecular level to the whole nervous system. The functional properties and gravity-dependent adaptations of these system levels have been investigated with no or barely any interconnection. This review summarizes the gravity-dependent adaptation processes in human and animal organisms from the in vitro cellular level with its biophysical properties to the in vivo motor responses and underlying sensorimotor functions of human subjects. Subsequently, a first model for short-term adaptation of neuronal transmission is presented and discussed for the first time, which integrates the responses of the different levels of organization to changes in gravity.

Recent advances in QM/MM free energy calculations using reference potentials.

PubMed

Duarte, Fernanda; Amrein, Beat A; Blaha-Nelson, David; Kamerlin, Shina C L

2015-05-01

Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way. Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field. The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed. As was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014. Published by Elsevier B.V.

Can we better predict the biologic behavior of incidental IPMN? A comprehensive analysis of molecular diagnostics and biomarkers in intraductal papillary mucinous neoplasms of the pancreas.

PubMed

Tulla, Kiara A; Maker, Ajay V

2018-03-01

Predicting the biologic behavior of intraductal papillary mucinous neoplasm (IPMN) remains challenging. Current guidelines utilize patient symptoms and imaging characteristics to determine appropriate surgical candidates. However, the majority of resected cysts remain low-risk lesions, many of which may be feasible to have under surveillance. We herein characterize the most promising and up-to-date molecular diagnostics in order to identify optimal components of a molecular signature to distinguish levels of IPMN dysplasia. A comprehensive systematic review of pertinent literature, including our own experience, was conducted based on the PRISMA guidelines. Molecular diagnostics in IPMN patient tissue, duodenal secretions, cyst fluid, saliva, and serum were evaluated and organized into the following categories: oncogenes, tumor suppressor genes, glycoproteins, markers of the immune response, proteomics, DNA/RNA mutations, and next-generation sequencing/microRNA. Specific targets in each of these categories, and in aggregate, were identified by their ability to both characterize a cyst as an IPMN and determine the level of cyst dysplasia. Combining molecular signatures with clinical and imaging features in this era of next-generation sequencing and advanced computational analysis will enable enhanced sensitivity and specificity of current models to predict the biologic behavior of IPMN.

Nonlinear microrheology and molecular imaging to map microscale deformations of entangled DNA networks

NASA Astrophysics Data System (ADS)

Wu, Tsai-Chin; Anderson, Rae

We use active microrheology coupled to single-molecule fluorescence imaging to elucidate the microscale dynamics of entangled DNA. DNA naturally exists in a wide range of lengths and topologies, and is often confined in cell nucleui, forming highly concentrated and entangled biopolymer networks. Thus, DNA is the model polymer for understanding entangled polymer dynamics as well as the crowded environment of cells. These networks display complex viscoelastic properties that are not well understood, especially at the molecular-level and in response to nonlinear perturbations. Specifically, how microscopic stresses and strains propagate through entangled networks, and what molecular deformations lead to the network stress responses are unknown. To answer these important questions, we optically drive a microsphere through entangled DNA, perturbing the system far from equilibrium, while measuring the resistive force the DNA exerts on the bead during and after bead motion. We simultaneously image single fluorescent-labeled DNA molecules throughout the network to directly link the microscale stress response to molecular deformations. We characterize the deformation of the network from the molecular-level to the mesoscale, and map the stress propagation throughout the network. We further study the impact of DNA length (11 - 115 kbp) and topology (linear vs ring DNA) on deformation and propagation dynamics, exploring key nonlinear features such as tube dilation and power-law relaxation.

Synergism of Saturn, Enceladus and Titan and Formation of HCNO Exobiological Molecules

NASA Technical Reports Server (NTRS)

Sittler, Edward C., Jr.; Cooper, John F.

2010-01-01

Saturn as a system has two very exotic moons Titan and Enceladus. Titan with energy input from Saturn's magnetosphere, solar UV irradiation, and cosmic rays can make HCN based molecules as discussed in earlier paper by [1]. Space radiation effects at both moons, and as coupled by the Saturn magnetosphere could cause an unexpected series of events leading to the evolution of biological models at Titan composed of HCNO with oxygen as the new ingredient. The "Old Faithful" model by [2] suggests that Enceladus, highly irradiated by Saturn magnetospheric electrons, has episodic ejections of water vapor driven by radiolytic oxidation gas products into Saturn's magnetosphere. At Titan Cassini discovered 1) that keV oxygen ions, evidently from Enceladus, are bombarding Titan's upper atmosphere [3] and 2) the discovery of heavy positive and negative ions within Titan's upper atmosphere [4]. Initial models of heavy ion formation in Titan's upper atmosphere invoked polymerization of aromatics such as Benzenes and their radicals to make PAHs [5], while a more recent model by [6] has raised the possibility of carbon chains forming from the polymerization of acetylene and its radicals to eventually make fullerenes. Laboratory measurements indicate that fullerenes, which are hollow carbon shells, can trap the keV oxygen and with the clustering of fullerenes and possible mixture with PAHs, some with nitrogen molecules, can make the larger aerosols with oxygen within them. Then with further ionizing irradiation from cosmic rays deep in the atmosphere "tholin" molecules are produced with all the molecular components present from which organic molecules can form. Among the molecular components are amino acids, the fundamental building blocks of life as we know it. This process maybe a common chemical pathway, both at the system level and at the molecular level, to form prebiotic and perhaps even biotic molecules. Such processes can be occurring throughout our universe, such as molecular clouds in the ISM.

Cascading network failure across the Alzheimer’s disease spectrum

PubMed Central

Knopman, David S.; Gunter, Jeffrey L.; Graff-Radford, Jonathan; Vemuri, Prashanthi; Boeve, Bradley F.; Petersen, Ronald C.; Weiner, Michael W.; Jack, Clifford R.

2016-01-01

Abstract Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer’s disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer’s disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer’s pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer’s disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer’s Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure—analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity ‘overload’ that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both. PMID:26586695

Gas-phase conformations of 2-methyl-1,3-dithiolane investigated by microwave spectroscopy

NASA Astrophysics Data System (ADS)

Van, Vinh; Stahl, Wolfgang; Schwell, Martin; Nguyen, Ha Vinh Lam

2018-03-01

The conformational analysis of 2-methyl-1,3-dithiolane using quantum chemical calculations at some levels of theory yielded only one stable conformer with envelope geometry. However, other levels of theory indicated two envelope conformers. Analysis of the microwave spectrum recorded using two molecular jet Fourier transform microwave spectrometers covering the frequency range from 2 to 40 GHz confirms that only one conformer exists under jet conditions. The experimental spectrum was reproduced using a rigid-rotor model with centrifugal distortion correction within the measurement accuracy of 1.5 kHz, and molecular parameters were determined with very high accuracy. The gas phase structure of the title molecule is compared with the structures of other related molecules studied under the same experimental conditions.

Molecular plasmonics: The role of rovibrational molecular states in exciton-plasmon materials under strong-coupling conditions

NASA Astrophysics Data System (ADS)

Sukharev, Maxim; Charron, Eric

2017-03-01

We extend the model of exciton-plasmon materials to include a rovibrational structure of molecules using wave-packet propagations on electronic potential energy surfaces. Our model replaces conventional two-level emitters with more complex molecules, allowing us to examine the influence of alignment and vibrational dynamics on strong coupling with surface plasmon-polaritons. We apply the model to a hybrid system comprising a thin layer of molecules placed on top of a periodic array of slits. Rigorous simulations are performed for two types of molecular systems described by vibrational bound-bound and bound-continuum electronic transitions. Calculations reveal new features in transmission, reflection, and absorption spectra, including the observation of significantly higher values of the Rabi splitting and vibrational patterns clearly seen in the corresponding spectra. We also examine the influence of anisotropic initial conditions on optical properties of hybrid materials, demonstrating that the optical response of the system is significantly affected by an initial prealignment of the molecules. Our work demonstrates that prealigned molecules could serve as an efficient probe for the subdiffraction characterization of the near-field near metal interfaces.

Multi-Scale Computational Enzymology: Enhancing Our Understanding of Enzymatic Catalysis

PubMed Central

Gherib, Rami; Dokainish, Hisham M.; Gauld, James W.

2014-01-01

Elucidating the origin of enzymatic catalysis stands as one the great challenges of contemporary biochemistry and biophysics. The recent emergence of computational enzymology has enhanced our atomistic-level description of biocatalysis as well the kinetic and thermodynamic properties of their mechanisms. There exists a diversity of computational methods allowing the investigation of specific enzymatic properties. Small or large density functional theory models allow the comparison of a plethora of mechanistic reactive species and divergent catalytic pathways. Molecular docking can model different substrate conformations embedded within enzyme active sites and determine those with optimal binding affinities. Molecular dynamics simulations provide insights into the dynamics and roles of active site components as well as the interactions between substrate and enzymes. Hybrid quantum mechanical/molecular mechanical (QM/MM) can model reactions in active sites while considering steric and electrostatic contributions provided by the surrounding environment. Using previous studies done within our group, on OvoA, EgtB, ThrRS, LuxS and MsrA enzymatic systems, we will review how these methods can be used either independently or cooperatively to get insights into enzymatic catalysis. PMID:24384841

Simulations of molecular self-assembled monolayers on surfaces: packing structures, formation processes and functions tuned by intermolecular and interfacial interactions.

PubMed

Wen, Jin; Li, Wei; Chen, Shuang; Ma, Jing

2016-08-17

Surfaces modified with a functional molecular monolayer are essential for the fabrication of nano-scale electronics or machines with novel physical, chemical, and/or biological properties. Theoretical simulation based on advanced quantum chemical and classical models is at present a necessary tool in the development, design, and understanding of the interfacial nanostructure. The nanoscale surface morphology, growth processes, and functions are controlled by not only the electronic structures (molecular energy levels, dipole moments, polarizabilities, and optical properties) of building units but also the subtle balance between intermolecular and interfacial interactions. The switchable surfaces are also constructed by introducing stimuli-responsive units like azobenzene derivatives. To bridge the gap between experiments and theoretical models, opportunities and challenges for future development of modelling of ferroelectricity, entropy, and chemical reactions of surface-supported monolayers are also addressed. Theoretical simulations will allow us to obtain important and detailed information about the structure and dynamics of monolayer modified interfaces, which will guide the rational design and optimization of dynamic interfaces to meet challenges of controlling optical, electrical, and biological functions.

Isoflavone-free soy protein diet inhibits LPS-induced inflammatory responses

USDA-ARS?s Scientific Manuscript database

Recently, we showed reduced atherosclerotic lesions in a hyperlipidemic mouse model fed isoflavone-free soy protein diet (SPI–) compared to casein (CAS)-fed mice, despite unchanged serum lipid levels. However, the molecular mechanisms contributing to the atheroprotective effect of soy-based diets is...

Modelling Photosynthesis to Increase Conceptual Understanding

ERIC Educational Resources Information Center

Ross, Pauline; Tronson, Deidre; Ritchie, Raymond J.

2006-01-01

Biology students in their first year at university have difficulty understanding the abstract concepts of photosynthesis. The traditional didactic lecture followed by practical exercises that show various macroscopic aspects of photosynthesis often do not help the students visualise or understand the submicroscopic (molecular-level) reactions that…

Yeast: An Experimental Organism for Modern Biology.

ERIC Educational Resources Information Center

Botstein, David; Fink, Gerald R.

1988-01-01

Discusses the applicability and advantages of using yeasts as popular and ideal model systems for studying and understanding eukaryotic biology at the cellular and molecular levels. Cites experimental tractability and the cooperative tradition of the research community of yeast biologists as reasons for this success. (RT)

Protective Effect of High Molecular Weight Protein Sub-fraction of Calotropis procera Latex in Monoarthritic Rats.

PubMed

Chaudhary, Priyanka; Ramos, Marcio V; Vasconcelos, Mirele da Silveira; Kumar, Vijay L

2016-05-01

Proteins present in the latex of Calotropis procera have been shown to produce anti-inflammatory effect and to afford protection in various disease models. To determine the efficacy of high molecular weight protein sub-fraction (LPPI) of latex of C. procera in ameliorating joint inflammation and hyperalgesia in a preclinical model of arthritis. Monoarthritis was induced in rats by intra-articular injection of Freund's complete adjuvant (FCA) and the effect of two doses of LPPI (5 and 25 mg/kg) and diclofenac (5 mg/kg) was evaluated on joint swelling, stair climbing ability, motility, and dorsal flexion pain on day 3. The rats were sacrificed on day 3 to measure tissue levels of reduced glutathione (GSH) and thiobarbituric acid reactive substances (TBARS). Evaluation of joint histology was also made. Intra-articular injection of FCA produced joint swelling and difficulty in stair climbing ability, motility, and pain on flexion of the joint as revealed by scores obtained for these functional parameters. LPPI produced a dose-dependent decrease in joint swelling and improved joint functions. Arthritic rats also revealed altered oxidative homeostasis where joint tissue GSH levels were decreased and TBARS levels were increased as compared to normal rats. The levels of these oxidative stress markers were near normal in arthritic rats treated with LPPI. Moreover, treatment with LPPI also maintained the structural integrity of the joint. The protective effect of LPPI was comparable to the standard anti-inflammatory drug, diclofenac. The findings of the present study show that LPPI fraction comprising high molecular weight proteins could be used for the alleviation of arthritic symptoms. High molecular weight protein sub-fraction of latex of Calotropis procera (LPPI) reduced joint swelling and hyperalgesia in arthritic ratsLPPI produced a significant improvement in stair climbing ability and motility in arthritic ratsLPPI normalized the levels of oxidative stress markers in the arthritic jointsTreatment with LPPI reduced neutrophil influx and edema in the arthritic joints Abbreviations used: FCA: Freund's complete adjuvant, GSH: Glutathione, TBARS: Thiobarbituric acid reactive substances, TBA: Thiobarbituric acid, MDA: Malondialdehyde, LPPI: Latex protein fraction PI.

Properties of Highly Rotationally Excited H2 in Photodissociation Regions

NASA Astrophysics Data System (ADS)

Cummings, Sally Jane; Wan, Yier; Stancil, Phillip C.; Yang, Benhui H.; Zhang, Ziwei

2018-06-01

H2 is the dominant molecular species in the vast majority of interstellar environments and it plays a crucial role as a radiative coolant. In photodissociation regions, it is one of the primary emitters in the near to mid-infrared which are due to lines originating from highly excited rotational levels. However, collisional data for rotational levels j>10 are sparse, particularly for H2-H2 collisions. Utilizing new calculations for para-H2 and ortho-H2 collisional rate coefficients with H2 for j as high as 30, we investigate the effects of the new results in standard PDR models with the spectral simulation package Cloudy. We also perform Cloudy models of the Orion Bar and use Radex to explore rotational line ratio diagnostics. The resulting dataset of H2 collisional data should find wide application to other molecular environments. This work was support by Hubble Space Telescope grant HST-AR-13899.001-A and NASA grants NNX15AI61G and NNX16AF09G.

Omics approaches to individual variation: modeling networks and the virtual patient.

PubMed

Lehrach, Hans

2016-09-01

Every human is unique. We differ in our genomes, environment, behavior, disease history, and past and current medical treatment-a complex catalog of differences that often leads to variations in the way each of us responds to a particular therapy. We argue here that true personalization of drug therapies will rely on "virtual patient" models based on a detailed characterization of the individual patient by molecular, imaging, and sensor techniques. The models will be based, wherever possible, on the molecular mechanisms of disease processes and drug action but can also expand to hybrid models including statistics/machine learning/artificial intelligence-based elements trained on available data to address therapeutic areas or therapies for which insufficient information on mechanisms is available. Depending on the disease, its mechanisms, and the therapy, virtual patient models can be implemented at a fairly high level of abstraction, with molecular models representing cells, cell types, or organs relevant to the clinical question, interacting not only with each other but also the environment. In the future, "virtual patient/in-silico self" models may not only become a central element of our health care system, reducing otherwise unavoidable mistakes and unnecessary costs, but also act as "guardian angels" accompanying us through life to protect us against dangers and to help us to deal intelligently with our own health and wellness.

