An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

DOE PAGES

Huang, Jing; Mei, Ye; König, Gerhard; ...

2017-01-24

Here in this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PADmore » energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R 2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other eleven solute molecules, while the PAD model has a much better performance with R 2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. Lastly, this suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.« less

An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches.

PubMed

Huang, Jing; Mei, Ye; König, Gerhard; Simmonett, Andrew C; Pickard, Frank C; Wu, Qin; Wang, Lee-Ping; MacKerell, Alexander D; Brooks, Bernard R; Shao, Yihan

2017-02-14

In this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PAD energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R 2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other 11 solute molecules, while the PAD model has a much better performance with R 2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. This suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.

An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

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

Huang, Jing; Mei, Ye; König, Gerhard

Here in this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PADmore » energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R 2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other eleven solute molecules, while the PAD model has a much better performance with R 2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. Lastly, this suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.« less

Cis-to- Trans Isomerization of Azobenzene Derivatives Studied with Transition Path Sampling and Quantum Mechanical/Molecular Mechanical Molecular Dynamics.

PubMed

Muždalo, Anja; Saalfrank, Peter; Vreede, Jocelyne; Santer, Mark

2018-04-10

Azobenzene-based molecular photoswitches are becoming increasingly important for the development of photoresponsive, functional soft-matter material systems. Upon illumination with light, fast interconversion between a more stable trans and a metastable cis configuration can be established resulting in pronounced changes in conformation, dipole moment or hydrophobicity. A rational design of functional photosensitive molecules with embedded azo moieties requires a thorough understanding of isomerization mechanisms and rates, especially the thermally activated relaxation. For small azo derivatives considered in the gas phase or simple solvents, Eyring's classical transition state theory (TST) approach yields useful predictions for trends in activation energies or corresponding half-life times of the cis isomer. However, TST or improved theories cannot easily be applied when the azo moiety is part of a larger molecular complex or embedded into a heterogeneous environment, where a multitude of possible reaction pathways may exist. In these cases, only the sampling of an ensemble of dynamic reactive trajectories (transition path sampling, TPS) with explicit models of the environment may reveal the nature of the processes involved. In the present work we show how a TPS approach can conveniently be implemented for the phenomenon of relaxation-isomerization of azobenzenes starting with the simple examples of pure azobenzene and a push-pull derivative immersed in a polar (DMSO) and apolar (toluene) solvent. The latter are represented explicitly at a molecular mechanical (MM) and the azo moiety at a quantum mechanical (QM) level. We demonstrate for the push-pull azobenzene that path sampling in combination with the chosen QM/MM scheme produces the expected change in isomerization pathway from inversion to rotation in going from a low to a high permittivity (explicit) solvent model. We discuss the potential of the simulation procedure presented for comparative calculation of

A Module Analysis Approach to Investigate Molecular Mechanism of TCM Formula: A Trial on Shu-feng-jie-du Formula

PubMed Central

Zhang, Fangbo; Tang, Shihuan; Liu, Xi; Gao, Yibo; Wang, Yanping

2013-01-01

At the molecular level, it is acknowledged that a TCM formula is often a complex system, which challenges researchers to fully understand its underlying pharmacological action. However, module detection technique developed from complex network provides new insight into systematic investigation of the mode of action of a TCM formula from the molecule perspective. We here proposed a computational approach integrating the module detection technique into a 2-class heterogeneous network (2-HN) which models the complex pharmacological system of a TCM formula. This approach takes three steps: construction of a 2-HN, identification of primary pharmacological units, and pathway analysis. We employed this approach to study Shu-feng-jie-du (SHU) formula, which aimed at discovering its molecular mechanism in defending against influenza infection. Actually, four primary pharmacological units were identified from the 2-HN for SHU formula and further analysis revealed numbers of biological pathways modulated by the four pharmacological units. 24 out of 40 enriched pathways that were ranked in top 10 corresponding to each of the four pharmacological units were found to be involved in the process of influenza infection. Therefore, this approach is capable of uncovering the mode of action underlying a TCM formula via module analysis. PMID:24376467

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

PubMed

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

2016-09-13

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

Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks.

PubMed

Shen, Lin; Wu, Jingheng; Yang, Weitao

2016-10-11

Molecular dynamics simulation with multiscale quantum mechanics/molecular mechanics (QM/MM) methods is a very powerful tool for understanding the mechanism of chemical and biological processes in solution or enzymes. However, its computational cost can be too high for many biochemical systems because of the large number of ab initio QM calculations. Semiempirical QM/MM simulations have much higher efficiency. Its accuracy can be improved with a correction to reach the ab initio QM/MM level. The computational cost on the ab initio calculation for the correction determines the efficiency. In this paper we developed a neural network method for QM/MM calculation as an extension of the neural-network representation reported by Behler and Parrinello. With this approach, the potential energy of any configuration along the reaction path for a given QM/MM system can be predicted at the ab initio QM/MM level based on the semiempirical QM/MM simulations. We further applied this method to three reactions in water to calculate the free energy changes. The free-energy profile obtained from the semiempirical QM/MM simulation is corrected to the ab initio QM/MM level with the potential energies predicted with the constructed neural network. The results are in excellent accordance with the reference data that are obtained from the ab initio QM/MM molecular dynamics simulation or corrected with direct ab initio QM/MM potential energies. Compared with the correction using direct ab initio QM/MM potential energies, our method shows a speed-up of 1 or 2 orders of magnitude. It demonstrates that the neural network method combined with the semiempirical QM/MM calculation can be an efficient and reliable strategy for chemical reaction simulations.

A Practical Quantum Mechanics Molecular Mechanics Method for the Dynamical Study of Reactions in Biomolecules.

PubMed

Mendieta-Moreno, Jesús I; Marcos-Alcalde, Iñigo; Trabada, Daniel G; Gómez-Puertas, Paulino; Ortega, José; Mendieta, Jesús

2015-01-01

Quantum mechanics/molecular mechanics (QM/MM) methods are excellent tools for the modeling of biomolecular reactions. Recently, we have implemented a new QM/MM method (Fireball/Amber), which combines an efficient density functional theory method (Fireball) and a well-recognized molecular dynamics package (Amber), offering an excellent balance between accuracy and sampling capabilities. Here, we present a detailed explanation of the Fireball method and Fireball/Amber implementation. We also discuss how this tool can be used to analyze reactions in biomolecules using steered molecular dynamics simulations. The potential of this approach is shown by the analysis of a reaction catalyzed by the enzyme triose-phosphate isomerase (TIM). The conformational space and energetic landscape for this reaction are analyzed without a priori assumptions about the protonation states of the different residues during the reaction. The results offer a detailed description of the reaction and reveal some new features of the catalytic mechanism. In particular, we find a new reaction mechanism that is characterized by the intramolecular proton transfer from O1 to O2 and the simultaneous proton transfer from Glu 165 to C2. Copyright © 2015 Elsevier Inc. All rights reserved.

A quantum-mechanics molecular-mechanics scheme for extended systems

NASA Astrophysics Data System (ADS)

Hunt, Diego; Sanchez, Veronica M.; Scherlis, Damián A.

2016-08-01

We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

A quantum-mechanics molecular-mechanics scheme for extended systems.

PubMed

Hunt, Diego; Sanchez, Veronica M; Scherlis, Damián A

2016-08-24

We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

Modelling approaches for evaluating multiscale tendon mechanics

PubMed Central

Fang, Fei; Lake, Spencer P.

2016-01-01

Tendon exhibits anisotropic, inhomogeneous and viscoelastic mechanical properties that are determined by its complicated hierarchical structure and varying amounts/organization of different tissue constituents. Although extensive research has been conducted to use modelling approaches to interpret tendon structure–function relationships in combination with experimental data, many issues remain unclear (i.e. the role of minor components such as decorin, aggrecan and elastin), and the integration of mechanical analysis across different length scales has not been well applied to explore stress or strain transfer from macro- to microscale. This review outlines mathematical and computational models that have been used to understand tendon mechanics at different scales of the hierarchical organization. Model representations at the molecular, fibril and tissue levels are discussed, including formulations that follow phenomenological and microstructural approaches (which include evaluations of crimp, helical structure and the interaction between collagen fibrils and proteoglycans). Multiscale modelling approaches incorporating tendon features are suggested to be an advantageous methodology to understand further the physiological mechanical response of tendon and corresponding adaptation of properties owing to unique in vivo loading environments. PMID:26855747

Exploring Protein-Peptide Recognition Pathways Using a Supervised Molecular Dynamics Approach.

PubMed

Salmaso, Veronica; Sturlese, Mattia; Cuzzolin, Alberto; Moro, Stefano

2017-04-04

Peptides have gained increased interest as therapeutic agents during recent years. The high specificity and relatively low toxicity of peptide drugs derive from their extremely tight binding to their targets. Indeed, understanding the molecular mechanism of protein-peptide recognition has important implications in the fields of biology, medicine, and pharmaceutical sciences. Even if crystallography and nuclear magnetic resonance are offering valuable atomic insights into the assembling of the protein-peptide complexes, the mechanism of their recognition and binding events remains largely unclear. In this work we report, for the first time, the use of a supervised molecular dynamics approach to explore the possible protein-peptide binding pathways within a timescale reduced up to three orders of magnitude compared with classical molecular dynamics. The better and faster understating of the protein-peptide recognition pathways could be very beneficial in enlarging the applicability of peptide-based drug design approaches in several biotechnological and pharmaceutical fields. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Mechanics: Illustrations of Its Application.

ERIC Educational Resources Information Center

Cox, Philip J.

1982-01-01

The application of molecular mechanics (a nonquantum mechanical method for solving problems concerning molecular geometries) to calculate force fields for n-butane and cyclohexane is discussed. Implications regarding the stable conformations of the example molecules are also discussed. (Author/SK)

Features of Knowledge Building in Biology: Understanding Undergraduate Students' Ideas about Molecular Mechanisms

ERIC Educational Resources Information Center

Southard, Katelyn; Wince, Tyler; Meddleton, Shanice; Bolger, Molly S.

2016-01-01

Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections…

Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

PubMed Central

Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

2011-01-01

Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

Application of high level wavefunction methods in quantum mechanics/molecular mechanics hybrid schemes.

PubMed

Mata, Ricardo A

2010-05-21

In this Perspective, several developments in the field of quantum mechanics/molecular mechanics (QM/MM) approaches are reviewed. Emphasis is placed on the use of correlated wavefunction theory and new state of the art methods for the treatment of large quantum systems. Until recently, computational chemistry approaches to large/complex chemical problems have seldom been considered as tools for quantitative predictions. However, due to the tremendous development of computational resources and new quantum chemical methods, it is nowadays possible to describe the electronic structure of biomolecules at levels of theory which a decade ago were only possible for system sizes of up to 20 atoms. These advances are here outlined in the context of QM/MM. The article concludes with a short outlook on upcoming developments and possible bottlenecks for future applications.

Artificial Bee Colony Optimization of Capping Potentials for Hybrid Quantum Mechanical/Molecular Mechanical Calculations.

PubMed

Schiffmann, Christoph; Sebastiani, Daniel

2011-05-10

We present an algorithmic extension of a numerical optimization scheme for analytic capping potentials for use in mixed quantum-classical (quantum mechanical/molecular mechanical, QM/MM) ab initio calculations. Our goal is to minimize bond-cleavage-induced perturbations in the electronic structure, measured by means of a suitable penalty functional. The optimization algorithm-a variant of the artificial bee colony (ABC) algorithm, which relies on swarm intelligence-couples deterministic (downhill gradient) and stochastic elements to avoid local minimum trapping. The ABC algorithm outperforms the conventional downhill gradient approach, if the penalty hypersurface exhibits wiggles that prevent a straight minimization pathway. We characterize the optimized capping potentials by computing NMR chemical shifts. This approach will increase the accuracy of QM/MM calculations of complex biomolecules.

Water Assisted Reaction Mechanism of OH- with CCl4 in Aqueous Solution - Hybrid Quantum Mechanical and Molecular Mechanics Investigation

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

Chen, Jie; Yin, Hongyun; Wang, Dunyou

2013-02-20

The OH- (H2O) + CCl4 reaction in aqueous solution was investigated using the combined quantum mechanical and molecular mechanics approach. The reaction mechanism of OH- (H2O) + CCl4 consists of two concerted steps - formation of OH- in the favorable attack conformation via the proton transfer process, and the nucleophilic substitution process in which the newly formed OH- attacks the CCl4. The free energy activation barrier is 38.2 kcal/mol at CCSD(T)/MM level of theory for this reaction, which is about 10.3 kcal/mol higher than that of the direct nucleophilic substitution mechanism of the OH- + CCl4 reaction in aqueous solution.

Effects of Maternal Obesity on Fetal Programming: Molecular Approaches

PubMed Central

Neri, Caterina; Edlow, Andrea G.

2016-01-01

Maternal obesity has become a worldwide epidemic. Obesity and a high-fat diet have been shown to have deleterious effects on fetal programming, predisposing offspring to adverse cardiometabolic and neurodevelopmental outcomes. Although large epidemiological studies have shown an association between maternal obesity and adverse outcomes for offspring, the underlying mechanisms remain unclear. Molecular approaches have played a key role in elucidating the mechanistic underpinnings of fetal malprogramming in the setting of maternal obesity. These approaches include, among others, characterization of epigenetic modifications, microRNA expression, the gut microbiome, the transcriptome, and evaluation of specific mRNA expression via quantitative reverse transcription polmerase chain reaction (RT-qPCR) in fetuses and offspring of obese females. This work will review the data from animal models and human fluids/cells regarding the effects of maternal obesity on fetal and offspring neurodevelopment and cardiometabolic outcomes, with a particular focus on molecular approaches. PMID:26337113

Holistic systems biology approaches to molecular mechanisms of human helper T cell differentiation to functionally distinct subsets.

PubMed

Chen, Z; Lönnberg, T; Lahesmaa, R

2013-08-01

Current knowledge of helper T cell differentiation largely relies on data generated from mouse studies. To develop therapeutical strategies combating human diseases, understanding the molecular mechanisms how human naïve T cells differentiate to functionally distinct T helper (Th) subsets as well as studies on human differentiated Th cell subsets is particularly valuable. Systems biology approaches provide a holistic view of the processes of T helper differentiation, enable discovery of new factors and pathways involved and generation of new hypotheses to be tested to improve our understanding of human Th cell differentiation and immune-mediated diseases. Here, we summarize studies where high-throughput systems biology approaches have been exploited to human primary T cells. These studies reveal new factors and signalling pathways influencing T cell differentiation towards distinct subsets, important for immune regulation. Such information provides new insights into T cell biology and into targeting immune system for therapeutic interventions. © 2013 John Wiley & Sons Ltd.

Axis of evil: molecular mechanisms of cancer metastasis.

PubMed

Bogenrieder, Thomas; Herlyn, Meenhard

2003-09-29

Although the genetic basis of tumorigenesis may vary greatly between different cancer types, the cellular and molecular steps required for metastasis are similar for all cancer cells. Not surprisingly, the molecular mechanisms that propel invasive growth and metastasis are also found in embryonic development, and to a less perpetual extent, in adult tissue repair processes. It is increasingly apparent that the stromal microenvironment, in which neoplastic cells develop, profoundly influences many steps of cancer progression, including the ability of tumor cells to metastasize. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. In this review, we summarize recent advances in understanding the molecular mechanisms that govern this frequently lethal metastatic progression along an axis from primary tumor to regional lymph nodes to distant organ sites. Affected proteins include growth factor signaling molecules, chemokines, cell-cell adhesion molecules (cadherins, integrins) as well as extracellular proteases (matrix metalloproteinases). We then discuss promising new therapeutic approaches targeting the microenvironment. We note, however, that there is still too little knowledge of how the many events are coordinated and integrated by the cancer cell, with conspiratorial help by the stromal component of the host. Before drug development can proceed with a legitimate chance of success, significant gaps in basic knowledge need to be filled.

The molecular mechanics of eukaryotic translation.

PubMed

Kapp, Lee D; Lorsch, Jon R

2004-01-01

Great advances have been made in the past three decades in understanding the molecular mechanics underlying protein synthesis in bacteria, but our understanding of the corresponding events in eukaryotic organisms is only beginning to catch up. In this review we describe the current state of our knowledge and ignorance of the molecular mechanics underlying eukaryotic translation. We discuss the mechanisms conserved across the three kingdoms of life as well as the important divergences that have taken place in the pathway.

Report on the Symposium “Molecular Mechanisms Involved in Neurodegeneration”

PubMed Central

Pentón-Rol, Giselle; Cervantes-Llanos, Majel

2018-01-01

The prevalence of neurodegenerative diseases is currently a major concern in public health because of the lack of neuroprotective and neuroregenerative drugs. The symposium on Molecular Mechanisms Involved in Neurodegeneration held in Varadero, Cuba, updated the participants on the basic mechanisms of neurodegeneration, on the different approaches for drug discovery, and on early research results on therapeutic approaches for the treatment of neurodegenerative diseases. Alzheimer’s disease and in silico research were covered by many of the presentations in the symposium, under the umbrella of the “State of the Art of Non-clinical Models for Neurodegenerative Diseases” International Congress, held from 20 to 24 June 2017. This paper summarizes the highlights of the symposium. PMID:29346273

Molecular Dynamics Simulations with Quantum Mechanics/Molecular Mechanics and Adaptive Neural Networks.

PubMed

Shen, Lin; Yang, Weitao

2018-03-13

Direct molecular dynamics (MD) simulation with ab initio quantum mechanical and molecular mechanical (QM/MM) methods is very powerful for studying the mechanism of chemical reactions in a complex environment but also very time-consuming. The computational cost of QM/MM calculations during MD simulations can be reduced significantly using semiempirical QM/MM methods with lower accuracy. To achieve higher accuracy at the ab initio QM/MM level, a correction on the existing semiempirical QM/MM model is an attractive idea. Recently, we reported a neural network (NN) method as QM/MM-NN to predict the potential energy difference between semiempirical and ab initio QM/MM approaches. The high-level results can be obtained using neural network based on semiempirical QM/MM MD simulations, but the lack of direct MD samplings at the ab initio QM/MM level is still a deficiency that limits the applications of QM/MM-NN. In the present paper, we developed a dynamic scheme of QM/MM-NN for direct MD simulations on the NN-predicted potential energy surface to approximate ab initio QM/MM MD. Since some configurations excluded from the database for NN training were encountered during simulations, which may cause some difficulties on MD samplings, an adaptive procedure inspired by the selection scheme reported by Behler [ Behler Int. J. Quantum Chem. 2015 , 115 , 1032 ; Behler Angew. Chem., Int. Ed. 2017 , 56 , 12828 ] was employed with some adaptions to update NN and carry out MD iteratively. We further applied the adaptive QM/MM-NN MD method to the free energy calculation and transition path optimization on chemical reactions in water. The results at the ab initio QM/MM level can be well reproduced using this method after 2-4 iteration cycles. The saving in computational cost is about 2 orders of magnitude. It demonstrates that the QM/MM-NN with direct MD simulations has great potentials not only for the calculation of thermodynamic properties but also for the characterization of

Elucidating the molecular mechanisms underlying cellular response to biophysical cues using synthetic biology approaches

PubMed Central

Denning, Denise; Roos, Wouter H.

2016-01-01

ABSTRACT The use of synthetic surfaces and materials to influence and study cell behavior has vastly progressed our understanding of the underlying molecular mechanisms involved in cellular response to physicochemical and biophysical cues. Reconstituting cytoskeletal proteins and interfacing them with a defined microenvironment has also garnered deep insight into the engineering mechanisms existing within the cell. This review presents recent experimental findings on the influence of several parameters of the extracellular environment on cell behavior and fate, such as substrate topography, stiffness, chemistry and charge. In addition, the use of synthetic environments to measure physical properties of the reconstituted cytoskeleton and their interaction with intracellular proteins such as molecular motors is discussed, which is relevant for understanding cell migration, division and structural integrity, as well as intracellular transport. Insight is provided regarding the next steps to be taken in this interdisciplinary field, in order to achieve the global aim of artificially directing cellular response. PMID:27266767

Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches.

PubMed

Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D

2015-01-01

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

Adult soft tissue sarcomas: conventional therapies and molecularly targeted approaches.

PubMed

Mocellin, Simone; Rossi, Carlo R; Brandes, Alba; Nitti, Donato

2006-02-01

The therapeutic approach to soft tissue sarcomas (STS) has evolved over the past two decades based on the results from randomized controlled trials, which are guiding physicians in the treatment decision-making process. Despite significant improvements in the control of local disease, a significant number of patients ultimately die of recurrent/metastatic disease following radical surgery due to a lack of effective adjuvant treatments. In addition, the characteristic chemoresistance of STS has compromised the therapeutic value of conventional antineoplastic agents in cases of unresectable advanced/metastatic disease. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with STS. Recent advances in STS biology are paving the way to the development of molecularly targeted therapeutic strategies, the efficacy of which relies not only on the knowledge of the molecular mechanisms underlying cancer development/progression but also on the personalization of the therapeutic regimen according to the molecular features of individual tumours. In this work, we review the state-of-the-art of conventional treatments for STS and summarize the most promising findings in the development of molecularly targeted therapeutic approaches.

Molecular approaches to epidemiology and clinical aspects of malaria.

PubMed

Brown, G V; Beck, H P; Molyneux, M; Marsh, K

2000-10-01

Malaria is a problem of global importance, responsible for 1-2 million deaths per year, mainly in African children, as well as considerable morbidity manifested as severe anaemia and encephalopathy in young children. Fundamental to the development of new tools for malaria control in humans is an increased understanding of key features of malaria infection, such as the diversity of outcome in different individuals, the understanding of different manifestations of the disease and of the mechanisms of immunity that allow clinical protection in the face of ongoing low-grade infection (concomitant immunity or premunition). Here, Graham Brown and colleagues review some of the ways in which molecular approaches might be used to increase our understanding of the epidemiology and clinical manifestations of malaria, as discussed at the Molecular Approaches to Malaria conference (MAM2000), Lorne, Australia, 2-5 February 2000.

Molecular mechanics of tropocollagen-hydroxyapatite biomaterials

NASA Astrophysics Data System (ADS)

Dubey, Devendra Kumar

Hard biomaterials such as bone, dentin, and nacre show remarkable mechanical performance and serve as inspiration for development of next generation of composite materials with high strength and toughness. Such materials have primarily an organic phase (e.g. tropocollagen (TC) or chitin) and a mineral phase (e.g. hydroxyapatite (HAP) or aragonite) arranged in a staggered arrangement at nanoscopic length scales. Interfacial interactions between the organic phases and the mineral phases and structural effects arising due to the staggered and hierarchical arrangements are identified to be the two most important determinants for high mechanical performance of such biomaterials. Effects of these determinants in such biomaterials are further intertwined with factors such as loading configuration, chemical environment, mineral crystal shape, and residue sequences in polymer chains. Atomistic modeling is a desired approach to investigate such sub nanoscale issues as experimental techniques for investigations at such small scale are still in nascent stage. For this purpose, explicit three dimensional (3D) molecular dynamics (MD) and ab initio MD simulations of quasi-static mechanical deformations of idealized Tropocollagen-Hydroxyapatite (TC-HAP) biomaterials with distinct interfacial arrangements and different loading configurations are performed. Focus is on developing insights into the molecular level mechanics of TC-HAP biomaterials at fundamental lengthscale with emphasis on interface phenomenon. Idealized TC-HAP atomistic models are analyzed for their mechanical strength and fracture failure behavior from the viewpoint of interfacial interactions between TC and HAP and associated molecular mechanisms. In particular, study focuses on developing an understanding of factors such as role of interfacial structural arrangement, hierarchical structure design, influence of water, effect of changes in HAP crystal shape, and mutations in TC molecule on the mechanical strength

Anisotropy induced Kondo splitting in a mechanically stretched molecular junction: A first-principles based study

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

Wang, Xiaoli; Hou, Dong, E-mail: houdong@ustc.edu.cn; Zheng, Xiao, E-mail: xz58@ustc.edu.cn

2016-01-21

The magnetic anisotropy and Kondo phenomena in a mechanically stretched magnetic molecular junction are investigated by combining the density functional theory (DFT) and hierarchical equations of motion (HEOM) approach. The system is comprised of a magnetic complex Co(tpy–SH){sub 2} sandwiched between adjacent gold electrodes, which is mechanically stretched in experiments done by Parks et al. [Science 328, 1370 (2010)]. The electronic structure and mechanical property of the stretched system are investigated via the DFT calculations. The HEOM approach is then employed to characterize the Kondo resonance features, based on the Anderson impurity model parameterized from the DFT results. It ismore » confirmed that the ground state prefers the S = 1 local spin state. The structural properties, the magnetic anisotropy, and corresponding Kondo peak splitting in the axial stretching process are systematically evaluated. The results reveal that the strong electron correlations and the local magnetic properties of the molecule magnet are very sensitive to structural distortion. This work demonstrates that the combined DFT+HEOM approach could be useful in understanding and designing mechanically controlled molecular junctions.« less

A Hierarchical Approach to Fracture Mechanics

NASA Technical Reports Server (NTRS)

Saether, Erik; Taasan, Shlomo

2004-01-01

Recent research conducted under NASA LaRC's Creativity and Innovation Program has led to the development of an initial approach for a hierarchical fracture mechanics. This methodology unites failure mechanisms occurring at different length scales and provides a framework for a physics-based theory of fracture. At the nanoscale, parametric molecular dynamic simulations are used to compute the energy associated with atomic level failure mechanisms. This information is used in a mesoscale percolation model of defect coalescence to obtain statistics of fracture paths and energies through Monte Carlo simulations. The mathematical structure of predicted crack paths is described using concepts of fractal geometry. The non-integer fractal dimension relates geometric and energy measures between meso- and macroscales. For illustration, a fractal-based continuum strain energy release rate is derived for inter- and transgranular fracture in polycrystalline metals.

Usher syndrome (sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches.

PubMed

Bonnet, Crystel; El-Amraoui, Aziz

2012-02-01

Usher syndrome (USH) is the most prevalent cause of hereditary deafness-blindness in humans. In this review, we pinpoint new insights regarding the molecular mechanisms defective in this syndrome, its molecular diagnosis and prospective therapies. Animal models wherein USH proteins were targeted at different maturation stages of the auditory hair cells have been engineered, shedding new light on the development and functioning of the hair bundle, the sound receptive structure. Improved protocols and guidelines for early molecular diagnosis of USH (USH genotyping microarrays, otochips and complete Sanger sequencing of the 366 coding exons of identified USH genes) have been developed. Approaches to alleviate or cure hearing and visual impairments have been initiated, leading to various degrees of functional rescuing. Whereas the mechanisms underlying hearing impairment in USH patients are being unraveled, showing in particular that USH1 proteins are involved in the shaping of the hair bundle and the functioning of the mechanoelectrical transduction machinery, the mechanisms underlying the retinal defects are still unclear. Efforts to improve clinical diagnosis have been successful. Yet, despite some encouraging results, further development of therapeutic approaches is necessary to ultimately treat this dual sensory defect.

Molecular mechanisms of liver preconditioning

PubMed Central

Alchera, Elisa; Dal Ponte, Caterina; Imarisio, Chiara; Albano, Emanuele; Carini, Rita

2010-01-01

Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed by reperfusion protects tissues against damage induced by subsequent I/R. This process known as ischemic preconditioning (IP) depends upon intrinsic cytoprotective systems whose activation can inhibit the progression of irreversible tissue damage. Compared to other organs, liver IP has additional features as it reduces inflammation and promotes hepatic regeneration. Our present understanding of the molecular mechanisms involved in liver IP is still largely incomplete. Experimental studies have shown that the protective effects of liver IP are triggered by the release of adenosine and nitric oxide and the subsequent activation of signal networks involving protein kinases such as phosphatidylinositol 3-kinase, protein kinase C δ/ε and p38 MAP kinase, and transcription factors such as signal transducer and activator of transcription 3, nuclear factor-κB and hypoxia-inducible factor 1. This article offers an overview of the molecular events underlying the preconditioning effects in the liver and points to the possibility of developing pharmacological approaches aimed at activating the intrinsic protective systems in patients undergoing liver surgery. PMID:21182220

Phosphorylation Reaction in cAPK Protein Kinase - Free Energy Quantum Mechanic/Molecular Mechanics Simulations.

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

Valiev, Marat; Yang, Jie; Adams, Joseph

2007-11-29

Protein kinases catalyze the transfer of the γ-phosphoryl group from ATP, a key regulatory process governing signalling pathways in eukaryotic cells. The structure of the active site in these enzymes is highly conserved implying common catalytic mechanism. In this work we investigate the reaction process in cAPK protein kinase (PKA) using a combined quantum mechanics and molecular mechanics approach. The novel computational features of our work include reaction pathway determination with nudged elastic band methodology and calculation of free energy profiles of the reaction process taking into account finite temperature fluctuations of the protein environment. We find that the transfermore » of the γ-phosphoryl group in the protein environment is an exothermic reaction with the reaction barrier of 15 kcal/mol.« less

Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds.

PubMed

Tungsukruthai, Sucharat; Petpiroon, Nalinrat; Chanvorachote, Pithi

2018-05-01

Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. The development of cancer molecular knowledge has surpassed the novel concept of cancer biology and unraveled principle targets for anticancer drug developments and treatment strategies. Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. Clearly, natural product-derived compounds have since long been recognized as an important source for anticancer drugs, several of which have been shown to have promising anti-metastasis activities by suppressing key molecular features supporting such cell aggressiveness. This review provides the essential details of breast cancer, the molecular-based insights into metastasis, as well as the effects and mechanisms of potential compounds for breast cancer therapeutic approaches. As the abilities of cancer cells to invade and metastasize are addressed as the hallmarks of cancer, compounds possessing anti-metastatic effects, together with their defined molecular drug action could benefit the development of new drugs as well as treatment strategies. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology

PubMed Central

Amemiya, Takahiro; Honma, Masashi; Kariya, Yoshiaki; Ghosh, Samik; Kitano, Hiroaki; Kurachi, Yoshihisa; Fujita, Ken-ichi; Sasaki, Yasutsuna; Homma, Yukio; Abernethy, Darrel R; Kume, Haruki; Suzuki, Hiroshi

2015-01-01

Background/Objectives: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. Methods: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. Results: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. Conclusions: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions. PMID:28725458

An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach.

PubMed

Cenini, Giovanna; Fiorini, Ada; Sultana, Rukhsana; Perluigi, Marzia; Cai, Jian; Klein, Jon B; Head, Elizabeth; Butterfield, D Allan

2014-11-01

Down syndrome (DS) is one of the most common causes of intellectual disability, owing to trisomy of all or part of chromosome 21. DS is also associated with the development of Alzheimer disease (AD) neuropathology after the age of 40 years. To better clarify the cellular and metabolic pathways that could contribute to the differences in DS brain, in particular those involved in the onset of neurodegeneration, we analyzed the frontal cortex of DS subjects with or without significant AD pathology in comparison with age-matched controls, using a proteomics approach. Proteomics represents an advantageous tool to investigate the molecular mechanisms underlying the disease. From these analyses, we investigated the effects that age, DS, and AD neuropathology could have on protein expression levels. Our results show overlapping and independent molecular pathways (including energy metabolism, oxidative damage, protein synthesis, and autophagy) contributing to DS, to aging, and to the presence of AD pathology in DS. Investigation of pathomechanisms involved in DS with AD may provide putative targets for therapeutic approaches to slow the development of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Molecular imaging and the unification of multilevel mechanisms and data in medical physics.

PubMed

Nikiforidis, George C; Sakellaropoulos, George C; Kagadis, George C

2008-08-01

Molecular imaging (MI) constitutes a recently developed approach of imaging, where modalities and agents have been reinvented and used in novel combinations in order to expose and measure biologic processes occurring at molecular and cellular levels. It is an approach that bridges the gap between modalities acquiring data from high (e.g., computed tomography, magnetic resonance imaging, and positron-emitting isotopes) and low (e.g., PCR, microarrays) levels of a biological organization. While data integration methodologies will lead to improved diagnostic and prognostic performance, interdisciplinary collaboration, triggered by MI, will result in a better perception of the underlying biological mechanisms. Toward the development of a unifying theory describing these mechanisms, medical physicists can formulate new hypotheses, provide the physical constraints bounding them, and consequently design appropriate experiments. Their new scientific and working environment calls for interventions in their syllabi to educate scientists with enhanced capabilities for holistic views and synthesis.

Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

PubMed

Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

2015-08-01

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by

Insights into the catalytic mechanism of dehydrogenase BphB: A quantum mechanics/molecular mechanics study.

PubMed

Zhang, Ruiming; Shi, Xiangli; Sun, Yanhui; Zhang, Qingzhu; Wang, Wenxing

2018-05-17

The present study delineated the dehydrogenation mechanism of cis-2,3-dihydro-2,3-dihydroxybiphenyl (2,3-DDBPH) and cis-2,3-dihydro-2,3-dihydroxy-4,4'-dichlorobiphenyl (2,3-DD-4,4'-DBPH) by Pandoraea pnomenusa strain B-356 cis-2,3-dihydro-2,3-dihydroxybiphenyl dehydrogenase (BphB) in atomistic detail. The enzymatic process was investigated by a combined quantum mechanics/molecular mechanics (QM/MM) approach. Five different snapshots were extracted and calculated, which revealed that the Boltzmann-weighted average barriers of 2,3-DDBPH and 2,3-DD-4,4'-DBPH dehydrogenation processes are 10.7 and 11.5 kcal mol -1 , respectively. The established dehydrogenation mechanism provides new insight into the degradation processes of other chlorinated 2,3-DDBPH. In addition to Asn115, Ser142, and Lys149, the importance of Ile 89, Asn143, Pro184, Met 187, Thr189, and Lue 191 during the dehydrogenation process of 2,3-DDBPH and 2,3-DD-4,4'-DBPH were also highlighted to search for promising mutation targets for improving the catalytic efficiency of BphB. Copyright © 2018. Published by Elsevier Ltd.

Molecular Mechanics

PubMed Central

Vanommeslaeghe, Kenno; Guvench, Olgun; MacKerell, Alexander D.

2014-01-01

Molecular Mechanics (MM) force fields are the methods of choice for protein simulations, which are essential in the study of conformational flexibility. Given the importance of protein flexibility in drug binding, MM is involved in most if not all Computational Structure-Based Drug Discovery (CSBDD) projects. This section introduces the reader to the fundamentals of MM, with a special emphasis on how the target data used in the parametrization of force fields determine their strengths and weaknesses. Variations and recent developments such as polarizable force fields are discussed. The section ends with a brief overview of common force fields in CSBDD. PMID:23947650

A theoretical study of the molecular mechanism of the GAPDH Trypanosoma cruzi enzyme involving iodoacetate inhibitor

NASA Astrophysics Data System (ADS)

Carneiro, Agnaldo Silva; Lameira, Jerônimo; Alves, Cláudio Nahum

2011-10-01

The glyceraldehyde-3-phosphate dehydrogenase enzyme (GAPDH) is an important biological target for the development of new chemotherapeutic agents against Chagas disease. In this Letter, the inhibition mechanism of GAPDH involving iodoacetate (IAA) inhibitor was studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and molecular dynamic simulations. Analysis of the potential energy surface and potential of mean force show that the covalent attachment of IAA inhibitor to the active site of the enzyme occurs as a concerted process. In addition, the energy terms decomposition shows that NAD+ plays an important role in stabilization of the reagents and transition state.

Molecular Mechanics: The Method and Its Underlying Philosophy.

ERIC Educational Resources Information Center

Boyd, Donald B.; Lipkowitz, Kenny B.

1982-01-01

Molecular mechanics is a nonquantum mechanical method for solving problems concerning molecular geometries and energy. Methodology based on: the principle of combining potential energy functions of all structural features of a particular molecule into a total force field; derivation of basic equations; and use of available computer programs is…

The molecular mechanism of plant gravitropism.

PubMed

Wu, Di; Huang, Lin-zhou; Gao, Jin; Wang, Yong-hong

2016-07-20

Gravity is an important environmental factor that regulates plant growth and morphogenesis. In response to gravity stimulus, plants can set the optimum angle between the organs and the gravity vector. Plant gravitropism is divided into four sequential steps, including gravity perception, signal transduction, asymmetrical distribution of auxin, and organ curvature. In recent years, large numbers of mutants with defective gravitropism have been identified and genes involved in the regulation of gravitropism have been functionally characterized. In particular, progress has been achieved on elucidating the molecular mechanisms of gravity perception and asymmetrical distribution of auxin. As one of the most important strategies for plant to adapt environmental changes, gravitropism is also involved in the regulation of rice plant architecture and grain yield through modulating rice tiller angle. Therefore, the investigation of plant gravitropism not only contributes to decipher the regulatory mechanisms of plant growth and development, but also helps to guide the genetic improvement of crop architecture. However, the molecular mechanisms and regulatory network of gravitropism remain to be elusive. In this review, we focus on recent progress on elucidating molecular mechanisms underlying gravitropism and its involvement in regulating rice tiller angle, which is an important agronomic trait that determines rice plant architecture and thus grain yields.

Geochemical Reaction Mechanism Discovery from Molecular Simulation

DOE PAGES

Stack, Andrew G.; Kent, Paul R. C.

2014-11-10

Methods to explore reactions using computer simulation are becoming increasingly quantitative, versatile, and robust. In this review, a rationale for how molecular simulation can help build better geochemical kinetics models is first given. We summarize some common methods that geochemists use to simulate reaction mechanisms, specifically classical molecular dynamics and quantum chemical methods and discuss their strengths and weaknesses. Useful tools such as umbrella sampling and metadynamics that enable one to explore reactions are discussed. Several case studies wherein geochemists have used these tools to understand reaction mechanisms are presented, including water exchange and sorption on aqueous species and mineralmore » surfaces, surface charging, crystal growth and dissolution, and electron transfer. The impact that molecular simulation has had on our understanding of geochemical reactivity are highlighted in each case. In the future, it is anticipated that molecular simulation of geochemical reaction mechanisms will become more commonplace as a tool to validate and interpret experimental data, and provide a check on the plausibility of geochemical kinetic models.« less

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.

The control of the controller: molecular mechanisms for robust perfect adaptation and temperature compensation.