Omics approaches to individual variation: modeling networks and the virtual patient

PubMed Central

Lehrach, Hans

2016-01-01

Every human is unique. We differ in our genomes, environment, behavior, disease history, and past and current medical treatment—a complex catalog of differences that often leads to variations in the way each of us responds to a particular therapy. We argue here that true personalization of drug therapies will rely on “virtual patient” models based on a detailed characterization of the individual patient by molecular, imaging, and sensor techniques. The models will be based, wherever possible, on the molecular mechanisms of disease processes and drug action but can also expand to hybrid models including statistics/machine learning/artificial intelligence-based elements trained on available data to address therapeutic areas or therapies for which insufficient information on mechanisms is available. Depending on the disease, its mechanisms, and the therapy, virtual patient models can be implemented at a fairly high level of abstraction, with molecular models representing cells, cell types, or organs relevant to the clinical question, interacting not only with each other but also the environment. In the future, “virtual patient/in-silico self” models may not only become a central element of our health care system, reducing otherwise unavoidable mistakes and unnecessary costs, but also act as “guardian angels” accompanying us through life to protect us against dangers and to help us to deal intelligently with our own health and wellness. PMID:27757060

Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies

PubMed Central

Guitart, Tanit; Picchioni, Daria; Piñeyro, David; Ribas de Pouplana, Lluís

2013-01-01

The translation of genes encoded in the mitochondrial genome requires specific machinery that functions in the organelle. Among the many mutations linked to human disease that affect mitochondrial translation, several are localized to nuclear genes coding for mitochondrial aminoacyl-transfer RNA synthetases. The molecular significance of these mutations is poorly understood, but it is expected to be similar to that of the mutations affecting mitochondrial transfer RNAs. To better understand the molecular features of diseases caused by these mutations, and to improve their diagnosis and therapeutics, we have constructed a Drosophila melanogaster model disrupting the mitochondrial seryl-tRNA synthetase by RNA interference. At the molecular level, the knockdown generates a reduction in transfer RNA serylation, which correlates with the severity of the phenotype observed. The silencing compromises viability, longevity, motility and tissue development. At the cellular level, the knockdown alters mitochondrial morphology, biogenesis and function, and induces lactic acidosis and reactive oxygen species accumulation. We report that administration of antioxidant compounds has a palliative effect of some of these phenotypes. In conclusion, the fly model generated in this work reproduces typical characteristics of pathologies caused by mutations in the mitochondrial aminoacylation system, and can be useful to assess therapeutic approaches. PMID:23677612

A Checklist for Successful Quantitative Live Cell Imaging in Systems Biology

PubMed Central

Sung, Myong-Hee

2013-01-01

Mathematical modeling of signaling and gene regulatory networks has provided unique insights about systems behaviors for many cell biological problems of medical importance. Quantitative single cell monitoring has a crucial role in advancing systems modeling of molecular networks. However, due to the multidisciplinary techniques that are necessary for adaptation of such systems biology approaches, dissemination to a wide research community has been relatively slow. In this essay, I focus on some technical aspects that are often under-appreciated, yet critical in harnessing live cell imaging methods to achieve single-cell-level understanding and quantitative modeling of molecular networks. The importance of these technical considerations will be elaborated with examples of successes and shortcomings. Future efforts will benefit by avoiding some pitfalls and by utilizing the lessons collectively learned from recent applications of imaging in systems biology. PMID:24709701

Molecular medicine: a path towards a personalized medicine.

PubMed

Miranda, Debora Marques de; Mamede, Marcelo; Souza, Bruno Rezende de; Almeida Barros, Alexandre Guimarães de; Magno, Luiz Alexandre; Alvim-Soares, Antônio; Rosa, Daniela Valadão; Castro, Célio José de; Malloy-Diniz, Leandro; Gomez, Marcus Vinícius; Marco, Luiz Armando De; Correa, Humberto; Romano-Silva, Marco Aurélio

2012-03-01

Psychiatric disorders are among the most common human illnesses; still, the molecular and cellular mechanisms underlying their complex pathophysiology remain to be fully elucidated. Over the past 10 years, our group has been investigating the molecular abnormalities in major signaling pathways involved in psychiatric disorders. Recent evidences obtained by the Instituto Nacional de Ciência e Tecnologia de Medicina Molecular (National Institute of Science and Technology - Molecular Medicine, INCT-MM) and others using behavioral analysis of animal models provided valuable insights into the underlying molecular alterations responsible for many complex neuropsychiatric disorders, suggesting that "defects" in critical intracellular signaling pathways have an important role in regulating neurodevelopment, as well as in pathophysiology and treatment efficacy. Resources from the INCT have allowed us to start doing research in the field of molecular imaging. Molecular imaging is a research discipline that visualizes, characterizes, and quantifies the biologic processes taking place at cellular and molecular levels in humans and other living systems through the results of image within the reality of the physiological environment. In order to recognize targets, molecular imaging applies specific instruments (e.g., PET) that enable visualization and quantification in space and in real-time of signals from molecular imaging agents. The objective of molecular medicine is to individualize treatment and improve patient care. Thus, molecular imaging is an additional tool to achieve our ultimate goal.

Modeling Fragile X Syndrome in Drosophila

PubMed Central

Drozd, Małgorzata; Bardoni, Barbara; Capovilla, Maria

2018-01-01

Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5′-UTR of the gene. Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. This enables a much easier approach for FMR1 genetic studies. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. These studies have the potential to aid the discovery of pharmacological therapies for FXS. PMID:29713264

The complex nature of calcium cation interactions with phospholipid bilayers

PubMed Central

Melcrová, Adéla; Pokorna, Sarka; Pullanchery, Saranya; Kohagen, Miriam; Jurkiewicz, Piotr; Hof, Martin; Jungwirth, Pavel; Cremer, Paul S.; Cwiklik, Lukasz

2016-01-01

Understanding interactions of calcium with lipid membranes at the molecular level is of great importance in light of their involvement in calcium signaling, association of proteins with cellular membranes, and membrane fusion. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic molecular dynamics simulations. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-containing environments. To gain additional atomic-level information, the experiments are complemented by molecular simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. Significantly, the binding mode depends on calcium concentration with important implications for calcium buffering, synaptic plasticity, and protein-membrane association. PMID:27905555

Uncovering the structure-function relationship in spider silk

NASA Astrophysics Data System (ADS)

Yarger, Jeffery L.; Cherry, Brian R.; van der Vaart, Arjan

2018-03-01

All spiders produce protein-based biopolymer fibres that we call silk. The most studied of these silks is spider dragline silk, which is very tough and relatively abundant compared with other types of spider silks. Considerable research has been devoted to understanding the relationship between the molecular structure and mechanical properties of spider dragline silks. In this Review, we overview experimental and computational studies that have provided a wealth of detail at the molecular level on the highly conserved repetitive core and terminal regions of spider dragline silk. We also discuss the role of the nanocrystalline β-sheets and amorphous regions in determining the properties of spider silk fibres, endowing them with strength and elasticity. Additionally, we outline imaging techniques and modelling studies that elucidate the importance of the hierarchical structure of silk fibres at the molecular level. These insights into structure-function relationships can guide the reverse engineering of spider silk to enable the production of superior synthetic fibres.

A molecular level prototype for mechanoelectrical transducer in mammalian hair cells

PubMed Central

Park, Jinkyoung

2013-01-01

The mechanoelectrical transducer (MET) is a crucial component of mammalian auditory system. The gating mechanism of the MET channel remains a puzzling issue, though there are many speculations, due to the lack of essential molecular building blocks. To understand the working principle of mammalian MET, we propose a molecular level prototype which constitutes a charged blocker, a realistic ion channel and its surrounding membrane. To validate the proposed prototype, we make use of a well-established ion channel theory, the Poisson-Nernst-Planck equations, for three-dimensional (3D) numerical simulations. A wide variety of model parameters, including bulk ion concentration, applied external voltage, blocker charge and blocker displacement, are explored to understand the basic function of the proposed MET prototype. We show that our prototype prediction of channel open probability in response to blocker relative displacement is in a remarkable accordance with experimental observation of rat cochlea outer hair cells. Our results appear to suggest that tip links which connect hair bundles gate MET channels. PMID:23625048

Exploring parameter space effects on structure-property relationships of surfactants at liquid-liquid interfaces.

PubMed

Emborsky, Christopher P; Cox, Kenneth R; Chapman, Walter G

2011-08-28

The ubiquitous use of surfactants in commercial and industrial applications has led to many experimental, theoretical, and simulation based studies. These efforts seek to provide a molecular level understanding of the effects on structuring behavior and the corresponding impacts on observable properties (e.g., interfacial tension). With such physical detail, targeted system design can be improved over typical techniques of observational trends and phenomenological correlations by taking advantage of predictive system response. This research provides a systematic study of part of the broad parameter space effects on equilibrium microstructure and interfacial properties of amphiphiles at a liquid-liquid interface using the interfacial statistical associating fluid theory density functional theory as a molecular model for the system from the bulk to the interface. Insights into the molecular level physics and thermodynamics governing the system behavior are discussed as they relate to both predictions qualitatively consistent with experimental observations and extensions beyond currently available studies. © 2011 American Institute of Physics

The complex nature of calcium cation interactions with phospholipid bilayers

NASA Astrophysics Data System (ADS)

Melcrová, Adéla; Pokorna, Sarka; Pullanchery, Saranya; Kohagen, Miriam; Jurkiewicz, Piotr; Hof, Martin; Jungwirth, Pavel; Cremer, Paul S.; Cwiklik, Lukasz

2016-12-01

Understanding interactions of calcium with lipid membranes at the molecular level is of great importance in light of their involvement in calcium signaling, association of proteins with cellular membranes, and membrane fusion. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic molecular dynamics simulations. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-containing environments. To gain additional atomic-level information, the experiments are complemented by molecular simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. Significantly, the binding mode depends on calcium concentration with important implications for calcium buffering, synaptic plasticity, and protein-membrane association.

A Comparison of Molecular Vibrational Theory to Huckel Molecular Orbital Theory.

ERIC Educational Resources Information Center

Keeports, David

1986-01-01

Compares the similar mathematical problems of molecular vibrational calculations (at any intermediate level of sophistication) and molecular orbital calculations (at the Huckel level). Discusses how the generalizations of Huckel treatment of molecular orbitals apply to vibrational theory. (TW)

Level crossings and zero-field splitting in the {Cr8}-cubane spin cluster studied using inelastic neutron scattering and magnetization

NASA Astrophysics Data System (ADS)

Vaknin, D.; Garlea, V. O.; Demmel, F.; Mamontov, E.; Nojiri, H.; Martin, C.; Chiorescu, I.; Qiu, Y.; Kögerler, P.; Fielden, J.; Engelhardt, L.; Rainey, C.; Luban, M.

2010-11-01

Inelastic neutron scattering (INS) in variable magnetic field and high-field magnetization measurements in the millikelvin temperature range were performed to gain insight into the low-energy magnetic excitation spectrum and the field-induced level crossings in the molecular spin cluster {Cr8}-cubane. These complementary techniques provide consistent estimates of the lowest level-crossing field. The overall features of the experimental data are explained using an isotropic Heisenberg model, based on three distinct exchange interactions linking the eight CrIII paramagnetic centers (spins s = 3/2), that is supplemented with a relatively large molecular magnetic anisotropy term for the lowest S = 1 multiplet. It is noted that the existence of the anisotropy is clearly evident from the magnetic field dependence of the excitations in the INS measurements, while the magnetization measurements are not sensitive to its effects.

Level crossings and zero-field splitting in the {Cr8}-cubane spin-cluster studied using inelastic neutron scattering and magnetization

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

Vaknin, D.; Garlea, Vasile O; Demmel, F.

Inelastic neutron scattering (INS) in variable magnetic field and high-field magnetization measurements in the millikelvin temperature range were performed to gain insight into the low-energy magnetic excitation spectrum and the field-induced level crossings in the molecular spin cluster {Cr8}-cubane. These complementary techniques provide consistent estimates of the lowest level-crossing field. The overall features of the experimental data are explained using an isotropic Heisenberg model, based on three distinct exchange interactions linking the eight CrIII paramagnetic centers (spins s = 3/2), that is supplemented with a relatively large molecular magnetic anisotropy term for the lowest S = 1 multiplet. It ismore » noted that the existence of the anisotropy is clearly evident from the magnetic field dependence of the excitations in the INS measurements, while the magnetization measurements are not sensitive to its effects.« less

Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches

PubMed Central

Gavériaux-Ruff, Claire; Kieffer, Brigitte Lina

2012-01-01

Delta opioid receptors represent a promising target for the development of novel analgesics. A number of tools have been developed recently that have significantly improved our knowledge of delta receptor function in pain control. These include several novel delta agonists with potent analgesic properties, as well as genetic mouse models with targeted mutations in the delta opioid receptor gene. Also, recent findings have further documented the regulation of delta receptor function at cellular level, which impacts on the pain-reducing activity of the receptor. These regulatory mechanisms occur at transcriptional and post-translational levels, along agonist-induced receptor activation, signaling and trafficking, or in interaction with other receptors and neuromodulatory systems. All these tools for in vivo research, as well as proposed mechanisms at molecular level, have tremendously increased our understanding of delta receptor physiology, and contribute to designing innovative strategies for the treatment of chronic pain and other diseases such as mood disorders. PMID:21836459

Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method

NASA Astrophysics Data System (ADS)

Zhang, Hua-xin; Xiong, Hang-xing; Li, Li-wei

2016-05-01

Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (ΔHθ) and entropy change (ΔSθ) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Förster's non-radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy.

Coenzyme Q10-Loaded Fish Oil-Based Bigel System: Probing the Delivery Across Porcine Skin and Possible Interaction with Fish Oil Fatty Acids.

PubMed

Zulfakar, Mohd Hanif; Chan, Lee Mei; Rehman, Khurram; Wai, Lam Kok; Heard, Charles M

2018-04-01

Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug-excipient relationships at the molecular level.

Collective synchronization of self/non-self discrimination in T cell activation, across multiple spatio-temporal scales

NASA Astrophysics Data System (ADS)

Altan-Bonnet, Gregoire

The immune system is a collection of cells whose function is to eradicate pathogenic infections and malignant tumors while protecting healthy tissues. Recent work has delineated key molecular and cellular mechanisms associated with the ability to discriminate self from non-self agents. For example, structural studies have quantified the biophysical characteristics of antigenic molecules (those prone to trigger lymphocyte activation and a subsequent immune response). However, such molecular mechanisms were found to be highly unreliable at the individual cellular level. We will present recent efforts to build experimentally validated computational models of the immune responses at the collective cell level. Such models have become critical to delineate how higher-level integration through nonlinear amplification in signal transduction, dynamic feedback in lymphocyte differentiation and cell-to-cell communication allows the immune system to enforce reliable self/non-self discrimination at the organism level. In particular, we will present recent results demonstrating how T cells tune their antigen discrimination according to cytokine cues, and how competition for cytokine within polyclonal populations of cells shape the repertoire of responding clones. Additionally, we will present recent theoretical and experimental results demonstrating how competition between diffusion and consumption of cytokines determine the range of cell-cell communications within lymphoid organs. Finally, we will discuss how biochemically explicit models, combined with quantitative experimental validation, unravel the relevance of new feedbacks for immune regulations across multiple spatial and temporal scales.

Multi-level quantum mechanics theories and molecular mechanics study of the double-inversion mechanism of the F- + CH3I reaction in aqueous solution.

PubMed

Liu, Peng; Zhang, Jingxue; Wang, Dunyou

2017-06-07

A double-inversion mechanism of the F - + CH 3 I reaction was discovered in aqueous solution using combined multi-level quantum mechanics theories and molecular mechanics. The stationary points along the reaction path show very different structures to the ones in the gas phase due to the interactions between the solvent and solute, especially strong hydrogen bonds. An intermediate complex, a minimum on the potential of mean force, was found to serve as a connecting-link between the abstraction-induced inversion transition state and the Walden-inversion transition state. The potentials of mean force were calculated with both the DFT/MM and CCSD(T)/MM levels of theory. Our calculated free energy barrier of the abstraction-induced inversion is 69.5 kcal mol -1 at the CCSD(T)/MM level of theory, which agrees with the one at 72.9 kcal mol -1 calculated using the Born solvation model and gas-phase data; and our calculated free energy barrier of the Walden inversion is 24.2 kcal mol -1 , which agrees very well with the experimental value at 25.2 kcal mol -1 in aqueous solution. The calculations show that the aqueous solution makes significant contributions to the potentials of mean force and exerts a big impact on the molecular-level evolution along the reaction pathway.

Comparative systems biology between human and animal models based on next-generation sequencing methods.

PubMed

Zhao, Yu-Qi; Li, Gong-Hua; Huang, Jing-Fei

2013-04-01

Animal models provide myriad benefits to both experimental and clinical research. Unfortunately, in many situations, they fall short of expected results or provide contradictory results. In part, this can be the result of traditional molecular biological approaches that are relatively inefficient in elucidating underlying molecular mechanism. To improve the efficacy of animal models, a technological breakthrough is required. The growing availability and application of the high-throughput methods make systematic comparisons between human and animal models easier to perform. In the present study, we introduce the concept of the comparative systems biology, which we define as "comparisons of biological systems in different states or species used to achieve an integrated understanding of life forms with all their characteristic complexity of interactions at multiple levels". Furthermore, we discuss the applications of RNA-seq and ChIP-seq technologies to comparative systems biology between human and animal models and assess the potential applications for this approach in the future studies.

Alterations of polyunsaturated fatty acid metabolism in ovarian tissues of polycystic ovary syndrome rats.

PubMed

Huang, Rong; Xue, Xinli; Li, Shengxian; Wang, Yuying; Sun, Yun; Liu, Wei; Yin, Huiyong; Tao, Tao

2018-03-30

The metabolism of polyunsaturated fatty acids (PUFAs) remains poorly characterized in ovarian tissues of patients with polycystic ovary syndrome (PCOS). This study aimed to explore alterations in the levels of PUFAs and their metabolites in serum and ovarian tissues in a PCOS rat model treated with a high-fat diet and andronate. Levels of PUFAs and their metabolites were measured using gas/liquid chromatography-mass spectrometry after the establishment of a PCOS rat model. Only 3 kinds of PUFAs [linoleic acid, arachidonic acid (AA) and docosahexaenoic acid] were detected in both the circulation and ovarian tissues of the rats, and their concentrations were lower in ovarian tissues than in serum. Moreover, significant differences in the ovarian levels of AA were observed between control, high-fat diet-fed and PCOS rats. The levels of prostaglandins, AA metabolites via the cyclooxygenase (COX) pathway, in ovarian tissues of the PCOS group were significantly increased compared to those in the controls. Further studies on the mechanism underlying this phenomenon showed a correlation between decreased expression of phosphorylated cytosolic phospholipase A2 (p-cPLA2) and increased mRNA and protein expression of COX2, potentially leading to a deeper understanding of altered AA and prostaglandin levels in ovarian tissues of PCOS rats. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Electronic coarse graining enhances the predictive power of molecular simulation allowing challenges in water physics to be addressed

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

Cipcigan, Flaviu S., E-mail: flaviu.cipcigan@ed.ac.uk; National Physical Laboratory, Hampton Road, Teddington, Middlesex TW11 0LW; Sokhan, Vlad P.

One key factor that limits the predictive power of molecular dynamics simulations is the accuracy and transferability of the input force field. Force fields are challenged by heterogeneous environments, where electronic responses give rise to biologically important forces such as many-body polarisation and dispersion. The importance of polarisation in the condensed phase was recognised early on, as described by Cochran in 1959 [Philosophical Magazine 4 (1959) 1082–1086] [32]. Currently in molecular simulation, dispersion forces are treated at the two-body level and in the dipole limit, although the importance of three-body terms in the condensed phase was demonstrated by Barker inmore » the 1980s [Phys. Rev. Lett. 57 (1986) 230–233] [72]. One approach for treating both polarisation and dispersion on an equal basis is to coarse grain the electrons surrounding a molecular moiety to a single quantum harmonic oscillator (cf. Hirschfelder, Curtiss and Bird 1954 [The Molecular Theory of Gases and Liquids (1954)] [37]). The approach, when solved in strong coupling beyond the dipole limit, gives a description of long-range forces that includes two- and many-body terms to all orders. In the last decade, the tools necessary to implement the strong coupling limit have been developed, culminating in a transferable model of water with excellent predictive power across the phase diagram. Transferability arises since the environment automatically identifies the important long range interactions, rather than the modeler through a limited set of expressions. Here, we discuss the role of electronic coarse-graining in predictive multiscale materials modelling and describe the first implementation of the method in a general purpose molecular dynamics software: QDO-MD. - Highlights: • Electronic coarse graining unites many-body dispersion and polarisation beyond the dipole limit. • It consists of replacing the electrons of a molecule using a quantum harmonic oscillator, called a Quantum Drude Oscillator. • We present the first general implementation of Quantum Drude Oscillators in the molecular dynamics package QDO-MD. • We highlight the successful construction of a new, transferable molecular model of water: QDO-water. - Graphical abstract:.« less

GEOCHEMICAL AND BIOLOGICAL ASPECTS OF SULFIDE MINERAL DISSOLUTION: LESSONS FROM IRON MOUNTAIN, CALIFORNIA. (R826189)

EPA Science Inventory

Abstract

The oxidative dissolution of sulfide minerals leading to acid mine drainage (AMD) involves a complex interplay between microorganisms, solutions, and mineral surfaces. Consequently, models that link molecular level reactions and the microbial communities that ...

Developing sensor activity relationships for the JPL electronic nose sensors using molecular modeling and QSAR techniques

NASA Technical Reports Server (NTRS)

Shevade, A. V.; Ryan, M. A.; Homer, M. L.; Jewell, A. D.; Zhou, H.; Manatt, K.; Kisor, A. K.

2005-01-01

We report a Quantitative Structure-Activity Relationships (QSAR) study using Genetic Function Approximations (GFA) to describe the polymer-carbon composite sensor activities in the JPL Electronic Nose, when exposed to chemical vapors at parts-per-million concentration levels.

Coalescent Modelling Suggests Recent Secondary-Contact of Cryptic Penguin Species

PubMed Central

Grosser, Stefanie; Burridge, Christopher P.; Peucker, Amanda J.; Waters, Jonathan M.

2015-01-01

Molecular genetic analyses present powerful tools for elucidating demographic and biogeographic histories of taxa. Here we present genetic evidence showing a dynamic history for two cryptic lineages within Eudyptula, the world's smallest penguin. Specifically, we use a suite of genetic markers to reveal that two congeneric taxa ('Australia' and 'New Zealand') co-occur in southern New Zealand, with only low levels of hybridization. Coalescent modelling suggests that the Australian little penguin only recently expanded into southern New Zealand. Analyses conducted under time-dependent molecular evolutionary rates lend support to the hypothesis of recent anthropogenic turnover, consistent with shifts detected in several other New Zealand coastal vertebrate taxa. This apparent turnover event highlights the dynamic nature of the region’s coastal ecosystem. PMID:26675310

Pericentrin in cellular function and disease

PubMed Central

Delaval, Benedicte

2010-01-01

Pericentrin is an integral component of the centrosome that serves as a multifunctional scaffold for anchoring numerous proteins and protein complexes. Through these interactions, pericentrin contributes to a diversity of fundamental cellular processes. Recent studies link pericentrin to a growing list of human disorders. Studies on pericentrin at the cellular, molecular, and, more recently, organismal level, provide a platform for generating models to elucidate the etiology of these disorders. Although the complexity of phenotypes associated with pericentrin-mediated disorders is somewhat daunting, insights into the cellular basis of disease are beginning to come into focus. In this review, we focus on human conditions associated with loss or elevation of pericentrin and propose cellular and molecular models that might explain them. PMID:19951897

Coalescent Modelling Suggests Recent Secondary-Contact of Cryptic Penguin Species.

PubMed

Grosser, Stefanie; Burridge, Christopher P; Peucker, Amanda J; Waters, Jonathan M

2015-01-01

Molecular genetic analyses present powerful tools for elucidating demographic and biogeographic histories of taxa. Here we present genetic evidence showing a dynamic history for two cryptic lineages within Eudyptula, the world's smallest penguin. Specifically, we use a suite of genetic markers to reveal that two congeneric taxa ('Australia' and 'New Zealand') co-occur in southern New Zealand, with only low levels of hybridization. Coalescent modelling suggests that the Australian little penguin only recently expanded into southern New Zealand. Analyses conducted under time-dependent molecular evolutionary rates lend support to the hypothesis of recent anthropogenic turnover, consistent with shifts detected in several other New Zealand coastal vertebrate taxa. This apparent turnover event highlights the dynamic nature of the region's coastal ecosystem.

An artificial muscle model unit based on inorganic nanosheet sliding by photochemical reaction.

PubMed

Nabetani, Yu; Takamura, Hazuki; Hayasaka, Yuika; Sasamoto, Shin; Tanamura, Yoshihiko; Shimada, Tetsuya; Masui, Dai; Takagi, Shinsuke; Tachibana, Hiroshi; Tong, Zhiwei; Inoue, Haruo

2013-04-21

From the viewpoint of developing photoresponsive supramolecular systems in microenvironments to exhibit more sophisticated photo-functions even at the macroscopic level, inorganic/organic hybrid compounds based on clay or niobate nanosheets as the microenvironments were prepared, characterized, and examined for their photoreactions. We show here a novel type of artificial muscle model unit having much similarity with that in natural muscle fibrils. Upon photoirradiation, the organic/inorganic hybrid nanosheets reversibly slide horizontally on a giant scale, and the interlayer spaces in the layered hybrid structure shrink and expand vertically. In particular, our layered hybrid molecular system exhibits a macroscopic morphological change on a giant scale (~1500 nm) compared with the molecular size of ~1 nm, based on a reversible sliding mechanism.

GPU accelerated Discrete Element Method (DEM) molecular dynamics for conservative, faceted particle simulations

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

Spellings, Matthew; Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109; Marson, Ryan L.

Faceted shapes, such as polyhedra, are commonly found in systems of nanoscale, colloidal, and granular particles. Many interesting physical phenomena, like crystal nucleation and growth, vacancy motion, and glassy dynamics are challenging to model in these systems because they require detailed dynamical information at the individual particle level. Within the granular materials community the Discrete Element Method has been used extensively to model systems of anisotropic particles under gravity, with friction. We provide an implementation of this method intended for simulation of hard, faceted nanoparticles, with a conservative Weeks–Chandler–Andersen (WCA) interparticle potential, coupled to a thermodynamic ensemble. This method ismore » a natural extension of classical molecular dynamics and enables rigorous thermodynamic calculations for faceted particles.« less

Geometric analysis characterizes molecular rigidity in generic and non-generic protein configurations

PubMed Central

Budday, Dominik; Leyendecker, Sigrid; van den Bedem, Henry

2015-01-01

Proteins operate and interact with partners by dynamically exchanging between functional substates of a conformational ensemble on a rugged free energy landscape. Understanding how these substates are linked by coordinated, collective motions requires exploring a high-dimensional space, which remains a tremendous challenge. While molecular dynamics simulations can provide atomically detailed insight into the dynamics, computational demands to adequately sample conformational ensembles of large biomolecules and their complexes often require tremendous resources. Kinematic models can provide high-level insights into conformational ensembles and molecular rigidity beyond the reach of molecular dynamics by reducing the dimensionality of the search space. Here, we model a protein as a kinematic linkage and present a new geometric method to characterize molecular rigidity from the constraint manifold Q and its tangent space Q at the current configuration q. In contrast to methods based on combinatorial constraint counting, our method is valid for both generic and non-generic, e.g., singular configurations. Importantly, our geometric approach provides an explicit basis for collective motions along floppy modes, resulting in an efficient procedure to probe conformational space. An atomically detailed structural characterization of coordinated, collective motions would allow us to engineer or allosterically modulate biomolecules by selectively stabilizing conformations that enhance or inhibit function with broad implications for human health. PMID:26213417

Geometric analysis characterizes molecular rigidity in generic and non-generic protein configurations

NASA Astrophysics Data System (ADS)

Budday, Dominik; Leyendecker, Sigrid; van den Bedem, Henry

2015-10-01

Proteins operate and interact with partners by dynamically exchanging between functional substates of a conformational ensemble on a rugged free energy landscape. Understanding how these substates are linked by coordinated, collective motions requires exploring a high-dimensional space, which remains a tremendous challenge. While molecular dynamics simulations can provide atomically detailed insight into the dynamics, computational demands to adequately sample conformational ensembles of large biomolecules and their complexes often require tremendous resources. Kinematic models can provide high-level insights into conformational ensembles and molecular rigidity beyond the reach of molecular dynamics by reducing the dimensionality of the search space. Here, we model a protein as a kinematic linkage and present a new geometric method to characterize molecular rigidity from the constraint manifold Q and its tangent space Tq Q at the current configuration q. In contrast to methods based on combinatorial constraint counting, our method is valid for both generic and non-generic, e.g., singular configurations. Importantly, our geometric approach provides an explicit basis for collective motions along floppy modes, resulting in an efficient procedure to probe conformational space. An atomically detailed structural characterization of coordinated, collective motions would allow us to engineer or allosterically modulate biomolecules by selectively stabilizing conformations that enhance or inhibit function with broad implications for human health.

Nature and nurture: environmental influences on a genetic rat model of depression.

PubMed

Mehta-Raghavan, N S; Wert, S L; Morley, C; Graf, E N; Redei, E E

2016-03-29

In this study, we sought to learn whether adverse events such as chronic restraint stress (CRS), or 'nurture' in the form of environmental enrichment (EE), could modify depression-like behavior and blood biomarker transcript levels in a genetic rat model of depression. The Wistar Kyoto More Immobile (WMI) is a genetic model of depression that aided in the identification of blood transcriptomic markers, which successfully distinguished adolescent and adult subjects with major depressive disorders from their matched no-disorder controls. Here, we followed the effects of CRS and EE in adult male WMIs and their genetically similar control strain, the Wistar Kyoto Less Immobile (WLI), that does not show depression-like behavior, by measuring the levels of these transcripts in the blood and hippocampus. In WLIs, increased depression-like behavior and transcriptomic changes were present in response to CRS, but in WMIs no behavioral or additive transcriptomic changes occurred. Environmental enrichment decreased both the inherent depression-like behavior in the WMIs and the behavioral difference between WMIs and WLIs, but did not reverse basal transcript level differences between the strains. The inverse behavioral change induced by CRS and EE in the WLIs did not result in parallel inverse expression changes of the transcriptomic markers, suggesting that these behavioral responses to the environment work via separate molecular pathways. In contrast, 'trait' transcriptomic markers with expression differences inherent and unchanging between the strains regardless of the environment suggest that in our model, environmental and genetic etiologies of depression work through independent molecular mechanisms.

Effect of PEO molecular weight on the miscibility and dynamics in epoxy/PEO blends.