PubMed

Ni, Xiao Yu; Drengstig, Tormod; Ruoff, Peter

2009-09-02

Organisms have the property to adapt to a changing environment and keep certain components within a cell regulated at the same level (homeostasis). "Perfect adaptation" describes an organism's response to an external stepwise perturbation by regulating some of its variables/components precisely to their original preperturbation values. Numerous examples of perfect adaptation/homeostasis have been found, as for example, in bacterial chemotaxis, photoreceptor responses, MAP kinase activities, or in metal-ion homeostasis. Two concepts have evolved to explain how perfect adaptation may be understood: In one approach (robust perfect adaptation), the adaptation is a network property, which is mostly, but not entirely, independent of rate constant values; in the other approach (nonrobust perfect adaptation), a fine-tuning of rate constant values is needed. Here we identify two classes of robust molecular homeostatic mechanisms, which compensate for environmental variations in a controlled variable's inflow or outflow fluxes, and allow for the presence of robust temperature compensation. These two classes of homeostatic mechanisms arise due to the fact that concentrations must have positive values. We show that the concept of integral control (or integral feedback), which leads to robust homeostasis, is associated with a control species that has to work under zero-order flux conditions and does not necessarily require the presence of a physico-chemical feedback structure. There are interesting links between the two identified classes of homeostatic mechanisms and molecular mechanisms found in mammalian iron and calcium homeostasis, indicating that homeostatic mechanisms may underlie similar molecular control structures.

Spiers Memorial Lecture. Molecular mechanics and molecular electronics.

PubMed

Beckman, Robert; Beverly, Kris; Boukai, Akram; Bunimovich, Yuri; Choi, Jang Wook; DeIonno, Erica; Green, Johnny; Johnston-Halperin, Ezekiel; Luo, Yi; Sheriff, Bonnie; Stoddart, Fraser; Heath, James R

2006-01-01

We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits.

Formation mechanism and mechanics of dip-pen nanolithography using molecular dynamics.

PubMed

Wu, Cheng-Da; Fang, Te-Hua; Lin, Jen-Fin

2010-03-02

Molecular dynamics simulations are used to investigate the mechanisms of molecular transference, pattern formation, and mechanical behavior in the dip-pen nanolithography (DPN) process. The effects of deposition temperature were studied using molecular trajectories, the meniscus characteristic, surface absorbed energy, and pattern formation analysis. At the first transferred stage (at the initial indentation depth), the conformation of SAM molecules lies almost on the substrate surface. The molecules start to stand on the substrate due to the pull and drag forces at the second transferred stage (after the tip is pulled up). According to the absorbed energy behavior, the second transferred stage has larger transferred amounts and the transfer rate is strongly related to temperature. When molecules were deposited at low temperature (e.g., room temperature), the pattern shape was more highly concentrated. The pattern shape at high temperatures expanded and the area increased because of good molecular diffusion.

Ocular diseases: immunological and molecular mechanisms.

PubMed

Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

2016-01-01

Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation.

Use of Nonequilibrium Work Methods to Compute Free Energy Differences Between Molecular Mechanical and Quantum Mechanical Representations of Molecular Systems.

PubMed

Hudson, Phillip S; Woodcock, H Lee; Boresch, Stefan

2015-12-03

Carrying out free energy simulations (FES) using quantum mechanical (QM) Hamiltonians remains an attractive, albeit elusive goal. Renewed efforts in this area have focused on using "indirect" thermodynamic cycles to connect "low level" simulation results to "high level" free energies. The main obstacle to computing converged free energy results between molecular mechanical (MM) and QM (ΔA(MM→QM)), as recently demonstrated by us and others, is differences in the so-called "stiff" degrees of freedom (e.g., bond stretching) between the respective energy surfaces. Herein, we demonstrate that this problem can be efficiently circumvented using nonequilibrium work (NEW) techniques, i.e., Jarzynski's and Crooks' equations. Initial applications of computing ΔA(NEW)(MM→QM), for blocked amino acids alanine and serine as well as to generate butane's potentials of mean force via the indirect QM/MM FES method, showed marked improvement over traditional FES approaches.

Molecular mechanisms in lithium-associated renal disease: a systematic review.

PubMed

Rej, Soham; Pira, Shamira; Marshe, Victoria; Do, André; Elie, Dominique; Looper, Karl J; Herrmann, Nathan; Müller, Daniel J

2016-11-01

Lithium is an essential treatment in bipolar disorder and treatment-resistant depression; however, its use has been limited by concerns regarding its renal adverse effects. An improved understanding of potential molecular mechanisms can help develop prevention and treatment strategies for lithium-associated renal disease. We conducted a systematic literature search using MEDLINE, Embase, and PsychINFO including English-language original research articles published prior to November 2015 that specifically investigated lithium's effects on nephrogenic diabetes insipidus (NDI) and chronic kidney disease (CKD), using molecular markers. From a total of 3510 records, 71 pre-clinical studies and two relevant clinical studies were identified. Molecular alterations were reported in calcium signaling, inositol monophosphate, extracellular-regulated, prostaglandin, sodium/solute transport, G-protein-coupled receptors, nitric oxide, vasopressin/aquaporin, and inflammation-related pathways in lithium-associated renal disease. The majority of studies found that these mechanisms were implicated in NDI, while few studies had examined CKD. Future studies will have to focus on (1) validating the present findings in human subjects and (2) examining CKD, which is the most clinically relevant lithium-associated renal effect. This will improve our understanding of lithium's biological effects, as well as inform a personalized medicine approach, which could lead to safer lithium prescribing and less renal adverse events.

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

Quantum Mechanics/Molecular Mechanics Study of the Sialyltransferase Reaction Mechanism.

PubMed

Hamada, Yojiro; Kanematsu, Yusuke; Tachikawa, Masanori

2016-10-11

The sialyltransferase is an enzyme that transfers the sialic acid moiety from cytidine 5'-monophospho-N-acetyl-neuraminic acid (CMP-NeuAc) to the terminal position of glycans. To elucidate the catalytic mechanism of sialyltransferase, we explored the potential energy surface along the sialic acid transfer reaction coordinates by the hybrid quantum mechanics/molecular mechanics method on the basis of the crystal structure of sialyltransferase CstII. Our calculation demonstrated that CstII employed an S N 1-like reaction mechanism via the formation of a short-lived oxocarbenium ion intermediate. The computational barrier height was 19.5 kcal/mol, which reasonably corresponded with the experimental reaction rate. We also found that two tyrosine residues (Tyr156 and Tyr162) played a vital role in stabilizing the intermediate and the transition states by quantum mechanical interaction with CMP.

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.

New insights into the molecular mechanism of intestinal fatty acid absorption

PubMed Central

Wang, Tony Y.; Liu, Min; Portincasa, Piero; Wang, David Q.-H.

2013-01-01

Background Dietary fat is the most important energy source of all the nutrients. Fatty acids, stored as triacylglycerols in the body, are an important reservoir of stored energy and derive primarily from animal fats and vegetable oils. Design Although the molecular mechanisms for the transport of water-insoluble amphipathic fatty acids across cell membranes have been debated for many years, it is now believed that the dominant means for intestinal fatty acid uptake is via membrane-associated fatty acid-binding proteins, i.e., fatty acid transporters on the apical membrane of enterocytes. Results These findings indicate that intestinal fatty acid absorption is a multistep process that is regulated by multiple genes at the enterocyte level, and intestinal fatty acid absorption efficiency could be determined by factors influencing intraluminal fatty acid molecules across the brush border membrane of enterocytes. To facilitate research on intestinal, hepatic and plasma triacylglycerol metabolism, it is imperative to establish standard protocols for precisely and accurately measuring the efficiency of intestinal fatty acid absorption in humans and animal models. In this review, we will discuss the chemical structure and nomenclature of fatty acids and summarize recent progress in investigating the molecular mechanisms underlying the intestinal absorption of fatty acids, with a particular emphasis on the physical-chemistry of intestinal lipids and the molecular physiology of intestinal fatty acid transporters. Conclusions A better understanding of the molecular mechanism of intestinal fatty acid absorption should lead to novel approaches to the treatment and the prevention of fatty acid-related metabolic diseases that are prevalent worldwide. PMID:24102389

A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host–Pathogen Interaction Networks

PubMed Central

Wu, Chia-Chou; Chen, Bor-Sen

2016-01-01

Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host–pathogen dynamic interaction networks. The consideration of host–pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host–pathogen molecular interaction networks, and consequent inferences of the host–pathogen relationship could be translated into biomedical applications. PMID:26881892

A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host-Pathogen Interaction Networks.

PubMed

Wu, Chia-Chou; Chen, Bor-Sen

2016-01-01

Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host-pathogen dynamic interaction networks. The consideration of host-pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host-pathogen molecular interaction networks, and consequent inferences of the host-pathogen relationship could be translated into biomedical applications.

Predicting cancer-relevant proteins using an improved molecular similarity ensemble approach.

PubMed

Zhou, Bin; Sun, Qi; Kong, De-Xin

2016-05-31

In this study, we proposed an improved algorithm for identifying proteins relevant to cancer. The algorithm was named two-layer molecular similarity ensemble approach (TL-SEA). We applied TL-SEA to analyzing the correlation between anticancer compounds (against cell lines K562, MCF7 and A549) and active compounds against separate target proteins listed in BindingDB. Several associations between cancer types and related proteins were revealed using this chemoinformatics approach. An analysis of the literature showed that 26 of 35 predicted proteins were correlated with cancer cell proliferation, apoptosis or differentiation. Additionally, interactions between proteins in BindingDB and anticancer chemicals were also predicted. We discuss the roles of the most important predicted proteins in cancer biology and conclude that TL-SEA could be a useful tool for inferring novel proteins involved in cancer and revealing underlying molecular mechanisms.

Ocular diseases: immunological and molecular mechanisms

PubMed Central

Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

2016-01-01

Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation. PMID:27275439

A Review of Enhanced Sampling Approaches for Accelerated Molecular Dynamics

NASA Astrophysics Data System (ADS)

Tiwary, Pratyush; van de Walle, Axel

Molecular dynamics (MD) simulations have become a tool of immense use and popularity for simulating a variety of systems. With the advent of massively parallel computer resources, one now routinely sees applications of MD to systems as large as hundreds of thousands to even several million atoms, which is almost the size of most nanomaterials. However, it is not yet possible to reach laboratory timescales of milliseconds and beyond with MD simulations. Due to the essentially sequential nature of time, parallel computers have been of limited use in solving this so-called timescale problem. Instead, over the years a large range of statistical mechanics based enhanced sampling approaches have been proposed for accelerating molecular dynamics, and accessing timescales that are well beyond the reach of the fastest computers. In this review we provide an overview of these approaches, including the underlying theory, typical applications, and publicly available software resources to implement them.

Next-Generation of Allergen-Specific Immunotherapies: Molecular Approaches.

PubMed

Curin, Mirela; Khaitov, Musa; Karaulov, Alexander; Namazova-Baranova, Leyla; Campana, Raffaela; Garib, Victoria; Valenta, Rudolf

2018-06-09

The aim of this article is to discuss how allergen-specific immunotherapy (AIT) can be improved through molecular approaches. We provide a summary of next-generation molecular AIT approaches and of their clinical evaluation. Furthermore, we discuss the potential of next generation molecular AIT forms for the treatment of severe manifestations of allergy and mention possible future molecular strategies for the secondary and primary prevention of allergy. AIT has important advantages over symptomatic forms of allergy treatment but its further development is limited by the quality of the therapeutic antigen preparations which are derived from natural allergen sources. The field of allergy diagnosis is currently undergoing a dramatic improvement through the use of molecular testing with defined, mainly recombinant allergens which allows high-resolution diagnosis. Several studies demonstrate that molecular testing in early childhood can predict the development of symptomatic allergy later on in life. Clinical studies indicate that molecular AIT approaches have the potential to improve therapy of allergic diseases and may be used as allergen-specific forms of secondary and eventually primary prevention for allergy.

Cellular and molecular investigations of the adhesion and mechanics of Listeria monocytogenes

NASA Astrophysics Data System (ADS)

Eskhan, Asma Omar

Atomic force microscopy has been used to quantify the adherence and mechanical properties of an array of L. monocytogenes strains and their surface biopolymers. First, eight L. monocytogenes strains that represented the two major lineages of the species were compared for their adherence and mechanics at cellular and molecular levels. Our results indicated that strains of lineage' II were characterized by higher adhesion and Young's moduli, longer and more rigid surface biopolymers and lower specific and nonspecific forces when compared to lineage' I strains. Additionally, adherence and mechanical properties of eight L. monocytogenes epidemic and environmental strains were probed. Our results pointed to that environmental and epidemic strains representative of a given lineage were similar in their adherence and mechanical properties when investigated at a cellular level. However, when the molecular properties of the strains were considered, epidemic strains were characterized by higher specific and nonspecific forces, shorter, denser and more flexible biopolymers compared to environmental strains. Second, the role of environmental pH conditions of growth on the adhesion and mechanics of a pathogenic L. monocytogenes EGDe was investigated. Our results pointed to a transition in the adhesion energies for cells cultured at pH 7. In addition, when the types of molecular forces that govern the adhesion were quantified using Poisson statistical approach and using a new proposed method, specific hydrogen-bond energies dominated the bacterial adhesion process. Such a finding is instrumental to researchers designing methods to control bacterial adhesion. Similarly, bacterial cells underwent a transition in their mechanical properties. We have shown that cells cultured at pH 7 were the most rigid compared to those cultured in lower or higher pH conditions of growth. Due to transitions observed in adherence and mechanics when cells were cultured at pH 7, we hypothesized that

Simulation with quantum mechanics/molecular mechanics for drug discovery.

PubMed

Barbault, Florent; Maurel, François

2015-10-01

Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

Simulation with quantum mechanics/molecular mechanics for drug discovery.

PubMed

Barbault, Florent; Maurel, François

2015-08-08

Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. Areas covered: In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. Expert opinion: QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

Molecular mechanisms of ionic liquid cytotoxicity probed by an integrated experimental and computational approach

NASA Astrophysics Data System (ADS)

Yoo, Brian; Jing, Benxin; Jones, Stuart E.; Lamberti, Gary A.; Zhu, Yingxi; Shah, Jindal K.; Maginn, Edward J.

2016-02-01

Ionic liquids (ILs) are salts that remain liquid down to low temperatures, and sometimes well below room temperature. ILs have been called “green solvents” because of their extraordinarily low vapor pressure and excellent solvation power, but ecotoxicology studies have shown that some ILs exhibit greater toxicity than traditional solvents. A fundamental understanding of the molecular mechanisms responsible for IL toxicity remains elusive. Here we show that one mode of IL toxicity on unicellular organisms is driven by swelling of the cell membrane. Cytotoxicity assays, confocal laser scanning microscopy, and molecular simulations reveal that IL cations nucleate morphological defects in the microbial cell membrane at concentrations near the half maximal effective concentration (EC50) of several microorganisms. Cytotoxicity increases with increasing alkyl chain length of the cation due to the ability of the longer alkyl chain to more easily embed in, and ultimately disrupt, the cell membrane.

Molecular mechanisms of ionic liquid cytotoxicity probed by an integrated experimental and computational approach

PubMed Central

Yoo, Brian; Jing, Benxin; Jones, Stuart E.; Lamberti, Gary A.; Zhu, Yingxi; Shah, Jindal K.; Maginn, Edward J.

2016-01-01

Ionic liquids (ILs) are salts that remain liquid down to low temperatures, and sometimes well below room temperature. ILs have been called “green solvents” because of their extraordinarily low vapor pressure and excellent solvation power, but ecotoxicology studies have shown that some ILs exhibit greater toxicity than traditional solvents. A fundamental understanding of the molecular mechanisms responsible for IL toxicity remains elusive. Here we show that one mode of IL toxicity on unicellular organisms is driven by swelling of the cell membrane. Cytotoxicity assays, confocal laser scanning microscopy, and molecular simulations reveal that IL cations nucleate morphological defects in the microbial cell membrane at concentrations near the half maximal effective concentration (EC50) of several microorganisms. Cytotoxicity increases with increasing alkyl chain length of the cation due to the ability of the longer alkyl chain to more easily embed in, and ultimately disrupt, the cell membrane. PMID:26831599

Molecular mechanisms of protein aggregation from global fitting of kinetic models.

PubMed

Meisl, Georg; Kirkegaard, Julius B; Arosio, Paolo; Michaels, Thomas C T; Vendruscolo, Michele; Dobson, Christopher M; Linse, Sara; Knowles, Tuomas P J

2016-02-01

The elucidation of the molecular mechanisms by which soluble proteins convert into their amyloid forms is a fundamental prerequisite for understanding and controlling disorders that are linked to protein aggregation, such as Alzheimer's and Parkinson's diseases. However, because of the complexity associated with aggregation reaction networks, the analysis of kinetic data of protein aggregation to obtain the underlying mechanisms represents a complex task. Here we describe a framework, using quantitative kinetic assays and global fitting, to determine and to verify a molecular mechanism for aggregation reactions that is compatible with experimental kinetic data. We implement this approach in a web-based software, AmyloFit. Our procedure starts from the results of kinetic experiments that measure the concentration of aggregate mass as a function of time. We illustrate the approach with results from the aggregation of the β-amyloid (Aβ) peptides measured using thioflavin T, but the method is suitable for data from any similar kinetic experiment measuring the accumulation of aggregate mass as a function of time; the input data are in the form of a tab-separated text file. We also outline general experimental strategies and practical considerations for obtaining kinetic data of sufficient quality to draw detailed mechanistic conclusions, and the procedure starts with instructions for extensive data quality control. For the core part of the analysis, we provide an online platform (http://www.amylofit.ch.cam.ac.uk) that enables robust global analysis of kinetic data without the need for extensive programming or detailed mathematical knowledge. The software automates repetitive tasks and guides users through the key steps of kinetic analysis: determination of constraints to be placed on the aggregation mechanism based on the concentration dependence of the aggregation reaction, choosing from several fundamental models describing assembly into linear aggregates and

Features of Knowledge Building in Biology: Understanding Undergraduate Students’ Ideas about Molecular Mechanisms

PubMed Central

Southard, Katelyn; Wince, Tyler; Meddleton, Shanice; Bolger, Molly S.

2016-01-01

Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning. PMID:26931398

Cell and molecular mechanisms behind diet-induced hypothalamic inflammation and obesity.

PubMed

Ávalos, Yenniffer; Kerr, Bredford; Maliqueo, Manuel; Dorfman, Mauricio

2018-04-12

Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus, a key regulator of energy homeostasis. Current studies have revealed the involvement of different cell types as well as cell and molecular mechanisms that contribute to diet-induced hypothalamic inflammation (DIHI) and DIO. Since the discovery that high-fat diet and saturated fatty acids (SFAs) increase the expression of hypothalamic cytokines prior to weight gain, research has focused on understanding the cellular and molecular mechanisms underlying these changes, and what the role of inflammation in the obesity pathogenesis. Recent studies have proposed that the inhibition of proinflammatory pathways in microglia and astrocytes is sufficient to protect against DIHI and prevent obesity. In addition, impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to DIHI and DIO. Interestingly, a sexual dimorphism has been found during DIO in hypothalamic inflammation, glial activation and metabolic diseases, and recent data support an important role of sex steroids in DIHI. These new exciting findings uncover novel obesity pathogenic mechanisms and provide targets to develop therapeutic approaches. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Systematic study of imidazoles inhibiting IDO1 via the integration of molecular mechanics and quantum mechanics calculations.

PubMed

Zou, Yi; Wang, Fang; Wang, Yan; Guo, Wenjie; Zhang, Yihua; Xu, Qiang; Lai, Yisheng

2017-05-05

Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as an attractive target for cancer immunotherapy. To rationalize the detailed interactions between IDO1 and its inhibitors at the atomic level, an integrated computational approach by combining molecular mechanics and quantum mechanics methods was employed in this report. Specifically, the binding modes of 20 inhibitors was initially investigated using the induced fit docking (IFD) protocol, which outperformed other two docking protocols in terms of correctly predicting ligand conformations. Secondly, molecular dynamics (MD) simulations and MM/PBSA free energy calculations were employed to determine the dynamic binding process and crucial residues were confirmed through close contact analysis, hydrogen-bond analysis and binding free energy decomposition calculations. Subsequent quantum mechanics and nonbonding interaction analysis were carried out to provide in-depth explanations on the critical role of those key residues, and Arg231 and 7-propionate of the heme group were major contributors to ligand binding, which lowed a great amount of interaction energy. We anticipate that these findings will be valuable for enzymatic studies and rational drug design. Copyright © 2017. Published by Elsevier Masson SAS.

Toward molecular mechanism of xenon anesthesia: a link to studies of xenon complexes with small aromatic molecules.

PubMed

Andrijchenko, Natalya N; Ermilov, Alexander Yu; Khriachtchev, Leonid; Räsänen, Markku; Nemukhin, Alexander V

2015-03-19

The present study illustrates the steps toward understanding molecular mechanism of xenon anesthesia by focusing on a link to the structures and spectra of intermolecular complexes of xenon with small aromatic molecules. A primary cause of xenon anesthesia is attributed to inhibition of N-methyl-D-aspartate (NMDA) receptors by an unknown mechanism. Following the results of quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) calculations we report plausible xenon action sites in the ligand binding domain of the NMDA receptor, which are due to interaction of xenon atoms with aromatic amino-acid residues. We rely in these calculations on computational protocols adjusted in combined experimental and theoretical studies of intermolecular complexes of xenon with phenol. Successful reproduction of vibrational shifts in molecular species upon complexation with xenon measured in low-temperature matrices allowed us to select a proper functional form in density functional theory (DFT) approach for use in QM subsystems, as well as to calibrate force field parameters for MD simulations. The results of molecular modeling show that xenon atoms can compete with agonists for a place in the corresponding protein cavity, thus indicating their active role in anesthetic action.

Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design

PubMed Central

2011-01-01

4-Aminopiperidines are a variety of therapeutic agents that are extensively metabolized by cytochrome P450s with CYP3A4 as a major isoform catalyzing their N-dealkylation reaction. However, its catalytic mechanism has not been fully elucidated in a molecular interaction level. Here, we applied theoretical approaches including the molecular mechanics-based docking to study the binding patterns and quantum mechanics-based reactivity calculations. They were supported by the experimental human liver microsomal clearance and P450 isoform phenotyping data. Our results herein suggested that the molecular interactions between substrates and CYP3A4 active site residues are essential for the N-dealkylation of 4-aminopiperidines. We also found that the serine 119 residue of CYP3A4 may serve as a key hydrogen-bonding partner to interact with the 4-amino groups of the studied drugs. The reactivity of the side chain α-carbon hydrogens drives the direction of catalysis as well. As a result, structure-based drug design approaches look promising to guide drug discovery programs into the optimized drug metabolism space. PMID:21841964

Structural distributions from single-molecule measurements as a tool for molecular mechanics

PubMed Central

Hanson, Jeffrey A.; Brokaw, Jason; Hayden, Carl C.; Chu, Jhih-Wei; Yang, Haw

2011-01-01

A mechanical view provides an attractive alternative for predicting the behavior of complex systems since it circumvents the resource-intensive requirements of atomistic models; however, it remains extremely challenging to characterize the mechanical responses of a system at the molecular level. Here, the structural distribution is proposed to be an effective means to extracting the molecular mechanical properties. End-to-end distance distributions for a series of short poly-L-proline peptides with the sequence PnCG3K-biotin (n = 8, 12, 15 and 24) were used to experimentally illustrate this new approach. High-resolution single-molecule Förster-type resonance energy transfer (FRET) experiments were carried out and the conformation-resolving power was characterized and discussed in the context of the conventional constant-time binning procedure for FRET data analysis. It was shown that the commonly adopted theoretical polymer models—including the worm-like chain, the freely jointed chain, and the self-avoiding chain—could not be distinguished by the averaged end-to-end distances, but could be ruled out using the molecular details gained by conformational distribution analysis because similar polymers of different sizes could respond to external forces differently. Specifically, by fitting the molecular conformational distribution to a semi-flexible polymer model, the effective persistence lengths for the series of short poly-L-proline peptides were found to be size-dependent with values of ~190 Å, ~67 Å, ~51 Å, and ~76 Å for n = 8, 12, 15, and 24, respectively. A comprehensive computational modeling was carried out to gain further insights for this surprising discovery. It was found that P8 exists as the extended all-trans isomaer whereas P12 and P15 predominantly contained one proline residue in the cis conformation. P24 exists as a mixture of one-cis (75%) and two-cis (25%) isomers where each isomer contributes to an experimentally resolvable

Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies.

PubMed

Marie, Pierre J

2015-04-01

Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury.

PubMed

van Niekerk, Erna A; Tuszynski, Mark H; Lu, Paul; Dulin, Jennifer N

2016-02-01

Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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.

Molecular mechanisms of ionic liquid cytotoxicity probed by an integrated experimental and computational approach

DOE PAGES

Yoo, Brian; Jing, Benxin; Jones, Stuart E.; ...

2016-02-02

Ionic liquids (ILs) are salts that remain liquid down to low temperatures, and sometimes well below room temperature. ILs have been called “green solvents” because of their extraordinarily low vapor pressure and excellent solvation power, but ecotoxicology studies have shown that some ILs exhibit greater toxicity than traditional solvents. A fundamental understanding of the molecular mechanisms responsible for IL toxicity remains elusive. Here we show that one mode of IL toxicity on unicellular organisms is driven by swelling of the cell membrane. Cytotoxicity assays, confocal laser scanning microscopy, and molecular simulations reveal that IL cations nucleate morphological defects in themore » microbial cell membrane at concentrations near the half maximal effective concentration (EC50) of several microorganisms. Lastly, cytotoxicity increases with increasing alkyl chain length of the cation due to the ability of the longer alkyl chain to more easily embed in, and ultimately disrupt, the cell membrane.« less

New insights into the molecular mechanism of intestinal fatty acid absorption.

PubMed

Wang, Tony Y; Liu, Min; Portincasa, Piero; Wang, David Q-H

2013-11-01

Dietary fat is one of the most important energy sources of all the nutrients. Fatty acids, stored as triacylglycerols (also called triglycerides) in the body, are an important reservoir of stored energy and derived primarily from animal fats and vegetable oils. Although the molecular mechanisms for the transport of water-insoluble amphipathic fatty acids across cell membranes have been debated for many years, it is now believed that the dominant means for intestinal fatty acid uptake is via membrane-associated fatty acid-binding proteins, that is, fatty acid transporters on the apical membrane of enterocytes. These findings indicate that intestinal fatty acid absorption is a multistep process that is regulated by multiple genes at the enterocyte level, and intestinal fatty acid absorption efficiency could be determined by factors influencing intraluminal fatty acid molecules across the brush border membrane of enterocytes. To facilitate research on intestinal, hepatic and plasma triacylglycerol metabolism, it is imperative to establish standard protocols for precisely and accurately measuring the efficiency of intestinal fatty acid absorption in humans and animal models. In this review, we will discuss the chemical structure and nomenclature of fatty acids and summarize recent progress in investigating the molecular mechanisms underlying the intestinal absorption of fatty acids, with a particular emphasis on the physical chemistry of intestinal lipids and the molecular physiology of intestinal fatty acid transporters. A better understanding of the molecular mechanism of intestinal fatty acid absorption should lead to novel approaches to the treatment and the prevention of fatty acid-related metabolic diseases that are prevalent worldwide. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

PubMed Central

Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E.

2011-01-01

Pavlovian fear conditioning is a useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Together, this research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals, and potentially for understanding fear related disorders, such as PTSD and phobias. PMID:22036561

Molecular mechanisms of fear learning and memory.

PubMed

Johansen, Joshua P; Cain, Christopher K; Ostroff, Linnaea E; LeDoux, Joseph E

2011-10-28

Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

[Neonatal hyperbilirubinemia and molecular mechanisms of jaundice].

PubMed

Jirsa, M; Sticová, E

2013-07-01

The introductory summarises the classical path of heme degradation and classification of jaundice. Subsequently, a description of neonatal types of jaundice is given, known as Crigler Najjar, Gilberts, DubinJohnson and Rotor syndromes, emphasising the explanation of the molecular mechanisms of these metabolic disorders. Special attention is given to a recently discovered molecular mechanism of the Rotor syndrome. The mechanism is based on the inability of the liver to retrospectively uptake the conjugated bilirubin fraction primarily excreted into the blood, not bile. A reduced ability of the liver to uptake the conjugated bilirubin contributes to the development of hyperbilirubinemia in common disorders of the liver and bile ducts and to the toxicity of xenobiotics and drugs using transport proteins for conjugated bilirubin.

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

PubMed Central

Tezcan, Gulcin; Tunca, Berrin; Ak, Secil; Cecener, Gulsah; Egeli, Unal

2016-01-01

Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach. PMID:26798439

Molecular pathogenesis and mechanisms of thyroid cancer

PubMed Central

Xing, Mingzhao

2013-01-01

Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer. PMID:23429735

Molecular Mechanisms of Right Ventricular Failure

PubMed Central

Reddy, Sushma; Bernstein, Daniel

2015-01-01

An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, as the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV vs. LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure vs. the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics. PMID:26527692

Towards a mechanism-based approach to pain diagnosis

PubMed Central

Vardeh, Daniel

2016-01-01

three steps: pain state, pain mechanism and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as one of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is both consistent with and an extension of the AAPT. PMID:27586831

Exploring the molecular mechanism of karrikins and strigolactones.

PubMed

Scaffidi, Adrian; Waters, Mark T; Bond, Charles S; Dixon, Kingsley W; Smith, Steven M; Ghisalberti, Emilio L; Flematti, Gavin R

2012-06-01

Karrikins and strigolactones are novel plant growth regulators that contain similar molecular features, but very little is known about how they elicit responses in plants. A tentative molecular mechanism has previously been proposed involving a Michael-type addition for both compounds. Through structure-activity studies with karrikins, we now propose an alternative mechanism for karrikin and strigolactone mode of action that involves hydrolysis of the butenolide ring. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

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.

[Molecular mechanisms of neurotransmission].

PubMed

Nagatsu, T

2000-12-01

Neurotransmission is regulated by neurotransmitters at the synapses in the neuronal circuits. Main neurotransmitters are classified into the groups of amino acids, amines, purines, peptides, and nitric oxide. In principle, neurotransmitters except peptides are synthesized in the presynaptic neuroterminals from the precursors by the synthesizing enzymes, stored in the synaptic vesicles, released by exocytosis into the synaptic cleft, combined with the postsynaptic membrane receptors, and induce a series of signal transduction to produce acute, short-term, or long-term physiological effects. Termination of the neurotransmission is carried out either by re-uptake into presynaptic nerve terminals through plasma membrane transporters and storage into synaptic vesicles through vesicular transporters or by degradation through metabolizing enzymes (acetylcholine and peptides). Almost all genes related to neurotransmitters have been cloned and the structures of the genes and the protein products have been characterized. Molecular mechanisms of neurotransmission have been elucidated by mouse molecular genetics such as transgenic or knockout mice. Over-expression of human tyrosine hydroxylase (TH). the rate-limiting enzyme of catecholamine synthesis, in transgenic mice (Kaneda et al, Neuron 6, 583-584, 1991) or conversion of norepinephrine neurons to epinephrine neurons (Kobayashi et al, Proc Natl Acad Sci USA 89, 1631-1635, 1992) does not significantly change the phenotype due to compensatory mechanisms such as receptor down-regulation. In contrast, TH (-/-) mutant mice die at perinatal period due to heart failure caused by norepinephrine deficiency in the sympathetic neurons (Kobayashi et al, J Biol Chem 270, 27235-27243, 1995). TH (+/-) mice show a partial decrease in norepinephrine and a modest memory impairment (Kobayashi et al, J Neurosci 20, 2418-2426, 2000). One problem with adult phenotype in transgenic or knockout mice is that mutations cause the confounding effect

Molecular mechanisms of peritoneal dissemination in gastric cancer.

PubMed

Kanda, Mitsuro; Kodera, Yasuhiro

2016-08-14

Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets.

Molecular Approaches to Sarcoma Therapy

PubMed Central

Olsen, R. J.; Tarantolo, S. R.

2002-01-01

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed. PMID:18521343

General Anesthetics and Molecular Mechanisms of Unconsciousness

PubMed Central

Forman, Stuart A.; Chin, Victor A.

2013-01-01

General anesthetic agents are unique in clinical medicine, because they are the only drugs used to produce unconsciousness as a therapeutic goal. In contrast to older hypotheses that assumed all general anesthetics produce their central nervous system effects through a common mechanism, we outline evidence that general anesthesia represents a number of distinct pharmacological effects that are likely mediated by different neural circuits, and perhaps via different molecular targets. Within the context of this neurobiological framework, we review recent molecular pharmacological and transgenic animal studies. These studies reveal that different groups of general anesthetics, which can be discerned based on their clinical features, produce unconsciousness via distinct molecular targets and therefore via distinct mechanisms. We further postulate that different types of general anesthetics selectively disrupt different critical steps (perhaps in different neuronal circuits) in the processing of sensory information and memory that results in consciousness. PMID:18617817

Mechanistic insights into Mg2+-independent prenylation by CloQ from classical molecular mechanics and hybrid quantum mechanics/molecular mechanics molecular dynamics simulations.

PubMed

Bayse, Craig A; Merz, Kenneth M

2014-08-05

Understanding the mechanism of prenyltransferases is important to the design of engineered proteins capable of synthesizing derivatives of naturally occurring therapeutic agents. CloQ is a Mg(2+)-independent aromatic prenyltransferase (APTase) that transfers a dimethylallyl group to 4-hydroxyphenylpyruvate in the biosynthetic pathway for clorobiocin. APTases consist of a common ABBA fold that defines a β-barrel containing the reaction cavity. Positively charged basic residues line the inside of the β-barrel of CloQ to activate the pyrophosphate leaving group to replace the function of the Mg(2+) cofactor in other APTases. Classical molecular dynamics simulations of CloQ, its E281G and F68S mutants, and the related NovQ were used to explore the binding of the 4-hydroxyphenylpyruvate (4HPP) and dimethylallyl diphosphate substrates in the reactive cavity and the role of various conserved residues. Hybrid quantum mechanics/molecular mechanics potential of mean force (PMF) calculations show that the effect of the replacement of the Mg(2+) cofactor with basic residues yields a similar activation barrier for prenylation to Mg(2+)-dependent APTases like NphB. The topology of the binding pocket for 4HPP is important for selective prenylation at the ortho position of the ring. Methylation at this position alters the conformation of the substrate for O-prenylation at the phenol group. Further, a two-dimensional PMF scan shows that a "reverse" prenylation product may be a possible target for protein engineering.

Molecular Mechanisms of Root Gravitropism.

PubMed

Su, Shih-Heng; Gibbs, Nicole M; Jancewicz, Amy L; Masson, Patrick H

2017-09-11

Plant shoots typically grow against the gravity vector to access light, whereas roots grow downward into the soil to take up water and nutrients. These gravitropic responses can be altered by developmental and environmental cues. In this review, we discuss the molecular mechanisms that govern the gravitropism of angiosperm roots, where a physical separation between sites for gravity sensing and curvature response has facilitated discovery. Gravity sensing takes place in the columella cells of the root cap, where sedimentation of starch-filled plastids (amyloplasts) triggers a pathway that results in a relocalization to the lower side of the cell of PIN proteins, which facilitate efflux of the plant hormone auxin efflux. Consequently, auxin accumulates in the lower half of the root, triggering bending of the root tip at the elongation zone. We review our understanding of the molecular mechanisms that control this process in primary roots, and discuss recent insights into the regulation of oblique growth in lateral roots and its impact on root-system architecture and soil exploration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular mechanisms of optic axon guidance

NASA Astrophysics Data System (ADS)

Inatani, Masaru

2005-12-01

Axon guidance is one of the critical processes during vertebrate central nervous system (CNS) development. The optic nerve, which contains the axons of retinal ganglion cells, has been used as a powerful model to elucidate some of the mechanisms underlying axon guidance because it is easily manipulated experimentally, and its function is well understood. Recent molecular biology studies have revealed that numerous guidance molecules control the development of the visual pathway. This review introduces the molecular mechanisms involved in each critical step during optic axon guidance. Axonal projections to the optic disc are thought to depend on adhesion molecules and inhibitory extracellular matrices such as chondroitin sulfate. The formation of the head of the optic nerve and the optic chiasm require ligand-receptor interactions between netrin-1 and the deleted in colorectal cancer receptor, and Slit proteins and Robo receptors, respectively. The gradient distributions of ephrin ligands and Eph receptors are essential for correct ipsilateral projections at the optic chiasm and the topographic mapping of axons in the superior colliculus/optic tectum. The precise gradient is regulated by transcription factors determining the retinal dorso-ventral and nasal-temporal polarities. Moreover, the axon guidance activities by Slit and semaphorin 5A require the existence of heparan sulfate, which binds to numerous guidance molecules. Recent discoveries about the molecular mechanisms underlying optic nerve guidance will facilitate progress in CNS developmental biology and axon-regeneration therapy.

Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches

PubMed Central

Chen, Mo; Manley, James L.

2010-01-01

Alternative splicing of mRNA precursors provides an important means of genetic control and is a crucial step in the expression of most genes. Alternative splicing markedly affects human development, and its misregulation underlies many human diseases. Although the mechanisms of alternative splicing have been studied extensively, until the past few years we had not begun to realize fully the diversity and complexity of alternative splicing regulation by an intricate protein–RNA network. Great progress has been made by studying individual transcripts and through genome-wide approaches, which together provide a better picture of the mechanistic regulation of alternative pre-mRNA splicing. PMID:19773805

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury*

PubMed Central

van Niekerk, Erna A.; Tuszynski, Mark H.; Lu, Paul; Dulin, Jennifer N.

2016-01-01

Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. PMID:26695766

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.

Integrated genomics and molecular breeding approaches for dissecting the complex quantitative traits in crop plants.

PubMed

Kujur, Alice; Saxena, Maneesha S; Bajaj, Deepak; Laxmi; Parida, Swarup K

2013-12-01

The enormous population growth, climate change and global warming are now considered major threats to agriculture and world's food security. To improve the productivity and sustainability of agriculture, the development of highyielding and durable abiotic and biotic stress-tolerant cultivars and/climate resilient crops is essential. Henceforth, understanding the molecular mechanism and dissection of complex quantitative yield and stress tolerance traits is the prime objective in current agricultural biotechnology research. In recent years, tremendous progress has been made in plant genomics and molecular breeding research pertaining to conventional and next-generation whole genome, transcriptome and epigenome sequencing efforts, generation of huge genomic, transcriptomic and epigenomic resources and development of modern genomics-assisted breeding approaches in diverse crop genotypes with contrasting yield and abiotic stress tolerance traits. Unfortunately, the detailed molecular mechanism and gene regulatory networks controlling such complex quantitative traits is not yet well understood in crop plants. Therefore, we propose an integrated strategies involving available enormous and diverse traditional and modern -omics (structural, functional, comparative and epigenomics) approaches/resources and genomics-assisted breeding methods which agricultural biotechnologist can adopt/utilize to dissect and decode the molecular and gene regulatory networks involved in the complex quantitative yield and stress tolerance traits in crop plants. This would provide clues and much needed inputs for rapid selection of novel functionally relevant molecular tags regulating such complex traits to expedite traditional and modern marker-assisted genetic enhancement studies in target crop species for developing high-yielding stress-tolerant varieties.

Atom Tunneling in the Hydroxylation Process of Taurine/α-Ketoglutarate Dioxygenase Identified by Quantum Mechanics/Molecular Mechanics Simulations.

PubMed

Álvarez-Barcia, Sonia; Kästner, Johannes

2017-06-01

Taurine/α-ketoglutarate dioxygenase is one of the most studied α-ketoglutarate-dependent dioxygenases (αKGDs), involved in several biotechnological applications. We investigated the key step in the catalytic cycle of the αKGDs, the hydrogen transfer process, by a quantum mechanics/molecular mechanics approach (B3LYP/CHARMM22). Analysis of the charge and spin densities during the reaction demonstrates that a concerted mechanism takes place, where the H atom transfer happens simultaneously with the electron transfer from taurine to the Fe═O cofactor. We found the quantum tunneling of the hydrogen atom to increase the rate constant by a factor of 40 at 5 °C. As a consequence, a quite high kinetic isotope effect close to 60 is obtained, which is consistent with the experimental value.

Toward a Mechanism-Based Approach to Pain Diagnosis.

PubMed

Vardeh, Daniel; Mannion, Richard J; Woolf, Clifford J

2016-09-01

identification of 3 steps: pain state, pain mechanism, and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as 1 of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is consistent with and an extension of the AAPT. We discuss how identifying the specific mechanisms that operate in the nervous system to produce chronic pain in individual patients could provide the basis for a targeted and rational precision medicine approach to controlling pain, using chronic low back pain as our example. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Molecular mechanics approach for design and conformational studies of macrocyclic ligands

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

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

2015-08-28

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

Physiological and molecular biochemical mechanisms of bile formation

PubMed Central

Reshetnyak, Vasiliy Ivanovich

2013-01-01

This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract. PMID:24259965

Internal force corrections with machine learning for quantum mechanics/molecular mechanics simulations.

PubMed

Wu, Jingheng; Shen, Lin; Yang, Weitao

2017-10-28

Ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulation is a useful tool to calculate thermodynamic properties such as potential of mean force for chemical reactions but intensely time consuming. In this paper, we developed a new method using the internal force correction for low-level semiempirical QM/MM molecular dynamics samplings with a predefined reaction coordinate. As a correction term, the internal force was predicted with a machine learning scheme, which provides a sophisticated force field, and added to the atomic forces on the reaction coordinate related atoms at each integration step. We applied this method to two reactions in aqueous solution and reproduced potentials of mean force at the ab initio QM/MM level. The saving in computational cost is about 2 orders of magnitude. The present work reveals great potentials for machine learning in QM/MM simulations to study complex chemical processes.

Quantum mechanical/molecular mechanical molecular dynamics and free energy simulations of the thiopurine S-methyltransferase reaction with 6-mercaptopurine.

PubMed

Pan, Xiao-Liang; Cui, Feng-Chao; Liu, Jing-Yao

2011-06-23

Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were performed to investigate the methylation of 6-mercaptopurine catalyzed by thiopurine S-methyltransferase. Several setups with different tautomeric forms and orientations of the substrate were considered. It is found that, with the orientation in chain A of the X-ray structure, the substrate can form an ideal near-attack configuration for the methylation reaction, which may take place after the deprotonation of the substrate by the conserved residue Asp23 through a water chain. The potential of mean force (PMF) of the methyl-transfer step for the most favorable pathway is 19.6 kcal/mol, which is in good agreement with the available experimental rate constant data.

Systematic analysis of molecular mechanisms for HCC metastasis via text mining approach.

PubMed

Zhen, Cheng; Zhu, Caizhong; Chen, Haoyang; Xiong, Yiru; Tan, Junyuan; Chen, Dong; Li, Jin

2017-02-21

To systematically explore the molecular mechanism for hepatocellular carcinoma (HCC) metastasis and identify regulatory genes with text mining methods. Genes with highest frequencies and significant pathways related to HCC metastasis were listed. A handful of proteins such as EGFR, MDM2, TP53 and APP, were identified as hub nodes in PPI (protein-protein interaction) network. Compared with unique genes for HBV-HCCs, genes particular to HCV-HCCs were less, but may participate in more extensive signaling processes. VEGFA, PI3KCA, MAPK1, MMP9 and other genes may play important roles in multiple phenotypes of metastasis. Genes in abstracts of HCC-metastasis literatures were identified. Word frequency analysis, KEGG pathway and PPI network analysis were performed. Then co-occurrence analysis between genes and metastasis-related phenotypes were carried out. Text mining is effective for revealing potential regulators or pathways, but the purpose of it should be specific, and the combination of various methods will be more useful.

Analysis of the mechanical behavior of single wall carbon nanotubes by a modified molecular structural mechanics model incorporating an advanced chemical force field

NASA Astrophysics Data System (ADS)

Eberhardt, Oliver; Wallmersperger, Thomas

2018-03-01

The outstanding properties of carbon nanotubes (CNTs) keep attracting the attention of researchers from different fields. CNTs are promising candidates for applications e.g. in lightweight construction but also in electronics, medicine and many more. The basis for the realization of the manifold applications is a detailed knowledge of the material properties of the carbon nanotubes. In particular for applications in lightweight constructions or in composites, the knowledge of the mechanical behavior of the CNTs is of vital interest. Hence, a lot of effort is put into the experimental and theoretical determination of the mechanical material properties of CNTs. Due to their small size, special techniques have to be applied. In this research, a modified molecular structural mechanics model for the numerical determination of the mechanical behavior of carbon nanotubes is presented. It uses an advanced approach for the geometrical representation of the CNT structure while the covalent bonds in the CNTs are represented by beam elements. Furthermore, the model is specifically designed to overcome major drawbacks in existing molecular structural mechanics models. This includes energetic consistency with the underlying chemical force field. The model is developed further to enable the application of a more advanced chemical force field representation. The developed model is able to predict, inter alia, the lateral and radial stiffness properties of the CNTs. The results for the lateral stiffness are given and discussed in order to emphasize the progress made with the presented approach.

Deciphering the molecular mechanisms underlying sea urchin reversible adhesion: A quantitative proteomics approach.

PubMed

Lebesgue, Nicolas; da Costa, Gonçalo; Ribeiro, Raquel Mesquita; Ribeiro-Silva, Cristina; Martins, Gabriel G; Matranga, Valeria; Scholten, Arjen; Cordeiro, Carlos; Heck, Albert J R; Santos, Romana

2016-04-14

Marine bioadhesives have unmatched performances in wet environments, being an inspiration for biomedical applications. In sea urchins specialized adhesive organs, tube feet, mediate reversible adhesion, being composed by a disc, producing adhesive and de-adhesive secretions, and a motile stem. After tube foot detachment, the secreted adhesive remains bound to the substratum as a footprint. Sea urchin adhesive is composed by proteins and sugars, but so far only one protein, Nectin, was shown to be over-expressed as a transcript in tube feet discs, suggesting its involvement in sea urchin adhesion. Here we use high-resolution quantitative mass-spectrometry to perform the first study combining the analysis of the differential proteome of an adhesive organ, with the proteome of its secreted adhesive. This strategy allowed us to identify 163 highly over-expressed disc proteins, specifically involved in sea urchin reversible adhesion; to find that 70% of the secreted adhesive components fall within five protein groups, involved in exocytosis and microbial protection; and to provide evidences that Nectin is not only highly expressed in tube feet discs but is an actual component of the adhesive. These results give an unprecedented insight into the molecular mechanisms underlying sea urchin adhesion, and opening new doors to develop wet-reliable, reversible, and ecological biomimetic adhesives. Sea urchins attach strongly but in a reversible manner to substratum, being a valuable source of inspiration for industrial and biomedical applications. Yet, the molecular mechanisms governing reversible adhesion are still poorly studied delaying the engineering of biomimetic adhesives. We used the latest mass spectrometry techniques to analyze the differential proteome of an adhesive organ and the proteome of its secreted adhesive, allowing us to uncover the key players in sea urchin reversible adhesion. We demonstrate, that Nectin, a protein previously pointed out as potentially

Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy.

PubMed

Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

2016-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

Molecular Approach to Conjugated Polymers with Biomimetic Properties.

PubMed

Baek, Paul; Voorhaar, Lenny; Barker, David; Travas-Sejdic, Jadranka

2018-06-13

The field of bioelectronics involves the fascinating interplay between biology and human-made electronics. Applications such as tissue engineering, biosensing, drug delivery, and wearable electronics require biomimetic materials that can translate the physiological and chemical processes of biological systems, such as organs, tissues. and cells, into electrical signals and vice versa. However, the difference in the physical nature of soft biological elements and rigid electronic materials calls for new conductive or electroactive materials with added biomimetic properties that can bridge the gap. Soft electronics that utilize organic materials, such as conjugated polymers, can bring many important features to bioelectronics. Among the many advantages of conjugated polymers, the ability to modulate the biocompatibility, solubility, functionality, and mechanical properties through side chain engineering can alleviate the issues of mechanical mismatch and provide better interface between the electronics and biological elements. Additionally, conjugated polymers, being both ionically and electrically conductive through reversible doping processes provide means for direct sensing and stimulation of biological processes in cells, tissues, and organs. In this Account, we focus on our recent progress in molecular engineering of conjugated polymers with tunable biomimetic properties, such as biocompatibility, responsiveness, stretchability, self-healing, and adhesion. Our approach is general and versatile, which is based on functionalization of conjugated polymers with long side chains, commonly polymeric or biomolecules. Applications for such materials are wide-ranging, where we have demonstrated conductive, stimuli-responsive antifouling, and cell adhesive biointerfaces that can respond to external stimuli such as temperature, salt concentration, and redox reactions, the processes that in turn modify and reversibly switch the surface properties. Furthermore, utilizing the

Nonlinear vibrational excitations in molecular crystals molecular mechanics calculations

NASA Astrophysics Data System (ADS)

Pumilia, P.; Abbate, S.; Baldini, G.; Ferro, D. R.; Tubino, R.

1992-03-01

The coupling constant for vibrational solitons χ has been examined in a molecular mechanics model for acetanilide (ACN) molecular crystal. According to A.C. Scott, solitons can form and propagate in solid acetanilide over a threshold energy value. This can be regarded as a structural model for the spines of hydrogen bond chains stabilizing the α helical structure of proteins. A one dimensional hydrogen bond chain of ACN has been built, for which we have found that, even though experimental parameters are correctly predicted, the excessive rigidity of the isolated chain prevents the formation of a localized distortion around the excitation. Yet, C=O coupling value with softer lattice modes could be rather high, allowing self-trapping to take place.

Molecular Mechanism of TRP Channels

PubMed Central

Zheng, Jie

2013-01-01

Transient receptor potential (TRP) channels are cellular sensors for a wide spectrum of physical and chemical stimuli. They are involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. TRP channels also play fundamental roles in cell signaling and allow the host cell to respond to benign or harmful environmental changes. As TRP channel activation is controlled by very diverse processes and, in many cases, exhibits complex polymodal properties, understanding how each TRP channel responds to its unique forms of activation energy is both crucial and challenging. The past two decades witnessed significant advances in understanding the molecular mechanisms that underlie TRP channels activation. This review focuses on our current understanding of the molecular determinants for TRP channel activation. PMID:23720286

Molecular mechanisms underlying deoxy‐ADP.Pi activation of pre‐powerstroke myosin

PubMed Central

Nowakowski, Sarah G.

2017-01-01

Abstract Myosin activation is a viable approach to treat systolic heart failure. We previously demonstrated that striated muscle myosin is a promiscuous ATPase that can use most nucleoside triphosphates as energy substrates for contraction. When 2‐deoxy ATP (dATP) is used, it acts as a myosin activator, enhancing cross‐bridge binding and cycling. In vivo, we have demonstrated that elevated dATP levels increase basal cardiac function and rescues function of infarcted rodent and pig hearts. Here we investigate the molecular mechanism underlying this physiological effect. We show with molecular dynamics simulations that the binding of dADP.Pi (dATP hydrolysis products) to myosin alters the structure and dynamics of the nucleotide binding pocket, myosin cleft conformation, and actin binding sites, which collectively yield a myosin conformation that we predict favors weak, electrostatic binding to actin. In vitro motility assays at high ionic strength were conducted to test this prediction and we found that dATP increased motility. These results highlight alterations to myosin that enhance cross‐bridge formation and reveal a potential mechanism that may underlie dATP‐induced improvements in cardiac function. PMID:28097776

Epigenetics: Behavioral Influences on Gene Function, Part II--Molecular Mechanisms

ERIC Educational Resources Information Center

Ogren, Marilee P.; Lombroso, Paul J.

2008-01-01

A study presented on the effect of parenting on stress response and other behaviors show that animals exposed to a high degree of nurturing show a blunted response to stress. Molecular mechanisms responsible for these differences in the adult offspring as well as the molecular mechanisms by which epigenetic effects are propagated from one…

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.

Simple and exact approach to the electronic polarization effect on the solvation free energy: formulation for quantum-mechanical/molecular-mechanical system and its applications to aqueous solutions.

PubMed

Takahashi, Hideaki; Omi, Atsushi; Morita, Akihiro; Matubayasi, Nobuyuki

2012-06-07

We present a simple and exact numerical approach to compute the free energy contribution δμ in solvation due to the electron density polarization and fluctuation of a quantum-mechanical solute in the quantum-mechanical/molecular-mechanical (QM/MM) simulation combined with the theory of the energy representation (QM/MM-ER). Since the electron density fluctuation is responsible for the many-body QM-MM interactions, the standard version of the energy representation method cannot be applied directly. Instead of decomposing the QM-MM polarization energy into the pairwise additive and non-additive contributions, we take sum of the polarization energies in the QM-MM interaction and adopt it as a new energy coordinate for the method of energy representation. Then, it is demonstrated that the free energy δμ can be exactly formulated in terms of the energy distribution functions for the solution and reference systems with respect to this energy coordinate. The benchmark tests were performed to examine the numerical efficiency of the method with respect to the changes in the individual properties of the solvent and the solute. Explicitly, we computed the solvation free energy of a QM water molecule in ambient and supercritical water, and also the free-energy change associated with the isomerization reaction of glycine from neutral to zwitterionic structure in aqueous solution. In all the systems examined, it was demonstrated that the computed free energy δμ agrees with the experimental value, irrespective of the choice of the reference electron density of the QM solute. The present method was also applied to a prototype reaction of adenosine 5'-triphosphate hydrolysis where the effect of the electron density fluctuation is substantial due to the excess charge. It was demonstrated that the experimental free energy of the reaction has been accurately reproduced with the present approach.

A molecular dynamics investigation into the mechanisms of alectinib resistance of three ALK mutants.

PubMed

He, Muyang; Li, Weikang; Zheng, Qingchuan; Zhang, Hongxing

2018-07-01

Alectinib, a highly selective next-genetation anaplastic lymphoma kinase (ALK) inhibitor, has demonstrated promising antitumor activity in patients with ALK-positive non-small cell lung carcinomas (NSCLC). However, the therapeutic benefits of alectinib is inescapably hampered by the development of acquired resistant mutations in ALK. Despite the availability of ample experimental mutagenesis data, the molecular origin and the structural motifs under alectinib binding affinity deficiencies are still ambiguous. Here, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) calculation approaches were employed to elucidate the mechanisms of alectinib resistance induced by the mutations I1171N, V1180L, and L1198F. The MD results reveal that the studied mutations could trigger the dislocation of alectinib as well as conformational changes at the inhibitor binding site, thus induce the interactional changes between alectinib and mutants. The most influenced regions are the ligand binding entrance and the hinge region, which are considered to be the dominant binding motifs accounting for the binding affinity loss in mutants. The "key and lock mechanism" between the ethyl group at position 9 of alectinib and a recognition cavity in the hinge region of ALK is presented to illustrate the major molecular origin of drug resistance. Our results provide mechanistic insight into the effect of ALK mutations resistant to alectinib, which could contribute to further rational design of inhibitors to combat the acquired resistance. © 2018 Wiley Periodicals, Inc.

Molecular mechanisms of fluoride toxicity.

PubMed

Barbier, Olivier; Arreola-Mendoza, Laura; Del Razo, Luz María

2010-11-05

Halfway through the twentieth century, fluoride piqued the interest of toxicologists due to its deleterious effects at high concentrations in human populations suffering from fluorosis and in in vivo experimental models. Until the 1990s, the toxicity of fluoride was largely ignored due to its "good reputation" for preventing caries via topical application and in dental toothpastes. However, in the last decade, interest in its undesirable effects has resurfaced due to the awareness that this element interacts with cellular systems even at low doses. In recent years, several investigations demonstrated that fluoride can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell-cell communications and signal transduction. The primary purpose of this review is to examine recent findings from our group and others that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.

PubMed

Canal, Clinton E

2018-03-13

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT 2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

Thumbs down: a molecular-morphogenetic approach to avian digit homology.

PubMed

Capek, Daniel; Metscher, Brian D; Müller, Gerd B

2014-01-01

Avian forelimb digit homology remains one of the standard themes in comparative biology and EvoDevo research. In order to resolve the apparent contradictions between embryological and paleontological evidence a variety of hypotheses have been presented in recent years. The proposals range from excluding birds from the dinosaur clade, to assignments of homology by different criteria, or even assuming a hexadactyl tetrapod limb ground state. At present two approaches prevail: the frame shift hypothesis and the pyramid reduction hypothesis. While the former postulates a homeotic shift of digit identities, the latter argues for a gradual bilateral reduction of phalanges and digits. Here we present a new model that integrates elements from both hypotheses with the existing experimental and fossil evidence. We start from the main feature common to both earlier concepts, the initiating ontogenetic event: reduction and loss of the anterior-most digit. It is proposed that a concerted mechanism of molecular regulation and developmental mechanics is capable of shifting the boundaries of hoxD expression in embryonic forelimb buds as well as changing the digit phenotypes. Based on a distinction between positional (topological) and compositional (phenotypic) homology criteria, we argue that the identity of the avian digits is II, III, IV, despite a partially altered phenotype. Finally, we introduce an alternative digit reduction scheme that reconciles the current fossil evidence with the presented molecular-morphogenetic model. Our approach identifies specific experiments that allow to test whether gene expression can be shifted and digit phenotypes can be altered by induced digit loss or digit gain. © 2013 Wiley Periodicals, Inc.

Quantum mechanical/molecular mechanical/continuum style solvation model: time-dependent density functional theory.

PubMed

Thellamurege, Nandun M; Cui, Fengchao; Li, Hui

2013-08-28

A combined quantum mechanical/molecular mechanical/continuum (QM/MMpol/C) style method is developed for time-dependent density functional theory (TDDFT, including long-range corrected TDDFT) method, induced dipole polarizable force field, and induced surface charge continuum model. Induced dipoles and induced charges are included in the TDDFT equations to solve for the transition energies, relaxed density, and transition density. Analytic gradient is derived and implemented for geometry optimization and molecular dynamics simulation. QM/MMpol/C style DFT and TDDFT methods are used to study the hydrogen bonding of the photoactive yellow protein chromopore in ground state and excited state.

Hybrid schemes based on quantum mechanics/molecular mechanics simulations goals to success, problems, and perspectives.

PubMed

Ferrer, Silvia; Ruiz-Pernía, Javier; Martí, Sergio; Moliner, Vicent; Tuñón, Iñaki; Bertrán, Juan; Andrés, Juan

2011-01-01

The development of characterization techniques, advanced synthesis methods, as well as molecular modeling has transformed the study of systems in a well-established research field. The current research challenges in biocatalysis and biotransformation evolve around enzyme discovery, design, and optimization. How can we find or create enzymes that catalyze important synthetic reactions, even reactions that may not exist in nature? What is the source of enzyme catalytic power? To answer these and other related questions, the standard strategies have evolved from trial-and-error methodologies based on chemical knowledge, accumulated experience, and common sense into a clearly multidisciplinary science that allows one to reach the molecular design of tailor-made enzyme catalysts. This is even more so when one refers to enzyme catalysts, for which the detailed structure and composition are known and can be manipulated to introduce well-defined residues which can be implicated in the chemical rearrangements taking place in the active site. The methods and techniques of theoretical and computational chemistry are becoming more and more important in both understanding the fundamental biological roles of enzymes and facilitating their utilization in biotechnology. Improvement of the catalytic function of enzymes is important from scientific and industrial viewpoints, and to put this fact in the actual perspective as well as the potentialities, we recommend the very recent report of Sanderson [Sanderson, K. (2011). Chemistry: enzyme expertise. Nature 471, 397.]. Great fundamental advances have been made toward the ab initio design of enzyme catalysts based on molecular modeling. This has been based on the molecular mechanistic knowledge of the reactions to be catalyzed, together with the development of advanced synthesis and characterization techniques. The corresponding molecular mechanism can be studied by means of powerful quantum chemical calculations. The catalytic

Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

DOE PAGES

Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika; ...

2016-01-19

In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

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

Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika

In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

Molecular Engineering for Mechanically Resilient and Stretchable Electronic Polymers and Composites

DTIC Science & Technology

2016-06-08

AFRL-AFOSR-VA-TR-2016-0231 Molecular Engineering for Mechanically Resilient and Stretchable Electronic Polymers and Composites Darren Lipomi...04-2013 to 31-03-2016 4. TITLE AND SUBTITLE Molecular Engineering for Mechanically Resilient and Stretchable Electronic Polymers and Composites 5a... Engineering for Mechanically Resilient and Stretchable Electronic Polymers and Composites PI: Prof. Darren J. Lipomi 9500 Gilman Dr., Mail Code #0448

Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma.

PubMed

Diaz, Giacomo; Engle, Ronald E; Tice, Ashley; Melis, Marta; Montenegro, Stephanie; Rodriguez-Canales, Jaime; Hanson, Jeffrey; Emmert-Buck, Michael R; Bock, Kevin W; Moore, Ian N; Zamboni, Fausto; Govindarajan, Sugantha; Kleiner, David; Farci, Patrizia

2018-06-01

There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n-5) and with non-HCC HDV cirrhosis (n=7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and non-malignant hepatocytes, tumorous and non-tumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of up-regulated transcripts associated with pathways involved in cell cycle/DNA replication, damage and repair (sonic hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell cycle regulation, cell cycle: G2/M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being over-expressed, these genes were also strongly co-regulated. Gene co-regulation was high not only when compared to non-malignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and co-regulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms. This study identifies a molecular signature of HDV

Physiological, Biochemical, and Molecular Mechanisms of Heat Stress Tolerance in Plants

PubMed Central

Hasanuzzaman, Mirza; Nahar, Kamrun; Alam, Md. Mahabub; Roychowdhury, Rajib; Fujita, Masayuki

2013-01-01

High temperature (HT) stress is a major environmental stress that limits plant growth, metabolism, and productivity worldwide. Plant growth and development involve numerous biochemical reactions that are sensitive to temperature. Plant responses to HT vary with the degree and duration of HT and the plant type. HT is now a major concern for crop production and approaches for sustaining high yields of crop plants under HT stress are important agricultural goals. Plants possess a number of adaptive, avoidance, or acclimation mechanisms to cope with HT situations. In addition, major tolerance mechanisms that employ ion transporters, proteins, osmoprotectants, antioxidants, and other factors involved in signaling cascades and transcriptional control are activated to offset stress-induced biochemical and physiological alterations. Plant survival under HT stress depends on the ability to perceive the HT stimulus, generate and transmit the signal, and initiate appropriate physiological and biochemical changes. HT-induced gene expression and metabolite synthesis also substantially improve tolerance. The physiological and biochemical responses to heat stress are active research areas, and the molecular approaches are being adopted for developing HT tolerance in plants. This article reviews the recent findings on responses, adaptation, and tolerance to HT at the cellular, organellar, and whole plant levels and describes various approaches being taken to enhance thermotolerance in plants. PMID:23644891

Protective molecular mechanisms of resveratrol in UVR-induced Skin carcinogenesis.

PubMed

Aziz, Saba W; Aziz, Moammir H

2018-01-01

Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effect of self-sorting and co-assembly on the mechanical properties of low molecular weight hydrogels

NASA Astrophysics Data System (ADS)

Colquhoun, Catherine; Draper, Emily R.; Eden, Edward G. B.; Cattoz, Beatrice N.; Morris, Kyle L.; Chen, Lin; McDonald, Tom O.; Terry, Ann E.; Griffiths, Peter C.; Serpell, Louise C.; Adams, Dave J.

2014-10-01

Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties.Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties. Electronic supplementary information (ESI) available: Full experimental and synthetic details for the dipeptides, full experimental descriptions, further NMR, single crystal diffraction data, fXRD data and SANS data. See DOI: 10.1039/c4nr04039b

Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach

DTIC Science & Technology

2016-03-01

Award Number: W81XWH-12-1-0323 TITLE: Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach PRINCIPAL...SUBTITLE Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...increasing its sensitivity and specificity through nanotechnology . Hypothesis: Detection of DNA methylation from individuals with cancer can be used to

Molecular mechanisms of floral mimicry in orchids.

PubMed

Schlüter, Philipp M; Schiestl, Florian P

2008-05-01

Deceptive plants do not produce floral rewards, but attract pollinators by mimicking signals of other organisms, such as food plants or female insects. Such floral mimicry is particularly common in orchids, in which flower morphology, coloration and odour play key roles in deceiving pollinators. A better understanding of the molecular bases for these traits should provide new insights into the occurrence, mechanisms and evolutionary consequences of floral mimicry. It should also reveal the molecular bases of pollinator-attracting signals, in addition to providing strategies for manipulating insect behaviour in general. Here, we review data on the molecular bases for traits involved in floral mimicry, and we describe methodological advances helpful for the functional evaluation of key genes.

Azobenzene as a photoregulator covalently attached to RNA: a quantum mechanics/molecular mechanics-surface hopping dynamics study.

PubMed

Mondal, Padmabati; Granucci, Giovanni; Rastädter, Dominique; Persico, Maurizio; Burghardt, Irene

2018-05-28

The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA-azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a β-deoxyribose linker. Due to the pronounced constraints of the local RNA environment, it is found that trans -to- cis isomerization is slowed down to a time scale of ∼10-15 picoseconds, in contrast to 500 femtoseconds in vacuo , with a quantum yield reduced by a factor of two. By contrast, cis -to- trans isomerization remains in a sub-picosecond regime. A volume-conserving isomerization mechanism is found, similarly to the pedal-like mechanism previously identified for azobenzene in solution phase. Strikingly, the chiral RNA environment induces opposite right-handed and left-handed helicities of the ground-state cis -azobenzene chromophore in the two RNA-azobenzene complexes, along with an almost completely chirality conserving photochemical pathway for these helical enantiomers.

Molecular and Microbial Mechanisms Increasing Soil C Storage Under Future Rates of Anthropogenic N Deposition

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

Zak, Donald R.

A growing body of evidence reveals that anthropogenic N deposition can reduce the microbial decay of plant detritus and increase soil C storage across a wide range of terrestrial ecosystems. This aspect of global change has the potential to constrain the accumulation of anthropogenic CO 2 in the Earth’s atmosphere, and hence slow the pace of climate warming. The molecular and microbial mechanisms underlying this biogeochemical response are not understood, and they are not a component of any coupled climate-biogeochemical model estimating ecosystem C storage, and hence, the future climate of an N-enriched Earth. Here, we report the use ofmore » genomic-enabled approaches to identify the molecular underpinnings of the microbial mechanisms leading to greater soil C storage in response to anthropogenic N deposition, thereby enabling us to better anticipate changes in soil C storage.« less

Molecular basis of glyphosate resistance: Different approaches through protein engineering

PubMed Central

Pollegioni, Loredano; Schonbrunn, Ernst; Siehl, Daniel

2011-01-01

Glyphosate (N-phosphonomethyl-glycine) is the most-used herbicide in the world: glyphosate-based formulations exhibit broad-spectrum herbicidal activity with minimal human and environmental toxicity. The extraordinary success of this simple small molecule is mainly due to the high specificity of glyphosate towards the plant enzyme enolpyruvylshikimate-3-phosphate synthase in the shikimate pathway leading to biosynthesis of aromatic amino acids. Starting in 1996, transgenic glyphosate-resistant plants were introduced thus allowing the application of the herbicide to the crop (post-emergence) to remove emerged weeds without crop damage. This review focuses on the evolution of mechanisms of resistance to glyphosate as obtained through natural diversity, the gene shuffling approach to molecular evolution, and a rational, structure-based approach to protein engineering. In addition, we offer rationale for the means by which the modifications made have had their intended effect. PMID:21668647

[Programmed necrosis and necroptosis - molecular mechanisms].

PubMed

Giżycka, Agata; Chorostowska-Wynimko, Joanna

2015-12-16

Programmed necrosis has been proven vital for organism development and homeostasis maintenance. Its regulatory effects on functional activity of the immune system, as well as on pathways regulating the death mechanisms in cells with diminished apoptotic activity, including malignant cells, have been confirmed. There is also increasing evidence indicating necrosis involvement in many human pathologies. Contrary to previous beliefs, necrosis is not only a passive, pathological, gene-independent process. However, the current knowledge regarding molecular regulation of programmed necrosis is scarce. In part this is due to the multiplicity and complexity of signaling pathways involved in programmed necrosis, as well as the absence of specific cellular markers identifying this process, but also the ambiguous and imprecise international terminology. This review presents the current state of the art on molecular mechanisms of programmed necrosis. In particular, its specific and frequent form, necroptosis, is discussed. The role of RIP1 and RIP3 kinases in this process is presented, as well as the diverse pathways induced by ligation of tumor necrosis factor α, to its receptor, TNFR1, i.e. cell survival, apoptosis or necroptosis.

Mechanisms of two-color laser-induced field-free molecular orientation.

PubMed

Spanner, Michael; Patchkovskii, Serguei; Frumker, Eugene; Corkum, Paul

2012-09-14

Two mechanisms of two-color (ω+2ω) laser-induced field-free molecular orientation, based on the hyperpolarizability and ionization depletion, are explored and compared. The CO molecule is used as a computational example. While the hyperpolarizability mechanism generates small amounts of orientation at intensities below the ionization threshold, ionization depletion quickly becomes the dominant mechanism as soon as ionizing intensities are reached. Only the ionization mechanism leads to substantial orientation (e.g., on the order of ≳0.1). For intensities typical of laser-induced molecular alignment and orientation experiments, the two mechanisms lead to robust, characteristic timings of the field-free orientation wave-packet revivals relative to the alignment revivals and the revival time. The revival timings can be used to detect the active orientation mechanism experimentally.

Molecular Mechanisms of Neuroplasticity: An Expanding Universe.

PubMed

Gulyaeva, N V

2017-03-01

Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.

In silico approach to explore the disruption in the molecular mechanism of human hyaluronidase 1 by mutant E268K that directs Natowicz syndrome.

PubMed

Meshach Paul, D; Rajasekaran, R

2017-03-01

Natowicz syndrome (mucopolysaccharidoses type 9) is a lysosomal storage disorder caused by deficient or defective human hyaluronidase 1. The disorder is not well studied at the molecular level. Therefore, a new in silico approach was proposed to study the molecular basis on which one clinically observed mutation, Glu268Lys, results in a defective enzyme. The native and mutant structures were subjected to comparative analyses using a conformational sampling approach for geometrical variables viz, RMSF, RMSD, and Ramachandran plot. In addition, the strength of a Cys207-Cys221 disulfide bond and electrostatic interaction between Arg265 and Asp206 were studied, as they are known to be involved in the catalytic activity of the enzyme. Native and mutant E268K showed statistically significant variations with p < 0.05 in RMSD, Ramachandran plot, strengths of disulfide bond, and electrostatic interactions. Further, single model analysis showed variations between native and mutant structures in terms of intra-protein interactions, hydrogen bond dilution, secondary structure, and dihedral angles. Docking analysis predicted the mutant to have a less favorable substrate binding energy compared to the native protein. Additionally, steered MD analysis indicated that the substrate should have more affinity to the native than mutant enzymes. The observed changes theoretically explain the less favorable binding energy of substrate towards mutant E268K, thereby providing a structural basis for its reduced catalytic activity. Hence, our study provides a basis for understanding the disruption in the molecular mechanism of human hyaluronidase 1 by mutation E268K, which may prove useful for the development of synthetic chaperones as a treatment option for Natowicz syndrome.

Molecular approaches for classifying endometrial carcinoma.

PubMed

Piulats, Josep M; Guerra, Esther; Gil-Martín, Marta; Roman-Canal, Berta; Gatius, Sonia; Sanz-Pamplona, Rebeca; Velasco, Ana; Vidal, August; Matias-Guiu, Xavier

2017-04-01

Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors. Third, we discuss the importance of applying TCGA molecular approach to clinical practice. We also comment on the impact of intratumor heterogeneity in classification, and finally, we will discuss briefly, the usefulness of TCGA classification in tailoring immunotherapy in endometrial cancer patients. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Multiresolution molecular mechanics: Implementation and efficiency

NASA Astrophysics Data System (ADS)

Biyikli, Emre; To, Albert C.

2017-01-01

Atomistic/continuum coupling methods combine accurate atomistic methods and efficient continuum methods to simulate the behavior of highly ordered crystalline systems. Coupled methods utilize the advantages of both approaches to simulate systems at a lower computational cost, while retaining the accuracy associated with atomistic methods. Many concurrent atomistic/continuum coupling methods have been proposed in the past; however, their true computational efficiency has not been demonstrated. The present work presents an efficient implementation of a concurrent coupling method called the Multiresolution Molecular Mechanics (MMM) for serial, parallel, and adaptive analysis. First, we present the features of the software implemented along with the associated technologies. The scalability of the software implementation is demonstrated, and the competing effects of multiscale modeling and parallelization are discussed. Then, the algorithms contributing to the efficiency of the software are presented. These include algorithms for eliminating latent ghost atoms from calculations and measurement-based dynamic balancing of parallel workload. The efficiency improvements made by these algorithms are demonstrated by benchmark tests. The efficiency of the software is found to be on par with LAMMPS, a state-of-the-art Molecular Dynamics (MD) simulation code, when performing full atomistic simulations. Speed-up of the MMM method is shown to be directly proportional to the reduction of the number of the atoms visited in force computation. Finally, an adaptive MMM analysis on a nanoindentation problem, containing over a million atoms, is performed, yielding an improvement of 6.3-8.5 times in efficiency, over the full atomistic MD method. For the first time, the efficiency of a concurrent atomistic/continuum coupling method is comprehensively investigated and demonstrated.

Congenital heart disease and genetic syndromes: new insights into molecular mechanisms.

PubMed

Calcagni, Giulio; Unolt, Marta; Digilio, Maria Cristina; Baban, Anwar; Versacci, Paolo; Tartaglia, Marco; Baldini, Antonio; Marino, Bruno

2017-09-01

Advances in genetics allowed a better definition of the role of specific genetic background in the etiology of syndromic congenital heart defects (CHDs). The identification of a number of disease genes responsible for different syndromes have led to the identification of several transcriptional regulators and signaling transducers and modulators that are critical for heart morphogenesis. Understanding the genetic background of syndromic CHDs allowed a better characterization of the genetic basis of non-syndromic CHDs. In this sense, the well-known association of typical CHDs in Down syndrome, 22q11.2 microdeletion and Noonan syndrome represent paradigms as chromosomal aneuploidy, chromosomal microdeletion and intragenic mutation, respectively. Area covered: For each syndrome the anatomical features, distinctive cardiac phenotype and molecular mechanisms are discussed. Moreover, the authors include recent genetic findings that may shed light on some aspects of still unclear molecular mechanisms of these syndromes. Expert commentary: Further investigations are needed to enhance the translational approach in the field of genetics of CHDs. When there is a well-established definition of genotype-phenotype (reverse medicine) and genotype-prognosis (predictive and personalized medicine) correlations, hopefully preventive medicine will make its way in this field. Subsequently a reduction will be achieved in the morbidity and mortality of children with CHDs.

Disease resistance: Molecular mechanisms and biotechnological applications

USDA-ARS?s Scientific Manuscript database

This special issue “Disease resistance: molecular mechanisms and biotechnological applications” contains 11 review articles and four original research papers. Research in the area of engineering for disease resistance continues to progress although only 10% of the transgenic plants registered for ...

Insights into the molecular mechanisms of Polygonum multiflorum Thunb-induced liver injury: a computational systems toxicology approach.

PubMed

Wang, Yin-Yin; Li, Jie; Wu, Zeng-Rui; Zhang, Bo; Yang, Hong-Bin; Wang, Qin; Cai, Ying-Chun; Liu, Gui-Xia; Li, Wei-Hua; Tang, Yun

2017-05-01

An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method. After screening for hepatotoxicity-related genes by assessing the symptoms of HILI, a compound-target interaction network was constructed. A scoring function, namely, Ascore, was developed to estimate the toxicity of chemicals in the liver. We conducted network analysis to determine the possible mechanisms of the biphasic effects using the analysis tools, including BiNGO, pathway enrichment, organ distribution analysis and predictions of interactions with CYP450 enzymes. Among the chemical components of PmT, 54 components with good intestinal absorption were used for analysis, and 2939 CTIs were obtained. After analyzing the mRNA expression data in the BioGPS database, 1599 CTIs and 125 targets related to liver diseases were identified. In the top 15 compounds, seven with Ascore values >3000 (emodin, quercetin, apigenin, resveratrol, gallic acid, kaempferol and luteolin) were obviously associated with hepatotoxicity. The results from the pathway enrichment analysis suggest that multiple interactions between apoptosis and metabolism may underlie PmT-induced liver injury. Many of the pathways have been verified in specific compounds, such as glutathione metabolism, cytochrome P450 metabolism, and the p53 pathway, among others. Hepatitis symptoms, the perturbation of nine bile acids and yellow or tawny urine also had corresponding pathways

Molecular mechanisms of curcumin action: gene expression.

PubMed

Shishodia, Shishir

2013-01-01

Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

MurD ligase from E. coli: Tetrahedral intermediate formation study by hybrid quantum mechanical/molecular mechanical replica path method.