PubMed

Lu, Shoudong; Zhang, Rongchun; Wang, Xiaoliang; Sun, Pingchuan; Lv, Weifeng; Liu, Qingjie; Jia, Ninghong

2015-11-01

In this work, the effect of poly(ethylene oxide) (PEO) molecular weight in blends of epoxy (ER) and PEO on the miscibility, inter-chain weak interactions and local dynamics were systematically investigated by multi-frequency temperature modulation DSC and solid-state NMR techniques. We found that the molecular weight (M(w)) of PEO was a crucial factor in controlling the miscibility, chain dynamics and hydrogen bonding interactions between PEO and ER. A critical PEO molecular weight (M(crit)) around 4.5k was found. PEO was well miscible with ER when the molecular weight was below M(crit), where the chain motion of PEO was restricted due to strong inter-chain hydrogen bonding interactions. However, for the blends with high molecular weight PEO (M(w) > M(crit)), the miscibility between PEO and ER was poor, and most of PEO chains were considerably mobile. Finally, polarization inversion spin exchange at magic angle (PISEMA) solid-state NMR experiment further revealed the different mobility of the PEO in ER/PEO blends with different molecular weight of PEO at molecular level. Based on the DSC and NMR results, a tentative model was proposed to illustrate the miscibility in ER/PEO blends.

The DNA Triangle and Its Application to Learning Meiosis

PubMed Central

Wright, L. Kate; Catavero, Christina M.; Newman, Dina L.

2017-01-01

Although instruction on meiosis is repeated many times during the undergraduate curriculum, many students show poor comprehension even as upper-level biology majors. We propose that the difficulty lies in the complexity of understanding DNA, which we explain through a new model, the DNA triangle. The DNA triangle integrates three distinct scales at which one can think about DNA: chromosomal, molecular, and informational. Through analysis of interview and survey data from biology faculty and students through the lens of the DNA triangle, we illustrate important differences in how novices and experts are able to explain the concepts of ploidy, homology, and mechanism of homologous pairing. Similarly, analysis of passages from 16 different biology textbooks shows a large divide between introductory and advanced material, with introductory books omitting explanations of meiosis-linked concepts at the molecular level of DNA. Finally, backed by textbook findings and feedback from biology experts, we show that the DNA triangle can be applied to teaching and learning meiosis. By applying the DNA triangle to topics on meiosis we present a new framework for educators and researchers that ties concepts of ploidy, homology, and mechanism of homologous pairing to knowledge about DNA on the chromosomal, molecular, and informational levels. PMID:28798212

The pathophysiology of post-stroke aphasia: A network approach.

PubMed

Thiel, Alexander; Zumbansen, Anna

2016-06-13

Post-stroke aphasia syndromes as a clinical entity arise from the disruption of brain networks specialized in language production and comprehension due to permanent focal ischemia. This approach to post-stroke aphasia is based on two pathophysiological concepts: 1) Understanding language processing in terms of distributed networks rather than language centers and 2) understanding the molecular pathophysiology of ischemic brain injury as a dynamic process beyond the direct destruction of network centers and their connections. While considerable progress has been made in the past 10 years to develop such models on a systems as well as a molecular level, the influence of these approaches on understanding and treating clinical aphasia syndromes has been limited. In this article, we review current pathophysiological concepts of ischemic brain injury, their relationship to altered information processing in language networks after ischemic stroke and how these mechanisms may be influenced therapeutically to improve treatment of post-stroke aphasia. Understanding the pathophysiological mechanism of post-stroke aphasia on a neurophysiological systems level as well as on the molecular level becomes more and more important for aphasia treatment, as the field moves from standardized therapies towards more targeted individualized treatment strategies comprising behavioural therapies as well as non-invasive brain stimulation (NIBS).

Identifying Molecular Targets for Chemoprevention in a Rat Model

DTIC Science & Technology

2005-12-01

95616-8671 REPORT DATE: December 2005 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command...California 95616-8671 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical Research and...addition, it induces high levels of oxidative damage in the target tissues. The scope of this research includes: 1) Generation of a rat model, 2) Analysis

Evaluation of Hydration Free Energy by Level-Set Variational Implicit-Solvent Model with Coulomb-Field Approximation.

PubMed

Guo, Zuojun; Li, Bo; Dzubiella, Joachim; Cheng, Li-Tien; McCammon, J Andrew; Che, Jianwei

2013-03-12

In this article, we systematically apply a novel implicit-solvent model, the variational implicit-solvent model (VISM) together with the Coulomb-Field Approximation (CFA), to calculate the hydration free energy of a large set of small organic molecules. Because these molecules have been studied in detail by molecular dynamics simulations and other implicit-solvent models, they provide a good benchmark for evaluating the performance of VISM-CFA. With all-atom Amber force field parameters, VISM-CFA is able to reproduce well not only the experimental and MD simulated total hydration free energy but also the polar and nonpolar contributions individually. The correlation between VISM-CFA and experiments is R 2 = 0.763 for the total hydration free energy, with a root-mean-square deviation (RMSD) of 1.83 kcal/mol, and the correlation to results from TIP3P explicit water MD simulations is R 2 = 0.839 with a RMSD = 1.36 kcal/mol. In addition, we demonstrate that VISM captures dewetting phenomena in the p53/MDM2 complex and hydrophobic characteristics in the system. This work demonstrates that the level-set VISM-CFA can be used to study the energetic behavior of realistic molecular systems with complicated geometries in solvation, protein-ligand binding, protein-protein association, and protein folding processes.

A Combination of Hand-held Models and Computer Imaging Programs Helps Students Answer Oral Questions about Molecular Structure and Function: A Controlled Investigation of Student Learning

PubMed Central

Peck, Ronald F.; Colton, Shannon; Morris, Jennifer; Chaibub Neto, Elias; Kallio, Julie

2009-01-01

We conducted a controlled investigation to examine whether a combination of computer imagery and tactile tools helps introductory cell biology laboratory undergraduate students better learn about protein structure/function relationships as compared with computer imagery alone. In all five laboratory sections, students used the molecular imaging program, Protein Explorer (PE). In the three experimental sections, three-dimensional physical models were made available to the students, in addition to PE. Student learning was assessed via oral and written research summaries and videotaped interviews. Differences between the experimental and control group students were not found in our typical course assessments such as research papers, but rather were revealed during one-on-one interviews with students at the end of the semester. A subset of students in the experimental group produced superior answers to some higher-order interview questions as compared with students in the control group. During the interview, students in both groups preferred to use either the hand-held models alone or in combination with the PE imaging program. Students typically did not use any tools when answering knowledge (lower-level thinking) questions, but when challenged with higher-level thinking questions, students in both the control and experimental groups elected to use the models. PMID:19255134

Molecular dynamics simulation of β₂-microglobulin in denaturing and stabilizing conditions.

PubMed

Fogolari, Federico; Corazza, Alessandra; Varini, Nicola; Rotter, Matteo; Gumral, Devrim; Codutti, Luca; Rennella, Enrico; Viglino, Paolo; Bellotti, Vittorio; Esposito, Gennaro

2011-03-01

β₂-Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β₂-microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β₂-microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β₂-microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis-trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native-like trans-conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis-trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β₂-microglobulin provides details of the binding modes of the drug and a rationale for its effect. Copyright © 2010 Wiley-Liss, Inc.

Extensive Evaluation of the Conductor-like Screening Model for Real Solvents Method in Predicting Liquid-Liquid Equilibria in Ternary Systems of Ionic Liquids with Molecular Compounds.

PubMed

Paduszyński, Kamil

2018-04-12

A conductor-like screening model for real solvents (COSMO-RS) is nowadays one of the most popular and commonly applied tools for the estimation of thermodynamic properties of complex fluids. The goal of this work is to provide a comprehensive review and analysis of the performance of this approach in calculating liquid-liquid equilibrium (LLE) phase diagrams in ternary systems composed of ionic liquid and two molecular compounds belonging to diverse families of chemicals (alkanes, aromatics, S/N-compounds, alcohols, ketones, ethers, carboxylic acid, esters, and water). The predictions are presented for extensive experimental database, including 930 LLE data sets and more than 9000 data points (LLE tie lines) reported for 779 unique ternary mixtures. An impact of the type of molecular binary subsystem on the accuracy of predictions is demonstrated and discussed on the basis of representative examples. The model's capability of capturing qualitative trends in the LLE distribution ratio and selectivity is also checked for a number of structural effects. Comparative analysis of two levels of quantum chemical theory (BP-TZVP-COSMO vs BP-TZVPD-FINE) for the input molecular data for COSMO-RS is presented. Finally, some general recommendations for the applicability of the model are indicated based on the analysis of the global performance as well as on the results obtained for systems relevant from the point of view of important separation problems.

Watson-Crick Base Pair Radical Cation as a Model for Oxidative Damage in DNA.

PubMed

Feketeová, Linda; Chan, Bun; Khairallah, George N; Steinmetz, Vincent; Maitre, Philippe; Radom, Leo; O'Hair, Richard A J

2017-07-06

The deleterious cellular effects of ionizing radiation are well-known, but the mechanisms causing DNA damage are poorly understood. The accepted molecular events involve initial oxidation and deprotonation at guanine sites, triggering hydrogen atom abstraction reactions from the sugar moieties, causing DNA strand breaks. Probing the chemistry of the initially formed radical cation has been challenging. Here, we generate, spectroscopically characterize, and examine the reactivity of the Watson-Crick nucleobase pair radical cation in the gas phase. We observe rich chemistry, including proton transfer between the bases and propagation of the radical site in deoxyguanosine from the base to the sugar, thus rupturing the sugar. This first example of a gas-phase model system providing molecular-level details on the chemistry of an ionized DNA base pair paves the way toward a more complete understanding of molecular processes induced by radiation. It also highlights the role of radical propagation in chemistry, biology, and nanotechnology.

Molecular Genetic Analysis of Ethanol Intoxication in Drosophila melanogaster.

PubMed

Heberlein, Ulrike; Wolf, Fred W; Rothenfluh, Adrian; Guarnieri, Douglas J

2004-08-01

Recently, the fruit fly Drosophila melanogaster has been introduced as a model system to study the molecular bases of a variety of ethanol-induced behaviors. It became immediately apparent that the behavioral changes elicited by acute ethanol exposure are remarkably similar in flies and mammals. Flies show signs of acute intoxication, which range from locomotor stimulation at low doses to complete sedation at higher doses and they develop tolerance upon intermittent ethanol exposure. Genetic screens for mutants with altered responsiveness to ethanol have been carried out and a few of the disrupted genes have been identified. This analysis, while still in its early stages, has already revealed some surprising molecular parallels with mammals. The availability of powerful tools for genetic manipulation in Drosophila, together with the high degree of conservation at the genomic level, make Drosophila a promising model organism to study the mechanism by which ethanol regulates behavior and the mechanisms underlying the organism's adaptation to long-term ethanol exposure.

An Investigation of G-Quadruplex Structural Polymorphism in the Human Telomere Using a Combined Approach of Hydrodynamic Bead Modeling and Molecular Dynamics Simulation

PubMed Central

2015-01-01

Guanine-rich oligonucleotides can adopt noncanonical tertiary structures known as G-quadruplexes, which can exist in different forms depending on experimental conditions. High-resolution structural methods, such as X-ray crystallography and NMR spectroscopy, have been of limited usefulness in resolving the inherent structural polymorphism associated with G-quadruplex formation. The lack of, or the ambiguous nature of, currently available high-resolution structural data, in turn, has severely hindered investigations into the nature of these structures and their interactions with small-molecule inhibitors. We have used molecular dynamics in conjunction with hydrodynamic bead modeling to study the structures of the human telomeric G-quadruplex-forming sequences at the atomic level. We demonstrated that molecular dynamics can reproduce experimental hydrodynamic measurements and thus can be a powerful tool in the structural study of existing G-quadruplex sequences or in the prediction of new G-quadruplex structures. PMID:24779348

An integrative model for in-silico clinical-genomics discovery science.

PubMed

Lussier, Yves A; Sarkar, Indra Nell; Cantor, Michael

2002-01-01

Human Genome discovery research has set the pace for Post-Genomic Discovery Research. While post-genomic fields focused at the molecular level are intensively pursued, little effort is being deployed in the later stages of molecular medicine discovery research, such as clinical-genomics. The objective of this study is to demonstrate the relevance and significance of integrating mainstream clinical informatics decision support systems to current bioinformatics genomic discovery science. This paper is a feasibility study of an original model enabling novel "in-silico" clinical-genomic discovery science and that demonstrates its feasibility. This model is designed to mediate queries among clinical and genomic knowledge bases with relevant bioinformatic analytic tools (e.g. gene clustering). Briefly, trait-disease-gene relationships were successfully illustrated using QMR, OMIM, SNOMED-RT, GeneCluster and TreeView. The analyses were visualized as two-dimensional dendrograms of clinical observations clustered around genes. To our knowledge, this is the first study using knowledge bases of clinical decision support systems for genomic discovery. Although this study is a proof of principle, it provides a framework for the development of clinical decision-support-system driven, high-throughput clinical-genomic technologies which could potentially unveil significant high-level functions of genes.

Tensegrity I. Cell structure and hierarchical systems biology

NASA Technical Reports Server (NTRS)

Ingber, Donald E.

2003-01-01

In 1993, a Commentary in this journal described how a simple mechanical model of cell structure based on tensegrity architecture can help to explain how cell shape, movement and cytoskeletal mechanics are controlled, as well as how cells sense and respond to mechanical forces (J. Cell Sci. 104, 613-627). The cellular tensegrity model can now be revisited and placed in context of new advances in our understanding of cell structure, biological networks and mechanoregulation that have been made over the past decade. Recent work provides strong evidence to support the use of tensegrity by cells, and mathematical formulations of the model predict many aspects of cell behavior. In addition, development of the tensegrity theory and its translation into mathematical terms are beginning to allow us to define the relationship between mechanics and biochemistry at the molecular level and to attack the larger problem of biological complexity. Part I of this two-part article covers the evidence for cellular tensegrity at the molecular level and describes how this building system may provide a structural basis for the hierarchical organization of living systems--from molecule to organism. Part II, which focuses on how these structural networks influence information processing networks, appears in the next issue.

Predicting absorption and dispersion in acoustics by direct simulation Monte Carlo: Quantum and classical models for molecular relaxation.

PubMed

Hanford, Amanda D; O'Connor, Patrick D; Anderson, James B; Long, Lyle N

2008-06-01

In the current study, real gas effects in the propagation of sound waves are simulated using the direct simulation Monte Carlo method for a wide range of frequencies. This particle method allows for treatment of acoustic phenomena at high Knudsen numbers, corresponding to low densities and a high ratio of the molecular mean free path to wavelength. Different methods to model the internal degrees of freedom of diatomic molecules and the exchange of translational, rotational and vibrational energies in collisions are employed in the current simulations of a diatomic gas. One of these methods is the fully classical rigid-rotor/harmonic-oscillator model for rotation and vibration. A second method takes into account the discrete quantum energy levels for vibration with the closely spaced rotational levels classically treated. This method gives a more realistic representation of the internal structure of diatomic and polyatomic molecules. Applications of these methods are investigated in diatomic nitrogen gas in order to study the propagation of sound and its attenuation and dispersion along with their dependence on temperature. With the direct simulation method, significant deviations from continuum predictions are also observed for high Knudsen number flows.

Windows in direct dissociative recombination cross sections

NASA Technical Reports Server (NTRS)

Guberman, Steven L.

1986-01-01

Model potential curves are used to show that large windows are present in direct dissociative-recombination cross sections from excited molecular-ion vibrational levels. The windows are due to the overlap of vibrational wave functions of the repulsive neutral states with the nodes of the ion vibrational wave function.

KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

USDA-ARS?s Scientific Manuscript database

Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-...