PubMed

Perdih, Andrej; Hodoscek, Milan; Solmajer, Tom

2009-02-15

MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase), a three-domain bacterial protein, catalyses a highly specific incorporation of D-glutamate to the cytoplasmic intermediate UDP-N-acetyl-muramoyl-L-alanine (UMA) utilizing ATP hydrolysis to ADP and P(i). This reaction is part of a biosynthetic path yielding bacterial peptidoglycan. On the basis of structural studies of MurD complexes, a stepwise catalytic mechanism was proposed that commences with a formation of the acyl-phosphate intermediate, followed by a nucleophilic attack of D-glutamate that, through the formation of a tetrahedral reaction intermediate and subsequent phosphate dissociation, affords the final product, UDP-N-acetyl-muramoyl-L-alanine-D-glutamate (UMAG). A hybrid quantum mechanical/molecular mechanical (QM/MM) molecular modeling approach was utilized, combining the B3LYP QM level of theory with empirical force field simulations to evaluate three possible reaction pathways leading to tetrahedral intermediate formation. Geometries of the starting structures based on crystallographic experimental data and tetrahedral intermediates were carefully examined together with a role of crucial amino acids and water molecules. The replica path method was used to generate the reaction pathways between the starting structures and the corresponding tetrahedral reaction intermediates, offering direct comparisons with a sequential kinetic mechanism and the available structural data for this enzyme. The acquired knowledge represents new and valuable information to assist in the ongoing efforts leading toward novel inhibitors of MurD as potential antibacterial drugs. (c) 2008 Wiley-Liss, Inc.

A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) study on Ornithine Cyclodeaminase (OCD): a tale of two iminiums.

PubMed

Ion, Bogdan F; Bushnell, Eric A C; Luna, Phil De; Gauld, James W

2012-10-11

Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine's C(α)-H group to the NAD+ cofactor with concomitant formation of a C(α)=NH(2)+ Schiff base with a barrier of 90.6 kJ mol-1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the C(α)=NH(2)+ intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the C(α)-position. This is then followed by cleavage and loss of the α-NH(2) group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline.

A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums

PubMed Central

Ion, Bogdan F.; Bushnell, Eric A. C.; De Luna, Phil; Gauld, James W.

2012-01-01

Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine’s Cα–H group to the NAD+ cofactor with concomitant formation of a Cα=NH2 + Schiff base with a barrier of 90.6 kJ mol−1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the Cα=NH2 + intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the Cα-position. This is then followed by cleavage and loss of the α-NH2 group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline. PMID:23202934

Prediction of Sliding Friction Coefficient Based on a Novel Hybrid Molecular-Mechanical Model.

PubMed

Zhang, Xiaogang; Zhang, Yali; Wang, Jianmei; Sheng, Chenxing; Li, Zhixiong

2018-08-01

Sliding friction is a complex phenomenon which arises from the mechanical and molecular interactions of asperities when examined in a microscale. To reveal and further understand the effects of micro scaled mechanical and molecular components of friction coefficient on overall frictional behavior, a hybrid molecular-mechanical model is developed to investigate the effects of main factors, including different loads and surface roughness values, on the sliding friction coefficient in a boundary lubrication condition. Numerical modelling was conducted using a deterministic contact model and based on the molecular-mechanical theory of friction. In the contact model, with given external loads and surface topographies, the pressure distribution, real contact area, and elastic/plastic deformation of each single asperity contact were calculated. Then asperity friction coefficient was predicted by the sum of mechanical and molecular components of friction coefficient. The mechanical component was mainly determined by the contact width and elastic/plastic deformation, and the molecular component was estimated as a function of the contact area and interfacial shear stress. Numerical results were compared with experimental results and a good agreement was obtained. The model was then used to predict friction coefficients in different operating and surface conditions. Numerical results explain why applied load has a minimum effect on the friction coefficients. They also provide insight into the effect of surface roughness on the mechanical and molecular components of friction coefficients. It is revealed that the mechanical component dominates the friction coefficient when the surface roughness is large (Rq > 0.2 μm), while the friction coefficient is mainly determined by the molecular component when the surface is relatively smooth (Rq < 0.2 μm). Furthermore, optimal roughness values for minimizing the friction coefficient are recommended.

Physiological and molecular mechanism of defense in cotton against Verticillium dahliae.

PubMed

Shaban, Muhammad; Miao, Yuhuan; Ullah, Abid; Khan, Anam Qadir; Menghwar, Hakim; Khan, Aamir Hamid; Ahmed, Muhammad Mahmood; Tabassum, Muhammad Adnan; Zhu, Longfu

2018-04-01

Cotton, a natural fiber producing crop of huge importance for textile industry, has been reckoned as the backbone in the economy of many developing countries. Verticillium wilt caused by Verticillium dahliae reflected as the most devastating disease of cotton crop in several parts of the world. Average losses due to attack of this disease are tremendous every year. There is urgent need to develop strategies for effective control of this disease. In the last decade, progress has been made to understand the interaction between cotton-V. dahliae and several growth and pathogenicity related genes were identified. Still, most of the molecular components and mechanisms of cotton defense against Verticillium wilt are poorly understood. However, from existing knowledge, it is perceived that cotton defense mechanism primarily depends on the pre-formed defense structures including thick cuticle, synthesis of phenolic compounds and delaying or hindering the expansion of the invader through advanced measures such as reinforcement of cell wall structure, accumulation of reactive oxygen species (ROS), release of phytoalexins, the hypersensitive response and the development of broad spectrum resistance named as, systemic acquired resistance (SAR). Investigation of these defense tactics provide valuable information about the improvement of cotton breeding strategies for the development of durable, cost effective, and broad spectrum resistant varieties. Consequently, this management approach will help to reduce the use of fungicides and also minimize other environmental hazards. In the present paper, we summarized the V. dahliae virulence mechanism and comprehensively discussed the cotton molecular mechanisms of defense such as physiological, biochemical responses with the addition of signaling pathways that are implicated towards attaining resistance against Verticillium wilt. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Mitochondrial diabetes: molecular mechanisms and clinical presentation.

PubMed

Maassen, J Antonie; 'T Hart, Leen M; Van Essen, Einar; Heine, Rob J; Nijpels, Giel; Jahangir Tafrechi, Roshan S; Raap, Anton K; Janssen, George M C; Lemkes, Herman H P J

2004-02-01

Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic beta-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic beta-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.

Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies

PubMed Central

Liu, Guangming; Wang, Yiwei; Zhao, Pengyao; Zhu, Yizhun; Yang, Xiaohan; Zheng, Tiezheng; Zhou, Xuezhong; Jin, Weilin; Sun, Changkai

2017-01-01

Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., “presynaptic nicotinic acetylcholine receptors”, “signaling by insulin receptor”). Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1) located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy. PMID:28388656

Molecular approaches towards the isolation of sleep-related genes.

PubMed

Schibler, U; Tafti, M

1999-06-01

Behavioural genetics is one of the most enticing fields in modern biology. Owing to straightforward and semiautomated techniques that can be used to measure locomotor activity, circadian rhythmicity is perhaps the best studied behaviour in animals. Thus, during the past decade, five essential circadian clock genes have been isolated in Drosophila, and homologous counterparts for all of these genes have also been found in mammals. As the sleep-wake cycle is under the control of the circadian clock, these circadian master genes are expected to influence sleeping behaviour. However, different vigilance states are regulated by additional mechanisms that also have a genetic basis. In this article we discuss molecular approaches that may prove useful in the search for sleep-related genes.

[Molecular mechanisms of thymocyte differentiation].

PubMed

Kuklina, E M

2003-01-01

A review of the main molecular events occurring during differentiation of T-lymphocytes in the thymus: T-cell specialization of early intrathymic precursors, formation and expression of antigen receptor, formation of antigen recognizing cell repertoire, and alpha beta/gamma beta- and CD4/CD8-commitment. The mechanisms of glucocorticoid-induced apoptosis of thymocytes and its blockade during antigen-dependent activation are considered. A special attention is paid to the analysis of intracellular signals underlying the clonal selection of thymocytes.

Features of Knowledge Building in Biology: Understanding Undergraduate Students' Ideas about Molecular Mechanisms.

PubMed

Southard, Katelyn; Wince, Tyler; Meddleton, Shanice; Bolger, Molly S

2016-01-01

Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning. © 2016 K. Southard et al. CBE—Life Sciences Education © 2016 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco

2016-09-13

The fast and constant development of drug resistant bacteria represents a serious medical emergency. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by OXA-23, a class D β-lactamase, combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture of the molecular steps leading to the formation of the Meropenem-OXA-23 covalent adduct, the subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements, validating the expected reaction path.

Molecular mechanics of mineralized collagen fibrils in bone

PubMed Central

Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

2013-01-01

Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents. PMID:23591891

Molecular mechanisms of nematode-nematophagous microbe interactions: basis for biological control of plant-parasitic nematodes.

PubMed

Li, Juan; Zou, Chenggang; Xu, Jianping; Ji, Xinglai; Niu, Xuemei; Yang, Jinkui; Huang, Xiaowei; Zhang, Ke-Qin

2015-01-01

Plant-parasitic nematodes cause significant damage to a broad range of vegetables and agricultural crops throughout the world. As the natural enemies of nematodes, nematophagous microorganisms offer a promising approach to control the nematode pests. Some of these microorganisms produce traps to capture and kill the worms from the outside. Others act as internal parasites to produce toxins and virulence factors to kill the nematodes from within. Understanding the molecular basis of microbe-nematode interactions provides crucial insights for developing effective biological control agents against plant-parasitic nematodes. Here, we review recent advances in our understanding of the interactions between nematodes and nematophagous microorganisms, with a focus on the molecular mechanisms by which nematophagous microorganisms infect nematodes and on the nematode defense against pathogenic attacks. We conclude by discussing several key areas for future research and development, including potential approaches to apply our recent understandings to develop effective biocontrol strategies.

Molecular mechanisms for protein-encoded inheritance

PubMed Central

Wiltzius, Jed J. W.; Landau, Meytal; Nelson, Rebecca; Sawaya, Michael R.; Apostol, Marcin I.; Goldschmidt, Lukasz; Soriaga, Angela B.; Cascio, Duilio; Rajashankar, Kanagalaghatta; Eisenberg, David

2013-01-01

Strains are phenotypic variants, encoded by nucleic acid sequences in chromosomal inheritance and by protein “conformations” in prion inheritance and transmission. But how is a protein “conformation” stable enough to endure transmission between cells or organisms? Here new polymorphic crystal structures of segments of prion and other amyloid proteins offer structural mechanisms for prion strains. In packing polymorphism, prion strains are encoded by alternative packings (polymorphs) of β-sheets formed by the same segment of a protein; in a second mechanism, segmental polymorphism, prion strains are encoded by distinct β-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring “conformations,” capable of encoding strains. These molecular mechanisms for transfer of information into prion strains share features with the familiar mechanism for transfer of information by nucleic acid inheritance, including sequence specificity and recognition by non-covalent bonds. PMID:19684598

Origin of microbial life: Nano- and molecular events, thermodynamics/entropy, quantum mechanisms and genetic instructions.

PubMed

Trevors, J T

2011-03-01

Currently, there are no agreed upon mechanisms and supporting evidence for the origin of the first microbial cells on the Earth. However, some hypotheses have been proposed with minimal supporting evidence and experimentation/observations. The approach taken in this article is that life originated at the nano- and molecular levels of biological organization, using quantum mechanic principles that became manifested as classical microbial cell(s), allowing the origin of microbial life on the Earth with a core or minimal, organic, genetic code containing the correct instructions for cell(s) for growth and division, in a micron dimension environment, with a local entropy range conducive to life (present about 4 billion years ago), and obeying the laws of thermodynamics. An integrated approach that explores all encompassing factors necessary for the origin of life, may bring forth plausible hypotheses (and mechanisms) with much needed supporting experimentation and observations for an origin of life theory. Copyright © 2010 Elsevier B.V. All rights reserved.

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

AC electrical characterisation and insight to charge transfer mechanisms in DNA molecular wires through temperature and UV effects.

PubMed

Kassegne, Sam; Wibowo, Denni; Chi, James; Ramesh, Varsha; Narenji, Alaleh; Khosla, Ajit; Mokili, John

2015-06-01

In this study, AC characterisation of DNA molecular wires, effects of frequency, temperature and UV irradiation on their conductivity is presented. λ-DNA molecular wires suspended between high aspect-ratio electrodes exhibit highly frequency-dependent conductivity that approaches metal-like behaviour at high frequencies (∼MHz). Detailed temperature dependence experiments were performed that traced the impedance response of λ-DNA until its denaturation. UV irradiation experiments where conductivity was lost at higher and longer UV exposures helped to establish that it is indeed λ-DNA molecular wires that generate conductivity. The subsequent renaturation of λ-DNA resulted in the recovery of current conduction, providing yet another proof of the conducting DNA molecular wire bridge. The temperature results also revealed hysteretic and bi-modal impedance responses that could make DNA a candidate for nanoelectronics components like thermal transistors and switches. Further, these experiments shed light on the charge transfer mechanism in DNA. At higher temperatures, the expected increase in thermal-induced charge hopping may account for the decrease in impedance supporting the 'charge hopping mechanism' theory. UV light, on the other hand, causes damage to GC base-pairs and phosphate groups reducing the path available both for hopping and short-range tunneling mechanisms, and hence increasing impedance--this again supporting both the 'charge hopping' and 'tunneling' mechanism theories.

A Proteomics View of the Molecular Mechanisms and Biomarkers of Glaucomatous Neurodegeneration

PubMed Central

Tezel, Gülgün

2013-01-01

Despite improving understanding of glaucoma, key molecular players of neurodegeneration that can be targeted for treatment of glaucoma, or molecular biomarkers that can be useful for clinical testing, remain unclear. Proteomics technology offers a powerful toolbox to accomplish these important goals of the glaucoma research and is increasingly being applied to identify molecular mechanisms and biomarkers of glaucoma. Recent studies of glaucoma using proteomics analysis techniques have resulted in the lists of differentially expressed proteins in human glaucoma and animal models. The global analysis of protein expression in glaucoma has been followed by cell-specific proteome analysis of retinal ganglion cells and astrocytes. The proteomics data have also guided targeted studies to identify post-translational modifications and protein-protein interactions during glaucomatous neurodegeneration. In addition, recent applications of proteomics have provided a number of potential biomarker candidates. Proteomics technology holds great promise to move glaucoma research forward toward new treatment strategies and biomarker discovery. By reviewing the major proteomics approaches and their applications in the field of glaucoma, this article highlights the power of proteomics in translational and clinical research related to glaucoma and also provides a framework for future research to functionally test the importance of specific molecular pathways and validate candidate biomarkers. PMID:23396249

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 mechanism for lipid flip-flops.

PubMed

Gurtovenko, Andrey A; Vattulainen, Ilpo

2007-12-06

Transmembrane lipid translocation (flip-flop) processes are involved in a variety of properties and functions of cell membranes, such as membrane asymmetry and programmed cell death. Yet, flip-flops are one of the least understood dynamical processes in membranes. In this work, we elucidate the molecular mechanism of pore-mediated transmembrane lipid translocation (flip-flop) acquired from extensive atomistic molecular dynamics simulations. On the basis of 50 successful flip-flop events resolved in atomic detail, we demonstrate that lipid flip-flops may spontaneously occur in protein-free phospholipid membranes under physiological conditions through transient water pores on a time scale of tens of nanoseconds. While the formation of a water pore is induced here by a transmembrane ion density gradient, the particular way by which the pore is formed is irrelevant for the reported flip-flop mechanism: the appearance of a transient pore (defect) in the membrane inevitably leads to diffusive translocation of lipids through the pore, which is driven by thermal fluctuations. Our findings strongly support the idea that the formation of membrane defects in terms of water pores is the rate-limiting step in the process of transmembrane lipid flip-flop, which, on average, requires several hours. The findings are consistent with available experimental and computational data and provide a view to interpret experimental observations. For example, the simulation results provide a molecular-level explanation in terms of pores for the experimentally observed fact that the exposure of lipid membranes to electric field pulses considerably reduces the time required for lipid flip-flops.

Molecular imaging in neuroendocrine tumors: molecular uptake mechanisms and clinical results.

PubMed

Koopmans, Klaas P; Neels, Oliver N; Kema, Ido P; Elsinga, Philip H; Links, Thera P; de Vries, Elisabeth G E; Jager, Pieter L

2009-09-01

Neuroendocrine tumors can originate almost everywhere in the body and consist of a great variety of subtypes. This paper focuses on molecular imaging methods using nuclear medicine techniques in neuroendocrine tumors, coupling molecular uptake mechanisms of radiotracers with clinical results. A non-systematic review is presented on receptor based and metabolic imaging methods. Receptor-based imaging covers the molecular backgrounds of somatostatin, vaso-intestinal peptide (VIP), bombesin and cholecystokinin (CCK) receptors and their link with nuclear imaging. Imaging methods based on specific metabolic properties include meta-iodo-benzylguanide (MIBG) and dimercapto-sulphuric acid (DMSA-V) scintigraphy as well as more modern positron emission tomography (PET)-based methods using radio-labeled analogues of amino acids, glucose, dihydroxyphenylalanine (DOPA), dopamine and tryptophan. Diagnostic sensitivities are presented for each imaging method and for each neuroendocrine tumor subtype. Finally, a Forest plot analysis of diagnostic performance is presented for each tumor type in order to provide a comprehensive overview for clinical use.

Submillisecond Elastic Recoil Reveals Molecular Origins of Fibrin Fiber Mechanics

PubMed Central

Hudson, Nathan E.; Ding, Feng; Bucay, Igal; O’Brien, E. Timothy; Gorkun, Oleg V.; Superfine, Richard; Lord, Susan T.; Dokholyan, Nikolay V.; Falvo, Michael R.

2013-01-01

Fibrin fibers form the structural scaffold of blood clots. Thus, their mechanical properties are of central importance to understanding hemostasis and thrombotic disease. Recent studies have revealed that fibrin fibers are elastomeric despite their high degree of molecular ordering. These results have inspired a variety of molecular models for fibrin’s elasticity, ranging from reversible protein unfolding to rubber-like elasticity. An important property that has not been explored is the timescale of elastic recoil, a parameter that is critical for fibrin’s mechanical function and places a temporal constraint on molecular models of fiber elasticity. Using high-frame-rate imaging and atomic force microscopy-based nanomanipulation, we measured the recoil dynamics of individual fibrin fibers and found that the recoil was orders of magnitude faster than anticipated from models involving protein refolding. We also performed steered discrete molecular-dynamics simulations to investigate the molecular origins of the observed recoil. Our results point to the unstructured αC regions of the otherwise structured fibrin molecule as being responsible for the elastic recoil of the fibers. PMID:23790375

Resolving the molecular mechanism of cadherin catch bond formation

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

Manibog, Kristine; Li, Hui; Rakshit, Sabyasachi

2014-06-02

Classical cadherin Ca(2+)-dependent cell-cell adhesion proteins play key roles in embryogenesis and in maintaining tissue integrity. Cadherins mediate robust adhesion by binding in multiple conformations. One of these adhesive states, called an X-dimer, forms catch bonds that strengthen and become longer lived in the presence of mechanical force. Here we use single-molecule force-clamp spectroscopy with an atomic force microscope along with molecular dynamics and steered molecular dynamics simulations to resolve the molecular mechanisms underlying catch bond formation and the role of Ca(2+) ions in this process. Our data suggest that tensile force bends the cadherin extracellular region such that theymore » form long-lived, force-induced hydrogen bonds that lock X-dimers into tighter contact. When Ca(2+) concentration is decreased, fewer de novo hydrogen bonds are formed and catch bond formation is eliminated« less

Combined quantum and molecular mechanics (QM/MM).

PubMed

Friesner, Richard A

2004-12-01

We describe the current state of the art of mixed quantum mechanics/molecular mechanics (QM/MM) methodology, with a particular focus on modeling of enzymatic reactions. Over the past decade, the effectiveness of these methods has increased dramatically, based on improved quantum chemical methods, advances in the description of the QM/MM interface, and reductions in the cost/performance of computing hardware. Two examples of pharmaceutically relevant applications, cytochrome P450 and class C β-lactamase, are presented.: © 2004 Elsevier Ltd . All rights reserved.

Polymer Fluid Dynamics: Continuum and Molecular Approaches.

PubMed

Bird, R B; Giacomin, A J

2016-06-07

To solve problems in polymer fluid dynamics, one needs the equations of continuity, motion, and energy. The last two equations contain the stress tensor and the heat-flux vector for the material. There are two ways to formulate the stress tensor: (a) One can write a continuum expression for the stress tensor in terms of kinematic tensors, or (b) one can select a molecular model that represents the polymer molecule and then develop an expression for the stress tensor from kinetic theory. The advantage of the kinetic theory approach is that one gets information about the relation between the molecular structure of the polymers and the rheological properties. We restrict the discussion primarily to the simplest stress tensor expressions or constitutive equations containing from two to four adjustable parameters, although we do indicate how these formulations may be extended to give more complicated expressions. We also explore how these simplest expressions are recovered as special cases of a more general framework, the Oldroyd 8-constant model. Studying the simplest models allows us to discover which types of empiricisms or molecular models seem to be worth investigating further. We also explore equivalences between continuum and molecular approaches. We restrict the discussion to several types of simple flows, such as shearing flows and extensional flows, which are of greatest importance in industrial operations. Furthermore, if these simple flows cannot be well described by continuum or molecular models, then it is not necessary to lavish time and energy to apply them to more complex flow problems.

Integrated structural biology to unravel molecular mechanisms of protein-RNA recognition.

PubMed

Schlundt, Andreas; Tants, Jan-Niklas; Sattler, Michael

2017-04-15

Recent advances in RNA sequencing technologies have greatly expanded our knowledge of the RNA landscape in cells, often with spatiotemporal resolution. These techniques identified many new (often non-coding) RNA molecules. Large-scale studies have also discovered novel RNA binding proteins (RBPs), which exhibit single or multiple RNA binding domains (RBDs) for recognition of specific sequence or structured motifs in RNA. Starting from these large-scale approaches it is crucial to unravel the molecular principles of protein-RNA recognition in ribonucleoprotein complexes (RNPs) to understand the underlying mechanisms of gene regulation. Structural biology and biophysical studies at highest possible resolution are key to elucidate molecular mechanisms of RNA recognition by RBPs and how conformational dynamics, weak interactions and cooperative binding contribute to the formation of specific, context-dependent RNPs. While large compact RNPs can be well studied by X-ray crystallography and cryo-EM, analysis of dynamics and weak interaction necessitates the use of solution methods to capture these properties. Here, we illustrate methods to study the structure and conformational dynamics of protein-RNA complexes in solution starting from the identification of interaction partners in a given RNP. Biophysical and biochemical techniques support the characterization of a protein-RNA complex and identify regions relevant in structural analysis. Nuclear magnetic resonance (NMR) is a powerful tool to gain information on folding, stability and dynamics of RNAs and characterize RNPs in solution. It provides crucial information that is complementary to the static pictures derived from other techniques. NMR can be readily combined with other solution techniques, such as small angle X-ray and/or neutron scattering (SAXS/SANS), electron paramagnetic resonance (EPR), and Förster resonance energy transfer (FRET), which provide information about overall shapes, internal domain

Molecular mechanisms in response to phosphate starvation in rice.

PubMed

Panigrahy, Madhusmita; Rao, D Nageswara; Sarla, N

2009-01-01

Phosphorus is one of the most important elements that significantly affect plant growth and metabolism. Among the macro-nutrients, phosphorus is the least available to the plants as major phosphorus content of the fertiliser is sorbed by soil particles. An increased knowledge of the regulatory mechanisms controlling plant's phosphorus status is vital for improving phosphorus uptake and P-use efficiency and for reducing excessive input of fertilisers, while maintaining an acceptable yield. Phosphorus use efficiency has been studied using forward and reverse genetic analyses of mutants, quantitative genomic approaches and whole plant physiology but all these studies need to be integrated for a clearer understanding. We provide a critical overview on the molecular mechanisms and the components involved in the plant during phosphorus starvation. Then we summarize the information available on the genes and QTLs involved in phosphorus signalling and also the methods to estimate total phosphate in plant tissue. Also, an effort is made to build a comprehensive picture of phosphorus uptake, homeostasis, assimilation, remobilization, its deposition in the grain and its interaction with other micro- and macro-nutrients as well as phytohormones.

Exploring the relative reactivities of the hydroxyl groups of monosaccharides by molecular modeling and molecular mechanics

NASA Astrophysics Data System (ADS)

Box, V. G. S.; Evans-Lora, T.

2000-01-01

The molecular modeling program STR3DI.EXE, and its molecular mechanics module, QVBMM, were used to simulate, and evaluate, the stereo-electronic effects in the mono-alkoxides of the 4,6- O-ethylideneglycopyranosides of allose, mannose, galactose and glucose. This study has confirmed the ability of these molecular modeling tools to predict the regiochemistry and reactivity of these sugar derivatives, and holds considerable implications for unraveling the chemistry of the rare monosaccharides.

Optimization and benchmarking of a perturbative Metropolis Monte Carlo quantum mechanics/molecular mechanics program

NASA Astrophysics Data System (ADS)

Feldt, Jonas; Miranda, Sebastião; Pratas, Frederico; Roma, Nuno; Tomás, Pedro; Mata, Ricardo A.

2017-12-01

In this work, we present an optimized perturbative quantum mechanics/molecular mechanics (QM/MM) method for use in Metropolis Monte Carlo simulations. The model adopted is particularly tailored for the simulation of molecular systems in solution but can be readily extended to other applications, such as catalysis in enzymatic environments. The electrostatic coupling between the QM and MM systems is simplified by applying perturbation theory to estimate the energy changes caused by a movement in the MM system. This approximation, together with the effective use of GPU acceleration, leads to a negligible added computational cost for the sampling of the environment. Benchmark calculations are carried out to evaluate the impact of the approximations applied and the overall computational performance.

Optimization and benchmarking of a perturbative Metropolis Monte Carlo quantum mechanics/molecular mechanics program.

PubMed

Feldt, Jonas; Miranda, Sebastião; Pratas, Frederico; Roma, Nuno; Tomás, Pedro; Mata, Ricardo A

2017-12-28

In this work, we present an optimized perturbative quantum mechanics/molecular mechanics (QM/MM) method for use in Metropolis Monte Carlo simulations. The model adopted is particularly tailored for the simulation of molecular systems in solution but can be readily extended to other applications, such as catalysis in enzymatic environments. The electrostatic coupling between the QM and MM systems is simplified by applying perturbation theory to estimate the energy changes caused by a movement in the MM system. This approximation, together with the effective use of GPU acceleration, leads to a negligible added computational cost for the sampling of the environment. Benchmark calculations are carried out to evaluate the impact of the approximations applied and the overall computational performance.

Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

PubMed Central

Samal, Jasmine; Kandpal, Manish

2012-01-01

Summary: Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section. PMID:22232374

Molecular mechanism of lytic polysaccharide monooxygenases.

PubMed

Hedegård, Erik Donovan; Ryde, Ulf

2018-04-21

The lytic polysaccharide monooxygenases (LPMOs) are copper metalloenzymes that can enhance polysaccharide depolymerization through an oxidative mechanism and hence boost generation of biofuel from e.g. cellulose. By employing density functional theory in a combination of quantum mechanics and molecular mechanics (QM/MM), we report a complete description of the molecular mechanism of LPMOs. The QM/MM scheme allows us to describe all reaction steps with a detailed protein environment and we show that this is necessary. Several active species capable of abstracting a hydrogen from the substrate have been proposed previously and starting from recent crystallographic work on a substrate-LPMO complex, we investigate previously suggested paths as well as new ones. We describe the generation of the reactive intermediates, the abstraction of a hydrogen atom from the polysaccharide substrate, as well as the final recombination step in which OH is transferred back to the substrate. We show that a superoxo [CuO 2 ] + complex can be protonated by a nearby histidine residue (suggested by recent mutagenesis studies and crystallographic work) and, provided an electron source is available, leads to formation of an oxyl-complex after cleavage of the O-O bond and dissociation of water. The oxyl complex either reacts with the substrate or is further protonated to a hydroxyl complex. Both the oxyl and hydroxyl complexes are also readily generated from a reaction with H 2 O 2 , which was recently suggested to be the true co-substrate, rather than O 2 . The C-H abstraction by the oxyl and hydroxy complexes is overall favorable with activation barriers of 69 and 94 kJ mol -1 , compared to the much higher barrier (156 kJ mol -1 ) obtained for the copper-superoxo species. We obtain good structural agreement for intermediates for which structural data are available and the estimated reaction energies agree with experimental rate constants. Thus, our suggested mechanism is the most complete

Autonomy, explanation, and theoretical values: physicists and chemists on molecular quantum mechanics.

PubMed

Hendry, Robin Findlay

2003-05-01

The emergence of quantum chemistry in the early twentieth century was an international as well as an interdisciplinary affair, involving dialogue between physicists and chemists in Germany, the United States, and Britain. Historians of science have recently documented both the causes and effects of this internationalism and interdisciplinarity. Chemists and physicists involved in the development of quantum chemistry in its first few decades tended to argue for opposing views on acceptable standards of explanation in their field, although the debate did not divide along disciplinary lines. The purpose of this paper is to investigate these different positions, through the methodological reflections of John Clarke Slater, Linus Pauling, and Charles Coulson. Slater tended to argue for quantum-mechanical rigor and the application of fundamental principles as the values guiding models of molecular bonding. Although they were on different sides of the debate between the valence-bond and molecular-orbital approaches, Pauling and Coulson both emphasized the recovery of traditional chemical explanations and systematic explanatory power within chemistry.

Molecular mechanism of Danshensu on platelet antiaggregation

NASA Astrophysics Data System (ADS)

Yu, Chen; Geng, Feng; Fan, Hua-Ying; Luan, Hai-Yun; Liu, Yue; Ji, Kai; Fu, Feng-Hua

2018-04-01

In this study, we detected the effect of Danshensu on PARs-PLCβsignaling pathway to elucidate molecular mechanism of Danshensu on platelet anti-aggregation. Our results demonstrate that Danshensu is able to decrease the levels of IP3, Ca2+ and AA secretion, which indicate that Danshensu may involve in PARs-PLCβ signaling pathways. Molecular docking study shows that Danshesu has similar polar interactions with PAR1 receptors as BMS200261 at the same position. The findings from our study enable a better understanding of Danshensu biological properties, which could ultimately lead to the development of multi-target antiplatelet natural medicine for the treatment and/or prevention of some thrombotic diseases.

Mechanical response of two polyimides through coarse-grained molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Sudarkodi, V.; Sooraj, K.; Nair, Nisanth N.; Basu, Sumit; Parandekar, Priya V.; Sinha, Nishant K.; Prakash, Om; Tsotsis, Tom

2018-03-01

Coarse-grained molecular dynamics (MD) simulations allow us to predict the mechanical responses of polymers, starting merely with a description of their molecular architectures. It is interesting to ask whether, given two competing molecular architectures, coarse-grained MD simulations can predict the differences that can be expected in their mechanical responses. We have studied two crosslinked polyimides PMR15 and HFPE52—both used in high- temperature applications—to assess whether the subtle differences in their uniaxial stress-strain responses, revealed by experiments, can be reproduced by carefully coarse-grained MD models. The coarse graining procedure for PMR15 is outlined in this work, while the coarse grain forcefields for HFPE52 are borrowed from an earlier one (Pandiyan et al 2015 Macromol. Theory Simul. 24 513-20). We show that the stress-strain responses of both these polyimides are qualitatively reproduced, and important insights into their deformation and failure mechanisms are obtained. More importantly, the differences in the molecular architecture between the polyimides carry over to the differences in the stress-strain responses in a manner that parallels the experimental results. A critical assessment of the successes and shortcomings of predicting mechanical responses through coarse-grained MD simulations has been made.

A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

ERIC Educational Resources Information Center

Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

2015-01-01

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do…

Mechanism of molecular recognition on molecular imprinted monolith by capillary electrochromatography.

PubMed

Liu, Zhao-Sheng; Xu, Yan-Li; Yan, Chao; Gao, Ru-Yu

2005-09-16

The recognition mechanism of molecularly imprinted polymer (MIP) in capillary electrochromatography (CEC) is complicated since it possesses a hybrid process, which comprises the features of chromatographic retention, electrophoretic migration and molecular imprinting. For an understanding of the molecular recognition of MIP in CEC, a monolithic MIP in a capillary with 1,1'-binaphthyl-2,2'-diamine (BNA) imprinting was prepared by in situ copolymerization of imprinted molecule, methacrylic acid and ethylene glycol dimethacrylate in porogenic solvent, a mixture of toluene-isooctane. Strong recognition ability and high column performance (theory plates was 43,000 plates/m) of BNA were achieved on this monolithic MIP in CEC mode. In addition, BNA and its structural analogue, 1,1'-bi-2, 2'-naphthol, differing in functional groups, were used as model compounds to study imprinting effect on the resultant BNA-imprinted monolithic column, a reference column without imprinting of BNA and a open capillary. The effects of organic modifier concentration, pH value of buffer, salt concentration of buffer and column temperature on the retention and recognition of two compounds were investigated. The results showed that the molecular recognition on MIP monolith in CEC mode mainly derived from imprinting cavities on BNA-imprinted polymer other than chromatographic retention and electrophoretic migration.

[Molecular Biology on the Mechanisms of Autism Spectrum Disorder for Clinical Psychiatrists].

PubMed

Makinodan, Manabu

2015-01-01

While, in general, a certain number of clinical psychiatrists might not be familiar with molecular biology, the mechanisms of mental illnesses have been uncovered by molecular biology for decades. Among mental illnesses, even biological psychiatrists and neuroscientists have paid less attention to the biological treatment of autism spectrum disorder (ASD) than Alzheimer's disease and schizophrenia since ASD has been regarded as a developmental disorder that was seemingly untreatable. However, multifaceted methods of molecular biology have revealed the mechanisms that would lead to the medication of ASD. In this article, how molecular biology dissects the pathobiology of ASD is described in order to announce the possibilities of biological treatment for clinical psychiatrists.

Revealing the Origins of Mechanically Induced Fluorescence Changes in Organic Molecular Crystals.

PubMed

Wilbraham, Liam; Louis, Marine; Alberga, Domenico; Brosseau, Arnaud; Guillot, Régis; Ito, Fuyuki; Labat, Frédéric; Métivier, Rémi; Allain, Clémence; Ciofini, Ilaria

2018-05-29

Mechanofluorochromic molecular materials display a change in fluorescence color through mechanical stress. Complex structure-property relationships in both the crystalline and amorphous phases of these materials govern both the presence and strength of this behavior, which is usually deemed the result of a mechanically induced phase transition. However, the precise nature of the emitting species in each phase is often a matter of speculation, resulting from experimental data that are difficult to interpret, and a lack of an acceptable theoretical model capable of capturing complex environmental effects. With a combined strategy using sophisticated experimental techniques and a new theoretical approach, here the varied mechanofluorochromic behavior of a series of difluoroboron diketonates is shown to be driven by the formation of low-energy exciton traps in the amorphous phase, with a limited number of traps giving rise to the full change in fluorescence color. The results highlight intrinsic structural links between crystalline and amorphous phases, and how these may be exploited for further development of powerful mechanofluorochromic assemblies, in line with modern crystal engineering approaches. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anticancer Molecular Mechanisms of Resveratrol

PubMed Central

Varoni, Elena M.; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

2016-01-01

Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment. PMID:27148534

Anticancer Molecular Mechanisms of Resveratrol.

PubMed

Varoni, Elena M; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

2016-01-01

Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment.

Submillisecond elastic recoil reveals molecular origins of fibrin fiber mechanics.

PubMed

Hudson, Nathan E; Ding, Feng; Bucay, Igal; O'Brien, E Timothy; Gorkun, Oleg V; Superfine, Richard; Lord, Susan T; Dokholyan, Nikolay V; Falvo, Michael R

2013-06-18

Fibrin fibers form the structural scaffold of blood clots. Thus, their mechanical properties are of central importance to understanding hemostasis and thrombotic disease. Recent studies have revealed that fibrin fibers are elastomeric despite their high degree of molecular ordering. These results have inspired a variety of molecular models for fibrin's elasticity, ranging from reversible protein unfolding to rubber-like elasticity. An important property that has not been explored is the timescale of elastic recoil, a parameter that is critical for fibrin's mechanical function and places a temporal constraint on molecular models of fiber elasticity. Using high-frame-rate imaging and atomic force microscopy-based nanomanipulation, we measured the recoil dynamics of individual fibrin fibers and found that the recoil was orders of magnitude faster than anticipated from models involving protein refolding. We also performed steered discrete molecular-dynamics simulations to investigate the molecular origins of the observed recoil. Our results point to the unstructured αC regions of the otherwise structured fibrin molecule as being responsible for the elastic recoil of the fibers. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach.

PubMed

Klimochkin, Yuri N; Shiryaev, Vadim A; Petrov, Pavel V; Radchenko, Eugene V; Palyulin, Vladimir A; Zefirov, Nikolay S

2016-01-01

The influenza A virus M2 proton channel plays a critical role in its life cycle. However, known M2 inhibitors have lost their clinical efficacy due to the spread of resistant mutant channels. Thus, the search for broad-spectrum M2 channel inhibitors is of great importance. The goal of the present work was to develop a general approach supporting the design of ligands interacting with multiple labile targets and to propose on its basis the potential broad-spectrum inhibitors of the M2 proton channel. The dynamic dimer-of-dimers structures of the three primary M2 target variants, wild-type, S31N and V27A, were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites. The potential inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics simulation. The binding sites of the M2 proton channel inhibitors were analyzed, a number of potential broad-spectrum inhibitors were identified and the binding modes and probable mechanisms of action of one promising compound were clarified. Using the molecular dynamics and molecular docking techniques, we have refined the dynamic dimer-ofdimers structures of the WT, S31N and V27A variants of the M2 proton channel of the influenza A virus, analyzed the inhibitor binding sites, identified a number of potential broad-spectrum inhibitor structures targeting them, and clarified the binding modes and probable mechanisms of action of one promising compound. The proposed approach is also suitable for the design of ligands interacting with other multiple labile targets.

Cellular and molecular mechanisms for the bone response to mechanical loading

NASA Technical Reports Server (NTRS)

Bloomfield, S. A.

2001-01-01

To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

Sampling enhancement for the quantum mechanical potential based molecular dynamics simulations: a general algorithm and its extension for free energy calculation on rugged energy surface.

PubMed

Li, Hongzhi; Yang, Wei

2007-03-21

An approach is developed in the replica exchange framework to enhance conformational sampling for the quantum mechanical (QM) potential based molecular dynamics simulations. Importantly, with our enhanced sampling treatment, a decent convergence for electronic structure self-consistent-field calculation is robustly guaranteed, which is made possible in our replica exchange design by avoiding direct structure exchanges between the QM-related replicas and the activated (scaled by low scaling parameters or treated with high "effective temperatures") molecular mechanical (MM) replicas. Although the present approach represents one of the early efforts in the enhanced sampling developments specifically for quantum mechanical potentials, the QM-based simulations treated with the present technique can possess the similar sampling efficiency to the MM based simulations treated with the Hamiltonian replica exchange method (HREM). In the present paper, by combining this sampling method with one of our recent developments (the dual-topology alchemical HREM approach), we also introduce a method for the sampling enhanced QM-based free energy calculations.

Multi-Targeted Molecular Effects of Hibiscus sabdariffa Polyphenols: An Opportunity for a Global Approach to Obesity

PubMed Central

Herranz-López, María; Olivares-Vicente, Mariló; Barrajón-Catalán, Enrique; Segura-Carretero, Antonio; Joven, Jorge; Micol, Vicente

2017-01-01

Improper diet can alter gene expression by breaking the energy balance equation and changing metabolic and oxidative stress biomarkers, which can result in the development of obesity-related metabolic disorders. The pleiotropic effects of dietary plant polyphenols are capable of counteracting by modulating different key molecular targets at the cell, as well as through epigenetic modifications. Hibiscus sabdariffa (HS)-derived polyphenols are known to ameliorate various obesity-related conditions. Recent evidence leads to propose the complex nature of the underlying mechanism of action. This multi-targeted mechanism includes the regulation of energy metabolism, oxidative stress and inflammatory pathways, transcription factors, hormones and peptides, digestive enzymes, as well as epigenetic modifications. This article reviews the accumulated evidence on the multiple anti-obesity effects of HS polyphenols in cell and animal models, as well as in humans, and its putative molecular targets. In silico studies reveal the capacity of several HS polyphenols to act as putative ligands for different digestive and metabolic enzymes, which may also deserve further attention. Therefore, a global approach including integrated and networked omics techniques, virtual screening and epigenetic analysis is necessary to fully understand the molecular mechanisms of HS polyphenols and metabolites involved, as well as their possible implications in the design of safe and effective polyphenolic formulations for obesity. PMID:28825642

Multi-Targeted Molecular Effects of Hibiscus sabdariffa Polyphenols: An Opportunity for a Global Approach to Obesity.

PubMed

Herranz-López, María; Olivares-Vicente, Mariló; Encinar, José Antonio; Barrajón-Catalán, Enrique; Segura-Carretero, Antonio; Joven, Jorge; Micol, Vicente

2017-08-20

Improper diet can alter gene expression by breaking the energy balance equation and changing metabolic and oxidative stress biomarkers, which can result in the development of obesity-related metabolic disorders. The pleiotropic effects of dietary plant polyphenols are capable of counteracting by modulating different key molecular targets at the cell, as well as through epigenetic modifications. Hibiscus sabdariffa (HS)-derived polyphenols are known to ameliorate various obesity-related conditions. Recent evidence leads to propose the complex nature of the underlying mechanism of action. This multi-targeted mechanism includes the regulation of energy metabolism, oxidative stress and inflammatory pathways, transcription factors, hormones and peptides, digestive enzymes, as well as epigenetic modifications. This article reviews the accumulated evidence on the multiple anti-obesity effects of HS polyphenols in cell and animal models, as well as in humans, and its putative molecular targets. In silico studies reveal the capacity of several HS polyphenols to act as putative ligands for different digestive and metabolic enzymes, which may also deserve further attention. Therefore, a global approach including integrated and networked omics techniques, virtual screening and epigenetic analysis is necessary to fully understand the molecular mechanisms of HS polyphenols and metabolites involved, as well as their possible implications in the design of safe and effective polyphenolic formulations for obesity.

Glauber-theory approach for molecular vibrational excitations

NASA Technical Reports Server (NTRS)

Chang, T. N.; Poe, R. T.; Ray, P.

1973-01-01

Molecular vibrational excitations by charged-particle impact are investigated within the Glauber-theory approach. Theoretical results for electron-H2 scattering give good agreement with experimental data. We study the physical effects responsible for the structures in the differential cross section.

Interlocking Mechanism between Molecular Gears Attached to Surfaces.

PubMed

Zhao, Rundong; Zhao, Yan-Ling; Qi, Fei; Hermann, Klaus E; Zhang, Rui-Qin; Van Hove, Michel A

2018-03-27

While molecular machines play an increasingly significant role in nanoscience research and applications, there remains a shortage of investigations and understanding of the molecular gear (cogwheel), which is an indispensable and fundamental component to drive a larger correlated molecular machine system. Employing ab initio calculations, we investigate model systems consisting of molecules adsorbed on metal or graphene surfaces, ranging from very simple triple-arm gears such as PF 3 and NH 3 to larger multiarm gears based on carbon rings. We explore in detail the transmission of slow rotational motion from one gear to the next by these relatively simple molecules, so as to isolate and reveal the mechanisms of the relevant intermolecular interactions. Several characteristics of molecular gears are discussed, in particular the flexibility of the arms and the slipping and skipping between interlocking arms of adjacent gears, which differ from familiar macroscopic rigid gears. The underlying theoretical concepts suggest strongly that other analogous structures may also exhibit similar behavior which may inspire future exploration in designing large correlated molecular machines.

Molecular mechanisms of immunosuppression.

PubMed

Baumann, G; Zenke, G; Wenger, R; Hiestand, P; Quesniaux, V; Andersen, E; Schreier, M H

1992-04-01

The immunosuppressive drug cyclosporin A (CsA, Sandimmun, SIM) is currently being evaluated in a variety of autoimmune disorders with some remarkable successes. Despite the wide empiric application of CsA, the precise mechanism of action of this drug remains elusive. To identify the molecular mode of action of CsA in the process of T cell activation, we have compared the biological profile of cyclophilin-binding cyclosporin analogues (CBCA), which lack immunosuppressive properties, with CsA. We have found that CsA binding to its intracellular receptor (cyclophilin) is required but not sufficient for immunosuppression. Moreover, inhibition of the peptidyl-prolyl cis-trans isomerase activity of cyclophilin does not seem to be relevant for the inhibitory effects of CsA. In analogy to the immunosuppressants FK506 and rapamycin, a specific structure at the 'effector' domain of the CsA molecule different from the immunophilin 'binding' domain determines the biological activity. Overall, a significant understanding of the structure-activity relationship of CsA has emerged. This will have a major impact on the identification of the precise mechanism of action of CsA and its side effects in the process of immunosuppression.

Graph-drawing algorithms geometries versus molecular mechanics in fullereness

NASA Astrophysics Data System (ADS)

Kaufman, M.; Pisanski, T.; Lukman, D.; Borštnik, B.; Graovac, A.

1996-09-01

The algorithms of Kamada-Kawai (KK) and Fruchterman-Reingold (FR) have been recently generalized (Pisanski et al., Croat. Chem. Acta 68 (1995) 283) in order to draw molecular graphs in three-dimensional space. The quality of KK and FR geometries is studied here by comparing them with the molecular mechanics (MM) and the adjacency matrix eigenvectors (AME) algorithm geometries. In order to compare different layouts of the same molecule, an appropriate method has been developed. Its application to a series of experimentally detected fullerenes indicates that the KK, FR and AME algorithms are able to reproduce plausible molecular geometries.

Force transduction and lipid binding in MscL: A continuum-molecular approach

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

Vanegas, Juan M.; Arroyo, Marino; Fotiadis, Dimitrios

2014-12-01

The bacterial mechanosensitive channel MscL, a small protein mainly activated by membrane tension, is a central model system to study the transduction of mechanical stimuli into chemical signals. Mutagenic studies suggest that MscL gating strongly depends on both intra-protein and interfacial lipid-protein interactions. However, there is a gap between this detailed chemical information and current mechanical models of MscL gating. Here, we investigate the MscL bilayer-protein interface through molecular dynamics simulations, and take a combined continuum-molecular approach to connect chemistry and mechanics. We quantify the effect of membrane tension on the forces acting on the surface of the channel, andmore » identify interactions that may be critical in the force transduction between the membrane and MscL. We find that the local stress distribution on the protein surface is largely asymmetric, particularly under tension, with the cytoplasmic side showing significantly larger and more localized forces, which pull the protein radially outward. The molecular interactions that mediate this behavior arise from hydrogen bonds between the electronegative oxygens in the lipid headgroup and a cluster of positively charged lysine residues on the amphipathic S1 domain and the C-terminal end of the second trans-membrane helix. We take advantage of this strong interaction (estimated to be 10–13 kT per lipid) to actuate the channel (by applying forces on protein-bound lipids) and explore its sensitivity to the pulling magnitude and direction. We conclude by highlighting the simple motif that confers MscL with strong anchoring to the bilayer, and its presence in various integral membrane proteins including the human mechanosensitive channel K2P1 and bovine rhodopsin.« less

How Molecular Structure Affects Mechanical Properties of an Advanced Polymer

NASA Technical Reports Server (NTRS)

Nicholson, Lee M.; Whitley, Karen S.; Gates, Thomas S.; Hinkley, Jeffrey A.

2000-01-01

density was performed over a range of temperatures below the glass transition temperature. The physical characterization, elastic properties and notched tensile strength all as a function of molecular weight and test temperature were determined. For the uncrosslinked SI material, it was shown that notched tensile strength is a strong function of both temperature and molecular weight, whereas stiffness is only a strong function of temperature. For the crosslinked PETI-SI material, it was shown that the effect of crosslinking significantly enhances the mechanical performance of the low molecular weight material; comparable to that exhibited by the high molecular weight material.

Some Fundamental Molecular Mechanisms of Contractility in Fibrous Macromolecules

PubMed Central

Mandelkern, L.

1967-01-01

The fundamental molecular mechanisms of contractility and tension development in fibrous macromolecules are developed from the point of view of the principles of polymer physical chemistry. The problem is treated in a general manner to encompass the behavior of all macromolecular systems irrespective of their detailed chemical structure and particular function, if any. Primary attention is given to the contractile process which accompanies the crystal-liquid transition in axially oriented macromolecular systems. The theoretical nature of the process is discussed, and many experimental examples are given from the literature which demonstrate the expected behavior. Experimental attention is focused on the contraction of fibrous proteins, and the same underlying molecular mechanism is shown to be operative for a variety of different systems. PMID:6050598

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

PubMed

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

2017-05-23

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

Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations

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

Ojeda-May, Pedro; Pu, Jingzhi, E-mail: jpu@iupui.edu

The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r{sup −1} term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as amore » Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN{sub 2} reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN{sub 2} reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, the QM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of

Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations.

PubMed

Ojeda-May, Pedro; Pu, Jingzhi

2015-11-07

The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r(-1) term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as a Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN2 reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN2 reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, the QM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of chemical reactions.

Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations

NASA Astrophysics Data System (ADS)

Ojeda-May, Pedro; Pu, Jingzhi

2015-11-01

The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r-1 term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as a Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN2 reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN2 reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, the QM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of chemical reactions.

Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides.

PubMed

Zitnay, Jared L; Li, Yang; Qin, Zhao; San, Boi Hoa; Depalle, Baptiste; Reese, Shawn P; Buehler, Markus J; Yu, S Michael; Weiss, Jeffrey A

2017-03-22

Mechanical injury to connective tissue causes changes in collagen structure and material behaviour, but the role and mechanisms of molecular damage have not been established. In the case of mechanical subfailure damage, no apparent macroscale damage can be detected, yet this damage initiates and potentiates in pathological processes. Here, we utilize collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched rat tail tendon fascicle. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury.

Mechanisms of bacterial morphogenesis: evolutionary cell biology approaches provide new insights.

PubMed

Jiang, Chao; Caccamo, Paul D; Brun, Yves V

2015-04-01

How Darwin's "endless forms most beautiful" have evolved remains one of the most exciting questions in biology. The significant variety of bacterial shapes is most likely due to the specific advantages they confer with respect to the diverse environments they occupy. While our understanding of the mechanisms generating relatively simple shapes has improved tremendously in the last few years, the molecular mechanisms underlying the generation of complex shapes and the evolution of shape diversity are largely unknown. The emerging field of bacterial evolutionary cell biology provides a novel strategy to answer this question in a comparative phylogenetic framework. This relatively novel approach provides hypotheses and insights into cell biological mechanisms, such as morphogenesis, and their evolution that would have been difficult to obtain by studying only model organisms. We discuss the necessary steps, challenges, and impact of integrating "evolutionary thinking" into bacterial cell biology in the genomic era. © 2015 WILEY Periodicals, Inc.

Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms.

PubMed

Croze, Marine L; Zimmer, Luc

2018-01-01

Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.

Quantum Mechanical Studies of Molecular Hyperpolarizabilities.

DTIC Science & Technology

1980-04-30

exponent , reflects the screening of an electron in a given orbital by the interior electrons in the atom or molecule. In practice, when studying...Basis sets have evolved over the years in molecular quantum mechanics until sets of orbital exponents for the different atoms composing the molecule have...and R. P. Hurst , J. Chem. Phys. 46, 2356 (1967); S. P. LickmannI and J. W. Moskowitz, J. Chem. Phys. 54, 3622 7T971). 26. T. H. Dunning, J. Chem. Phys

Multi-level molecular modelling for plasma medicine

NASA Astrophysics Data System (ADS)

Bogaerts, Annemie; Khosravian, Narjes; Van der Paal, Jonas; Verlackt, Christof C. W.; Yusupov, Maksudbek; Kamaraj, Balu; Neyts, Erik C.

2016-02-01

Modelling at the molecular or atomic scale can be very useful for obtaining a better insight in plasma medicine. This paper gives an overview of different atomic/molecular scale modelling approaches that can be used to study the direct interaction of plasma species with biomolecules or the consequences of these interactions for the biomolecules on a somewhat longer time-scale. These approaches include density functional theory (DFT), density functional based tight binding (DFTB), classical reactive and non-reactive molecular dynamics (MD) and united-atom or coarse-grained MD, as well as hybrid quantum mechanics/molecular mechanics (QM/MM) methods. Specific examples will be given for three important types of biomolecules, present in human cells, i.e. proteins, DNA and phospholipids found in the cell membrane. The results show that each of these modelling approaches has its specific strengths and limitations, and is particularly useful for certain applications. A multi-level approach is therefore most suitable for obtaining a global picture of the plasma-biomolecule interactions.

Insights into the interaction of methotrexate and human serum albumin: A spectroscopic and molecular modeling approach.

PubMed

Cheng, Li-Yang; Fang, Min; Bai, Ai-Min; Ouyang, Yu; Hu, Yan-Jun

2017-08-01

In this study, fluorescence spectroscopy and molecular modeling approaches were employed to investigate the binding of methotrexate to human serum albumin (HSA) under physiological conditions. From the mechanism, it was demonstrated that fluorescence quenching of HSA by methotrexate results from the formation of a methotrexate/HSA complex. Binding parameters calculated using the Stern-Volmer method and the Scatchard method showed that methotrexate binds to HSA with binding affinities in the order 10 4  L·mol -1 . Thermodynamic parameter studies revealed that the binding reaction is spontaneous, and that hydrogen bonds and van der Waals interactions play a major role in the reaction. Site marker competitive displacement experiments and a molecular modeling approach demonstrated that methotrexate binds with appropriate affinity to site I (subdomain IIA) of HSA. Furthermore, we discuss some factors that influence methotrexate binding to HSA. Copyright © 2017 John Wiley & Sons, Ltd.

Molecular Engineering for Mechanically Resilient and Stretchable Electronic Polymers and Composites

DTIC Science & Technology

2016-06-08

conjugated polymers and composites by analysis of the structural determinants of the mechanical properties. We developed coarse-grained molecular...dynamics simulations that predicted the mechanical properties of conjugated polymers and polymer -fullerene composites. We elucidated the mechanical...We also determined the effect of cyclic stretching on the microstructure and mechanical properties of conjugated polymers . We used many of

Pipeline for inferring protein function from dynamics using coarse-grained molecular mechanics forcefield.

PubMed

Bhadra, Pratiti; Pal, Debnath

2017-04-01

Dynamics is integral to the function of proteins, yet the use of molecular dynamics (MD) simulation as a technique remains under-explored for molecular function inference. This is more important in the context of genomics projects where novel proteins are determined with limited evolutionary information. Recently we developed a method to match the query protein's flexible segments to infer function using a novel approach combining analysis of residue fluctuation-graphs and auto-correlation vectors derived from coarse-grained (CG) MD trajectory. The method was validated on a diverse dataset with sequence identity between proteins as low as 3%, with high function-recall rates. Here we share its implementation as a publicly accessible web service, named DynFunc (Dynamics Match for Function) to query protein function from ≥1 µs long CG dynamics trajectory information of protein subunits. Users are provided with the custom-developed coarse-grained molecular mechanics (CGMM) forcefield to generate the MD trajectories for their protein of interest. On upload of trajectory information, the DynFunc web server identifies specific flexible regions of the protein linked to putative molecular function. Our unique application does not use evolutionary information to infer molecular function from MD information and can, therefore, work for all proteins, including moonlighting and the novel ones, whenever structural information is available. Our pipeline is expected to be of utility to all structural biologists working with novel proteins and interested in moonlighting functions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Advances on molecular mechanism of the adaptive evolution of Chiroptera (bats).

PubMed

Yunpeng, Liang; Li, Yu

2015-01-01

As the second biggest animal group in mammals, Chiroptera (bats) demonstrates many unique adaptive features in terms of flight, echolocation, auditory acuity, feeding habit, hibernation and immune defense, providing an excellent system for understanding the molecular basis of how organisms adapt to the living environments encountered. In this review, we summarize the researches on the molecular mechanism of the adaptive evolution of Chiroptera, especially the recent researches at the genome levels, suggesting a far more complex evolutionary pattern and functional diversity than previously thought. In the future, along with the increasing numbers of Chiroptera species genomes available, new evolutionary patterns and functional divergence will be revealed, which can promote the further understanding of this animal group and the molecular mechanism of adaptive evolution.

Heat-transport mechanisms in molecular building blocks of inorganic/organic hybrid superlattices

NASA Astrophysics Data System (ADS)

Giri, Ashutosh; Niemelä, Janne-Petteri; Tynell, Tommi; Gaskins, John T.; Donovan, Brian F.; Karppinen, Maarit; Hopkins, Patrick E.

2016-03-01

Nanomaterial interfaces and concomitant thermal resistances are generally considered as atomic-scale planes that scatter the fundamental energy carriers. Given that the nanoscale structural and chemical properties of solid interfaces can strongly influence this thermal boundary conductance, the ballistic and diffusive nature of phonon transport along with the corresponding phonon wavelengths can affect how energy is scattered and transmitted across an interfacial region between two materials. In hybrid composites composed of atomic layer building blocks of inorganic and organic constituents, the varying interaction between the phononic spectrum in the inorganic crystals and vibronic modes in the molecular films can provide a new avenue to manipulate the energy exchange between the fundamental vibrational energy carriers across interfaces. Here, we systematically study the heat transfer mechanisms in hybrid superlattices of atomic- and molecular-layer-grown zinc oxide and hydroquinone with varying thicknesses of the inorganic and organic layers in the superlattices. We demonstrate ballistic energy transfer of phonons in the zinc oxide that is limited by scattering at the zinc oxide/hydroquinone interface for superlattices with a single monolayer of hydroquinone separating the thicker inorganic layers. The concomitant thermal boundary conductance across the zinc oxide interfacial region approaches the maximal thermal boundary conductance of a zinc oxide phonon flux, indicative of the contribution of long wavelength vibrations across the aromatic molecular monolayers in transmitting energy across the interface. This transmission of energy across the molecular interface decreases considerably as the thickness of the organic layers are increased.

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

Self-renewal molecular mechanisms of colorectal cancer stem cells.

PubMed

Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

2017-01-01

Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) and Hedgehog-Gli (HH-GLI), specific roles mediated by cell surface markers and micro-environmental factors are involved in the regulation of self-renewal. The elucidation of the molecular mechanisms behind self-renewal may lead to the development of novel targeted interventions for the treatment of colorectal cancer.

Differentiating snail intermediate hosts of Schistosoma spp. using molecular approaches: fundamental to successful integrated control mechanism in Africa.

PubMed

Abe, Eniola Michael; Guan, Wei; Guo, Yun-Hai; Kassegne, Kokouvi; Qin, Zhi-Qiang; Xu, Jing; Chen, Jun-Hu; Ekpo, Uwem Friday; Li, Shi-Zhu; Zhou, Xiao-Nong

2018-03-26

Snail intermediate hosts play active roles in the transmission of snail-borne trematode infections in Africa. A good knowledge of snail-borne diseases epidemiology particularly snail intermediate host populations would provide the necessary impetus to complementing existing control strategy. This review highlights the importance of molecular approaches in differentiating snail hosts population structure and the need to provide adequate information on snail host populations by updating snail hosts genome database for Africa, in order to equip different stakeholders with adequate information on the ecology of snail intermediate hosts and their roles in the transmission of different diseases. Also, we identify the gaps and areas where there is need for urgent intervention to facilitate effective integrated control of schistosomiasis and other snail-borne trematode infections. Prioritizing snail studies, especially snail differentiation using molecular tools will boost disease surveillance and also enhance efficient schistosomaisis control programme in Africa.

A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest

NASA Astrophysics Data System (ADS)

Arenz, Stefan; Bock, Lars V.; Graf, Michael; Innis, C. Axel; Beckmann, Roland; Grubmüller, Helmut; Vaiana, Andrea C.; Wilson, Daniel N.

2016-07-01

Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice. These two effects combine to perturb peptide-bond formation by increasing the distance between the attacking Lys11 amine and the Asp10 carbonyl carbon. The interplay between drug, peptide and ribosome uncovered here also provides insight into the fundamental mechanism of peptide-bond formation.

Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Moreira, Cátia; Ramos, Maria J; Fernandes, Pedro Alexandrino

2016-06-27

This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular mechanisms of mechanotransduction in integrin-mediated cell-matrix adhesion

PubMed Central

Li, Zhenhai; Lee, Hyunjung; Zhu, Cheng

2016-01-01

Cell-matrix adhesion complexes are multi-protein structures linking the extracellular matrix (ECM) to the cytoskeleton. They are essential to both cell motility and function by bidirectionally sensing and transmitting mechanical and biochemical stimulations. Several types of cell-matrix adhesions have been identified and they share many key molecular components, such as integrins and actin-integrin linkers. Mechanochemical coupling between ECM molecules and the actin cytoskeleton has been observed from the single cell to the single molecule level and from immune cells to neuronal cells. However, the mechanisms underlying force regulation of integrin-mediated mechanotransduction still need to be elucidated. In this review article, we focus on integrin-mediated adhesions and discuss force regulation of cell-matrix adhesions and key adaptor molecules, three different force-dependent behaviors, and molecular mechanisms for mechanochemical coupling in force regulation. PMID:27720950

Quantum mechanics/molecular mechanics studies on the mechanism of action of cofactor pyridoxal 5'-phosphate in ornithine 4,5-aminomutase.

PubMed

Pang, Jiayun; Scrutton, Nigel S; Sutcliffe, Michael J

2014-09-01

A computational study was performed on the experimentally elusive cyclisation step in the cofactor pyridoxal 5'-phosphate (PLP)-dependent D-ornithine 4,5-aminomutase (OAM)-catalysed reaction. Calculations using both model systems and a combined quantum mechanics/molecular mechanics approach suggest that regulation of the cyclic radical intermediate is achieved through the synergy of the intrinsic catalytic power of cofactor PLP and the active site of the enzyme. The captodative effect of PLP is balanced by an enzyme active site that controls the deprotonation of both the pyridine nitrogen atom (N1) and the Schiff-base nitrogen atom (N2). Furthermore, electrostatic interactions between the terminal carboxylate and amino groups of the substrate and Arg297 and Glu81 impose substantial "strain" energy on the orientation of the cyclic intermediate to control its trajectory. In addition the "strain" energy, which appears to be sensitive to both the number of carbon atoms in the substrate/analogue and the position of the radical intermediates, may play a key role in controlling the transition of the enzyme from the closed to the open state. Our results provide new insights into several aspects of the radical mechanism in aminomutase catalysis and broaden our understanding of cofactor PLP-dependent reactions. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular tandem repeat strategy for elucidating mechanical properties of high-strength proteins

PubMed Central

Jung, Huihun; Pena-Francesch, Abdon; Saadat, Alham; Sebastian, Aswathy; Kim, Dong Hwan; Hamilton, Reginald F.; Albert, Istvan; Allen, Benjamin D.; Demirel, Melik C.

2016-01-01

Many globular and structural proteins have repetitions in their sequences or structures. However, a clear relationship between these repeats and their contribution to the mechanical properties remains elusive. We propose a new approach for the design and production of synthetic polypeptides that comprise one or more tandem copies of a single unit with distinct amorphous and ordered regions. Our designed sequences are based on a structural protein produced in squid suction cups that has a segmented copolymer structure with amorphous and crystalline domains. We produced segmented polypeptides with varying repeat number, while keeping the lengths and compositions of the amorphous and crystalline regions fixed. We showed that mechanical properties of these synthetic proteins could be tuned by modulating their molecular weights. Specifically, the toughness and extensibility of synthetic polypeptides increase as a function of the number of tandem repeats. This result suggests that the repetitions in native squid proteins could have a genetic advantage for increased toughness and flexibility. PMID:27222581

A systems biology strategy to identify molecular mechanisms of action and protein indicators of traumatic brain injury.

PubMed

Yu, Chenggang; Boutté, Angela; Yu, Xueping; Dutta, Bhaskar; Feala, Jacob D; Schmid, Kara; Dave, Jitendra; Tawa, Gregory J; Wallqvist, Anders; Reifman, Jaques

2015-02-01

The multifactorial nature of traumatic brain injury (TBI), especially the complex secondary tissue injury involving intertwined networks of molecular pathways that mediate cellular behavior, has confounded attempts to elucidate the pathology underlying the progression of TBI. Here, systems biology strategies are exploited to identify novel molecular mechanisms and protein indicators of brain injury. To this end, we performed a meta-analysis of four distinct high-throughput gene expression studies involving different animal models of TBI. By using canonical pathways and a large human protein-interaction network as a scaffold, we separately overlaid the gene expression data from each study to identify molecular signatures that were conserved across the different studies. At 24 hr after injury, the significantly activated molecular signatures were nonspecific to TBI, whereas the significantly suppressed molecular signatures were specific to the nervous system. In particular, we identified a suppressed subnetwork consisting of 58 highly interacting, coregulated proteins associated with synaptic function. We selected three proteins from this subnetwork, postsynaptic density protein 95, nitric oxide synthase 1, and disrupted in schizophrenia 1, and hypothesized that their abundance would be significantly reduced after TBI. In a penetrating ballistic-like brain injury rat model of severe TBI, Western blot analysis confirmed our hypothesis. In addition, our analysis recovered 12 previously identified protein biomarkers of TBI. The results suggest that systems biology may provide an efficient, high-yield approach to generate testable hypotheses that can be experimentally validated to identify novel mechanisms of action and molecular indicators of TBI. © 2014 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Inactivation of TEM-1 by avibactam (NXL-104): insights from quantum mechanics/molecular mechanics metadynamics simulations.

PubMed

Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco; Colombo, Giorgio

2014-08-12

The fast and constant development of drug-resistant bacteria represents a serious medical emergence. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this context, avibactam represents a promising, innovative inhibitor of beta-lactamases with a novel molecular structure compared to previously developed inhibitors, showing a promising inhibitory activity toward a significant number of beta-lactamase enzymes. In this work, we studied, at the atomistic level, the mechanisms of formation of the covalent complex between avibactam and TEM-1, an experimentally well-characterized class A beta-lactamase, using classical and quantum mechanics/molecular mechanics (QM/MM) simulations combined with metadynamics. Our simulations provide a detailed structural and energetic picture of the molecular steps leading to the formation of the avibactam/TEM-1 covalent adduct. In particular, they support a mechanism in which the rate-determining step is the water-assisted Glu166 deprotonation by Ser70. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements. Additionally, our simulations highlight the important role of Lys73 in assisting the Ser70 and Ser130 deprotonations. While based on the specific case of the avibactam/TEM-1, the simple protocol we present here can be immediately extended and applied to the study of covalent complex formation in different enzyme-inhibitor pairs.

Molecular mechanisms underlying the diverse array of petal colors in chrysanthemum flowers.

PubMed

Ohmiya, Akemi

2018-01-01

Chrysanthemum ( Chrysanthemum morifolium Ramat.) is one of the most important floricultural crops in the world. Although the origin of modern chrysanthemum cultivars is uncertain, several species belonging to the family Asteraceae are considered to have been integrated during the long history of breeding. The flower color of ancestral species is limited to yellow, pink, and white, and is derived from carotenoids, anthocyanins, and the absence of both pigments, respectively. A wide range of flower colors, including purplish-red, orange, red, and dark red, has been developed by increasing the range of pigment content or the combination of both pigments. Recently, green-flowered cultivars containing chlorophylls in their ray petals have been produced, and have gained popularity. In addition, blue/violet flowers have been developed using a transgenic approach. Flower color is an important trait that influences the commercial value of chrysanthemum cultivars. Understanding the molecular mechanisms that regulate flower pigmentation may provide important implications for the rationale manipulation of flower color. This review describes the pigment composition, genetics, and molecular basis of ray petal color formation in chrysanthemum cultivars.

Nanostructure and molecular mechanics of spider dragline silk protein assemblies

PubMed Central

Keten, Sinan; Buehler, Markus J.

2010-01-01

Spider silk is a self-assembling biopolymer that outperforms most known materials in terms of its mechanical performance, despite its underlying weak chemical bonding based on H-bonds. While experimental studies have shown that the molecular structure of silk proteins has a direct influence on the stiffness, toughness and failure strength of silk, no molecular-level analysis of the nanostructure and associated mechanical properties of silk assemblies have been reported. Here, we report atomic-level structures of MaSp1 and MaSp2 proteins from the Nephila clavipes spider dragline silk sequence, obtained using replica exchange molecular dynamics, and subject these structures to mechanical loading for a detailed nanomechanical analysis. The structural analysis reveals that poly-alanine regions in silk predominantly form distinct and orderly beta-sheet crystal domains, while disorderly regions are formed by glycine-rich repeats that consist of 31-helix type structures and beta-turns. Our structural predictions are validated against experimental data based on dihedral angle pair calculations presented in Ramachandran plots, alpha-carbon atomic distances, as well as secondary structure content. Mechanical shearing simulations on selected structures illustrate that the nanoscale behaviour of silk protein assemblies is controlled by the distinctly different secondary structure content and hydrogen bonding in the crystalline and semi-amorphous regions. Both structural and mechanical characterization results show excellent agreement with available experimental evidence. Our findings set the stage for extensive atomistic investigations of silk, which may contribute towards an improved understanding of the source of the strength and toughness of this biological superfibre. PMID:20519206

Nanostructure and molecular mechanics of spider dragline silk protein assemblies.

PubMed

Keten, Sinan; Buehler, Markus J

2010-12-06

Spider silk is a self-assembling biopolymer that outperforms most known materials in terms of its mechanical performance, despite its underlying weak chemical bonding based on H-bonds. While experimental studies have shown that the molecular structure of silk proteins has a direct influence on the stiffness, toughness and failure strength of silk, no molecular-level analysis of the nanostructure and associated mechanical properties of silk assemblies have been reported. Here, we report atomic-level structures of MaSp1 and MaSp2 proteins from the Nephila clavipes spider dragline silk sequence, obtained using replica exchange molecular dynamics, and subject these structures to mechanical loading for a detailed nanomechanical analysis. The structural analysis reveals that poly-alanine regions in silk predominantly form distinct and orderly beta-sheet crystal domains, while disorderly regions are formed by glycine-rich repeats that consist of 3₁-helix type structures and beta-turns. Our structural predictions are validated against experimental data based on dihedral angle pair calculations presented in Ramachandran plots, alpha-carbon atomic distances, as well as secondary structure content. Mechanical shearing simulations on selected structures illustrate that the nanoscale behaviour of silk protein assemblies is controlled by the distinctly different secondary structure content and hydrogen bonding in the crystalline and semi-amorphous regions. Both structural and mechanical characterization results show excellent agreement with available experimental evidence. Our findings set the stage for extensive atomistic investigations of silk, which may contribute towards an improved understanding of the source of the strength and toughness of this biological superfibre.

Individual Biomarkers Using Molecular Personalized Medicine Approaches.

PubMed

Zenner, Hans P

2017-01-01

Molecular personalized medicine tries to generate individual predictive biomarkers to assist doctors in their decision making. These are thought to improve the efficacy and lower the toxicity of a treatment. The molecular basis of the desired high-precision prediction is modern "omex" technologies providing high-throughput bioanalytical methods. These include genomics and epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, imaging, and functional analyses. In most cases, producing big data also requires a complex biomathematical analysis. Using molecular personalized medicine, the conventional physician's check of biomarker results may no longer be sufficient. By contrast, the physician may need to cooperate with the biomathematician to achieve the desired prediction on the basis of the analysis of individual big data typically produced by omex technologies. Identification of individual biomarkers using molecular personalized medicine approaches is thought to allow a decision-making for the precise use of a targeted therapy, selecting the successful therapeutic tool from a panel of preexisting drugs or medical products. This should avoid the treatment of nonresponders and responders that produces intolerable unwanted effects. © 2017 S. Karger AG, Basel.

A Statistical Approach to Exoplanetary Molecular Spectroscopy Using Spitzer Eclipses

NASA Astrophysics Data System (ADS)

Deming, Drake; Garhart, Emily; Burrows, Adam; Fortney, Jonathan; Knutson, Heather; Todorov, Kamen

2018-01-01

Secondary eclipses of exoplanets observed using the Spitzer Space Telescope measure the total emission emergent from exoplanetary atmospheres integrated over broad photometric bands. Spitzer photometry is excellent for measuring day side temperatures, but is less well suited to the detection of molecular absorption or emission features. Even for very hot exoplanets, it can be difficult to attain the accuracy on eclipse depth that is needed to unambiguously interpret the Spitzer results in terms of molecular absorption or emission. However, a statistical approach, wherein we seek deviations from a simple blackbody planet as a function of the planet's equilibrium temperature, shows promise for defining the nature and strength of molecular absorption in ensembles of planets. In this paper, we explore such an approach using secondary eclipses observed for tens of hot exoplanets during Spitzer's Cycles 10, 12, and 13. We focus on the possibility that the hottest planets exhibit molecular features in emission, due to temperature inversions.

Molecular mechanisms for vascular complications of targeted cancer therapies.

PubMed

Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

2016-10-01

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Molecular medicine of fragile X syndrome: based on known molecular mechanisms.

PubMed

Luo, Shi-Yu; Wu, Ling-Qian; Duan, Ran-Hui

2016-02-01

Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome (FXS). In light of these findings, several clinical trials are now underway for therapeutic translation to humans. Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov. The search terms included "fragile X syndrome", "FXS and medication", "FXS and therapeutics" and "FXS and treatment". Based on the publications identified in this search, we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research, from basic studies to clinical trials. The pathological mechanisms of FXS were categorized on the basis of neuroanatomy, synaptic structure, synaptic transmission and fragile X mental retardation protein (FMRP) loss of function. The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations. Mechanism-directed molecular medicines were classified according to their target pathological mechanisms, and the most recent progress in clinical trials was discussed. Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics. Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the efficacy of treatments.

Exploring Molecular Mechanisms of Ligand Recognition by Opioid Receptors with Metadynamics†

PubMed Central

Provasi, Davide; Bortolato, Andrea; Filizola, Marta

2009-01-01

Opioid receptors are G protein-coupled receptors (GPCRs) of utmost significance in the development of potent analgesic drugs for the treatment of severe pain. An accurate evaluation at the molecular level of the ligand binding pathways into these receptors may play a key role in the design of new molecules with more desirable properties and reduced side effects. The recent characterization of high-resolution X-ray crystal structures of non-rhodopsin GPCRs for diffusible hormones and neurotransmitters presents an unprecedented opportunity to build improved homology models of opioid receptors, and to study in more detail their molecular mechanisms of ligand recognition. In this study, possible entry pathways of the non-selective antagonist naloxone (NLX) from the water environment into the well-accepted alkaloid binding pocket of a delta opioid receptor (DOR) molecular model based on the β2-adrenergic receptor crystal structure are explored using microsecond-scale well-tempered metadynamics simulations. Using as collective variables distances that account for the position of NLX and of the receptor extracellular loop 2 in relation to the DOR binding pocket, we were able to distinguish between the different states visited by the ligand (i.e., docked, undocked, and metastable bound intermediates), and to predict a free energy of binding close to experimental values after correcting for possible drawbacks of the sampling approach. The strategy employed herein holds promise for its application to the docking of diverse ligands to the opioid receptors as well as to other GPCRs. PMID:19785461

Exploring molecular mechanisms of ligand recognition by opioid receptors with metadynamics.

PubMed

Provasi, Davide; Bortolato, Andrea; Filizola, Marta

2009-10-27

Opioid receptors are G protein-coupled receptors (GPCRs) of utmost significance in the development of potent analgesic drugs for the treatment of severe pain. An accurate evaluation at the molecular level of the ligand binding pathways into these receptors may play a key role in the design of new molecules with more desirable properties and reduced side effects. The recent characterization of high-resolution X-ray crystal structures of non-rhodopsin GPCRs for diffusible hormones and neurotransmitters presents an unprecedented opportunity to build improved homology models of opioid receptors, and to study in more detail their molecular mechanisms of ligand recognition. In this study, possible pathways for entry of the nonselective antagonist naloxone (NLX) from the water environment into the well-accepted alkaloid binding pocket of a delta opioid receptor (DOR) molecular model based on the beta2-adrenergic receptor crystal structure are explored using microsecond-scale well-tempered metadynamics simulations. Using as collective variables distances that account for the position of NLX and of the receptor extracellular loop 2 in relation to the DOR binding pocket, we were able to distinguish between the different states visited by the ligand (i.e., docked, undocked, and metastable bound intermediates) and to predict a free energy of binding close to experimental values after correcting for possible drawbacks of the sampling approach. The strategy employed herein holds promise for its application to the docking of diverse ligands to the opioid receptors as well as to other GPCRs.