Students' Levels of Explanations, Models, and Misconceptions in Basic Quantum Chemistry: A Phenomenographic Study

ERIC Educational Resources Information Center

Stefani, Christina; Tsaparlis, Georgios

2009-01-01

We investigated students' knowledge constructions of basic quantum chemistry concepts, namely atomic orbitals, the Schrodinger equation, molecular orbitals, hybridization, and chemical bonding. Ausubel's theory of meaningful learning provided the theoretical framework and phenomenography the method of analysis. The semi-structured interview with…

Simulating Limb Formation in the U.S. EPA Virtual Embryo - Risk Assessment Project

EPA Science Inventory

The U.S. EPA’s Virtual Embryo project (v-Embryo™) is a computer model simulation of morphogenesis that integrates cell and molecular level data from mechanistic and in vitro assays with knowledge about normal development processes to assess in silico the effects of chemicals on d...

Molecular mechanism of the sweet taste enhancers.

PubMed

Zhang, Feng; Klebansky, Boris; Fine, Richard M; Liu, Haitian; Xu, Hong; Servant, Guy; Zoller, Mark; Tachdjian, Catherine; Li, Xiaodong

2010-03-09

Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor.

Bacterial Adherence and Dwelling Probability: Two Drivers of Early Alveolar Infection by Streptococcus pneumoniae Identified in Multi-Level Mathematical Modeling.

PubMed

Santos, Guido; Lai, Xin; Eberhardt, Martin; Vera, Julio

2018-01-01

Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their response to vaccines is lower, and antibiotic treatment often does not take place until the inflammatory response triggered is already overwhelming. The immune response to bacterial lung infections involves dynamic interactions between several types of cells whose activation is driven by intracellular molecular networks. A feasible approach to the integration of knowledge and data linking tissue, cellular and intracellular events and the construction of hypotheses in this area is the use of mathematical modeling. For this paper, we used a multi-level computational model to analyse the role of cellular and molecular interactions during the first 10 h after alveolar invasion of Streptococcus pneumoniae bacteria. By "multi-level" we mean that we simulated the interplay between different temporal and spatial scales in a single computational model. In this instance, we included the intracellular scale of processes driving lung epithelial cell activation together with the scale of cell-to-cell interactions at the alveolar tissue. In our analysis, we combined systematic model simulations with logistic regression analysis and decision trees to find genotypic-phenotypic signatures that explain differences in bacteria strain infectivity. According to our simulations, pneumococci benefit from a high dwelling probability and a high proliferation rate during the first stages of infection. In addition to this, the model predicts that during the very early phases of infection the bacterial capsule could be an impediment to the establishment of the alveolar infection because it impairs bacterial colonization.

MAP3K11/GDF15 axis is a critical driver of cancer cachexia

PubMed Central

Tao, Julie; Liu, Qing; Nicoletti, Richard; Feng, Bin; Krieger, Brian; Mazsa, Elizabeth; Siddiquee, Zakir; Wang, Ruoji; Huang, Lucia; Shen, Luhua; Lin, Jie; Vigano, Antonio; Chiu, M. Isabel; Weng, Zhigang; Winston, William; Weiler, Solly

2015-01-01

Abstract Background Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro‐inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. Methods Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non‐cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. Results Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour‐produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. Conclusions The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome. PMID:27239403

Electronic coarse graining enhances the predictive power of molecular simulation allowing challenges in water physics to be addressed

NASA Astrophysics Data System (ADS)

Cipcigan, Flaviu S.; Sokhan, Vlad P.; Crain, Jason; Martyna, Glenn J.

2016-12-01

One key factor that limits the predictive power of molecular dynamics simulations is the accuracy and transferability of the input force field. Force fields are challenged by heterogeneous environments, where electronic responses give rise to biologically important forces such as many-body polarisation and dispersion. The importance of polarisation in the condensed phase was recognised early on, as described by Cochran in 1959 [Philosophical Magazine 4 (1959) 1082-1086] [32]. Currently in molecular simulation, dispersion forces are treated at the two-body level and in the dipole limit, although the importance of three-body terms in the condensed phase was demonstrated by Barker in the 1980s [Phys. Rev. Lett. 57 (1986) 230-233] [72]. One approach for treating both polarisation and dispersion on an equal basis is to coarse grain the electrons surrounding a molecular moiety to a single quantum harmonic oscillator (cf. Hirschfelder, Curtiss and Bird 1954 [The Molecular Theory of Gases and Liquids (1954)] [37]). The approach, when solved in strong coupling beyond the dipole limit, gives a description of long-range forces that includes two- and many-body terms to all orders. In the last decade, the tools necessary to implement the strong coupling limit have been developed, culminating in a transferable model of water with excellent predictive power across the phase diagram. Transferability arises since the environment automatically identifies the important long range interactions, rather than the modeller through a limited set of expressions. Here, we discuss the role of electronic coarse-graining in predictive multiscale materials modelling and describe the first implementation of the method in a general purpose molecular dynamics software: QDO_MD.

Changes of rat plasma total low molecular weight antioxidant level after tabun exposure and consequent treatment by acetylcholinesterase reactivators.

PubMed

Pohanka, Miroslav; Karasova, Jana Zdarova; Musilek, Kamil; Kuca, Kamil; Jung, Young-Sik; Kassa, Jiri

2011-02-01

These experiments were performed on a rat model. The rats were divided into eight groups and consequently exposed to either a saline solution (control), atropine or a combination of atropine and tabun. The reactivation efficacy of the oximes was estimated on the rats exposed to tabun, atropine and a reactivator of AChE. The oximes HI-6, obidoxime, trimedoxime, K203 and KR-22836 were used as representative compounds of commonly available and new AChE reactivators. Besides the positive effect of the administered reactivators on blood AChE activity, the sizable modulation of low molecular weight antioxidant (LMWA) levels was also determined. The LMWA levels in the the animals treated with the oxime reactivators were decreased in comparison with the animals treated by atropine alone. It was found that the levels of LMWA returned to the level found in the control animals when either trimedoxime, K203 or KR-22836 were administered. The principle of oxime reactivator function and a novel insight into AChE activity regulation and oxidative stress is discussed.

Molecular-level simulations of turbulence and its decay

DOE PAGES

Gallis, M. A.; Bitter, N. P.; Koehler, T. P.; ...

2017-02-08

Here, we provide the first demonstration that molecular-level methods based on gas kinetic theory and molecular chaos can simulate turbulence and its decay. The direct simulation Monte Carlo (DSMC) method, a molecular-level technique for simulating gas flows that resolves phenomena from molecular to hydrodynamic (continuum) length scales, is applied to simulate the Taylor-Green vortex flow. The DSMC simulations reproduce the Kolmogorov –5/3 law and agree well with the turbulent kinetic energy and energy dissipation rate obtained from direct numerical simulation of the Navier-Stokes equations using a spectral method. This agreement provides strong evidence that molecular-level methods for gases can bemore » used to investigate turbulent flows quantitatively.« less

Theoretical and Experimental Study of Inclusion Complexes of β-Cyclodextrins with Chalcone and 2',4'-Dihydroxychalcone.

PubMed

Sancho, Matias I; Andujar, Sebastian; Porasso, Rodolfo D; Enriz, Ricardo D

2016-03-31

The inclusion complexes formed by chalcone and 2',4'-dihydroxychalcone with β-cyclodextrin have been studied combining experimental (phase solubility diagrams, Fourier transform infrared spectroscopy) and molecular modeling (molecular dynamics, quantum mechanics/molecular mechanics calculations) techniques. The formation constants of the complexes were determined at different temperatures, and the thermodynamic parameters of the process were obtained. The inclusion of chalcone in β-cyclodextrin is an exothermic process, while the inclusion of 2',4'-dihydroxychalcone is endothermic. Free energy profiles, derived from umbrella sampling using molecular dynamics simulations, were constructed to analyze the binding affinity and the complexation reaction at a molecular level. Hybrid QM/MM calculations were also employed to obtain a better description of the energetic and structural aspects of the complexes. The intermolecular interactions that stabilize both inclusion complexes were characterized by means of quantum atoms in molecules theory and reduce density gradient method. The calculated interactions were experimentally observed using FTIR.

Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins

PubMed Central

2016-01-01

An important challenge in the simulation of biomolecular systems is a quantitative description of the protonation and deprotonation process of amino acid residues. Despite the seeming simplicity of adding or removing a positively charged hydrogen nucleus, simulating the actual protonation/deprotonation process is inherently difficult. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino residues), and extensive sampling of coupled condensed phase motions. In a recent paper (J. Chem. Theory Comput.2014, 10, 2729−273725061442), a multiscale approach was developed to map high-level quantum mechanics/molecular mechanics (QM/MM) data into a multiscale reactive molecular dynamics (MS-RMD) model in order to describe amino acid deprotonation in bulk water. In this article, we extend the fitting approach (called FitRMD) to create MS-RMD models for ionizable amino acids within proteins. The resulting models are shown to faithfully reproduce the free energy profiles of the reference QM/MM Hamiltonian for PT inside an example protein, the ClC-ec1 H+/Cl– antiporter. Moreover, we show that the resulting MS-RMD models are computationally efficient enough to then characterize more complex 2-dimensional free energy surfaces due to slow degrees of freedom such as water hydration of internal protein cavities that can be inherently coupled to the excess proton charge translocation. The FitRMD method is thus shown to be an effective way to map ab initio level accuracy into a much more computationally efficient reactive MD method in order to explicitly simulate and quantitatively describe amino acid protonation/deprotonation in proteins. PMID:26734942

Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins.

PubMed

Lee, Sangyun; Liang, Ruibin; Voth, Gregory A; Swanson, Jessica M J

2016-02-09

An important challenge in the simulation of biomolecular systems is a quantitative description of the protonation and deprotonation process of amino acid residues. Despite the seeming simplicity of adding or removing a positively charged hydrogen nucleus, simulating the actual protonation/deprotonation process is inherently difficult. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino residues), and extensive sampling of coupled condensed phase motions. In a recent paper (J. Chem. Theory Comput. 2014, 10, 2729-2737), a multiscale approach was developed to map high-level quantum mechanics/molecular mechanics (QM/MM) data into a multiscale reactive molecular dynamics (MS-RMD) model in order to describe amino acid deprotonation in bulk water. In this article, we extend the fitting approach (called FitRMD) to create MS-RMD models for ionizable amino acids within proteins. The resulting models are shown to faithfully reproduce the free energy profiles of the reference QM/MM Hamiltonian for PT inside an example protein, the ClC-ec1 H(+)/Cl(-) antiporter. Moreover, we show that the resulting MS-RMD models are computationally efficient enough to then characterize more complex 2-dimensional free energy surfaces due to slow degrees of freedom such as water hydration of internal protein cavities that can be inherently coupled to the excess proton charge translocation. The FitRMD method is thus shown to be an effective way to map ab initio level accuracy into a much more computationally efficient reactive MD method in order to explicitly simulate and quantitatively describe amino acid protonation/deprotonation in proteins.

Modeling forest ecosystem responses to elevated carbon dioxide and ozone using artificial neural networks.

PubMed

Larsen, Peter E; Cseke, Leland J; Miller, R Michael; Collart, Frank R

2014-10-21

Rising atmospheric levels of carbon dioxide and ozone will impact productivity and carbon sequestration in forest ecosystems. The scale of this process and the potential economic consequences provide an incentive for the development of models to predict the types and rates of ecosystem responses and feedbacks that result from and influence of climate change. In this paper, we use phenotypic and molecular data derived from the Aspen Free Air CO2 Enrichment site (Aspen-FACE) to evaluate modeling approaches for ecosystem responses to changing conditions. At FACE, it was observed that different aspen clones exhibit clone-specific responses to elevated atmospheric levels of carbon dioxide and ozone. To identify the molecular basis for these observations, we used artificial neural networks (ANN) to examine above and below-ground community phenotype responses to elevated carbon dioxide, elevated ozone and gene expression profiles. The aspen community models generated using this approach identified specific genes and subnetworks of genes associated with variable sensitivities for aspen clones. The ANN model also predicts specific co-regulated gene clusters associated with differential sensitivity to elevated carbon dioxide and ozone in aspen species. The results suggest ANN is an effective approach to predict relevant gene expression changes resulting from environmental perturbation and provides useful information for the rational design of future biological experiments. Copyright © 2014 Elsevier Ltd. All rights reserved.

Human Pyruvate Dehydrogenase Complex E2 and E3BP Core Subunits: New Models and Insights from Molecular Dynamics Simulations.

PubMed

Hezaveh, Samira; Zeng, An-Ping; Jandt, Uwe

2016-05-19

Targeted manipulation and exploitation of beneficial properties of multienzyme complexes, especially for the design of novel and efficiently structured enzymatic reaction cascades, require a solid model understanding of mechanistic principles governing the structure and functionality of the complexes. This type of system-level and quantitative knowledge has been very scarce thus far. We utilize the human pyruvate dehydrogenase complex (hPDC) as a versatile template to conduct corresponding studies. Here we present new homology models of the core subunits of the hPDC, namely E2 and E3BP, as the first time effort to elucidate the assembly of hPDC core based on molecular dynamic simulation. New models of E2 and E3BP were generated and validated at atomistic level for different properties of the proteins. The results of the wild type dimer simulations showed a strong hydrophobic interaction between the C-terminal and the hydrophobic pocket which is the main driving force in the intertrimer binding and the core self-assembly. On the contrary, the C-terminal truncated versions exhibited a drastic loss of hydrophobic interaction leading to a dimeric separation. This study represents a significant step toward a model-based understanding of structure and function of large multienzyme systems like PDC for developing highly efficient biocatalyst or bioreaction cascades.

Exploring the Interaction of SV2A with Racetams Using Homology Modelling, Molecular Dynamics and Site-Directed Mutagenesis

PubMed Central

Lee, Joanna; Daniels, Veronique; Sands, Zara A.; Lebon, Florence; Shi, Jiye; Biggin, Philip C.

2015-01-01

The putative Major Facilitator Superfamily (MFS) transporter, SV2A, is the target for levetiracetam (LEV), which is a successful anti-epileptic drug. Furthermore, SV2A knock out mice display a severe seizure phenotype and die after a few weeks. Despite this, the mode of action of LEV is not known at the molecular level. It would be extremely desirable to understand this more fully in order to aid the design of improved anti-epileptic compounds. Since there is no structure for SV2A, homology modelling can provide insight into the ligand-binding site. However, it is not a trivial process to build such models, since SV2A has low sequence identity to those MFS transporters whose structures are known. A further level of complexity is added by the fact that it is not known which conformational state of the receptor LEV binds to, as multiple conformational states have been inferred by tomography and ligand binding assays or indeed, if binding is exclusive to a single state. Here, we explore models of both the inward and outward facing conformational states of SV2A (according to the alternating access mechanism for MFS transporters). We use a sequence conservation analysis to help guide the homology modelling process and generate the models, which we assess further with Molecular Dynamics (MD). By comparing the MD results in conjunction with docking and simulation of a LEV-analogue used in radioligand binding assays, we were able to suggest further residues that line the binding pocket. These were confirmed experimentally. In particular, mutation of D670 leads to a complete loss of binding. The results shed light on the way LEV analogues may interact with SV2A and may help with the on-going design of improved anti-epileptic compounds. PMID:25692762

Recent advances in QM/MM free energy calculations using reference potentials☆

PubMed Central

Duarte, Fernanda; Amrein, Beat A.; Blaha-Nelson, David; Kamerlin, Shina C.L.

2015-01-01

Background Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way. Scope of review Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field. Major conclusions The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed. General significance As was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics. PMID:25038480

Gene knockdown by morpholino-modified oligonucleotides in the zebrafish (Danio rerio) model: applications for developmental toxicology.