A molecular cross-linking approach for hybrid metal oxides

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

Jung, Dahee; Saleh, Liban A. M.; Berkson, Zachariah J.

Developing methods to create hybrid materials to maximize their transformative capabilities has been the subject of significant interest. In particular, several key methods have been developed to manipulate earth abundant metal oxides such as TiO 2 to produce hybrid materials with improved or new properties relevant to a broad spectrum of applications. Here, we introduce a new approach we refer to as “molecular doping”, whereby a hybrid molecular boron oxide material is formed from polyhedral boron cluster precursors of the type [B 12(OH) 12] 2-. This new approach is enabled by the inherent robustness of the boron cluster molecular buildingmore » block, which is compatible with harsh thermal and oxidizing conditions that are necessary for the synthesis of many metal oxides. In this work, we show how this material can be successfully interfaced with TiO 2, resulting in boron-rich hybrid materials with unprecedented photophysical and electrochemical properties.« less

A molecular cross-linking approach for hybrid metal oxides.

PubMed

Jung, Dahee; Saleh, Liban M A; Berkson, Zachariah J; El-Kady, Maher F; Hwang, Jee Youn; Mohamed, Nahla; Wixtrom, Alex I; Titarenko, Ekaterina; Shao, Yanwu; McCarthy, Kassandra; Guo, Jian; Martini, Ignacio B; Kraemer, Stephan; Wegener, Evan C; Saint-Cricq, Philippe; Ruehle, Bastian; Langeslay, Ryan R; Delferro, Massimiliano; Brosmer, Jonathan L; Hendon, Christopher H; Gallagher-Jones, Marcus; Rodriguez, Jose; Chapman, Karena W; Miller, Jeffrey T; Duan, Xiangfeng; Kaner, Richard B; Zink, Jeffrey I; Chmelka, Bradley F; Spokoyny, Alexander M

2018-04-01

There is significant interest in the development of methods to create hybrid materials that transform capabilities, in particular for Earth-abundant metal oxides, such as TiO 2 , to give improved or new properties relevant to a broad spectrum of applications. Here we introduce an approach we refer to as 'molecular cross-linking', whereby a hybrid molecular boron oxide material is formed from polyhedral boron-cluster precursors of the type [B 12 (OH) 12 ] 2- . This new approach is enabled by the inherent robustness of the boron-cluster molecular building block, which is compatible with the harsh thermal and oxidizing conditions that are necessary for the synthesis of many metal oxides. In this work, using a battery of experimental techniques and materials simulation, we show how this material can be interfaced successfully with TiO 2 and other metal oxides to give boron-rich hybrid materials with intriguing photophysical and electrochemical properties.

A molecular cross-linking approach for hybrid metal oxides

NASA Astrophysics Data System (ADS)

Jung, Dahee; Saleh, Liban M. A.; Berkson, Zachariah J.; El-Kady, Maher F.; Hwang, Jee Youn; Mohamed, Nahla; Wixtrom, Alex I.; Titarenko, Ekaterina; Shao, Yanwu; McCarthy, Kassandra; Guo, Jian; Martini, Ignacio B.; Kraemer, Stephan; Wegener, Evan C.; Saint-Cricq, Philippe; Ruehle, Bastian; Langeslay, Ryan R.; Delferro, Massimiliano; Brosmer, Jonathan L.; Hendon, Christopher H.; Gallagher-Jones, Marcus; Rodriguez, Jose; Chapman, Karena W.; Miller, Jeffrey T.; Duan, Xiangfeng; Kaner, Richard B.; Zink, Jeffrey I.; Chmelka, Bradley F.; Spokoyny, Alexander M.

2018-03-01

There is significant interest in the development of methods to create hybrid materials that transform capabilities, in particular for Earth-abundant metal oxides, such as TiO2, to give improved or new properties relevant to a broad spectrum of applications. Here we introduce an approach we refer to as `molecular cross-linking', whereby a hybrid molecular boron oxide material is formed from polyhedral boron-cluster precursors of the type [B12(OH)12]2-. This new approach is enabled by the inherent robustness of the boron-cluster molecular building block, which is compatible with the harsh thermal and oxidizing conditions that are necessary for the synthesis of many metal oxides. In this work, using a battery of experimental techniques and materials simulation, we show how this material can be interfaced successfully with TiO2 and other metal oxides to give boron-rich hybrid materials with intriguing photophysical and electrochemical properties.

Atomic Spectral Methods for Ab Initio Molecular Electronic Energy Surfaces: Transitioning From Small-Molecule to Biomolecular-Suitable Approaches.

PubMed

Mills, Jeffrey D; Ben-Nun, Michal; Rollin, Kyle; Bromley, Michael W J; Li, Jiabo; Hinde, Robert J; Winstead, Carl L; Sheehy, Jeffrey A; Boatz, Jerry A; Langhoff, Peter W

2016-08-25

Continuing attention has addressed incorportation of the electronically dynamical attributes of biomolecules in the largely static first-generation molecular-mechanical force fields commonly employed in molecular-dynamics simulations. We describe here a universal quantum-mechanical approach to calculations of the electronic energy surfaces of both small molecules and large aggregates on a common basis which can include such electronic attributes, and which also seems well-suited to adaptation in ab initio molecular-dynamics applications. In contrast to the more familiar orbital-product-based methodologies employed in traditional small-molecule computational quantum chemistry, the present approach is based on an "ex-post-facto" method in which Hamiltonian matrices are evaluated prior to wave function antisymmetrization, implemented here in the support of a Hilbert space of orthonormal products of many-electron atomic spectral eigenstates familiar from the van der Waals theory of long-range interactions. The general theory in its various forms incorporates the early semiempirical atoms- and diatomics-in-molecules approaches of Moffitt, Ellison, Tully, Kuntz, and others in a comprehensive mathematical setting, and generalizes the developments of Eisenschitz, London, Claverie, and others addressing electron permutation symmetry adaptation issues, completing these early attempts to treat van der Waals and chemical forces on a common basis. Exact expressions are obtained for molecular Hamiltonian matrices and for associated energy eigenvalues as sums of separate atomic and interaction-energy terms, similar in this respect to the forms of classical force fields. The latter representation is seen to also provide a long-missing general definition of the energies of individual atoms and of their interactions within molecules and matter free from subjective additional constraints. A computer code suite is described for calculations of the many-electron atomic eigenspectra and

Taxonomy of Mechanitis (f.) (Lepidoptera: Nymphalidae) from the west Colombian Andes: an integrative approach.

PubMed

Giraldo, C E; Uribe, S I

2012-12-01

Species identification in the butterfly genus Mechanitis (F.) (Lepidoptera: Nymphalidae) becomes difficult when it is based only on wing color patterns, a common practice in butterfly taxonomy. Difficulties in Mechanitis taxonomy are related to the widespread mimicry and polymorphism among species belonging to this genus. Species recognition and inventories of Mechanitis genus in geographic areas as the Andean region of Colombia are of particular interest and the use of more than one character for taxonomic identification is desirable. In this study, we included morphological, ecological, and mitochondrial DNA data to identify the occurring species in this region. Species of Mechanitis were studied from ecological, morphological, and molecular perspectives considering host plant identification, oviposition behavior, and life cycles under laboratory conditions. Immature morphology, patterns of wing color, and genital structures of adults were also studied. The genetic barcoding region of the cytochrome oxidase I mitochondrial gene was sequenced and used to verify the limits between species previously defined by the other characters and to validate its usefulness for species delimitation in this particular genus. The integrative approach combining independent datasets successfully allowed species identification as compared to the approach based on a single dataset. Three well-differentiated species were found in the studied region, Mechanitis menapis (Hewitson), Mechanitis polymnia (Linnaeus), and Mechanitis lysimnia (Fabricius). New valuable characters that could improve taxonomic identification in this genus are considered.

Exact and Optimal Quantum Mechanics/Molecular Mechanics Boundaries.

PubMed

Sun, Qiming; Chan, Garnet Kin-Lic

2014-09-09

Motivated by recent work in density matrix embedding theory, we define exact link orbitals that capture all quantum mechanical (QM) effects across arbitrary quantum mechanics/molecular mechanics (QM/MM) boundaries. Exact link orbitals are rigorously defined from the full QM solution, and their number is equal to the number of orbitals in the primary QM region. Truncating the exact set yields a smaller set of link orbitals optimal with respect to reproducing the primary region density matrix. We use the optimal link orbitals to obtain insight into the limits of QM/MM boundary treatments. We further analyze the popular general hybrid orbital (GHO) QM/MM boundary across a test suite of molecules. We find that GHOs are often good proxies for the most important optimal link orbital, although there is little detailed correlation between the detailed GHO composition and optimal link orbital valence weights. The optimal theory shows that anions and cations cannot be described by a single link orbital. However, expanding to include the second most important optimal link orbital in the boundary recovers an accurate description. The second optimal link orbital takes the chemically intuitive form of a donor or acceptor orbital for charge redistribution, suggesting that optimal link orbitals can be used as interpretative tools for electron transfer. We further find that two optimal link orbitals are also sufficient for boundaries that cut across double bonds. Finally, we suggest how to construct "approximately" optimal link orbitals for practical QM/MM calculations.

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.

Molecular mechanisms of magnetosome formation.

PubMed

Komeili, Arash

2007-01-01

Magnetotactic bacteria are a diverse group of microorganisms with the ability to use geomagnetic fields for direction sensing. This unique feat is accomplished with the help of magnetosomes, nanometer-sized magnetic crystals surrounded by a lipid bilayer membrane and organized into chains via a dedicated cytoskeleton within the cell. Because of the special properties of these magnetic crystals, magnetotactic bacteria have been exploited for a variety of applications in diverse disciplines from geobiology to biotechnology. In addition, magnetosomes have served as a powerful model system for the study of biomineralization and cell biology in bacteria. This review focuses on recent advances in understanding the molecular mechanisms of magnetosome formation and magnetite biomineralization.

Hyperthermophilic enzymes: sources, uses, and molecular mechanisms for thermostability.

PubMed

Vieille, C; Zeikus, G J

2001-03-01

Enzymes synthesized by hyperthermophiles (bacteria and archaea with optimal growth temperatures of > 80 degrees C), also called hyperthermophilic enzymes, are typically thermostable (i.e., resistant to irreversible inactivation at high temperatures) and are optimally active at high temperatures. These enzymes share the same catalytic mechanisms with their mesophilic counterparts. When cloned and expressed in mesophilic hosts, hyperthermophilic enzymes usually retain their thermal properties, indicating that these properties are genetically encoded. Sequence alignments, amino acid content comparisons, crystal structure comparisons, and mutagenesis experiments indicate that hyperthermophilic enzymes are, indeed, very similar to their mesophilic homologues. No single mechanism is responsible for the remarkable stability of hyperthermophilic enzymes. Increased thermostability must be found, instead, in a small number of highly specific alterations that often do not obey any obvious traffic rules. After briefly discussing the diversity of hyperthermophilic organisms, this review concentrates on the remarkable thermostability of their enzymes. The biochemical and molecular properties of hyperthermophilic enzymes are described. Mechanisms responsible for protein inactivation are reviewed. The molecular mechanisms involved in protein thermostabilization are discussed, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions. Finally, current uses and potential applications of thermophilic and hyperthermophilic enzymes as research reagents and as catalysts for industrial processes are described.

Evolution from S3 to S4 States of the Oxygen-Evolving Complex in Photosystem II Monitored by Quantum Mechanics/Molecular Mechanics (QM/MM) Dynamics.

PubMed

Narzi, Daniele; Capone, Matteo; Bovi, Daniele; Guidoni, Leonardo

2018-04-16

Water oxidation in the early steps of natural photosynthesis is fulfilled by photosystem II, which is a protein complex embedded in the thylakoid membrane inside chloroplasts. The water oxidation reaction occurs in the catalytic core of photosystem II, which consists of a Mn4Ca metal cluster, at which, after the accumulation of four oxidising equivalents through five steps (S0-S4) of the Kok-Joliot cycle, two water molecules are split into electrons, protons, and molecular oxygen. In recent years, by combining experimental and theoretical approaches, new insights have been achieved into the structural and electronic properties of different steps of the catalytic cycle. Nevertheless, the exact catalytic mechanism, especially concerning the final stages of the cycle, remains elusive and greatly debated. Herein, by means of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, from the structural, electronic, and magnetic points of view, the S 3 state before and upon oxidation has been characterised. In contrast with the S 2 state, the oxidation of the S 3 state is not followed by a spontaneous proton-coupled electron-transfer event. Nevertheless, upon modelling the reduction of the tyrosine residue in photosystem II (Tyr Z ) and the protonation of Asp61, spontaneous proton transfer occurs, leading to the deprotonation of an oxygen atom bound to Mn1; thus making it available for O-O bond formation. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

An integrated approach of network-based systems biology, molecular docking, and molecular dynamics approach to unravel the role of existing antiviral molecules against AIDS-associated cancer.

PubMed

Omer, Ankur; Singh, Poonam

2017-05-01

A serious challenge in cancer treatment is to reposition the activity of various already known drug candidates against cancer. There is a need to rewrite and systematically analyze the detailed mechanistic aspect of cellular networks to gain insight into the novel role played by various molecules. Most Human Immunodeficiency Virus infection-associated cancers are caused by oncogenic viruses like Human Papilloma Viruses and Epstein-Bar Virus. As the onset of AIDS-associated cancers marks the severity of AIDS, there might be possible interconnections between the targets and mechanism of both the diseases. We have explored the possibility of certain antiviral compounds to act against major AIDS-associated cancers: Kaposi's Sarcoma, Non-Hodgkin Lymphoma, and Cervical Cancer with the help of systems pharmacology approach that includes screening for targets and molecules through the construction of a series of drug-target and drug-target-diseases network. Two molecules (Calanolide A and Chaetochromin B) and the target "HRAS" were finally screened with the help of molecular docking and molecular dynamics simulation. The results provide novel antiviral molecules against HRAS target to treat AIDS defining cancers and an insight for understanding the pharmacological, therapeutic aspects of similar unexplored molecules against various cancers.

[Molecular mechanisms in vascular osteocartilaginous metaplasia: systematic review].

PubMed

Rosero Salazar, Doris Haydee

2016-01-01

The cartilage and bone metaplasia occurring in both the heart and blood vessels, are the result of risk factors or chronic diseases that gradually adversely affect the performance of a person in society; however, clinical signs are reversible in early and intermediate stages of alterations. To establish how the molecular mechanisms underlying the increased vascular metaplastic changes and possible aspects of treatment and prevention. A systematic review was performed by searching for articles indexed in PubMed, Scopus and Science Direct data from 1995 to 2015. The MeSH descriptors used were metaplasia and vascular calcification, which terms associated were molecular mechanisms, condrogenic and osteogenic. Multiple factors influence the metaplastic change, especially the pro-inflammatory associated with vascular oxidation and the presence of free radicals; this development is reversible by treatment with antioxidants and changes in lifestyle and secondary prevention as there is a diagnosis of chronic degenerative disease. The literature evidences that factors that reduce the tissue oxidative stress and promote the maintenance of vascular phenotype are protective and / or reducing the osteochondral metaplastic formations.

Molecular approaches towards development of purified natural products and their structurally known derivatives as efficient anti-cancer drugs: current trends.

PubMed

Saha, Santu Kumar; Khuda-Bukhsh, Anisur Rahman

2013-08-15

Several natural products and their derivatives, either in purified or structurally identified form, exhibit immense pharmacological and biological properties, some of them showing considerable anticancer potential. Although the molecular mechanisms of action of some of these products are yet to be elucidated, extensive research in this area continues to generate new data that are clinically exploitable. Recent advancement in molecular biology, high throughput screening, biomarker identifications, target selection and genomic approaches have enabled us to understand salient interactions of natural products and their derivatives with cancer cells vis-à-vis normal cells. In this review we highlight the recent approaches and application of innovative technologies made to improve quality as well as efficiency of structurally identified natural products and their derivatives, particularly in small molecular forms capable of being used in "targeted therapies" in oncology. These products preferentially involve multiple mechanistic pathways and overcome chemo-resistance in tumor types with cumulative action. We also mention briefly a few physico-chemical features that compare natural products with drugs in recent natural product discovery approaches. We further report here a few purified natural products as examples that provide molecular interventions in cancer therapeutics to give the reader a glimpse of the current trends of approach for discovering useful anticancer drugs. © 2013 Elsevier B.V. All rights reserved.

In silico simulations of tunneling barrier measurements for molecular orbital-mediated junctions: A molecular orbital theory approach to scanning tunneling microscopy

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

Terryn, Raymond J.; Sriraman, Krishnan; Olson, Joel A., E-mail: jolson@fit.edu

A new simulator for scanning tunneling microscopy (STM) is presented based on the linear combination of atomic orbitals molecular orbital (LCAO-MO) approximation for the effective tunneling Hamiltonian, which leads to the convolution integral when applied to the tip interaction with the sample. This approach intrinsically includes the structure of the STM tip. Through this mechanical emulation and the tip-inclusive convolution model, dI/dz images for molecular orbitals (which are closely associated with apparent barrier height, ϕ{sub ap}) are reported for the first time. For molecular adsorbates whose experimental topographic images correspond well to isolated-molecule quantum chemistry calculations, the simulator makes accuratemore » predictions, as illustrated by various cases. Distortions in these images due to the tip are shown to be in accord with those observed experimentally and predicted by other ab initio considerations of tip structure. Simulations of the tunneling current dI/dz images are in strong agreement with experiment. The theoretical framework provides a solid foundation which may be applied to LCAO cluster models of adsorbate–substrate systems, and is extendable to emulate several aspects of functional STM operation.« less

Molecular mechanisms underlying the exceptional adaptations of batoid fins.

PubMed

Nakamura, Tetsuya; Klomp, Jeff; Pieretti, Joyce; Schneider, Igor; Gehrke, Andrew R; Shubin, Neil H

2015-12-29

Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)-Fibroblast growth factor (Fgf)-Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies.

Molecular mechanisms underlying the exceptional adaptations of batoid fins

PubMed Central

Nakamura, Tetsuya; Klomp, Jeff; Pieretti, Joyce; Schneider, Igor; Gehrke, Andrew R.; Shubin, Neil H.

2015-01-01

Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)–Fibroblast growth factor (Fgf)–Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies. PMID:26644578

A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatments

PubMed Central

Masui, Kenta; Gini, Beatrice; Wykosky, Jill; Zanca, Ciro; Cavenee, Webster K.

2013-01-01

Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested clinically. This analysis supports the contention that understanding modes of resistance to both chemotherapy and molecularly targeted therapies may be very useful in selecting those drugs of each class that will have complementing mechanisms of sensitivity and thereby represent reasonable combination therapies. PMID:23455378

Cis-pent-2-ene. Electron diffraction, vibrational analysis and molecular mechanics

NASA Astrophysics Data System (ADS)

Ter Brake, J. H. M.

1984-08-01

The molecular structure of cis-pent-2-ene has been investigated by using electron diffraction, vibrational analysis and molecular mechanics. It is possible to fit a model, describing cis-pent-2-ene as a semi-rigid molecule with one conformer only, to the electron diffraction data. However, molecular mechanics, ab initio self-consistent field molecular orbital calculations and microwave spectroscopy show that cis-pent-2-ene is not a semi-rigid molecule. The large-amplitude motion is described, using all pseudo-conformers at 10° intervals around the circle of rotation. The resulting rα structure is: r[CC] = 149.0(1), r[CC] = 133.8(2), r[CC] = 156.1(2), r[CH] = 109.2(2), r[CH] = 105.8(5) pm, ∠[CCC] = 127.4(2), ∠[CCC] = 112.4(4), ∠[CCH] = 124(2), ∠[CCH] = 114.2(3)° (standard deviations given in parentheses refer to the last significant digit).

Molecular dynamics simulations of graphoepitaxy of organic semiconductors, sexithiophene, and pentacene: Molecular-scale mechanisms of organic graphoepitaxy

NASA Astrophysics Data System (ADS)

Ikeda, Susumu

2018-03-01

Molecular dynamics (MD) simulations of the organic semiconductors α-sexithiophene (6T) and pentacene were carried out to clarify the mechanism of organic graphoepitaxy at the molecular level. First, the models of the grooved substrates were made and the surfaces of the inside of the grooves were modified with -OH or -OSi(CH3)3, making the surfaces hydrophilic or hydrophobic. By the MD simulations of 6T, it was found that three stable azimuthal directions exist (0, ˜45, and 90° the angle that the c-axis makes with the groove), being consistent with experimental results. MD simulations of deposition processes of 6T and pentacene were also carried out, and pentacene molecules showed the spontaneous formation of herringbone packing during deposition. Some pentacene molecules stood on the surface and formed a cluster whose a-axis was parallel to the groove. It is expected that a deep understanding of the molecular-scale mechanisms will lead graphoepitaxy to practical applications, improving the performance of organic devices.

Multi-Phase Solvation Model for Biological Membranes: Molecular Action Mechanism of Amphotericin B.

PubMed

Falcón-González, J M; Jiménez-Domínguez, G; Ortega-Blake, I; Carrillo-Tripp, M

2017-07-11

Amphotericin B (AmB) is still the most effective drug for the treatment of systemic fungal infections in humans. Despite significant theoretical and experimental efforts trying to understand its molecular mechanism of action, the answer has remained elusive. In this work, we present a computational methodology to test the current membrane related hypotheses, namely, transmembrane ion channel, adsorption, and sterol sponge. We use a thermodynamic approach in which we represent the membrane by a multiphase solvation model with atomic detail (MMPSM) and calculate the free energy of transferring the drug between phases with different dielectric properties. Furthermore, we compare AmB to a chemical analogue with increased safety, an l-histidine methyl ester of AmB. Our findings reveal that both drugs dimerize in all solvents studied here. Also, it is energetically unfavorable for the drugs to penetrate into the hydrophobic core of the membrane, unless their concentration is high. Finally, it is thermodynamically possible that the sterols migrate from the membrane into a drug droplet adsorbed at the surface of the bilayer. In light of our results, several effects could take place in the complex antibiotic process. We suggest a molecular mechanism that connects all three hypotheses through a drug concentration dependence and propose that the drug promotes the formation of membrane toroidal pores. Because MMPSM is of general interest, we made it available at http://tripplab.com/tools/mmpsm .

A Network Pharmacology Approach to Understanding the Mechanisms of Action of Traditional Medicine: Bushenhuoxue Formula for Treatment of Chronic Kidney Disease

PubMed Central

Zheng, Xiao-yong; Cao, Dong-sheng; Ye, Fa-qing; Xiang, Zheng

2014-01-01

Traditional Chinese medicine (TCM) has unique therapeutic effects for complex chronic diseases. However, for the lack of an effective systematic approach, the research progress on the effective substances and pharmacological mechanism of action has been very slow. In this paper, by incorporating network biology, bioinformatics and chemoinformatics methods, an integrated approach was proposed to systematically investigate and explain the pharmacological mechanism of action and effective substances of TCM. This approach includes the following main steps: First, based on the known drug targets, network biology was used to screen out putative drug targets; Second, the molecular docking method was used to calculate whether the molecules from TCM and drug targets related to chronic kidney diseases (CKD) interact or not; Third, according to the result of molecular docking, natural product-target network, main component-target network and compound-target network were constructed; Finally, through analysis of network characteristics and literature mining, potential effective multi-components and their synergistic mechanism were putatively identified and uncovered. Bu-shen-Huo-xue formula (BSHX) which was frequently used for treating CKD, was used as the case to demonstrate reliability of our proposed approach. The results show that BSHX has the therapeutic effect by using multi-channel network regulation, such as regulating the coagulation and fibrinolytic balance, and the expression of inflammatory factors, inhibiting abnormal ECM accumulation. Tanshinone IIA, rhein, curcumin, calycosin and quercetin may be potential effective ingredients of BSHX. This research shows that the integration approach can be an effective means for discovering active substances and revealing their pharmacological mechanisms of TCM. PMID:24598793

A quantum mechanic/molecular mechanic study of the wild-type and N155S mutant HIV-1 integrase complexed with diketo acid.

PubMed

Alves, Cláudio Nahum; Martí, Sergio; Castillo, Raquel; Andrés, Juan; Moliner, Vicent; Tuñón, Iñaki; Silla, Estanislao

2008-04-01

Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. Recently, mutation studies have been reported that have shown that a certain degree of viral resistance to diketo acids (DKAs) appears when some amino acid residues of the IN active site are mutated. Mutations represent a fascinating experimental challenge, and we invite theoretical simulations for the disclosure of still unexplored features of enzyme reactions. The aim of this work is to understand the molecular mechanisms of HIV-1 IN drug resistance, which will be useful for designing anti-HIV inhibitors with unique resistance profiles. In this study, we use molecular dynamics simulations, within the hybrid quantum mechanics/molecular mechanics (QM/MM) approach, to determine the protein-ligand interaction energy for wild-type and N155S mutant HIV-1 IN, both complexed with a DKA. This hybrid methodology has the advantage of the inclusion of quantum effects such as ligand polarization upon binding, which can be very important when highly polarizable groups are embedded in anisotropic environments, for example in metal-containing active sites. Furthermore, an energy terms decomposition analysis was performed to determine contributions of individual residues to the enzyme-inhibitor interactions. The results reveal that there is a strong interaction between the Lys-159, Lys-156, and Asn-155 residues and Mg(2+) cation and the DKA inhibitor. Our calculations show that the binding energy is higher in wild-type than in the N155S mutant, in accordance with the experimental results. The role of the mutated residue has thus been checked as maintaining the structure of the ternary complex formed by the protein, the Mg(2+) cation, and the inhibitor. These results might be useful to design compounds with more interesting anti-HIV-1 IN activity on the basis of its three-dimensional structure.

Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer.

PubMed

Gutiérrez-Salmerón, María; Chocarro-Calvo, Ana; García-Martínez, José Manuel; de la Vieja, Antonio; García-Jiménez, Custodia

2017-02-01

The association between diabetes and cancer was hypothesized almost one century ago. Today, a vast number of epidemiological studies support that obese and diabetic populations are more likely to experience tissue-specific cancers, but the underlying molecular mechanisms remain unknown. Obesity, diabetes, and cancer share many hormonal, immune, and metabolic changes that may account for the relationship between diabetes and cancer. In addition, antidiabetic treatments may have an impact on the occurrence and course of some cancers. Moreover, some anticancer treatments may induce diabetes. These observations aroused a great controversy because of the ethical implications and the associated commercial interests. We report an epidemiological update from a mechanistic perspective that suggests the existence of many common and differential individual mechanisms linking obesity and type 1 and 2 diabetes mellitus to certain cancers. The challenge today is to identify the molecular links responsible for this association. Classification of cancers by their molecular signatures may facilitate future mechanistic and epidemiological studies. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

Molecular Mechanisms of Induced Pluripotency

PubMed Central

Muchkaeva, I.A.; Dashinimaev, E.B.; Terskikh, V.V.; Sukhanov, Y.V.; Vasiliev, A.V.

2012-01-01

In this review the distinct aspects of somatic cell reprogramming are discussed. The molecular mechanisms of generation of induced pluripotent stem (iPS) cells from somatic cells via the introduction of transcription factors into adult somatic cells are considered. Particular attention is focused on the generation of iPS cells without genome modifications via the introduction of the mRNA of transcription factors or the use of small molecules. Furthermore, the strategy of direct reprogramming of somatic cells omitting the generation of iPS cells is considered. The data concerning the differences between ES and iPS cells and the problem of epigenetic memory are also discussed. In conclusion, the possibility of using iPS cells in regenerative medicine is considered. PMID:22708059

Molecular Mechanisms of Inner Ear Development

PubMed Central

Wu, Doris K.; Kelley, Matthew W.

2012-01-01

The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms. PMID:22855724

Molecular mechanisms of inner ear development.

PubMed

Wu, Doris K; Kelley, Matthew W

2012-08-01

The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms.

Enhanced densification, strength and molecular mechanisms in shock compressed porous silicon

NASA Astrophysics Data System (ADS)

Lane, J. Matthew D.; Vogler, Tracy J.

2015-06-01

In most porous materials, void collapse during shock compression couples mechanical energy to thermal energy. Increased temperature drives up pressures and lowers densities in the final Hugoniot states as compared to full-density samples. Some materials, however, exhibit an anomalous enhanced densification in their Hugoniot states when porosity is introduced. We have recently shown that silicon is such a material, and demonstrated a molecular mechanism for the effect using molecular simulation. We will review results from large-scale non-equilibrium molecular dynamics (NEMD) and Hugoniotstat simulations of shock compressed porous silicon, highlighting the mechanism by which porosity produces local shear which nucleate partial phase transition and localized melting at shock pressures below typical thresholds in these materials. Further, we will characterize the stress states and strength of the material as a function of porosity from 5 to 50 percent and with various porosity microstructures. Sandia National Laboratories is a multi program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

Desiccation stress and tolerance in green algae: consequences for ultrastructure, physiological and molecular mechanisms

PubMed Central

Holzinger, Andreas; Karsten, Ulf

2013-01-01

Although most green algae typically occur in aquatic ecosystems, many species also live partly or permanently under aeroterrestrial conditions, where the cells are exposed to the atmosphere and hence regularly experience dehydration. The ability of algal cells to survive in an air-dried state is termed desiccation tolerance. The mechanisms involved in desiccation tolerance of green algae are still poorly understood, and hence the aim of this review is to summarize recent findings on the effects of desiccation and osmotic water loss. Starting from structural changes, physiological, and biochemical consequences of desiccation will be addressed in different green-algal lineages. The available data clearly indicate a range of strategies, which are rather different in streptophycean and non-streptophycean green algae. While members of the Trebouxiophyceae exhibit effective water loss-prevention mechanisms based on the biosynthesis and accumulation of particular organic osmolytes such as polyols, these compounds are so far not reported in representatives of the Streptophyta. In members of the Streptophyta such as Klebsormidium, the most striking observation is the appearance of cross-walls in desiccated samples, which are strongly undulating, suggesting a high degree of mechanical flexibility. This aids in maintaining structural integrity in the dried state and allows the cell to maintain turgor pressure for a prolonged period of time during the dehydration process. Physiological strategies in aeroterrestrial green algae generally include a rapid reduction of photosynthesis during desiccation, but also a rather quick recovery after rewetting, whereas aquatic species are sensitive to drying. The underlying mechanisms such as the affected molecular components of the photosynthetic machinery are poorly understood in green algae. Therefore, modern approaches based on transcriptomics, proteomics, and/or metabolomics are urgently needed to better understand the molecular

Trans-pent-2-ene. Electron diffraction, vibrational analysis and molecular mechanics

NASA Astrophysics Data System (ADS)

Ter Brake, J. H. M.; Mijlhoff, F. C.

1981-12-01

The molecular structure of trans-pent-2-ene has been investigated, using electron diffraction, vibrational analysis and molecular mechanics. It is possible to Fit a model, describing trans-pent-2-ene as a semi-rigid molecule with one conformer only, to the electron diffraction data. However, molecular mechanics shows that trans-pent-2-ene is not a semi-rigid molecule. The large-amplitude motion is described, using all pseudo-conformers at 10° intervals around the circle of rotation. The resulting rα structure is: r[-C-C] = 148.4(1), r[-CC-] = 133.4(2), r[-C-C-] = 157.6(5), r[C-H] = 108.2(1)pm; ∠[-C-CC-] = 125.4(3), ∠[C-C-C-] = 115.6(6), ∠[-C-C-H] = 12.7(6), ∠[-CC-H] = 129(2)°. Standard deviations given in parentheses refer to the last significant digit.

Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability

PubMed Central

Vieille, Claire; Zeikus, Gregory J.

2001-01-01

Enzymes synthesized by hyperthermophiles (bacteria and archaea with optimal growth temperatures of >80°C), also called hyperthermophilic enzymes, are typically thermostable (i.e., resistant to irreversible inactivation at high temperatures) and are optimally active at high temperatures. These enzymes share the same catalytic mechanisms with their mesophilic counterparts. When cloned and expressed in mesophilic hosts, hyperthermophilic enzymes usually retain their thermal properties, indicating that these properties are genetically encoded. Sequence alignments, amino acid content comparisons, crystal structure comparisons, and mutagenesis experiments indicate that hyperthermophilic enzymes are, indeed, very similar to their mesophilic homologues. No single mechanism is responsible for the remarkable stability of hyperthermophilic enzymes. Increased thermostability must be found, instead, in a small number of highly specific alterations that often do not obey any obvious traffic rules. After briefly discussing the diversity of hyperthermophilic organisms, this review concentrates on the remarkable thermostability of their enzymes. The biochemical and molecular properties of hyperthermophilic enzymes are described. Mechanisms responsible for protein inactivation are reviewed. The molecular mechanisms involved in protein thermostabilization are discussed, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions. Finally, current uses and potential applications of thermophilic and hyperthermophilic enzymes as research reagents and as catalysts for industrial processes are described. PMID:11238984

Molecular mechanism for the effects of trehalose on beta-hairpin folding revealed by molecular dynamics simulation.

PubMed

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

2008-11-01

Recent work has shown that trehalose can facilitate and inhibit protein folding, but little is known about the molecular basis of these effects. Molecular-level insights into how the osmolyte affects protein folding are of significance for the rational design of small molecular additives for enhancing or hindering the folding of proteins. To investigate the molecular mechanisms of the facilitation and inhibition effects of trehalose on protein folding, molecular dynamics (MD) simulation of a beta-hairpin peptide (Trp-Arg-Tyr-Tyr-Glu-Ser-Ser-Leu-Glu-Pro-Glu-Pro-Asp) in different trehalose concentrations (0-0.26 mol/L) is performed using an all-atom model. It is found that at a proper trehalose concentration (0.065 mol/L), the peptide folds faster than that in water, but it cannot fold to the beta-hairpin at higher trehalose concentrations. Free energy landscape analysis indicates the presence of three intermediate states in both pure water and in 0.065 mol/L trehalose, but the potential energy barriers in the folding pathway decrease greatly in 0.065 mol/L trehalose, so the peptide folding is facilitated. Moreover, at this trehalose concentration, there is a favorable balance between the peptide backbone hydrogen bonds (H-bonds) and the peptide-trehalose H-bonds, leading to the stabilization of the folded peptide. At higher trehalose concentrations, however, trehalose molecules cluster in the peptide region and interact with the peptide via many H-bonds that prevent the peptide from folding to its native structure. The energy landscape analysis indicates that the potential energy barriers increase so greatly that the peptide cannot overcome it, getting trapped in a local free energy basin. The work reported herein has elucidated the molecular mechanism of the peptide folding in the presence of trehalose.

Theoretical Characterization of the Spectral Density of the Water-Soluble Chlorophyll-Binding Protein from Combined Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulations.

PubMed

Rosnik, Andreana M; Curutchet, Carles

2015-12-08

Over the past decade, both experimentalists and theorists have worked to develop methods to describe pigment-protein coupling in photosynthetic light-harvesting complexes in order to understand the molecular basis of quantum coherence effects observed in photosynthesis. Here we present an improved strategy based on the combination of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations and excited-state calculations to predict the spectral density of electronic-vibrational coupling. We study the water-soluble chlorophyll-binding protein (WSCP) reconstituted with Chl a or Chl b pigments as the system of interest and compare our work with data obtained by Pieper and co-workers from differential fluorescence line-narrowing spectra (Pieper et al. J. Phys. Chem. B 2011, 115 (14), 4042-4052). Our results demonstrate that the use of QM/MM MD simulations where the nuclear positions are still propagated at the classical level leads to a striking improvement of the predicted spectral densities in the middle- and high-frequency regions, where they nearly reach quantitative accuracy. This demonstrates that the so-called "geometry mismatch" problem related to the use of low-quality structures in QM calculations, not the quantum features of pigments high-frequency motions, causes the failure of previous studies relying on similar protocols. Thus, this work paves the way toward quantitative predictions of pigment-protein coupling and the comprehension of quantum coherence effects in photosynthesis.

Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.

PubMed

Lodola, Alessio; Mor, Marco; Sirirak, Jitnapa; Mulholland, Adrian J

2009-04-01

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target.

New approaches to molecular cancer therapeutics.

PubMed

Collins, Ian; Workman, Paul

2006-12-01

Cancer drug development is leading the way in exploiting molecular biological and genetic information to develop "personalized" medicine. The new paradigm is to develop agents that target the precise molecular pathology driving the progression of individual cancers. Drug developers have benefited from decades of academic cancer research and from investment in genomics, genetics and automation; their success is exemplified by high-profile drugs such as Herceptin (trastuzumab), Gleevec (imatinib), Tarceva (erlotinib) and Avastin (bevacizumab). However, only 5% of cancer drugs entering clinical trials reach marketing approval. Cancer remains a high unmet medical need, and many potential cancer targets remain undrugged. In this review we assess the status of the discovery and development of small-molecule cancer therapeutics. We show how chemical biology approaches offer techniques for interconnecting elements of the traditional linear progression from gene to drug, thereby providing a basis for increasing speed and success in cancer drug discovery.

Molecular intravascular imaging approaches for atherosclerosis.

PubMed

Press, Marcella Calfon; Jaffer, Farouc A

2014-10-01

Coronary artery disease (CAD) is an inflammatory process that results in buildup of atherosclerosis, typically lipid-rich plaque in the arterial wall. Progressive narrowing of the vessel wall and subsequent plaque rupture can lead to myocardial infarction and death. Recent advances in intravascular fluorescence imaging techniques have provided exciting coronary artery-targeted platforms to further characterize the molecular changes that occur within the vascular wall as a result of atherosclerosis and following coronary stent-induced vascular injury. This review will summarize exciting recent developments in catheter-based imaging of coronary arterial-sized vessels; focusing on two-dimensional near-infrared fluorescence imaging (NIRF) molecular imaging technology as an approach to specifically identify inflammation and fibrin directly within coronary artery-sized vessels. Intravascular NIRF is anticipated to provide new insights into the in vivo biology underlying high-risk plaques, as well as high-risks stents prone to stent restenosis or stent thrombosis.

Probing Molecular Mechanisms of the Hsp90 Chaperone: Biophysical Modeling Identifies Key Regulators of Functional Dynamics

PubMed Central

Dixit, Anshuman; Verkhivker, Gennady M.

2012-01-01

Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based “conformational selection” of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters

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

Antigenic variation: Molecular and genetic mechanisms of relapsing disease

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

Cruse, J.M.; Lewis, R.E.

1987-01-01

This book contains 10 chapters. They are: Contemporary Concepts of Antigenic Variation; Antigenic Variation in the Influenza Viruses; Mechanisms of Escape of Visna Lentiviruses from Immunological Control; A Review of Antigenic Variation by the Equine Infectious Anemia Virus; Biologic and Molecular Variations in AIDS Retrovirus Isolates; Rabies Virus Infection: Genetic Mutations and the Impact on Viral Pathogenicity and Immunity; Immunobiology of Relapsing Fever; Antigenic Variation in African Trypanosomes; Antigenic Variation and Antigenic Diversity in Malaria; and Mechanisms of Immune Evasion in Schistosomiasis.

Theoretical Modeling of Hydrogen Bonding in omolecular Solutions: The Combination of Quantum Mechanics and Molecular Mechanics

NASA Astrophysics Data System (ADS)

Ma, Jing; Jiang, Nan; Li, Hui

Hydrogen bonding interaction takes an important position in solutions. The non-classic nature of hydrogen bonding requires the resource-demanding quantum mechanical (QM) calculations. The molecular mechanics (MM) method, with much lower computational load, is applicable to the large-sized system. The combination of QM and MM is an efficient way in the treatment of solution. Taking advantage of the low-cost energy-based fragmentation QM approach (in which the o-molecule is divided into several subsystems, and QM calculation is carried out on each subsystem that is embedded in the environment of background charges of distant parts), the fragmentation-based QM/MM and polarization models have been implemented for the modeling of o-molecule in aqueous solutions, respectively. Within the framework of the fragmentation-based QM/MM hybrid model, the solute is treated by the fragmentation QM calculation while the numerous solvent molecules are described by MM. In the polarization model, the polarizability is considered by allowing the partial charges and fragment-centered dipole moments to be variables, with values coming from the energy-based fragmentation QM calculations. Applications of these two methods to the solvated long oligomers and cyclic peptides have demonstrated that the hydrogen bonding interaction affects the dynamic change in chain conformations of backbone.

Simulation of Young’s moduli for hexagonal ZnO [0 0 0 1]-oriented nanowires: first principles and molecular mechanical calculations

NASA Astrophysics Data System (ADS)

Bandura, Andrei V.; Evarestov, Robert A.; Lukyanov, Sergey I.; Piskunov, Sergei; Zhukovskii, Yuri F.

2017-08-01

Morphologically reproducible wurtzite-structured zinc oxide nanowires (ZnO NWs) can be synthesized by different methods. Since ZnO NWs have been found to possess piezoelectricity, a comprehensive study of their mechanical properties, e.g. deformations caused by external compression or stretching, is one of the actual tasks of this paper. We have calculated wurtzite-structured [0 0 0 1]-oriented ZnO NWs whose diameters have been varied within 1-5 nm and 1-20 nm ranges when using either ab initio (hybrid DFT-LCAO) or force-field (molecular mechanical) methods, respectively (the minimum diameter d NW of experimentally synthesized NWs has been estimated on average to be ~20 nm). When using both chosen calculation approaches, the values of Young’s moduli determined for the mentioned ranges of NW diameters have been found to be qualitatively compatible (168-169 GPa for 5 nm NW thickness), whereas results of molecular mechanical simulations on Y NW for 20 nm-thick NWs (160-162 GPa) have been qualitatively comparable with those experimentally measured along the [0 0 0 1] direction of NW loading. In all the cases, a gradual increase of the NW diameter has resulted in an asymptotic decrease of Young’s modulus consequently approaching that (Y b) of wurtzite-structured ZnO bulk along its [0 0 0 1] axis. The novelty of this study is that we combine the computation methods of quantum chemistry and molecular mechanics, while the majority of previous studies with the same aim have focused on the application of different classical molecular dynamical methods.

Molecular Mechanics of the Moisture Effect on Epoxy/Carbon Nanotube Nanocomposites.

PubMed

Tam, Lik-Ho; Wu, Chao

2017-10-13

The strong structural integrity of polymer nanocomposite is influenced in the moist environment; but the fundamental mechanism is unclear, including the basis for the interactions between the absorbed water molecules and the structure, which prevents us from predicting the durability of its applications across multiple scales. In this research, a molecular dynamics model of the epoxy/single-walled carbon nanotube (SWCNT) nanocomposite is constructed to explore the mechanism of the moisture effect, and an analysis of the molecular interactions is provided by focusing on the hydrogen bond (H-bond) network inside the nanocomposite structure. The simulations show that at low moisture concentration, the water molecules affect the molecular interactions by favorably forming the water-nanocomposite H-bonds and the small cluster, while at high concentration the water molecules predominantly form the water-water H-bonds and the large cluster. The water molecules in the epoxy matrix and the epoxy-SWCNT interface disrupt the molecular interactions and deteriorate the mechanical properties. Through identifying the link between the water molecules and the nanocomposite structure and properties, it is shown that the free volume in the nanocomposite is crucial for its structural integrity, which facilitates the moisture accumulation and the distinct material deteriorations. This study provides insights into the moisture-affected structure and properties of the nanocomposite from the nanoscale perspective, which contributes to the understanding of the nanocomposite long-term performance under the moisture effect.

Molecular Mechanics of the Moisture Effect on Epoxy/Carbon Nanotube Nanocomposites

PubMed Central

2017-01-01

The strong structural integrity of polymer nanocomposite is influenced in the moist environment; but the fundamental mechanism is unclear, including the basis for the interactions between the absorbed water molecules and the structure, which prevents us from predicting the durability of its applications across multiple scales. In this research, a molecular dynamics model of the epoxy/single-walled carbon nanotube (SWCNT) nanocomposite is constructed to explore the mechanism of the moisture effect, and an analysis of the molecular interactions is provided by focusing on the hydrogen bond (H-bond) network inside the nanocomposite structure. The simulations show that at low moisture concentration, the water molecules affect the molecular interactions by favorably forming the water-nanocomposite H-bonds and the small cluster, while at high concentration the water molecules predominantly form the water-water H-bonds and the large cluster. The water molecules in the epoxy matrix and the epoxy-SWCNT interface disrupt the molecular interactions and deteriorate the mechanical properties. Through identifying the link between the water molecules and the nanocomposite structure and properties, it is shown that the free volume in the nanocomposite is crucial for its structural integrity, which facilitates the moisture accumulation and the distinct material deteriorations. This study provides insights into the moisture-affected structure and properties of the nanocomposite from the nanoscale perspective, which contributes to the understanding of the nanocomposite long-term performance under the moisture effect. PMID:29027979

Effect of mechanical load on the shuttling operation of molecular muscles

NASA Astrophysics Data System (ADS)

Lee, Seungjun; Lu, Wei

2009-06-01

We use molecular dynamics simulations to investigate the effect of mechanical force on stimulus-induced deformation of rotaxane-based artificial molecular muscles. The study shows that a small external force slows down the shuttling motion and leads to longer actuation time for a muscle to reach its full extension. Further increase in the force can significantly reduce the traveling distance of the ring, leading to reduced strain output. A force larger than 28 pN can completely suppress the shuttling motion, suggesting a limit of force output of molecular muscles.

Genomic, transcriptomic, and proteomic approaches towards understanding the molecular mechanisms of salt tolerance in Frankia strains isolated from Casuarina trees.

PubMed

Oshone, Rediet; Ngom, Mariama; Chu, Feixia; Mansour, Samira; Sy, Mame Ourèye; Champion, Antony; Tisa, Louis S

2017-08-18

Soil salinization is a worldwide problem that is intensifying because of the effects of climate change. An effective method for the reclamation of salt-affected soils involves initiating plant succession using fast growing, nitrogen fixing actinorhizal trees such as the Casuarina. The salt tolerance of Casuarina is enhanced by the nitrogen-fixing symbiosis that they form with the actinobacterium Frankia. Identification and molecular characterization of salt-tolerant Casuarina species and associated Frankia is imperative for the successful utilization of Casuarina trees in saline soil reclamation efforts. In this study, salt-tolerant and salt-sensitive Casuarina associated Frankia strains were identified and comparative genomics, transcriptome profiling, and proteomics were employed to elucidate the molecular mechanisms of salt and osmotic stress tolerance. Salt-tolerant Frankia strains (CcI6 and Allo2) that could withstand up to 1000 mM NaCl and a salt-sensitive Frankia strain (CcI3) which could withstand only up to 475 mM NaCl were identified. The remaining isolates had intermediate levels of salt tolerance with MIC values ranging from 650 mM to 750 mM. Comparative genomic analysis showed that all of the Frankia isolates from Casuarina belonged to the same species (Frankia casuarinae). Pangenome analysis revealed a high abundance of singletons among all Casuarina isolates. The two salt-tolerant strains contained 153 shared single copy genes (most of which code for hypothetical proteins) that were not found in the salt-sensitive(CcI3) and moderately salt-tolerant (CeD) strains. RNA-seq analysis of one of the two salt-tolerant strains (Frankia sp. strain CcI6) revealed hundreds of genes differentially expressed under salt and/or osmotic stress. Among the 153 genes, 7 and 7 were responsive to salt and osmotic stress, respectively. Proteomic profiling confirmed the transcriptome results and identified 19 and 8 salt and/or osmotic stress-responsive proteins in the

Mechanically controllable break junctions for molecular electronics.

PubMed

Xiang, Dong; Jeong, Hyunhak; Lee, Takhee; Mayer, Dirk

2013-09-20

A mechanically controllable break junction (MCBJ) represents a fundamental technique for the investigation of molecular electronic junctions, especially for the study of the electronic properties of single molecules. With unique advantages, the MCBJ technique has provided substantial insight into charge transport processes in molecules. In this review, the techniques for sample fabrication, operation and the various applications of MCBJs are introduced and the history, challenges and future of MCBJs are discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantum Mechanics/Molecular Mechanics Modeling of Enzymatic Processes: Caveats and Breakthroughs.

PubMed

Quesne, Matthew G; Borowski, Tomasz; de Visser, Sam P

2016-02-18

Nature has developed large groups of enzymatic catalysts with the aim to transfer substrates into useful products, which enables biosystems to perform all their natural functions. As such, all biochemical processes in our body (we drink, we eat, we breath, we sleep, etc.) are governed by enzymes. One of the problems associated with research on biocatalysts is that they react so fast that details of their reaction mechanisms cannot be obtained with experimental work. In recent years, major advances in computational hardware and software have been made and now large (bio)chemical systems can be studied using accurate computational techniques. One such technique is the quantum mechanics/molecular mechanics (QM/MM) technique, which has gained major momentum in recent years. Unfortunately, it is not a black-box method that is easily applied, but requires careful set-up procedures. In this work we give an overview on the technical difficulties and caveats of QM/MM and discuss work-protocols developed in our groups for running successful QM/MM calculations. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Candida albicans biofilms: development, regulation, and molecular mechanisms

PubMed Central

Gulati, Megha; Nobile, Clarissa J.

2016-01-01

A major virulence attribute of Candida albicans is its ability to form biofilms, densely packed communities of cells adhered to a surface. These biofilms are intrinsically resistant to conventional antifungal therapeutics, the host immune system, and other environmental factors, making biofilm-associated infections a significant clinical challenge. Here, we review current knowledge on the development, regulation, and molecular mechanisms of C. albicans biofilms. PMID:26806384

System-based approaches to decode the molecular links in Parkinson's disease and diabetes.

PubMed

Santiago, Jose A; Potashkin, Judith A

2014-12-01

A growing body of evidence indicates an increased risk for developing Parkinson's disease (PD) among people with type 2 diabetes (T2DM). The relationship between the etiology and development of both chronic diseases is beginning to be uncovered and recent studies show that PD and T2DM share remarkably similar dysregulated pathways. It has been proposed that a cascade of events including mitochondrial dysfunction, impaired insulin signaling, and metabolic inflammation trigger neurodegeneration in T2DM models. Network-based approaches have elucidated a potential molecular framework linking both diseases. Further, transcriptional signatures that modulate the neurodegenerative phenotype in T2DM have been identified. Here we contextualize the current experimental approaches to dissect the mechanisms underlying the association between PD and T2DM and discuss the existing challenges toward the understanding of the coexistence of these devastating aging diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

Exploring the inter-molecular interactions in amyloid-β protofibril with molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area free energy calculations.

PubMed

Liu, Fu-Feng; Liu, Zhen; Bai, Shu; Dong, Xiao-Yan; Sun, Yan

2012-04-14

Aggregation of amyloid-β (Aβ) peptides correlates with the pathology of Alzheimer's disease. However, the inter-molecular interactions between Aβ protofibril remain elusive. Herein, molecular mechanics Poisson-Boltzmann surface area analysis based on all-atom molecular dynamics simulations was performed to study the inter-molecular interactions in Aβ(17-42) protofibril. It is found that the nonpolar interactions are the important forces to stabilize the Aβ(17-42) protofibril, while electrostatic interactions play a minor role. Through free energy decomposition, 18 residues of the Aβ(17-42) are identified to provide interaction energy lower than -2.5 kcal/mol. The nonpolar interactions are mainly provided by the main chain of the peptide and the side chains of nine hydrophobic residues (Leu17, Phe19, Phe20, Leu32, Leu34, Met35, Val36, Val40, and Ile41). However, the electrostatic interactions are mainly supplied by the main chains of six hydrophobic residues (Phe19, Phe20, Val24, Met35, Val36, and Val40) and the side chains of the charged residues (Glu22, Asp23, and Lys28). In the electrostatic interactions, the overwhelming majority of hydrogen bonds involve the main chains of Aβ as well as the guanidinium group of the charged side chain of Lys28. The work has thus elucidated the molecular mechanism of the inter-molecular interactions between Aβ monomers in Aβ(17-42) protofibril, and the findings are considered critical for exploring effective agents for the inhibition of Aβ aggregation.

Exploring the inter-molecular interactions in amyloid-β protofibril with molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area free energy calculations

NASA Astrophysics Data System (ADS)

Liu, Fu-Feng; Liu, Zhen; Bai, Shu; Dong, Xiao-Yan; Sun, Yan

2012-04-01

Aggregation of amyloid-β (Aβ) peptides correlates with the pathology of Alzheimer's disease. However, the inter-molecular interactions between Aβ protofibril remain elusive. Herein, molecular mechanics Poisson-Boltzmann surface area analysis based on all-atom molecular dynamics simulations was performed to study the inter-molecular interactions in Aβ17-42 protofibril. It is found that the nonpolar interactions are the important forces to stabilize the Aβ17-42 protofibril, while electrostatic interactions play a minor role. Through free energy decomposition, 18 residues of the Aβ17-42 are identified to provide interaction energy lower than -2.5 kcal/mol. The nonpolar interactions are mainly provided by the main chain of the peptide and the side chains of nine hydrophobic residues (Leu17, Phe19, Phe20, Leu32, Leu34, Met35, Val36, Val40, and Ile41). However, the electrostatic interactions are mainly supplied by the main chains of six hydrophobic residues (Phe19, Phe20, Val24, Met35, Val36, and Val40) and the side chains of the charged residues (Glu22, Asp23, and Lys28). In the electrostatic interactions, the overwhelming majority of hydrogen bonds involve the main chains of Aβ as well as the guanidinium group of the charged side chain of Lys28. The work has thus elucidated the molecular mechanism of the inter-molecular interactions between Aβ monomers in Aβ17-42 protofibril, and the findings are considered critical for exploring effective agents for the inhibition of Aβ aggregation.

Influence of metal cofactors and water on the catalytic mechanism of creatininase-creatinine in aqueous solution from molecular dynamics simulation and quantum study

NASA Astrophysics Data System (ADS)

Lee, Vannajan Sanghiran; Kodchakorn, Kanchanok; Jitonnom, Jitrayut; Nimmanpipug, Piyarat; Kongtawelert, Prachya; Premanode, Bhusana

2010-10-01

The reaction mechanism of creatinine-creatininase binding to form creatine as a final product has been investigated by using a combined ab initio quantum mechanical/molecular mechanical approach and classical molecular dynamics (MD) simulations. In MD simulations, an X-ray crystal structure of the creatininase/creatinine was modified for creatininase/creatinine complexes and the MD simulations were run for free creatininase and creatinine in water. MD results reveal that two X-ray water molecules can be retained in the active site as catalytic water. The binding free energy from Molecular Mechanics Poisson-Boltzmann Surface Area calculation predicted the strong binding of creatinine with Zn2+, Asp45 and Glu183. Two step mechanisms via Mn2+/Zn2+ (as in X-ray structure) and Zn2+/Zn2+ were proposed for water adding step and ring opening step with two catalytic waters. The pathway using synchronous transit methods with local density approximations with PWC functional for the fragment in the active region were obtained. Preferable pathway Zn2+/Zn2+ was observed due to lower activation energy in water adding step. The calculated energy in the second step for both systems were comparable with the barrier of 26.03 and 24.44 kcal/mol for Mn2+/Zn2+ and Zn2+/Zn2+, respectively.

Nitrergic Mechanisms for Management of Recurrent Priapism

PubMed Central

Anele, Uzoma A.; Burnett, Arthur L.

2015-01-01

Introduction Priapism is a condition involving prolonged penile erection unrelated to sexual interest or desire. The ischemic type, including its recurrent variant, is often associated with both physical and psychological complications. As such, management is of critical importance. Ideal therapies for recurrent priapism should address its underlying pathophysiology. Aim To review the available literature on priapism management approaches particularly related to nitrergic mechanisms. Methods A literature review of the pathophysiology and management of priapism was performed using PubMed. Main Outcome Measure Publications pertaining to mechanisms of the molecular pathophysiology of priapism. Results Nitrergic mechanisms are characterized as major players in the molecular pathophysiology of priapism. PDE5 inhibitors represent an available therapeutic option with demonstrated ability in attenuating these underlying nitrergic derangements. Several additional signaling pathways have been found to play a role in the molecular pathophysiology of priapism and have also been associated with these nitrergic mechanisms. Conclusion An increasing understanding of the molecular pathophysiology of priapism has led to the discovery of new potential targets. Several mechanism-based therapeutic approaches may become available in the future. PMID:26478814

Sexual polyploidization in plants--cytological mechanisms and molecular regulation.

PubMed

De Storme, Nico; Geelen, Danny

2013-05-01

In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. © 2013 Ghent University. New Phytologist © 2013 New Phytologist Trust.

Physiological, Molecular and Genetic Mechanisms of Long-Term Habituation

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

Calin-Jageman, Robert J

Work funded on this grant has explored the mechanisms of long-term habituation, a ubiquitous form of learning that plays a key role in basic cognitive functioning. Specifically, behavioral, physiological, and molecular mechanisms of habituation have been explored using a simple model system, the tail-elicited siphon-withdrawal reflex (T-SWR) in the marine mollusk Aplysia californica. Substantial progress has been made on the first and third aims, providing some fundamental insights into the mechanisms by which memories are stored. We have characterized the physiological correlates of short- and long-term habituation. We found that short-term habituation is accompanied by a robust sensory adaptation, whereasmore » long-term habituation is accompanied by alterations in sensory and interneuron synaptic efficacy. Thus, our data indicates memories can be shifted between different sites in a neural network as they are consolidated from short to long term. At the molecular level, we have accomplished microarray analysis comparing gene expression in both habituated and control ganglia. We have identified a network of putatively regulated transcripts that seems particularly targeted towards synaptic changes (e.g. SNAP25, calmodulin) . We are now beginning additional work to confirm regulation of these transcripts and build a more detailed understanding of the cascade of molecular events leading to the permanent storage of long-term memories. On the third aim, we have fostered a nascent neuroscience program via a variety of successful initiatives. We have funded over 11 undergraduate neuroscience scholars, several of whom have been recognized at national and regional levels for their research. We have also conducted a pioneering summer research program for community college students which is helping enhance access of underrepresented groups to life science careers. Despite minimal progress on the second aim, this project has provided a) novel insight into the network

Molecular mechanisms of aging and immune system regulation in Drosophila.

PubMed

Eleftherianos, Ioannis; Castillo, Julio Cesar

2012-01-01

Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span.

Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease.

PubMed

Xu, Wei-Ming; Yang, Kuo; Jiang, Li-Jie; Hu, Jing-Qing; Zhou, Xue-Zhong

2018-01-01

-based approach was proposed to identify the underlying molecular modules of PSCS complicated with IHD, which could be used for interpreting the pharmacological mechanisms of well-established Chinese herbal formulas ( e.g., Tao Hong Si Wu Tang, Dan Shen Yin, Hunag Lian Wen Dan Tang and Gua Lou Xie Bai Ban Xia Tang ). In addition, these results delivered novel understandings of the molecular network mechanisms of IHD phenotype subtypes with PSCS complications, which would be both insightful for IHD precision medicine and the integration of disease and TCM syndrome diagnoses.

Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease

PubMed Central

Xu, Wei-Ming; Yang, Kuo; Jiang, Li-Jie; Hu, Jing-Qing; Zhou, Xue-Zhong

2018-01-01

-based approach was proposed to identify the underlying molecular modules of PSCS complicated with IHD, which could be used for interpreting the pharmacological mechanisms of well-established Chinese herbal formulas (e.g., Tao Hong Si Wu Tang, Dan Shen Yin, Hunag Lian Wen Dan Tang and Gua Lou Xie Bai Ban Xia Tang). In addition, these results delivered novel understandings of the molecular network mechanisms of IHD phenotype subtypes with PSCS complications, which would be both insightful for IHD precision medicine and the integration of disease and TCM syndrome diagnoses. PMID:29403392

A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

PubMed Central

Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

2015-01-01

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular mechanism of their choice. Data were collected from interviews, artifacts, and drawings, and then subjected to thematic analysis. We found that biologists explained the specific activities and organization of entities of the mechanism. In addition, they contextualized explanations according to their biological and social significance; integrated explanations with methods, instruments, and measurements; and used analogies and narrated stories. The derived methods, analogies, context, and how themes informed the development of our final MACH model of mechanistic explanations. Future research will test the potential of the MACH model as a guiding framework for instruction to enhance the quality of student explanations. PMID:25999313

Cation solvation with quantum chemical effects modeled by a size-consistent multi-partitioning quantum mechanics/molecular mechanics method.

PubMed

Watanabe, Hiroshi C; Kubillus, Maximilian; Kubař, Tomáš; Stach, Robert; Mizaikoff, Boris; Ishikita, Hiroshi

2017-07-21

In the condensed phase, quantum chemical properties such as many-body effects and intermolecular charge fluctuations are critical determinants of the solvation structure and dynamics. Thus, a quantum mechanical (QM) molecular description is required for both solute and solvent to incorporate these properties. However, it is challenging to conduct molecular dynamics (MD) simulations for condensed systems of sufficient scale when adapting QM potentials. To overcome this problem, we recently developed the size-consistent multi-partitioning (SCMP) quantum mechanics/molecular mechanics (QM/MM) method and realized stable and accurate MD simulations, using the QM potential to a benchmark system. In the present study, as the first application of the SCMP method, we have investigated the structures and dynamics of Na + , K + , and Ca 2+ solutions based on nanosecond-scale sampling, a sampling 100-times longer than that of conventional QM-based samplings. Furthermore, we have evaluated two dynamic properties, the diffusion coefficient and difference spectra, with high statistical certainty. Furthermore the calculation of these properties has not previously been possible within the conventional QM/MM framework. Based on our analysis, we have quantitatively evaluated the quantum chemical solvation effects, which show distinct differences between the cations.

The epidemiology of supernumerary teeth and the associated molecular mechanism

PubMed Central

Lu, Xi; Yu, Fang; Liu, Junjun; Cai, Wenping; Zhao, Yumei; Zhao, Shouliang; Liu, Shangfeng

2017-01-01

ABSTRACT Supernumerary teeth are common clinical dental anomalies. Although various studies have provided abundant information regarding genes and signaling pathways involved in tooth morphogenesis, which include Wnt, FGF, BMP, and Shh, the molecular mechanism of tooth formation, especially for supernumerary teeth, is still unclear. In the population, some cases of supernumerary teeth are sporadic, while others are syndrome-related with familial hereditary. The prompt and accurate diagnosis of syndrome related supernumerary teeth is quite important for some distinctive disorders. Mice are the most commonly used model system for investigating supernumerary teeth. The upregulation of Wnt and Shh signaling in the dental epithelium results in the formation of multiple supernumerary teeth in mice. Understanding the molecular mechanism of supernumerary teeth is also a component of understanding tooth formation in general and provides clinical guidance for early diagnosis and treatment in the future. PMID:28598258

Measuring the mechanical properties of molecular conformers

NASA Astrophysics Data System (ADS)

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

2015-09-01

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

Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by quantum mechanics/molecular mechanics studies.

PubMed

Huang, Meilan; Li, Xiaozhou; Zou, Jian-Wei; Timson, David J

2013-07-16

GHMP kinases are a group of structurally related small molecule kinases. They have been found in all kingdoms of life and are mostly responsible for catalyzing the ATP-dependent phosphorylation of intermediary metabolites. Although the GHMP kinases are of clinical, pharmaceutical, and biotechnological importance, the mechanism of GHMP kinases is controversial. A catalytic base mechanism was suggested for mevalonate kinase that has a structural feature of the γ-phosphate of ATP close to an aspartate residue; however, for one GHMP family member, homoserine kinase, where the residue acting as general base is absent, a direct phosphorylation mechanism was suggested. Furthermore, it was proposed by some authors that all the GHMP kinases function by a similar mechanism. This controversy in mechanism has limited our ability to exploit these enzymes as drug targets and in biotechnology. Here the phosphorylation reaction mechanism of the human galactokinase, a member of the GHMP kinase family, was investigated using molecular dynamics simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B3LYP-D/AMBER99). The reaction coordinates were localized by potential energy scan using an adiabatic mapping method. Our results indicate that a highly conserved Glu174 captures Arg105 in the proximity of the α-phosphate of ATP, forming a H-bond network; therefore, the mobility of ATP in the large oxyanion hole is restricted. Arg228 functions to stabilize the negative charge developed at the β,γ-bridging oxygen of the ATP during bond cleavage. The reaction occurs via a direct phosphorylation mechanism, and the Asp186 in the proximity of ATP does not directly participate in the reaction pathway. Because Arg228 is not conserved among GHMP kinases, reagents which form interactions with Arg228, and therefore can interrupt its function in phosphorylation, may be developed into potential selective inhibitors for galactokinase.

Prediction of clathrate structure type and guest position by molecular mechanics.

PubMed

Fleischer, Everly B; Janda, Kenneth C

2013-05-16

The clathrate hydrates occur in various types in which the number, size, and shape of the various cages differ. Usually the clathrate type of a specific guest is predicted by the size and shape of the molecular guest. We have developed a methodology to determine the clathrate type employing molecular mechanics with the MMFF force field employing a strategy to calculate the energy of formation of the clathrate from the sum of the guest/cage energies. The clathrate type with the most negative (most stable) energy of formation would be the type predicted (we mainly focused on type I, type II, or bromine type). This strategy allows for a calculation to predict the clathrate type for any cage guest in a few minutes on a laptop computer. It proved successful in predicting the clathrate structure for 46 out of 47 guest molecules. The molecular mechanics calculations also provide a prediction of the guest position within the cage and clathrate structure. These predictions are generally consistent with the X-ray and neutron diffraction studies. By supplementing the diffraction study with molecular mechanics, we gain a more detailed insight regarding the details of the structure. We have also compared MM calculations to studies of the multiple occupancy of the cages. Finally, we present a density functional calculation that demonstrates that the inside of the clathrates cages have a relatively uniform and low electrostatic potential in comparison with the outside oxygen and hydrogen atoms. This implies that van der Waals forces will usually be dominant in the guest-cage interactions.

Structure of Low-Lying Excited States of Guanine in DNA and Solution: Combined Molecular Mechanics and High-Level Coupled Cluster Studies

DOE PAGES

Kowalski, Karol; Valiev, Marat

2007-01-01

High-level ab-initio equation-of-motion coupled-cluster methods with singles, doubles, and noniterative triples are used, in conjunction with the combined quantum mechanical molecular mechanics approach, to investigate the structure of low-lying excited states of the guanine base in DNA and solvated environments. Our results indicate that while the excitation energy of the first excited state is barely changed compared to its gas-phase counterpart, the excitation energy of the second excited state is blue-shifted by 0.24 eV.

Combinatorial Broadening Mechanism of O-H Stretching Bands in H-Bonded Molecular Clusters

NASA Astrophysics Data System (ADS)

Pitsevich, G. A.; Doroshenko, I. Yu.; Pogorelov, V. E.; Pettersson, L. G. M.; Sablinskas, V.; Sapeshko, V. V.; Balevicius, V.

2016-07-01

A new mechanism for combinatorial broadening of donor-OH stretching-vibration absorption bands in molecular clusters with H-bonds is proposed. It enables the experimentally observed increase of the O-H stretching-vibration bandwidth with increasing number of molecules in H-bonded clusters to be explained. Knowledge of the half-width of the OH stretching-vibration absorption band in the dimer and the number of H-bonds in the analyzed cluster is suffi cient in the zeroth-order approximation to estimate the O-H stretching-absorption bands in clusters containing several molecules. Good agreement between the calculated and published experimental half-widths of the OH stretching-vibration absorption bands in MeOH and PrOH clusters was obtained using this approach.

Monoatomic layer removal mechanism in chemical mechanical polishing process: A molecular dynamics study

NASA Astrophysics Data System (ADS)

Si, Lina; Guo, Dan; Luo, Jianbin; Lu, Xinchun

2010-03-01

Molecular dynamics simulations of nanoscratching processes were used to study the atomic-scale removal mechanism of single crystalline silicon in chemical mechanical polishing (CMP) process and particular attention was paid to the effect of scratching depth. The simulation results under a scratching depth of 1 nm showed that a thick layer of silicon material was removed by chip formation and an amorphous layer was formed on the silicon surface after nanoscratching. By contrast, the simulation results with a depth of 0.1 nm indicated that just one monoatomic layer of workpiece was removed and a well ordered crystalline surface was obtained, which is quite consistent with previous CMP experimental results. Therefore, monoatomic layer removal mechanism was presented, by which it is considered that during CMP process the material was removed by one monoatomic layer after another, and the mechanism could provide a reasonable understanding on how the high precision surface was obtained. Also, the effects of the silica particle size and scratching velocity on the removal mechanism were investigated; the wear regimes and interatomic forces between silica particle and workpiece were studied to account for the different removal mechanisms with indentation depths of 0.1 and 1 nm.

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.

Molecular Mechanisms of Bacterial Pathogenicity

NASA Astrophysics Data System (ADS)

Fuchs, Thilo Martin

Cautious optimism has arisen over recent decades with respect to the long struggle against bacteria, viruses, and parasites. This has been offset, however, by a fatal complacency stemming from previous successes such as the development of antimicrobial drugs, the eradication of smallpox, and global immunization programs. Infectious diseases nevertheless remain the world's leading cause of death, killing at least 17 million persons annually [61]. Diarrheal diseases caused by Vibrio cholerae or Shigella dysenteriae kill about 3 million persons every year, most of them young children: Another 4 million die of tuberculosis or tetanus. Outbreaks of diphtheria in Eastern Europe threatens the population with a disease that had previously seemed to be overcome. Efforts to control infectious diseases more comprehensively are undermined not only by socioeconomic conditions but also by the nature of the pathogenic organisms itself; some isolates of Staphylococcus aureus and Enterobacter have become so resistant to drugs by horizontal gene transfer that they are almost untreatable. In addition, the mechanism of genetic variability helps pathogens to evade the human immune system, thus compromising the development of powerful vaccines. Therefore detailed knowledge of the molecular mechanisms of microbial pathogenicity is absolutely necessary to develop new strategies against infectious diseases and thus to lower their impact on human health and social development.

Chemical Shifts of the Carbohydrate Binding Domain of Galectin-3 from Magic Angle Spinning NMR and Hybrid Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Kraus, Jodi; Gupta, Rupal; Yehl, Jenna; Lu, Manman; Case, David A; Gronenborn, Angela M; Akke, Mikael; Polenova, Tatyana

2018-03-22

Magic angle spinning NMR spectroscopy is uniquely suited to probe the structure and dynamics of insoluble proteins and protein assemblies at atomic resolution, with NMR chemical shifts containing rich information about biomolecular structure. Access to this information, however, is problematic, since accurate quantum mechanical calculation of chemical shifts in proteins remains challenging, particularly for 15 N H . Here we report on isotropic chemical shift predictions for the carbohydrate recognition domain of microcrystalline galectin-3, obtained from using hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, implemented using an automated fragmentation approach, and using very high resolution (0.86 Å lactose-bound and 1.25 Å apo form) X-ray crystal structures. The resolution of the X-ray crystal structure used as an input into the AF-NMR program did not affect the accuracy of the chemical shift calculations to any significant extent. Excellent agreement between experimental and computed shifts is obtained for 13 C α , while larger scatter is observed for 15 N H chemical shifts, which are influenced to a greater extent by electrostatic interactions, hydrogen bonding, and solvation.

The Electrical Response to Injury: Molecular Mechanisms and Wound Healing

PubMed Central

Reid, Brian; Zhao, Min

2014-01-01

Significance: Natural, endogenous electric fields (EFs) and currents arise spontaneously after wounding of many tissues, especially epithelia, and are necessary for normal healing. This wound electrical activity is a long-lasting and regulated response. Enhancing or inhibiting this electrical activity increases or decreases wound healing, respectively. Cells that are responsible for wound closure such as corneal epithelial cells or skin keratinocytes migrate directionally in EFs of physiological magnitude. However, the mechanisms of how the wound electrical response is initiated and regulated remain unclear. Recent Advances: Wound EFs and currents appear to arise by ion channel up-regulation and redistribution, which are perhaps triggered by an intracellular calcium wave or cell depolarization. We discuss the possibility of stimulation of wound healing via pharmacological enhancement of the wound electric signal by stimulation of ion pumping. Critical Issues: Chronic wounds are a major problem in the elderly and diabetic patient. Any strategy to stimulate wound healing in these patients is desirable. Applying electrical stimulation directly is problematic, but pharmacological enhancement of the wound signal may be a promising strategy. Future Directions: Understanding the molecular regulation of wound electric signals may reveal some fundamental mechanisms in wound healing. Manipulating fluxes of ions and electric currents at wounds might offer new approaches to achieve better wound healing and to heal chronic wounds. PMID:24761358

Molecular mechanisms of action of bacterial exotoxins.

PubMed

Balfanz, J; Rautenberg, P; Ullmann, U

1996-07-01

Toxins are one of the inventive strategies that bacteria have developed in order to survive. As virulence factors, they play a major role in the pathogenesis of infectious diseases. Recent discoveries have once more highlighted the effectiveness of these precisely adjusted bacterial weapons. Furthermore, toxins have become an invaluable tool in the investigation of fundamental cell processes, including regulation of cellular functions by various G proteins, cytoskeletal dynamics and neural transmission. In this review, the bacterial toxins are presented in a rational classification based on the molecular mechanisms of action.

Molecular Mechanisms and Management of a Cutaneous Inflammatory Disorder: Psoriasis

PubMed Central

Cho, Dae Ho; Park, Hyun Jeong

2017-01-01

Psoriasis is a complex chronic inflammatory cutaneous disorder. To date, robust molecular mechanisms of psoriasis have been reported. Among diverse aberrant immunopathogenetic mechanisms, the current model emphasizes the role of Th1 and the IL-23/Th17 axis, skin-resident immune cells and major signal transduction pathways involved in psoriasis. The multiple genetic risk loci for psoriasis have been rapidly revealed with the advent of a novel technology. Moreover, identifying epigenetic modifications could bridge the gap between genetic and environmental risk factors in psoriasis. This review will provide a better understanding of the pathogenesis of psoriasis by unraveling the complicated interplay among immunological abnormalities, genetic risk foci, epigenetic modification and environmental factors of psoriasis. With advances in molecular biology, diverse new targets are under investigation to manage psoriasis. The recent advances in treatment modalities for psoriasis based on targeted molecules are also discussed. PMID:29232931

Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

PubMed Central

de las Vecillas Sánchez, Leticia; Alenazy, Leila A.; Garcia-Neuer, Marlene; Castells, Mariana C.

2017-01-01

Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a “bench to bedside” approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications. PMID:28632196

Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer.

PubMed

Yang, Wanli; Ma, Jiaojiao; Zhou, Wei; Cao, Bo; Zhou, Xin; Yang, Zhiping; Zhang, Hongwei; Zhao, Qingchuan; Fan, Daiming; Hong, Liu

2017-11-01

Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.

Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms.

PubMed

Larizza, L; Finelli, P

2018-04-19

Advances in genomic analyses based on next-generation sequencing and integrated omics approaches, have accelerated in an unprecedented way the discovery of causative genes of developmental delay (DD) and intellectual disability (ID) disorders. Chromatin dysregulation has been recognized as common pathomechanism of mendelian DD/ID syndromes due to mutation in genes encoding chromatin regulators referred as transcriptomopathies or epigenetic disorders. Common to these syndromes are the wide phenotypic breadth and the recognition of groups of distinct syndromes with shared signs besides cognitive impairment, likely mirroring common molecular mechanisms. Disruption of chromatin-associated transcription machinery accounts for the phenotypic overlap of Cornelia de Lange with KBG and with syndromes of the epigenetic machinery. The genes responsible for Smith-Magenis-related disorders act in interconnected networks and the molecular signature of histone acetylation disorders joins Rubinstein-Taybi-related syndromes. Deciphering pathway interconnection of clinically similar ID syndromes may enhance search of common targets useful for developing new therapeutics. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Practical quantum mechanics-based fragment methods for predicting molecular crystal properties.

PubMed

Wen, Shuhao; Nanda, Kaushik; Huang, Yuanhang; Beran, Gregory J O

2012-06-07

Significant advances in fragment-based electronic structure methods have created a real alternative to force-field and density functional techniques in condensed-phase problems such as molecular crystals. This perspective article highlights some of the important challenges in modeling molecular crystals and discusses techniques for addressing them. First, we survey recent developments in fragment-based methods for molecular crystals. Second, we use examples from our own recent research on a fragment-based QM/MM method, the hybrid many-body interaction (HMBI) model, to analyze the physical requirements for a practical and effective molecular crystal model chemistry. We demonstrate that it is possible to predict molecular crystal lattice energies to within a couple kJ mol(-1) and lattice parameters to within a few percent in small-molecule crystals. Fragment methods provide a systematically improvable approach to making predictions in the condensed phase, which is critical to making robust predictions regarding the subtle energy differences found in molecular crystals.

Cofacial Assembly of Metallomacrocycles. A Molecular Engineering Approach to Electrically Conductive Polymers.