PubMed

Timme-Laragy, Alicia R; Karchner, Sibel I; Hahn, Mark E

2012-01-01

The zebrafish (Danio rerio) has long been used as a model for developmental biology, making it an excellent model to use also in developmental toxicology. The many advantages of zebrafish include their small size, prolific spawning, rapid development, and transparent embryos. They can be easily manipulated genetically through the use of transgenic technology and gene knockdown via morpholino-modified antisense oligonucleotides (MOs). Knocking down specific genes to assess their role in the response to toxicant exposure provides a way to further our knowledge of how developmental toxicants work on a molecular and mechanistic level while establishing a relationship between these molecular events and morphological, behavioral, and/or physiological effects (i.e., phenotypic anchoring). In this chapter, we address important considerations for using MOs to study developmental toxicology in zebrafish embryos and provide a protocol for their use.

Gene knockdown by morpholino-modified oligonucleotides in the zebrafish model: applications for developmental toxicology

PubMed Central

Timme-Laragy, Alicia R.; Karchner, Sibel I.; Hahn, Mark E.

2014-01-01

Summary The zebrafish (Danio rerio) has long been used as a model for developmental biology, making it an excellent model to use also in developmental toxicology. The many advantages of zebrafish include their small size, prolific spawning, rapid development, and transparent embryos. They can be easily manipulated genetically through the use of transgenic technology and gene knock-down via morpholino-modified antisense oligonucleotides (MOs). Knocking down specific genes to assess their role in the response to toxicant exposure provides a way to further our knowledge of how developmental toxicants work on a molecular and mechanistic level, while establishing a relationship between these molecular events and morphological, behavioral, and/or physiological effects (i.e. phenotypic anchoring). In this chapter we address important considerations for using MOs to study developmental toxicology in zebrafish embryos and provide a protocol for their use. PMID:22669659

The atomic scale structure of CXV carbon: wide-angle x-ray scattering and modeling studies.

PubMed

Hawelek, L; Brodka, A; Dore, J C; Honkimaki, V; Burian, A

2013-11-13

The disordered structure of commercially available CXV activated carbon produced from finely powdered wood-based carbon has been studied using the wide-angle x-ray scattering technique, molecular dynamics and density functional theory simulations. The x-ray scattering data has been converted to the real space representation in the form of the pair correlation function via the Fourier transform. Geometry optimizations using classical molecular dynamics based on the reactive empirical bond order potential and density functional theory at the B3LYP/6-31g* level have been performed to generate nanoscale models of CXV carbon consistent with the experimental data. The final model of the structure comprises four chain-like and buckled graphitic layers containing a small percentage of four-fold coordinated atoms (sp(3) defects) in each layer. The presence of non-hexagonal rings in the atomic arrangement has been also considered.

Density functional theory molecular modeling and antimicrobial behaviour of selected 1,2,3,4,5,6,7,8-octahydroacridine-N(10)-oxides

NASA Astrophysics Data System (ADS)

Marinescu, Maria; Cinteza, Ludmila Otilia; Marton, George Iuliu; Marutescu, Luminita Gabriela; Chifiriuc, Mariana-Carmen; Constantinescu, Catalin

2017-09-01

A series of 9-substituted 1,2,3,4,5,6,7,8-octahydroacridine-N(10)-oxides is evaluated against 12 bacterial and fungal strains, for their microbicidal and anti-pathogenic features. The largest spectrum of the antibacterial activity is evidenced for the nitro- (2b) and hydroxy- (5b) N-oxides, followed by the amino-N-oxide (3b). Density functional theory (DFT) modeling of the molecular structure and frontier molecular orbitals, i.e. highest occupied/lowest unoccupied molecular orbital (HOMO/LUMO), is accomplished by using the GAMESS 2012 software at M11/ktzvp level of theory in order to find their structural and electronic parameters. We show that the planarity of the molecules and the presence of the electron withdrawing group are advantages for its antimicrobial activity. Finally, we briefly present and discuss results on the processing of such compounds into thin films and hybrid structures by laser-assisted techniques, i.e. matrix-assisted pulsed laser evaporation (MAPLE) or laser-induced forward transfer (LIFT), to provide simple and environmental friendly, state-of-the-art solutions for antimicrobial/medical coatings and devices.

Structure of a tethered polymer under flow using molecular dynamics and hybrid molecular-continuum simulations

NASA Astrophysics Data System (ADS)

Delgado-Buscalioni, Rafael; Coveney, Peter V.

2006-03-01

We analyse the structure of a single polymer tethered to a solid surface undergoing a Couette flow. We study the problem using molecular dynamics (MD) and hybrid MD-continuum simulations, wherein the polymer and the surrounding solvent are treated via standard MD, and the solvent flow farther away from the polymer is solved by continuum fluid dynamics (CFD). The polymer represents a freely jointed chain (FJC) and is modelled by Lennard-Jones (LJ) beads interacting through the FENE potential. The solvent (modelled as a LJ fluid) and a weakly attractive wall are treated at the molecular level. At large shear rates the polymer becomes more elongated than predicted by existing theoretical scaling laws. Also, along the normal-to-wall direction the structure observed for the FJC is, surprisingly, very similar to that predicted for a semiflexible chain. Comparison with previous Brownian dynamics simulations (which exclude both solvent and wall potential) indicates that these effects are due to the polymer-solvent and polymer-wall interactions. The hybrid simulations are in perfect agreement with the MD simulations, showing no trace of finite size effects. Importantly, the extra cost required to couple the MD and CFD domains is negligible.

Molecular-orbital models for the catalytic activity and selectivity of coordinatively unsaturated platinum surfaces and complexes

NASA Astrophysics Data System (ADS)

Balazs, A. C.; Johnson, K. H.

1982-01-01

Electronic structures have been calculated for 5-, 6-, and 10-atom Pt clusters, as well as for a Pt(PH 3) 4 coordination complex, using the self-consistent-field X-alpha scattered-wave (SCF-Xα-SW) molecular-orbital technique. The 10-atom cluster models the local geometry of a flat, unreconstructed Pt(100) surface, while the 5- and 6-atom clusters show features of a stepped Pt surface. Pt(PH 3) 4 resembles the chemically similar homogeneous catalyst Pt(PPh 3) 4. Common to all these coordinatively unsaturated complexes are orbitals lying near or coinciding with the highest occupied molecular orbital ("Fermi level") which show pronounced d lobes pointing directly into the vacuum. Under the hypothesis that these molecular orbitals are mainly responsible for the chemical activities of the above species, one can account for the relative similarities and differences in catalytic activity and selectivity displayed by unreconstructed Pt(100) surfaces, stepped Pt surfaces or particles, and isolated Pt(PPh 3) 4 coordination complexes. The relevance of these findings to catalyst-support interactions is also discussed. Finally, relativistic corrections to the electronic structures are calculated and their implications on catalytic properties discussed.

A multiscale computational approach to dissect early events in the Erb family receptor mediated activation, differential signaling, and relevance to oncogenic transformations.

PubMed

Liu, Yingting; Purvis, Jeremy; Shih, Andrew; Weinstein, Joshua; Agrawal, Neeraj; Radhakrishnan, Ravi

2007-06-01

We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/continuum stochastic dynamics protocols to study the dimer-mediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry.

PubMed

Ejsing, Christer S; Sampaio, Julio L; Surendranath, Vineeth; Duchoslav, Eva; Ekroos, Kim; Klemm, Robin W; Simons, Kai; Shevchenko, Andrej

2009-02-17

Although the transcriptome, proteome, and interactome of several eukaryotic model organisms have been described in detail, lipidomes remain relatively uncharacterized. Using Saccharomyces cerevisiae as an example, we demonstrate that automated shotgun lipidomics analysis enabled lipidome-wide absolute quantification of individual molecular lipid species by streamlined processing of a single sample of only 2 million yeast cells. By comparative lipidomics, we achieved the absolute quantification of 250 molecular lipid species covering 21 major lipid classes. This analysis provided approximately 95% coverage of the yeast lipidome achieved with 125-fold improvement in sensitivity compared with previous approaches. Comparative lipidomics demonstrated that growth temperature and defects in lipid biosynthesis induce ripple effects throughout the molecular composition of the yeast lipidome. This work serves as a resource for molecular characterization of eukaryotic lipidomes, and establishes shotgun lipidomics as a powerful platform for complementing biochemical studies and other systems-level approaches.

Computational assignment of redox states to Coulomb blockade diamonds.

PubMed

Olsen, Stine T; Arcisauskaite, Vaida; Hansen, Thorsten; Kongsted, Jacob; Mikkelsen, Kurt V

2014-09-07

With the advent of molecular transistors, electrochemistry can now be studied at the single-molecule level. Experimentally, the redox chemistry of the molecule manifests itself as features in the observed Coulomb blockade diamonds. We present a simple theoretical method for explicit construction of the Coulomb blockade diamonds of a molecule. A combined quantum mechanical/molecular mechanical method is invoked to calculate redox energies and polarizabilities of the molecules, including the screening effect of the metal leads. This direct approach circumvents the need for explicit modelling of the gate electrode. From the calculated parameters the Coulomb blockade diamonds are constructed using simple theory. We offer a theoretical tool for assignment of Coulomb blockade diamonds to specific redox states in particular, and a study of chemical details in the diamonds in general. With the ongoing experimental developments in molecular transistor experiments, our tool could find use in molecular electronics, electrochemistry, and electrocatalysis.

Faunus: An object oriented framework for molecular simulation

PubMed Central

Lund, Mikael; Trulsson, Martin; Persson, Björn

2008-01-01

Background We present a C++ class library for Monte Carlo simulation of molecular systems, including proteins in solution. The design is generic and highly modular, enabling multiple developers to easily implement additional features. The statistical mechanical methods are documented by extensive use of code comments that – subsequently – are collected to automatically build a web-based manual. Results We show how an object oriented design can be used to create an intuitively appealing coding framework for molecular simulation. This is exemplified in a minimalistic C++ program that can calculate protein protonation states. We further discuss performance issues related to high level coding abstraction. Conclusion C++ and the Standard Template Library (STL) provide a high-performance platform for generic molecular modeling. Automatic generation of code documentation from inline comments has proven particularly useful in that no separate manual needs to be maintained. PMID:18241331

Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

PubMed Central

Annambhotla, Suman; Bourgeois, Sebastian; Wang, Xinwen; Lin, Peter H.; Yao, Qizhi; Chen, Changyi

2010-01-01

Abdominal Aortic Aneurysm (AAA) is an increasingly common clinical condition with fatal implications. It is associated with advanced age, male gender, cigarette smoking, atherosclerosis, hypertension, and genetic predisposition. Although significant evidence has emerged in the last decade, the molecular mechanisms of AAA formation remains poorly understood. Currently, the treatment for AAA remains primarily surgical with the lone innovation of endovascular therapy. With advance in the human genome, understanding precisely which molecules and genes mediate AAA development and blocking their activity at the molecular level could lead to important new discoveries and therapies. This review summarizes recent updates in molecular mechanisms of AAA formation including animal models, autoimmune components, infection, key molecules and cytokines, mechanical forces, genetics and pharmacotherapy. This review will be helpful to those who want to recognize the newest endeavors within the field and identify possible lines of investigation in AAA. PMID:18259804

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH.

PubMed

Wallace, Jason A; Shen, Jana K

2012-11-14

Recent development of constant pH molecular dynamics (CpHMD) methods has offered promise for adding pH-stat in molecular dynamics simulations. However, until now the working pH molecular dynamics (pHMD) implementations are dependent in part or whole on implicit-solvent models. Here we show that proper treatment of long-range electrostatics and maintaining charge neutrality of the system are critical for extending the continuous pHMD framework to the all-atom representation. The former is achieved here by adding forces to titration coordinates due to long-range electrostatics based on the generalized reaction field method, while the latter is made possible by a charge-leveling technique that couples proton titration with simultaneous ionization or neutralization of a co-ion in solution. We test the new method using the pH-replica-exchange CpHMD simulations of a series of aliphatic dicarboxylic acids with varying carbon chain length. The average absolute deviation from the experimental pK(a) values is merely 0.18 units. The results show that accounting for the forces due to extended electrostatics removes the large random noise in propagating titration coordinates, while maintaining charge neutrality of the system improves the accuracy in the calculated electrostatic interaction between ionizable sites. Thus, we believe that the way is paved for realizing pH-controlled all-atom molecular dynamics in the near future.

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

PubMed Central

Wallace, Jason A.; Shen, Jana K.

2012-01-01

Recent development of constant pH molecular dynamics (CpHMD) methods has offered promise for adding pH-stat in molecular dynamics simulations. However, until now the working pH molecular dynamics (pHMD) implementations are dependent in part or whole on implicit-solvent models. Here we show that proper treatment of long-range electrostatics and maintaining charge neutrality of the system are critical for extending the continuous pHMD framework to the all-atom representation. The former is achieved here by adding forces to titration coordinates due to long-range electrostatics based on the generalized reaction field method, while the latter is made possible by a charge-leveling technique that couples proton titration with simultaneous ionization or neutralization of a co-ion in solution. We test the new method using the pH-replica-exchange CpHMD simulations of a series of aliphatic dicarboxylic acids with varying carbon chain length. The average absolute deviation from the experimental pKa values is merely 0.18 units. The results show that accounting for the forces due to extended electrostatics removes the large random noise in propagating titration coordinates, while maintaining charge neutrality of the system improves the accuracy in the calculated electrostatic interaction between ionizable sites. Thus, we believe that the way is paved for realizing pH-controlled all-atom molecular dynamics in the near future. PMID:23163362

Electrofluorescence polarity in a molecular diode

NASA Astrophysics Data System (ADS)

Petrov, E. G.; Leonov, V. A.; Shevchenko, E. V.

2017-11-01

The kinetic equations describing the transmission of an electron in the molecular compound "electrode 1-molecule-electrode 2" (1M2 system) are derived using the method of a nonequilibrium density matrix. The steady-state transmission regime is considered, for which detailed analysis of the kinetics of electrofluorescence formation in systems with symmetric and asymmetric couplings between the molecule and the electrodes is carried out. It is shown that the optically active state of the molecule is formed as a result of electron hops between the molecule and each of the electrodes, as well as due to inelastic interelectrode tunneling of the electron. The electrofluorescence power for a molecular diode (asymmetric 1M2 system) depends on the polarity of the voltage bias applied to the electrodes. The polarity is explained using a model in which the optically active part of the molecule (chromophore group) is represented by the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). Two mechanisms of the emergence of polarity are revealed. One mechanism is associated with nonidentical Stark shifts of the HOMO and LUMO levels relative to the Fermi levels of the electrodes. The second mechanism is associated with the fact that the rates of an electron hopping between HOMO (LUMO) and one of the electrodes are much higher than the rates of such a hopping with the other electrode. The conditions in which each mechanism can be implemented experimentally are indicated.

Molecular Insights into the Potential Toxicological Interaction of 2-Mercaptothiazoline with the Antioxidant Enzyme—Catalase

PubMed Central

Huang, Zhenxing; Huang, Ming; Mi, Chenyu; Wang, Tao; Chen, Dong; Teng, Yue

2016-01-01

2-mercaptothiazoline (2-MT) is widely used in many industrial fields, but its residue is potentially harmful to the environment. In this study, to evaluate the biological toxicity of 2-MT at protein level, the interaction between 2-MT and the pivotal antioxidant enzyme—catalase (CAT) was investigated using multiple spectroscopic techniques and molecular modeling. The results indicated that the CAT fluorescence quenching caused by 2-MT should be dominated by a static quenching mechanism through formation of a 2-MT/CAT complex. Furthermore, the identifications of the binding constant, binding forces, and the number of binding sites demonstrated that 2-MT could spontaneously interact with CAT at one binding site mainly via Van der Waals’ forces and hydrogen bonding. Based on the molecular docking simulation and conformation dynamic characterization, it was found that 2-MT could bind into the junctional region of CAT subdomains and that the binding site was close to enzyme active sites, which induced secondary structural and micro-environmental changes in CAT. The experiments on 2-MT toxicity verified that 2-MT significantly inhibited CAT activity via its molecular interaction, where 2-MT concentration and exposure time both affected the inhibitory action. Therefore, the present investigation provides useful information for understanding the toxicological mechanism of 2-MT at the molecular level. PMID:27537873

Force-field parameters from the SAFT-γ equation of state for use in coarse-grained molecular simulations.

PubMed

Müller, Erich A; Jackson, George

2014-01-01

A description of fluid systems with molecular-based algebraic equations of state (EoSs) and by direct molecular simulation is common practice in chemical engineering and the physical sciences, but the two approaches are rarely closely coupled. The key for an integrated representation is through a well-defined force field and Hamiltonian at the molecular level. In developing coarse-grained intermolecular potential functions for the fluid state, one typically starts with a detailed, bottom-up quantum-mechanical or atomic-level description and then integrates out the unwanted degrees of freedom using a variety of techniques; an iterative heuristic simulation procedure is then used to refine the parameters of the model. By contrast, with a top-down technique, one can use an accurate EoS to link the macroscopic properties of the fluid and the force-field parameters. We discuss the latest developments in a top-down representation of fluids, with a particular focus on a group-contribution formulation of the statistical associating fluid theory (SAFT-γ). The accurate SAFT-γ EoS is used to estimate the parameters of the Mie force field, which can then be used with confidence in direct molecular simulations to obtain thermodynamic, structural, interfacial, and dynamical properties that are otherwise inaccessible from the EoS. This is exemplified for several prototypical fluids and mixtures, including carbon dioxide, hydrocarbons, perfluorohydrocarbons, and aqueous surfactants.

Development of the relaxation-assisted 2DIR method for accessing structures of molecules and its application for studying the energy transport on a molecular level

NASA Astrophysics Data System (ADS)

Kasyanenko, Valeriy Mitrofanovich

Measuring the three-dimensional structure of molecules, dynamics of structural changes, and energy transport on a molecular scale is important for many areas of natural science. Supplementing the widely used methods of x-ray diffraction, NMR, and optical spectroscopies, a two-dimensional infrared spectroscopy (2DIR) method was introduced about a decade ago. The 2DIR method measures pair-wise interactions between vibrational modes in molecules, thus acquiring molecular structural constraints such as distances between vibrating groups and the angles between their transition dipoles. The 2DIR method has been applied to a variety of molecular systems but in studying larger molecules such as proteins and peptides the method is facing challenges associated with the congestion of their vibrational spectra and delocalized character of their vibrational modes. To help extract structural information from such spectra and make efficient use of vibrational modes separated by large distances, a novel relaxation-assisted 2DIR method (RA 2DIR) has recently been proposed, which exploits the transport of excess vibrational energy from the initially excited mode. With the goal of further development of RA 2DIR, we applied it to a variety of molecular systems, including model compounds, transition-metal complexes, and isomers. The experiments revealed several novel effects which both enhance the power of RA 2DIR and bring a deeper understanding to the fundamental process of energy transport on a molecular level. We demonstrated that RA 2DIR can enhance greatly (27-fold) the cross-peak amplitude among spatially remote modes, which leads to an increase of the range of distances accessible for structural measurements by several fold. We demonstrated that the energy transport time correlates with the intermode distance. This correlation offers a new way for identifying connectivity patterns in molecules. We developed two models of energy transport in molecules. In one, a spatial overlap of vibrational modes determines the rate of energy transfer. Another model uses generalizations of Marcus theory of electron transfer applied to anharmonic vibrational transitions. These theoretical models reproduce well the main features of RA 2DIR measurements in a set of isomers where the energy transport is found to be affected by the three-dimensional structure as well as in transition-metal complexes, where the energy transport has to go through relatively weak coordination bonds and can be different from that occurring via covalent bonds.

Molecular-level chemistry of model single-crystal oxide surfaces with model halogenated compounds

NASA Astrophysics Data System (ADS)

Adib, Kaveh

Synchrotron-based X-ray photoelectron spectroscopy (XPS), temperature-programmed desorption (TPD) and low energy electron diffraction (LEED) have been used to investigate, at a molecular level, the chemistry of different terminations of single crystal iron-oxide surfaces with probe molecules (CCl4 and D2O). Comparisons of the reactivity of these surfaces towards CCl4, indicate that the presence of an uncapped surface Fe cation (strong Lewis acid site) and an adjacent oxygen site capped by that cation can effect the C-Cl bond cleavage in CCl4, resulting in dissociatively adsorbed Cl-adatoms and carbon-containing fragments. If in addition to these sites, an uncapped surface oxygen (Lewis base) site is also available, the carbon-containing moiety can then move that site, coordinate itself with that uncapped oxygen, and stabilize itself. At a later step, the carbon-containing fragment may form a strong covalent bond with the uncapped oxygen and may even abstract that surface oxygen. On the other hand, if an uncapped oxygen is not available to stabilize the carbon-containing fragment, the surface coordination will not occur and upon the subsequent thermal annealing of the surface the Cl-adatoms and the carbon-containing fragments will recombine and desorb as CCl4. Finally, the presence of surface deuteroxyls blocking the strong Lewis acid and base sites of the reactive surface, passivates this surface. Such a deuteroxylated surface will be unreactive towards CCl 4. Such a molecular level understanding of the surface chemistry of metal-oxides will have applications in the areas of selective catalysis, including environmental catalysis, and chemical sensor technology.

Logic-based models in systems biology: a predictive and parameter-free network analysis method†

PubMed Central

Wynn, Michelle L.; Consul, Nikita; Merajver, Sofia D.

2012-01-01

Highly complex molecular networks, which play fundamental roles in almost all cellular processes, are known to be dysregulated in a number of diseases, most notably in cancer. As a consequence, there is a critical need to develop practical methodologies for constructing and analysing molecular networks at a systems level. Mathematical models built with continuous differential equations are an ideal methodology because they can provide a detailed picture of a network’s dynamics. To be predictive, however, differential equation models require that numerous parameters be known a priori and this information is almost never available. An alternative dynamical approach is the use of discrete logic-based models that can provide a good approximation of the qualitative behaviour of a biochemical system without the burden of a large parameter space. Despite their advantages, there remains significant resistance to the use of logic-based models in biology. Here, we address some common concerns and provide a brief tutorial on the use of logic-based models, which we motivate with biological examples. PMID:23072820

Next generation patient-derived prostate cancer xenograft models

PubMed Central

Lin, Dong; Xue, Hui; Wang, Yuwei; Wu, Rebecca; Watahiki, Akira; Dong, Xin; Cheng, Hongwei; Wyatt, Alexander W; Collins, Colin C; Gout, Peter W; Wang, Yuzhuo

2014-01-01

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients’ tumor tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer. PMID:24589467

Reinforcement learning in depression: A review of computational research.

PubMed

Chen, Chong; Takahashi, Taiki; Nakagawa, Shin; Inoue, Takeshi; Kusumi, Ichiro

2015-08-01

Despite being considered primarily a mood disorder, major depressive disorder (MDD) is characterized by cognitive and decision making deficits. Recent research has employed computational models of reinforcement learning (RL) to address these deficits. The computational approach has the advantage in making explicit predictions about learning and behavior, specifying the process parameters of RL, differentiating between model-free and model-based RL, and the computational model-based functional magnetic resonance imaging and electroencephalography. With these merits there has been an emerging field of computational psychiatry and here we review specific studies that focused on MDD. Considerable evidence suggests that MDD is associated with impaired brain signals of reward prediction error and expected value ('wanting'), decreased reward sensitivity ('liking') and/or learning (be it model-free or model-based), etc., although the causality remains unclear. These parameters may serve as valuable intermediate phenotypes of MDD, linking general clinical symptoms to underlying molecular dysfunctions. We believe future computational research at clinical, systems, and cellular/molecular/genetic levels will propel us toward a better understanding of the disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary

PubMed Central

Liu, Liang; Zhang, Jin; Rheindt, Frank E.; Lei, Fumin; Qu, Yanhua; Wang, Yu; Zhang, Yu; Sullivan, Corwin; Nie, Wenhui; Wang, Jinhuan; Yang, Fengtang; Chen, Jinping; Edwards, Scott V.; Meng, Jin; Wu, Shaoyuan

2017-01-01

The timing of the diversification of placental mammals relative to the Cretaceous–Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms. PMID:28808022

Mapping biological process relationships and disease perturbations within a pathway network.

PubMed

Stoney, Ruth; Robertson, David L; Nenadic, Goran; Schwartz, Jean-Marc

2018-01-01

Molecular interaction networks are routinely used to map the organization of cellular function. Edges represent interactions between genes, proteins, or metabolites. However, in living cells, molecular interactions are dynamic, necessitating context-dependent models. Contextual information can be integrated into molecular interaction networks through the inclusion of additional molecular data, but there are concerns about completeness and relevance of this data. We developed an approach for representing the organization of human cellular processes using pathways as the nodes in a network. Pathways represent spatial and temporal sets of context-dependent interactions, generating a high-level network when linked together, which incorporates contextual information without the need for molecular interaction data. Analysis of the pathway network revealed linked communities representing functional relationships, comparable to those found in molecular networks, including metabolism, signaling, immunity, and the cell cycle. We mapped a range of diseases onto this network and find that pathways associated with diseases tend to be functionally connected, highlighting the perturbed functions that result in disease phenotypes. We demonstrated that disease pathways cluster within the network. We then examined the distribution of cancer pathways and showed that cancer pathways tend to localize within the signaling, DNA processes and immune modules, although some cancer-associated nodes are found in other network regions. Altogether, we generated a high-confidence functional network, which avoids some of the shortcomings faced by conventional molecular models. Our representation provides an intuitive functional interpretation of cellular organization, which relies only on high-quality pathway and Gene Ontology data. The network is available at https://data.mendeley.com/datasets/3pbwkxjxg9/1.

Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary.

PubMed

Liu, Liang; Zhang, Jin; Rheindt, Frank E; Lei, Fumin; Qu, Yanhua; Wang, Yu; Zhang, Yu; Sullivan, Corwin; Nie, Wenhui; Wang, Jinhuan; Yang, Fengtang; Chen, Jinping; Edwards, Scott V; Meng, Jin; Wu, Shaoyuan

2017-08-29

The timing of the diversification of placental mammals relative to the Cretaceous-Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth-death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms.

Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2.

PubMed

Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik; Harvey, Jeremy N; Mulholland, Adrian J

2016-06-20

The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site, but this is not a prerequisite for reaction via either mechanism. Several active site residues play a role in the binding of mexiletine in the active site, including Thr124 and Phe226. This work reveals key details of the N-hydroxylation of mexiletine and further demonstrates that mechanistic studies using QM/MM methods are useful for understanding drug metabolism.

Chemistry of dense clumps near moving Herbig-Haro objects

NASA Astrophysics Data System (ADS)

Christie, H.; Viti, S.; Williams, D. A.; Girart, J. M.; Morata, O.

2011-09-01

Localized regions of enhanced emission from HCO+, NH3 and other species near Herbig-Haro objects (HHOs) have been interpreted as arising in a photochemistry stimulated by the HHO radiation on high-density quiescent clumps in molecular clouds. Static models of this process have been successful in accounting for the variety of molecular species arising ahead of the jet; however, recent observations show that the enhanced molecular emission is widespread along the jet as well as ahead. Hence, a realistic model must take into account the movement of the radiation field past the clump. It was previously unclear as to whether the short interaction time between the clump and the HHO in a moving source model would allow molecules such as HCO+ to reach high enough levels, and to survive for long enough to be observed. In this work we model a moving radiation source that approaches and passes a clump. The chemical picture is qualitatively unchanged by the addition of the moving source, strengthening the idea that enhancements are due to evaporation of molecules from dust grains. In addition, in the case of several molecules, the enhanced emission regions are longer lived. Some photochemically induced species, including methanol, are expected to maintain high abundances for ˜104 yr.

Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease.

PubMed

Zeynalzadeh, Monica; Tafazoli, Alireza; Aarabi, Azadeh; Moghaddassian, Morteza; Ashrafzadeh, Farah; Houshmand, Massoud; Taghehchian, Negin; Abbaszadegan, Mohammad Reza

2018-01-26

Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by dysfunction of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. The current study analyzed seven Iranian MSUD patients genetically and explored probable correlations between their genotype and phenotype. The panel of genes, including BCKDHA, BCKDHB and DBT, was evaluated, using routine the polymerase chain reaction (PCR)-sequencing method. In addition, protein modeling (homology and threading modeling) of the deduced novel mutations was performed. The resulting structures were then analyzed, using state-of-the-art bioinformatics tools to better understand the structural and functional effects caused by mutations. Seven mutations were detected in seven patients, including four novel pathogenic mutations in BCKDHA (c.1198delA, c.629C>T), BCKDHB (c.652C>T) and DBT (c.1150A>G) genes. Molecular modeling of the novel mutations revealed clear changes in the molecular energy levels and stereochemical traits of the modeled proteins, which may be indicative of strong correlations with the functional modifications of the genes. Structural deficiencies were compatible with the observed phenotypes. Any type of MSUD can show heterogeneous clinical manifestations in different ethnic groups. Comprehensive molecular investigations would be necessary for differential diagnosis.

The heuristic value of redundancy models of aging.

PubMed

Boonekamp, Jelle J; Briga, Michael; Verhulst, Simon

2015-11-01

Molecular studies of aging aim to unravel the cause(s) of aging bottom-up, but linking these mechanisms to organismal level processes remains a challenge. We propose that complementary top-down data-directed modelling of organismal level empirical findings may contribute to developing these links. To this end, we explore the heuristic value of redundancy models of aging to develop a deeper insight into the mechanisms causing variation in senescence and lifespan. We start by showing (i) how different redundancy model parameters affect projected aging and mortality, and (ii) how variation in redundancy model parameters relates to variation in parameters of the Gompertz equation. Lifestyle changes or medical interventions during life can modify mortality rate, and we investigate (iii) how interventions that change specific redundancy parameters within the model affect subsequent mortality and actuarial senescence. Lastly, as an example of data-directed modelling and the insights that can be gained from this, (iv) we fit a redundancy model to mortality patterns observed by Mair et al. (2003; Science 301: 1731-1733) in Drosophila that were subjected to dietary restriction and temperature manipulations. Mair et al. found that dietary restriction instantaneously reduced mortality rate without affecting aging, while temperature manipulations had more transient effects on mortality rate and did affect aging. We show that after adjusting model parameters the redundancy model describes both effects well, and a comparison of the parameter values yields a deeper insight in the mechanisms causing these contrasting effects. We see replacement of the redundancy model parameters by more detailed sub-models of these parameters as a next step in linking demographic patterns to underlying molecular mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

Petri net modelling of biological networks.

PubMed

Chaouiya, Claudine

2007-07-01

Mathematical modelling is increasingly used to get insights into the functioning of complex biological networks. In this context, Petri nets (PNs) have recently emerged as a promising tool among the various methods employed for the modelling and analysis of molecular networks. PNs come with a series of extensions, which allow different abstraction levels, from purely qualitative to more complex quantitative models. Noteworthily, each of these models preserves the underlying graph, which depicts the interactions between the biological components. This article intends to present the basics of the approach and to foster the potential role PNs could play in the development of the computational systems biology.

Molecular environmental geochemistry

NASA Astrophysics Data System (ADS)

O'Day, Peggy A.

1999-05-01

The chemistry, mobility, and bioavailability of contaminant species in the natural environment are controlled by reactions that occur in and among solid, aqueous, and gas phases. These reactions are varied and complex, involving changes in chemical form and mass transfer among inorganic, organic, and biochemical species. The field of molecular environmental geochemistry seeks to apply spectroscopic and microscopic probes to the mechanistic understanding of environmentally relevant chemical processes, particularly those involving contaminants and Earth materials. In general, empirical geochemical models have been shown to lack uniqueness and adequate predictive capability, even in relatively simple systems. Molecular geochemical tools, when coupled with macroscopic measurements, can provide the level of chemical detail required for the credible extrapolation of contaminant reactivity and bioavailability over ranges of temperature, pressure, and composition. This review focuses on recent advances in the understanding of molecular chemistry and reaction mechanisms at mineral surfaces and mineral-fluid interfaces spurred by the application of new spectroscopies and microscopies. These methods, such as synchrotron X-ray absorption and scattering techniques, vibrational and resonance spectroscopies, and scanning probe microscopies, provide direct chemical information that can elucidate molecular mechanisms, including element speciation, ligand coordination and oxidation state, structural arrangement and crystallinity on different scales, and physical morphology and topography of surfaces. Nonvacuum techniques that allow examination of reactions in situ (i.e., with water or fluids present) and in real time provide direct links between molecular structure and reactivity and measurements of kinetic rates or thermodynamic properties. Applications of these diverse probes to laboratory model systems have provided fundamental insight into inorganic and organic reactions at mineral surfaces and mineral-water interfaces. A review of recent studies employing molecular characterizations of soils, sediments, and biological samples from contaminated sites exemplifies the utility and benefits, as well as the challenge, of applying molecular probes to complicated natural materials. New techniques, technological advances, and the crossover of methods from other disciplines such as biochemistry and materials science promise better examination of environmental chemical processes in real time and at higher resolution, and will further the integration of molecular information into field-scale chemical and hydrologic models.

Carbohydrate-protein interactions: molecular modeling insights.

PubMed

Pérez, Serge; Tvaroška, Igor

2014-01-01

The article reviews the significant contributions to, and the present status of, applications of computational methods for the characterization and prediction of protein-carbohydrate interactions. After a presentation of the specific features of carbohydrate modeling, along with a brief description of the experimental data and general features of carbohydrate-protein interactions, the survey provides a thorough coverage of the available computational methods and tools. At the quantum-mechanical level, the use of both molecular orbitals and density-functional theory is critically assessed. These are followed by a presentation and critical evaluation of the applications of semiempirical and empirical methods: QM/MM, molecular dynamics, free-energy calculations, metadynamics, molecular robotics, and others. The usefulness of molecular docking in structural glycobiology is evaluated by considering recent docking- validation studies on a range of protein targets. The range of applications of these theoretical methods provides insights into the structural, energetic, and mechanistic facets that occur in the course of the recognition processes. Selected examples are provided to exemplify the usefulness and the present limitations of these computational methods in their ability to assist in elucidation of the structural basis underlying the diverse function and biological roles of carbohydrates in their dialogue with proteins. These test cases cover the field of both carbohydrate biosynthesis and glycosyltransferases, as well as glycoside hydrolases. The phenomenon of (macro)molecular recognition is illustrated for the interactions of carbohydrates with such proteins as lectins, monoclonal antibodies, GAG-binding proteins, porins, and viruses. © 2014 Elsevier Inc. All rights reserved.

Integral control of plant gravitropism through the interplay of hormone signaling and gene regulation.

PubMed

Rodrigo, Guillermo; Jaramillo, Alfonso; Blázquez, Miguel A

2011-08-17

The interplay between hormone signaling and gene regulatory networks is instrumental in promoting the development of living organisms. In particular, plants have evolved mechanisms to sense gravity and orient themselves accordingly. Here, we present a mathematical model that reproduces plant gravitropic responses based on known molecular genetic interactions for auxin signaling coupled with a physical description of plant reorientation. The model allows one to analyze the spatiotemporal dynamics of the system, triggered by an auxin gradient that induces differential growth of the plant with respect to the gravity vector. Our model predicts two important features with strong biological implications: 1), robustness of the regulatory circuit as a consequence of integral control; and 2), a higher degree of plasticity generated by the molecular interplay between two classes of hormones. Our model also predicts the ability of gibberellins to modulate the tropic response and supports the integration of the hormonal role at the level of gene regulation. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Exploring molecular genetics of bladder cancer: lessons learned from mouse models

PubMed Central

Ahmad, Imran; Sansom, Owen J.; Leung, Hing Y.

2012-01-01

Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies worldwide, causing considerable morbidity and mortality. It is unusual among the epithelial carcinomas because tumorigenesis can occur by two distinct pathways: low-grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS, whereas high-grade, muscle-invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma (RB). Over the past 20 years, a plethora of genetically engineered mouse (GEM) models of UCC have been developed, containing deletions or mutations of key tumour suppressor genes or oncogenes. In this review, we provide an up-to-date summary of these GEM models, analyse their flaws and weaknesses, discuss how they have advanced our understanding of UCC at the molecular level, and comment on their translational potential. We also highlight recent studies supporting a role for dysregulated Wnt signalling in UCC and the development of mouse models that recapitulate this dysregulation. PMID:22422829

First principle chemical kinetics in zeolites: the methanol-to-olefin process as a case study.

PubMed

Van Speybroeck, Veronique; De Wispelaere, Kristof; Van der Mynsbrugge, Jeroen; Vandichel, Matthias; Hemelsoet, Karen; Waroquier, Michel

2014-11-07

To optimally design next generation catalysts a thorough understanding of the chemical phenomena at the molecular scale is a prerequisite. Apart from qualitative knowledge on the reaction mechanism, it is also essential to be able to predict accurate rate constants. Molecular modeling has become a ubiquitous tool within the field of heterogeneous catalysis. Herein, we review current computational procedures to determine chemical kinetics from first principles, thus by using no experimental input and by modeling the catalyst and reacting species at the molecular level. Therefore, we use the methanol-to-olefin (MTO) process as a case study to illustrate the various theoretical concepts. This process is a showcase example where rational design of the catalyst was for a long time performed on the basis of trial and error, due to insufficient knowledge of the mechanism. For theoreticians the MTO process is particularly challenging as the catalyst has an inherent supramolecular nature, for which not only the Brønsted acidic site is important but also organic species, trapped in the zeolite pores, must be essentially present during active catalyst operation. All these aspects give rise to specific challenges for theoretical modeling. It is shown that present computational techniques have matured to a level where accurate enthalpy barriers and rate constants can be predicted for reactions occurring at a single active site. The comparison with experimental data such as apparent kinetic data for well-defined elementary reactions has become feasible as current computational techniques also allow predicting adsorption enthalpies with reasonable accuracy. Real catalysts are truly heterogeneous in a space- and time-like manner. Future theory developments should focus on extending our view towards phenomena occurring at longer length and time scales and integrating information from various scales towards a unified understanding of the catalyst. Within this respect molecular dynamics methods complemented with additional techniques to simulate rare events are now gradually making their entrance within zeolite catalysis. Recent applications have already given a flavor of the benefit of such techniques to simulate chemical reactions in complex molecular environments.

Modeling Complex Workflow in Molecular Diagnostics

PubMed Central

Gomah, Mohamed E.; Turley, James P.; Lu, Huimin; Jones, Dan

2010-01-01

One of the hurdles to achieving personalized medicine has been implementing the laboratory processes for performing and reporting complex molecular tests. The rapidly changing test rosters and complex analysis platforms in molecular diagnostics have meant that many clinical laboratories still use labor-intensive manual processing and testing without the level of automation seen in high-volume chemistry and hematology testing. We provide here a discussion of design requirements and the results of implementation of a suite of lab management tools that incorporate the many elements required for use of molecular diagnostics in personalized medicine, particularly in cancer. These applications provide the functionality required for sample accessioning and tracking, material generation, and testing that are particular to the evolving needs of individualized molecular diagnostics. On implementation, the applications described here resulted in improvements in the turn-around time for reporting of more complex molecular test sets, and significant changes in the workflow. Therefore, careful mapping of workflow can permit design of software applications that simplify even the complex demands of specialized molecular testing. By incorporating design features for order review, software tools can permit a more personalized approach to sample handling and test selection without compromising efficiency. PMID:20007844

Genomic signatures characterize leukocyte infiltration in myositis muscles.

PubMed

Zhu, Wei; Streicher, Katie; Shen, Nan; Higgs, Brandon W; Morehouse, Chris; Greenlees, Lydia; Amato, Anthony A; Ranade, Koustubh; Richman, Laura; Fiorentino, David; Jallal, Bahija; Greenberg, Steven A; Yao, Yihong

2012-11-21

Leukocyte infiltration plays an important role in the pathogenesis and progression of myositis, and is highly associated with disease severity. Currently, there is a lack of: efficacious therapies for myositis; understanding of the molecular features important for disease pathogenesis; and potential molecular biomarkers for characterizing inflammatory myopathies to aid in clinical development. In this study, we developed a simple model and predicted that 1) leukocyte-specific transcripts (including both protein-coding transcripts and microRNAs) should be coherently overexpressed in myositis muscle and 2) the level of over-expression of these transcripts should be correlated with leukocyte infiltration. We applied this model to assess immune cell infiltration in myositis by examining mRNA and microRNA (miRNA) expression profiles in muscle biopsies from 31 myositis patients and 5 normal controls. Several gene signatures, including a leukocyte index, type 1 interferon (IFN), MHC class I, and immunoglobulin signature, were developed to characterize myositis patients at the molecular level. The leukocyte index, consisting of genes predominantly associated with immune function, displayed strong concordance with pathological assessment of immune cell infiltration. This leukocyte index was subsequently utilized to differentiate transcriptional changes due to leukocyte infiltration from other alterations in myositis muscle. Results from this differentiation revealed biologically relevant differences in the relationship between the type 1 IFN pathway, miR-146a, and leukocyte infiltration within various myositis subtypes. Results indicate that a likely interaction between miR-146a expression and the type 1 IFN pathway is confounded by the level of leukocyte infiltration into muscle tissue. Although the role of miR-146a in myositis remains uncertain, our results highlight the potential benefit of deconvoluting the source of transcriptional changes in myositis muscle or other heterogeneous tissue samples. Taken together, the leukocyte index and other gene signatures developed in this study may be potential molecular biomarkers to help to further characterize inflammatory myopathies and aid in clinical development. These hypotheses need to be confirmed in separate and sufficiently powered clinical trials.

Functional proteomic analysis revels that the ethanol extract of Annona muricata L. induces liver cancer cell apoptosis through endoplasmic reticulum stress pathway.

PubMed

Liu, Na; Yang, Hua Li; Wang, Pu; Lu, Yu Cheng; Yang, Ying Juan; Wang, Lan; Lee, Shao Chin

2016-08-02

Annona muricata L. is used to treat cancer in some countries. Extracts of Annona muricata have been shown to cause apoptosis of various cancer cells in vitro, and inhibit tumor growth in vivo in animal models. However, the molecular mechanisms underlying its anti-cancer and apoptotic effects of the herb remain to be explored. The study investigated the molecular mechanisms underlying liver cancer cell apoptosis triggered by the ethanol extract of leaves of Annona muricata L. Liver cancer HepG2 cells were used as experimental model. MTT assay was employed to evaluate cell viability. Flow cytometry and TUNEL assays were performed to confirm apoptosis. We employed functional proteomic analysis to delineate molecular pathways underlying apoptosis triggered by the herbal extract. We showed that the extract was able to reduce viability and trigger apoptosis of the cancer cells. Proteomic analysis identified 14 proteins associated with the extract-elicited apoptosis, which included the increased expression levels of HSP70, GRP94 and DPI-related protein 5. Western blot analysis confirmed that the extract did up-regulated the protein levels of HSP70 and GRP94. Results from bioinformatic annotation pulled out two molecular pathways for the extract, which, notably, included endoplasmic reticulum (ER) stress which was evidenced by the up-regulation of HSP70, GRP94 and PDI-related protein 5. Further examinations of typical protein signaling events in ER stress using western blot analysis have shown that the extract up-regulated the phorsphorelation of PERK and eIF2α as well as the expression level of Bip and CHOP. Our results indicate that the ethanol extract of leaves of Annona muricata L. causes apoptosis of liver cancer cells through ER stress pathway, which supports the ethnomedicinal use of this herb as an alternative or complementary therapy for cancer. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Molecular Electronic Angular Motion Transducer Broad Band Self-Noise.

PubMed

Zaitsev, Dmitry; Agafonov, Vadim; Egorov, Egor; Antonov, Alexander; Shabalina, Anna

2015-11-20

Modern molecular electronic transfer (MET) angular motion sensors combine high technical characteristics with low cost. Self-noise is one of the key characteristics which determine applications for MET sensors. However, until the present there has not been a model describing the sensor noise in the complete operating frequency range. The present work reports the results of an experimental study of the self-noise level of such sensors in the frequency range of 0.01-200 Hz. Based on the experimental data, a theoretical model is developed. According to the model, self-noise is conditioned by thermal hydrodynamic fluctuations of the operating fluid flow in the frequency range of 0.01-2 Hz. At the frequency range of 2-100 Hz, the noise power spectral density has a specific inversely proportional dependence of the power spectral density on the frequency that could be attributed to convective processes. In the high frequency range of 100-200 Hz, the noise is conditioned by the voltage noise of the electronics module input stage operational amplifiers and is heavily reliant to the sensor electrical impedance. The presented results allow a deeper understanding of the molecular electronic sensor noise nature to suggest the ways to reduce it.

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

Kitagawa, Norihito; Oda, Mayuko; Nobutaka, I.

Although amitriptyline has gained attention as a potent local anesthetic, recent animal studies showed that it can cause irreversible neural impairment. We hypothesized that nerve membrane disruption caused by solubilization, a common detergent property, accounted for amitriptyline neurotoxicity. We used a two-phase approach to test our hypothesis. Firstly, we determined (1) the molecular aggregation concentration of amitriptyline (2) the concentration of amitriptyline that disrupts artificial lipid membranes and (3) the concentration of amitriptyline that causes hemolysis. Secondly, we compared these levels with neurotoxic concentrations determined from assessment in a rat model of spinal anesthesia using changes in cutaneous stimulus thresholdmore » (CST). Amitriptyline concentrations that caused molecular aggregation, model membrane disruption and hemolysis were 0.46%, 0.35% and 0.3%, respectively. Animal study showed a significant increase in CST at {>=} 0.3% of amitriptyline, indicating neurological impairment. Since amitriptyline caused model membrane disruption and hemolysis at the molecular aggregation concentration, solubilization plays a role in the destruction of artificial membranes and erythrocytes. Furthermore, these concentrations are also in good agreement with the minimum concentration causing neurological injury. Therefore, while additional studies, including histopathology, are necessary to clarify this observation, amitriptyline neurotoxicity appears to be associated with its detergent nature.« less

Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method.

PubMed

Zhang, Hua-xin; Xiong, Hang-xing; Li, Li-wei

2016-05-15

Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (ΔH(θ)) and entropy change (ΔS(θ)) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Förster's non-radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia.

PubMed

Lin, Hong; Magrane, Jordi; Clark, Elisia M; Halawani, Sarah M; Warren, Nathan; Rattelle, Amy; Lynch, David R

2017-12-19

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model. © 2017. Published by The Company of Biologists Ltd.

Spectral studies related to dissociation of HBr, HCl and BrO

NASA Technical Reports Server (NTRS)

Ginter, M. L.

1986-01-01

Concern over halogen catalyzed decomposition of O3 in the upper atmosphere has generated need for data on the atomic and molecular species X, HX and XO (where X is Cl and Br). Of special importance are Cl produced from freon decomposition and Cl and Br produced from natural processes and from other industrial and agricultural chemicals. Basic spectral data is provided on HCl, HBr, and BrO necessary to detect specific states and energy levels, to enable detailed modeling of the processes involving molecular dissociation, ionization, etc., and to help evaluate field experiments to check the validity of model calculations for these species in the upper atmosphere. Results contained in four published papers and two major spectral compilations are summarized together with other results obtained.