DTIC Science & Technology

1981-05-13

34molecular metals." THE COFACIAL ASSEMBLY STRATEGY Although the above molecular macrocycle, halogen cocrystalli - zation approach to the synthesis of...substitute various oxidizing quinones for halogens in the cocrystallization synthesis have failed because integrated stacK (Figure 2C,D) insulators are

Molecular Mechanisms of Olfactory Responses to Stimulus Mixtures

DTIC Science & Technology

1991-02-26

demonstrated that the amino acid chemoreceptors in this organism are function- ally coupled to one or more G-proteins (19). Biochemical studies have also shown...Hwang, P.M. and Pevsner, J. (1989) Molecular mechanisms of olfaction. TINS 12, 35-38. 3. Bruch, R.C. (1990) Signal transduction in olfaction and taste ...amino acid olfactory receptor. Comp. Biochem. Physiol. 91B, 535-540. 17. Caprio, J. (1978) Olfaction and taste in the channel catfish: An

Reverse Cholesterol Transport: Molecular Mechanisms and the Non-medical Approach to Enhance HDL Cholesterol

PubMed Central

Marques, Leandro R.; Diniz, Tiego A.; Antunes, Barbara M.; Rossi, Fabrício E.; Caperuto, Erico C.; Lira, Fábio S.; Gonçalves, Daniela C.

2018-01-01

Dyslipidemia (high concentrations of LDL-c and low concentrations of HDL-c) is a major cause of cardiovascular events, which are the leading cause of death in the world. On the other hand, nutrition and regular exercise can be an interesting strategy to modulate lipid profile, acting as prevention or treatment, inhibiting the risk of diseases due to its anti-inflammatory and anti-atherogenic characteristics. Additionally, the possibility of controlling different training variables, such as type, intensity and recovery interval, can be used to maximize the benefits of exercise in promoting cardiovascular health. However, the mechanisms by which exercise and nutrients act in the regulation of cholesterol and its fractions, such as reverse cholesterol transport, receptors and transcription factors involved, such as PPARs and their role related to exercise, deserve further discussion. Therefore, the objective of this review is to debate about non-medical approaches to increase HDL-c, such as nutritional and training strategies, and to discuss the central mechanisms involved in the modulation of lipid profile during exercise, as well as that can be controlled by physical trainers or sports specialists in attempt to maximize the benefits promoted by exercise. The search for papers was performed in the databases: Medline (Pubmed), Science Direct, Scopus, Sport Discus, Web of Science, Scielo and Lilacs until February 2016. PMID:29867567

Sexual polyploidization in plants – cytological mechanisms and molecular regulation

PubMed Central

De Storme, Nico; Geelen, Danny

2013-01-01

In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. PMID:23421646

Lipid Raft Redox Signaling: Molecular Mechanisms in Health and Disease

PubMed Central

Zhou, Fan; Katirai, Foad

2011-01-01

Abstract Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial-temporal regulations, and physiological, pathophysiological relevances to human health and diseases. Antioxid. Redox Signal. 15, 1043–1083. PMID:21294649

Molecular mechanisms of dominance evolution in Müllerian mimicry.

PubMed

Llaurens, V; Joron, M; Billiard, S

2015-12-01

Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Müllerian mimicry as a case-study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Müllerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency-dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration-selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Molecular Characterisation of Transport Mechanisms at the Developing Mouse Blood–CSF Interface: A Transcriptome Approach

PubMed Central

Liddelow, Shane A.; Temple, Sally; Møllgård, Kjeld; Gehwolf, Renate; Wagner, Andrea; Bauer, Hannelore; Bauer, Hans-Christian; Phoenix, Timothy N.; Dziegielewska, Katarzyna M.; Saunders, Norman R.

2012-01-01

Exchange mechanisms across the blood–cerebrospinal fluid (CSF) barrier in the choroid plexuses within the cerebral ventricles control access of molecules to the central nervous system, especially in early development when the brain is poorly vascularised. However, little is known about their molecular or developmental characteristics. We examined the transcriptome of lateral ventricular choroid plexus in embryonic day 15 (E15) and adult mice. Numerous genes identified in the adult were expressed at similar levels at E15, indicating substantial plexus maturity early in development. Some genes coding for key functions (intercellular/tight junctions, influx/efflux transporters) changed expression during development and their expression patterns are discussed in the context of available physiological/permeability results in the developing brain. Three genes: Secreted protein acidic and rich in cysteine (Sparc), Glycophorin A (Gypa) and C (Gypc), were identified as those whose gene products are candidates to target plasma proteins to choroid plexus cells. These were investigated using quantitative- and single-cell-PCR on plexus epithelial cells that were albumin- or total plasma protein-immunopositive. Results showed a significant degree of concordance between plasma protein/albumin immunoreactivity and expression of the putative transporters. Immunohistochemistry identified SPARC and GYPA in choroid plexus epithelial cells in the embryo with a subcellular distribution that was consistent with transport of albumin from blood to cerebrospinal fluid. In adult plexus this pattern of immunostaining was absent. We propose a model of the cellular mechanism in which SPARC and GYPA, together with identified vesicle-associated membrane proteins (VAMPs) may act as receptors/transporters in developmentally regulated transfer of plasma proteins at the blood–CSF interface. PMID:22457777

Molecular Mechanisms of Aging and Immune System Regulation in Drosophila

PubMed Central

Eleftherianos, Ioannis; Castillo, Julio Cesar

2012-01-01

Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span. PMID:22949833

Nanotechnology Review: Molecular Electronics to Molecular Motors

NASA Technical Reports Server (NTRS)

Srivastava, Deepak; Saini, Subhash (Technical Monitor)

1998-01-01

Reviewing the status of current approaches and future projections, as already published in scientific journals and books, the talk will summarize the direction in which computational and experimental nanotechnologies are progressing. Examples of nanotechnological approaches to the concepts of design and simulation of carbon nanotube based molecular electronic and mechanical devices will be presented. The concepts of nanotube based gears and motors will be discussed. The above is a non-technical review talk which covers long term precompetitive basic research in already published material that has been presented before many US scientific meeting audiences.

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

PubMed

Iborra-Egea, Oriol; Gálvez-Montón, Carolina; Roura, Santiago; Perea-Gil, Isaac; Prat-Vidal, Cristina; Soler-Botija, Carolina; Bayes-Genis, Antoni

2017-01-01

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post

Computerized approaches to enhance understanding of organic reaction mechanisms: CAN reaction mechanisms and CPLEX prelaboratory methodology

NASA Astrophysics Data System (ADS)

Al-Shammari, Abdulrahman G. Alhamzani

2008-10-01

Two approaches to enhance the understanding of organic reaction mechanisms are described. First, a new method for teaching organic reaction mechanisms that can be used in a Computer-Assisted Instruction (CAI) environment is proposed and tested (Chapter 1). The method concentrates upon the important intermediate structures, which are assumed to be on the reaction coordinate, and which can be evaluated and graded by currently available computer techniques. At the same time, the "curved arrows" that show the electron flow in a reaction mechanism are neglected, since they cannot be evaluated and graded with currently available computer techniques. By allowing student practice for learning organic reaction mechanisms using the Curved Arrow Neglect (CAN) method within a "Practice Makes Perfect" CAI method, student performance in the drawing of traditional reaction mechanisms, in which students had to include the "curved arrows" on their written classroom exams, was significantly enhanced. Second, computerized prelaboratory experiments (CPLEX) for organic chemistry laboratory 1 & 2 courses have been created, used, and evaluated (Chapters 2 and 3). These computerized prelabs are unique because they combine both "dry lab" actions with detailed animations of the actual chemistry occurring at the molecular level. The "dry lab" serves to simulate the actual physical manipulations of equipment and chemicals that occur in the laboratory experiment through the use of drag-and-drop computer technology. At the same time, these physical actions are accompanied on a separate part of the computer screen by animations showing the chemistry at the molecular level that is occurring in the experiment. These CPLEX modules were made into Internet accessible modules. The students were allowed to access the CPLEX modules prior to performing the actual laboratory experiment. A detailed evaluation of students' perception of the modules was accomplished via survey methodology during the entire

Degradation mechanisms of bioresorbable polyesters. Part 2. Effects of initial molecular weight and residual monomer.

PubMed

Gleadall, Andrew; Pan, Jingzhe; Kruft, Marc-Anton; Kellomäki, Minna

2014-05-01

This paper presents an understanding of how initial molecular weight and initial monomer fraction affect the degradation of bioresorbable polymers in terms of the underlying hydrolysis mechanisms. A mathematical model was used to analyse the effects of initial molecular weight for various hydrolysis mechanisms including noncatalytic random scission, autocatalytic random scission, noncatalytic end scission or autocatalytic end scission. Different behaviours were identified to relate initial molecular weight to the molecular weight half-life and to the time until the onset of mass loss. The behaviours were validated by fitting the model to experimental data for molecular weight reduction and mass loss of samples with different initial molecular weights. Several publications that consider initial molecular weight were reviewed. The effect of residual monomer on degradation was also analysed, and shown to accelerate the reduction of molecular weight and mass loss. An inverse square root law relationship was found between molecular weight half-life and initial monomer fraction for autocatalytic hydrolysis. The relationship was tested by fitting the model to experimental data with various residual monomer contents. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Molecular mechanisms of cryptococcal meningitis

PubMed Central

Liu, Tong-Bao; Perlin, David; Xue, Chaoyang

2012-01-01

Fungal meningitis is a serious disease caused by a fungal infection of the central nervous system (CNS) mostly in individuals with immune system deficiencies. Fungal meningitis is often fatal without proper treatment, and the mortality rate remains unacceptably high even with antifungal drug interventions. Currently, cryptococcal meningitis is the most common fungal meningitis in HIV-1/AIDS, and its disease mechanism has been extensively studied. The key steps for fungi to infect brain and cause meningitis after establishment of local infection are the dissemination of fungal cells to the bloodstream and invasion through the blood brain barrier to reach the CNS. In this review, we use cryptococcal CNS infection as an example to describe the current molecular understanding of fungal meningitis, including the establishment of the infection, dissemination, and brain invasion. Host and microbial factors that contribute to these infection steps are also discussed. PMID:22460646

From Genomics to Omics Landscapes of Parkinson's Disease: Revealing the Molecular Mechanisms

PubMed Central

Redenšek, Sara; Dolžan, Vita

2018-01-01

Abstract Molecular mechanisms of Parkinson's disease (PD) have already been investigated in various different omics landscapes. We reviewed the literature about different omics approaches between November 2005 and November 2017 to depict the main pathological pathways for PD development. In total, 107 articles exploring different layers of omics data associated with PD were retrieved. The studies were grouped into 13 omics layers: genomics–DNA level, transcriptomics, epigenomics, proteomics, ncRNomics, interactomics, metabolomics, glycomics, lipidomics, phenomics, environmental omics, pharmacogenomics, and integromics. We discussed characteristics of studies from different landscapes, such as main findings, number of participants, sample type, methodology, and outcome. We also performed curation and preliminary synthesis of multiple omics data, and identified overlapping results, which could lead toward selection of biomarkers for further validation of PD risk loci. Biomarkers could support the development of targeted prognostic/diagnostic panels as a tool for early diagnosis and prediction of progression rate and prognosis. This review presents an example of a comprehensive approach to revealing the underlying processes and risk factors of a complex disease. It urges scientists to structure the already known data and integrate it into a meaningful context. PMID:29356624

The ligand binding mechanism to purine nucleoside phosphorylase elucidated via molecular dynamics and machine learning.

PubMed

Decherchi, Sergio; Berteotti, Anna; Bottegoni, Giovanni; Rocchia, Walter; Cavalli, Andrea

2015-01-27

The study of biomolecular interactions between a drug and its biological target is of paramount importance for the design of novel bioactive compounds. In this paper, we report on the use of molecular dynamics (MD) simulations and machine learning to study the binding mechanism of a transition state analogue (DADMe-immucillin-H) to the purine nucleoside phosphorylase (PNP) enzyme. Microsecond-long MD simulations allow us to observe several binding events, following different dynamical routes and reaching diverse binding configurations. These simulations are used to estimate kinetic and thermodynamic quantities, such as kon and binding free energy, obtaining a good agreement with available experimental data. In addition, we advance a hypothesis for the slow-onset inhibition mechanism of DADMe-immucillin-H against PNP. Combining extensive MD simulations with machine learning algorithms could therefore be a fruitful approach for capturing key aspects of drug-target recognition and binding.

Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.

PubMed

Jitonnom, Jitrayut; Mujika, Jon I; van der Kamp, Marc W; Mulholland, Adrian J

2017-12-05

Creatininase catalyzes the conversion of creatinine (a biosensor for kidney function) to creatine via a two-step mechanism: water addition followed by ring opening. Water addition is common to other known cyclic amidohydrolases, but the precise mechanism for ring opening is still under debate. The proton donor in this step is either His178 or a water molecule bound to one of the metal ions, and the roles of His178 and Glu122 are unclear. Here, the two possible reaction pathways have been fully examined by means of combined quantum mechanics/molecular mechanics simulations at the SCC-DFTB/CHARMM22 level of theory. The results indicate that His178 is the main catalytic residue for the whole reaction and explain its role as proton shuttle during the ring-opening step. In the first step, His178 provides electrostatic stabilization to the gem-diolate tetrahedral intermediate. In the second step, His178 abstracts the hydroxyl proton of the intermediate and delivers it to the cyclic amide nitrogen, leading to ring opening. The latter is the rate-limiting step with a free energy barrier of 18.5 kcal/mol, in agreement with the experiment. We find that Glu122 must be protonated during the enzyme reaction, so that it can form a stable hydrogen bond with its neighboring water molecule. Simulations of the E122Q mutant showed that this replacement disrupts the H-bond network formed by three conserved residues (Glu34, Ser78, and Glu122) and water, increasing the energy barrier. Our computational studies provide a comprehensive explanation for previous structural and kinetic observations, including why the H178A mutation causes a complete loss of activity but the E122Q mutation does not.

Molecular mechanism of the Syk activation switch.

PubMed

Tsang, Emily; Giannetti, Anthony M; Shaw, David; Dinh, Marie; Tse, Joyce K Y; Gandhi, Shaan; Ho, Hoangdung; Wang, Sandra; Papp, Eva; Bradshaw, J Michael

2008-11-21

Many immune signaling pathways require activation of the Syk tyrosine kinase to link ligation of surface receptors to changes in gene expression. Despite the central role of Syk in these pathways, the Syk activation process remains poorly understood. In this work we quantitatively characterized the molecular mechanism of Syk activation in vitro using a real time fluorescence kinase assay, mutagenesis, and other biochemical techniques. We found that dephosphorylated full-length Syk demonstrates a low initial rate of substrate phosphorylation that increases during the kinase reaction due to autophosphorylation. The initial rate of Syk activity was strongly increased by either pre-autophosphorylation or binding of phosphorylated immune tyrosine activation motif peptides, and each of these factors independently fully activated Syk. Deletion mutagenesis was used to identify regions of Syk important for regulation, and residues 340-356 of the SH2 kinase linker region were identified to be important for suppression of activity before activation. Comparison of the activation processes of Syk and Zap-70 revealed that Syk is more readily activated by autophosphorylation than Zap-70, although both kinases are rapidly activated by Src family kinases. We also studied Syk activity in B cell lysates and found endogenous Syk is also activated by phosphorylation and immune tyrosine activation motif binding. Together these experiments show that Syk functions as an "OR-gate" type of molecular switch. This mechanism of switch-like activation helps explain how Syk is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression.

Influence of Molecular Weight on the Mechanical Performance of a Thermoplastic Glassy Polyimide

NASA Technical Reports Server (NTRS)

Nicholson, Lee M.; Whitley, Karen S.; Gates, Thomas S.; Hinkley, Jeffrey A.

1999-01-01

Mechanical Testing of an advanced thermoplastic polyimide (LaRC-TM-SI) with known variations in molecular weight was performed over a range of temperatures below the glass transition temperature. The physical characterization, elastic properties and notched tensile strength were all determined as a function of molecular weight and test temperature. It was shown that notched tensile strength is a strong function of both temperature and molecular weight, whereas stiffness is only a strong function of temperature. A critical molecular weight (Mc) was observed to occur at a weight-average molecular weight (Mw) of approx. 22000 g/mol below which, the notched tensile strength decreases rapidly. This critical molecular weight transition is temperature-independent. Furthermore, inelastic analysis showed that low molecular weight materials tended to fail in a brittle manner, whereas high molecular weight materials exhibited ductile failure. The microstructural images supported these findings.

Low- and high-spin iron (II) complexes studied by effective crystal field method combined with molecular mechanics.

PubMed

Darkhovskii, M B; Pletnev, I V; Tchougréeff, A L

2003-11-15

A computational method targeted to Werner-type complexes is developed on the basis of quantum mechanical effective Hamiltonian crystal field (EHCF) methodology (previously proposed for describing electronic structure of transition metal complexes) combined with the Gillespie-Kepert version of molecular mechanics (MM). It is a special version of the hybrid quantum/MM approach. The MM part is responsible for representing the whole molecule, including ligand atoms and metal ion coordination sphere, but leaving out the effects of the d-shell. The quantum mechanical EHCF part is limited to the metal ion d-shell. The method reproduces with reasonable accuracy geometry and spin states of the Fe(II) complexes with monodentate and polydentate aromatic ligands with nitrogen donor atoms. In this setting a single set of MM parameters set is shown to be sufficient for handling all spin states of the complexes under consideration. Copyright 2003 Wiley Periodicals, Inc.

Cardiotoxicity of the new cancer therapeutics- mechanisms of, and approaches to, the problem

PubMed Central

Force, Thomas; Kerkelä, Risto

2009-01-01

Cardiotoxicity of some targeted therapeutics, including monoclonal antibodies and small molecule inhibitors, is a reality. Herein we will examine why it occurs, focusing on molecular mechanisms to better understand the issue. We will also examine how big the problem is and, more importantly, how big it may become in the future. We will review models for detecting cardiotoxicity in the pre-clinical phase. We will also focus on two key areas that drive cardiotoxicity- multi-targeting and the inherent lack of selectivity of ATP-competitive antagonists. Finally, we will examine the issue of reversibility and discuss possible approaches to keeping patients on therapy. PMID:18617014

Fusarium diversity in soil using a specific molecular approach and a cultural approach.

PubMed

Edel-Hermann, Véronique; Gautheron, Nadine; Mounier, Arnaud; Steinberg, Christian

2015-04-01

Fusarium species are ubiquitous in soil. They cause plant and human diseases and can produce mycotoxins. Surveys of Fusarium species diversity in environmental samples usually rely on laborious culture-based methods. In the present study, we have developed a molecular method to analyze Fusarium diversity directly from soil DNA. We designed primers targeting the translation elongation factor 1-alpha (EF-1α) gene and demonstrated their specificity toward Fusarium using a large collection of fungi. We used the specific primers to construct a clone library from three contrasting soils. Sequence analysis confirmed the specificity of the assay, with 750 clones identified as Fusarium and distributed among eight species or species complexes. The Fusarium oxysporum species complex (FOSC) was the most abundant one in the three soils, followed by the Fusarium solani species complex (FSSC). We then compared our molecular approach results with those obtained by isolating Fusarium colonies on two culture media and identifying species by sequencing part of the EF-1α gene. The 750 isolates were distributed into eight species or species complexes, with the same dominant species as with the cloning method. Sequence diversity was much higher in the clone library than in the isolate collection. The molecular approach proved to be a valuable tool to assess Fusarium diversity in environmental samples. Combined with high throughput sequencing, it will allow for in-depth analysis of large numbers of samples. Published by Elsevier B.V.

Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach.

PubMed

Dahan, Arik; Khamis, Mustafa; Agbaria, Riad; Karaman, Rafik

2012-08-01

The molecular revolution greatly impacted the field of drug design and delivery in general, and the utilization of the prodrug approach in particular. The increasing understanding of membrane transporters has promoted a novel 'targeted-prodrug' approach utilizing carrier-mediated transport to increase intestinal permeability, as well as specific enzymes to promote activation to the parent drug. This article provides the reader with a concise overview of this modern approach to prodrug design. Targeting the oligopeptide transporter PEPT1 for absorption and the serine hydrolase valacyclovirase for activation will be presented as examples for the successful utilization of this approach. Additionally, the use of computational approaches, such as DFT and ab initio molecular orbital methods, in modern prodrugs design will be discussed. Overall, in the coming years, more and more information will undoubtedly become available regarding intestinal transporters and potential enzymes that may be exploited for the targeted modern prodrug approach. Hence, the concept of prodrug design can no longer be viewed as merely a chemical modification to solve problems associated with parent compounds. Rather, it opens promising opportunities for precise and efficient drug delivery, as well as enhancement of treatment options and therapeutic efficacy.

Multiresolution molecular mechanics: Surface effects in nanoscale materials

NASA Astrophysics Data System (ADS)

Yang, Qingcheng; To, Albert C.

2017-05-01

Surface effects have been observed to contribute significantly to the mechanical response of nanoscale structures. The newly proposed energy-based coarse-grained atomistic method Multiresolution Molecular Mechanics (MMM) (Yang, To (2015), [57]) is applied to capture surface effect for nanosized structures by designing a surface summation rule SRS within the framework of MMM. Combined with previously proposed bulk summation rule SRB, the MMM summation rule SRMMM is completed. SRS and SRB are consistently formed within SRMMM for general finite element shape functions. Analogous to quadrature rules in finite element method (FEM), the key idea to the good performance of SRMMM lies in that the order or distribution of energy for coarse-grained atomistic model is mathematically derived such that the number, position and weight of quadrature-type (sampling) atoms can be determined. Mathematically, the derived energy distribution of surface area is different from that of bulk region. Physically, the difference is due to the fact that surface atoms lack neighboring bonding. As such, SRS and SRB are employed for surface and bulk domains, respectively. Two- and three-dimensional numerical examples using the respective 4-node bilinear quadrilateral, 8-node quadratic quadrilateral and 8-node hexahedral meshes are employed to verify and validate the proposed approach. It is shown that MMM with SRMMM accurately captures corner, edge and surface effects with less 0.3% degrees of freedom of the original atomistic system, compared against full atomistic simulation. The effectiveness of SRMMM with respect to high order element is also demonstrated by employing the 8-node quadratic quadrilateral to solve a beam bending problem considering surface effect. In addition, the introduced sampling error with SRMMM that is analogous to numerical integration error with quadrature rule in FEM is very small.

Ab initio study of structural and mechanical property of solid molecular hydrogens

NASA Astrophysics Data System (ADS)

Ye, Yingting; Yang, Li; Yang, Tianle; Nie, Jinlan; Peng, Shuming; Long, Xinggui; Zu, Xiaotao; Du, Jincheng

2015-06-01

Ab initio calculations based on density functional theory (DFT) were performed to investigate the structural and the elastic properties of solid molecular hydrogens (H2). The influence of molecular axes of H2 on structural relative stabilities of hexagonal close-packed (hcp) and face-centered cubic (fcc) structured hydrogen molecular crystals were systematically investigated. Our results indicate that for hcp structures, disordered hydrogen molecule structure is more stable, while for fcc structures, Pa3 hydrogen molecular crystal is most stable. The cohesive energy of fcc H2 crystal was found to be lower than hcp. The mechanical properties of fcc and hcp hydrogen molecular crystals were obtained, with results consistent with previous theoretical calculations. In addition, the effects of zero point energy (ZPE) and van der Waals (vdW) correction on the cohesive energy and the stability of hydrogen molecular crystals were systematically studied and discussed.

Towards a mechanism-based approach to pain management in osteoarthritis

PubMed Central

Malfait, Anne-Marie; Schnitzer, Thomas J.

2014-01-01

Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management. PMID:24045707

The molecular mechanisms underlying lens fiber elongation

PubMed Central

Audette, Dylan S.; Scheiblin, David A.; Duncan, Melinda K.

2016-01-01

Lens fiber cells are highly elongated cells with complex membrane morphologies that are critical for the transparency of the ocular lens. Investigations into the molecular mechanisms underlying lens fiber cell elongation were first reported in the 1960s, however, our understanding of the process is still poor nearly 50 years later. This review summarizes what is currently hypothesized about the regulation of lens fiber cell elongation along with the available experimental evidence, and how this information relates to what is known about the regulation of cell shape/elongation in other cell types, particularly neurons. PMID:27015931

Investigation of deformation mechanisms of staggered nanocomposites using molecular dynamics

NASA Astrophysics Data System (ADS)

Mathiazhagan, S.; Anup, S.

2016-08-01

Biological materials with nanostructure of regularly or stair-wise staggered arrangements of hard platelets reinforced in a soft protein matrix have superior mechanical properties. Applications of these nanostructures to ceramic matrix composites could enhance their toughness. Using molecular dynamics simulations, mechanical behaviour of the bio-inspired nanocomposites is studied. Regularly staggered model shows better flow behaviour compared to stair-wise staggered model due to the symmetrical crack propagation along the interface. Though higher stiffness and strength are obtained for stair-wise staggered models, rapid crack propagation reduces the toughness. Arresting this crack propagation could lead to superior mechanical properties in stair-wise staggered models.

Active cell mechanics: Measurement and theory.

PubMed

Ahmed, Wylie W; Fodor, Étienne; Betz, Timo

2015-11-01

Living cells are active mechanical systems that are able to generate forces. Their structure and shape are primarily determined by biopolymer filaments and molecular motors that form the cytoskeleton. Active force generation requires constant consumption of energy to maintain the nonequilibrium activity to drive organization and transport processes necessary for their function. To understand this activity it is necessary to develop new approaches to probe the underlying physical processes. Active cell mechanics incorporates active molecular-scale force generation into the traditional framework of mechanics of materials. This review highlights recent experimental and theoretical developments towards understanding active cell mechanics. We focus primarily on intracellular mechanical measurements and theoretical advances utilizing the Langevin framework. These developing approaches allow a quantitative understanding of nonequilibrium mechanical activity in living cells. This article is part of a Special Issue entitled: Mechanobiology. Copyright © 2015. Published by Elsevier B.V.

Molecular genetic approaches to the study of cellular senescence.

PubMed

Goletz, T J; Smith, J R; Pereira-Smith, O M

1994-01-01

Cellular senescence is an inability of cells to synthesize DNA and divide, which results in a terminal loss of proliferation despite the maintenance of basic metabolic processes. Senescence has been proposed as a model for the study of aging at the cellular level, and the basis for this model system and its features have been summarized. Although strong experimental evidence exists to support the hypothesis that cellular senescence is a dominant active process, the mechanisms responsible for this phenomenon remain a mystery. Investigators have taken several approaches to gain a better understanding of senescence. Several groups have documented the differences between young and senescent cells, and others have identified changes that occur during the course of a cell's in vitro life span. Using molecular and biochemical approaches, important changes in gene expression and function of cell-cycle-associated products have been identified. The active production of an inhibitor of DNA synthesis has been demonstrated. This may represent the final step in a cascade of events governing senescence. The study of immortal cells which have escaped senescence has also provided useful information, particularly with regard to the genes governing the senescence program. These studies have identified four complementation groups for indefinite division, which suggests that there are at least four genes or gene pathways in the senescence program. Through the use of microcell-mediated chromosome transfer, chromosomes encoding senescence genes have been identified; efforts to clone these genes are ongoing.(ABSTRACT TRUNCATED AT 250 WORDS)

Review on Molecular Mechanisms of Antifouling Compounds: An Update since 2012.

PubMed

Chen, Lianguo; Qian, Pei-Yuan

2017-08-28

Better understanding of the mechanisms of antifouling compounds is recognized to be of high value in establishing sensitive biomarkers, allowing the targeted optimization of antifouling compounds and guaranteeing environmental safety. Despite vigorous efforts to find new antifouling compounds, information about the mechanisms of antifouling is still scarce. This review summarizes the progress into understanding the molecular mechanisms underlying antifouling activity since 2012. Non-toxic mechanisms aimed at specific targets, including inhibitors of transmembrane transport, quorum sensing inhibitors, neurotransmission blockers, adhesive production/release inhibitors and enzyme/protein inhibitors, are put forward for natural antifouling products or shelf-stable chemicals. Several molecular targets show good potential for use as biomarkers in future mechanistic screening, such as acetylcholine esterase for neurotransmission, phenoloxidase/tyrosinase for the formation of adhesive plaques, N -acyl homoserine lactone for quorum sensing and intracellular Ca 2+ levels as second messenger. The studies on overall responses to challenges by antifoulants can be categorized as general targets, including protein expression/metabolic activity regulators, oxidative stress inducers, neurotransmission blockers, surface modifiers, biofilm inhibitors, adhesive production/release inhibitors and toxic killing. Given the current situation and the knowledge gaps regarding the development of alternative antifoulants, a basic workflow is proposed that covers the indispensable steps, including preliminary mechanism- or bioassay-guided screening, evaluation of environmental risks, field antifouling performance, clarification of antifouling mechanisms and the establishment of sensitive biomarkers, which are combined to construct a positive feedback loop.

Review on Molecular Mechanisms of Antifouling Compounds: An Update since 2012

PubMed Central

Chen, Lianguo; Qian, Pei-Yuan

2017-01-01

Better understanding of the mechanisms of antifouling compounds is recognized to be of high value in establishing sensitive biomarkers, allowing the targeted optimization of antifouling compounds and guaranteeing environmental safety. Despite vigorous efforts to find new antifouling compounds, information about the mechanisms of antifouling is still scarce. This review summarizes the progress into understanding the molecular mechanisms underlying antifouling activity since 2012. Non-toxic mechanisms aimed at specific targets, including inhibitors of transmembrane transport, quorum sensing inhibitors, neurotransmission blockers, adhesive production/release inhibitors and enzyme/protein inhibitors, are put forward for natural antifouling products or shelf-stable chemicals. Several molecular targets show good potential for use as biomarkers in future mechanistic screening, such as acetylcholine esterase for neurotransmission, phenoloxidase/tyrosinase for the formation of adhesive plaques, N-acyl homoserine lactone for quorum sensing and intracellular Ca2+ levels as second messenger. The studies on overall responses to challenges by antifoulants can be categorized as general targets, including protein expression/metabolic activity regulators, oxidative stress inducers, neurotransmission blockers, surface modifiers, biofilm inhibitors, adhesive production/release inhibitors and toxic killing. Given the current situation and the knowledge gaps regarding the development of alternative antifoulants, a basic workflow is proposed that covers the indispensable steps, including preliminary mechanism- or bioassay-guided screening, evaluation of environmental risks, field antifouling performance, clarification of antifouling mechanisms and the establishment of sensitive biomarkers, which are combined to construct a positive feedback loop. PMID:28846624

Computation of the free energy change associated with one-electron reduction of coenzyme immersed in water: a novel approach within the framework of the quantum mechanical/molecular mechanical method combined with the theory of energy representation.

PubMed

Takahashi, Hideaki; Ohno, Hajime; Kishi, Ryohei; Nakano, Masayoshi; Matubayasi, Nobuyuki

2008-11-28

The isoalloxazine ring (flavin ring) is a part of the coenzyme flavin adenine dinucleotide and acts as an active site in the oxidation of a substrate. We have computed the free energy change Deltamicro(red) associated with one-electron reduction of the flavin ring immersed in water by utilizing the quantum mechanical/molecular mechanical method combined with the theory of energy representation (QM/MM-ER method) recently developed. As a novel treatment in implementing the QM/MM-ER method, we have identified the excess charge to be attached on the flavin ring as a solute while the remaining molecules, i.e., flavin ring and surrounding water molecules, are treated as solvent species. Then, the reduction free energy can be decomposed into the contribution Deltamicro(red)(QM) due to the oxidant described quantum chemically and the free energy Deltamicro(red)(MM) due to the water molecules represented by a classical model. By the sum of these contributions, the total reduction free energy Deltamicro(red) has been given as -80.1 kcal/mol. To examine the accuracy and efficiency of this approach, we have also conducted the Deltamicro(red) calculation using the conventional scheme that Deltamicro(red) is constructed from the solvation free energies of the flavin rings at the oxidized and reduced states. The conventional scheme has been implemented with the QM/MM-ER method and the calculated Deltamicro(red) has been estimated as -81.0 kcal/mol, showing excellent agreement with the value given by the new approach. The present approach is efficient, in particular, to compute free energy change for the reaction occurring in a protein since it enables ones to circumvent the numerical problem brought about by subtracting the huge solvation free energies of the proteins in two states before and after the reduction.

Virtual screening using molecular simulations.

PubMed

Yang, Tianyi; Wu, Johnny C; Yan, Chunli; Wang, Yuanfeng; Luo, Ray; Gonzales, Michael B; Dalby, Kevin N; Ren, Pengyu

2011-06-01

Effective virtual screening relies on our ability to make accurate prediction of protein-ligand binding, which remains a great challenge. In this work, utilizing the molecular-mechanics Poisson-Boltzmann (or Generalized Born) surface area approach, we have evaluated the binding affinity of a set of 156 ligands to seven families of proteins, trypsin β, thrombin α, cyclin-dependent kinase (CDK), cAMP-dependent kinase (PKA), urokinase-type plasminogen activator, β-glucosidase A, and coagulation factor Xa. The effect of protein dielectric constant in the implicit-solvent model on the binding free energy calculation is shown to be important. The statistical correlations between the binding energy calculated from the implicit-solvent approach and experimental free energy are in the range of 0.56-0.79 across all the families. This performance is better than that of typical docking programs especially given that the latter is directly trained using known binding data whereas the molecular mechanics is based on general physical parameters. Estimation of entropic contribution remains the barrier to accurate free energy calculation. We show that the traditional rigid rotor harmonic oscillator approximation is unable to improve the binding free energy prediction. Inclusion of conformational restriction seems to be promising but requires further investigation. On the other hand, our preliminary study suggests that implicit-solvent based alchemical perturbation, which offers explicit sampling of configuration entropy, can be a viable approach to significantly improve the prediction of binding free energy. Overall, the molecular mechanics approach has the potential for medium to high-throughput computational drug discovery. Copyright © 2011 Wiley-Liss, Inc.

MECHANISM OF ALPHA-SYNUCLEIN OLIGOMERIZATION AND MEMBRANE INTERACTION: THEORETICAL APPROACH TO UNSTRUCTURED PROTEINS STUDIES

PubMed Central

Tsigelny, Igor F.; Sharikov, Yuriy; Miller, Mark A.; Masliah, Eliezer

2008-01-01

Misfolding and oligomerization of unstructured proteins is involved in the pathogenesis of Parkinson’s (PD), Alzheimer’s (AD), Huntington’s, and other neurodegenerative disorders. Elucidation of possible conformations of these proteins and their interactions with the membrane is necessary to understand the molecular mechanisms of neurodegeneration. We developed a strategy that makes it possible to elucidate the molecular mechanisms of of alpha-synuclein aggregation- a key molecular event in the pathogenesis of PD. This strategy can be also useful for the study of other unstructured proteins involved in neurodegeneration. The results of these theoretical studies have been confirmed with biochemical and electrophysiological studies. Our studies provide insights into the molecular mechanism for PD initiation and progression, and provide a useful paradigm for identifying possible therapeutic interventions through computational modeling. PMID:18640077

Mechanisms of plastic deformation in highly cross-linked UHMWPE for total hip components--the molecular physics viewpoint.

PubMed

Takahashi, Yasuhito; Shishido, Takaaki; Yamamoto, Kengo; Masaoka, Toshinori; Kubo, Kosuke; Tateiwa, Toshiyuki; Pezzotti, Giuseppe

2015-02-01

Plastic deformation is an unavoidable event in biomedical polymeric implants for load-bearing application during long-term in-vivo service life, which involves a mass transfer process, irreversible chain motion, and molecular reorganization. Deformation-induced microstructural alterations greatly affect mechanical properties and durability of implant devices. The present research focused on evaluating, from a molecular physics viewpoint, the impact of externally applied strain (or stress) in ultra-high molecular weight polyethylene (UHMWPE) prostheses, subjected to radiation cross-linking and subsequent remelting for application in total hip arthroplasty (THA). Two different types of commercial acetabular liners, which belong to the first-generation highly cross-linked UHMWPE (HXLPE), were investigated by means of confocal/polarized Raman microprobe spectroscopy. The amount of crystalline region and the spatial distribution of molecular chain orientation were quantitatively analyzed according to a combined theory including Raman selection rules for the polyethylene orthorhombic structure and the orientation distribution function (ODF) statistical approach. The structurally important finding was that pronounced recrystallization and molecular reorientation increasingly appeared in the near-surface regions of HXLPE liners with increasing the amount of plastic (compressive) deformation stored in the microstructure. Such molecular rearrangements, occurred in response to external strains, locally increase surface cross-shear (CS) stresses, which in turn trigger microscopic wear processes in HXLPE acetabular liners. Thus, on the basis of the results obtained at the molecular scale, we emphasize here the importance of minimizing the development of irrecoverable deformation strain in order to retain the pristine and intrinsically high wear performance of HXLPE components. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular mechanisms of CRISPR-mediated microbial immunity.

PubMed

Gasiunas, Giedrius; Sinkunas, Tomas; Siksnys, Virginijus

2014-02-01

Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems.

Molecular mechanisms of methicillin resistance in Staphylococcus aureus.

PubMed

Domínguez, M A; Liñares, J; Martín, R

1997-09-01

Methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most common nosocomial pathogens. The most significant mechanism of resistance to methicillin in this-species is the acquisition of a genetic determinant (mecA gene). However, resistance seems to have a more complex molecular basis, since additional chromosomal material is involved in such resistance. Besides, overproduction of penicillinase and/or alterations in the PBPs can contribute to the formation of resistance phenotypes. Genetic and environmental factors leading to MRSA are reviewed.

Dual-tracer background subtraction approach for fluorescent molecular tomography

PubMed Central

Holt, Robert W.; El-Ghussein, Fadi; Davis, Scott C.; Samkoe, Kimberley S.; Gunn, Jason R.; Leblond, Frederic

2013-01-01

Abstract. Diffuse fluorescence tomography requires high contrast-to-background ratios to accurately reconstruct inclusions of interest. This is a problem when imaging the uptake of fluorescently labeled molecularly targeted tracers in tissue, which can result in high levels of heterogeneously distributed background uptake. We present a dual-tracer background subtraction approach, wherein signal from the uptake of an untargeted tracer is subtracted from targeted tracer signal prior to image reconstruction, resulting in maps of targeted tracer binding. The approach is demonstrated in simulations, a phantom study, and in a mouse glioma imaging study, demonstrating substantial improvement over conventional and homogenous background subtraction image reconstruction approaches. PMID:23292612

Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical-Molecular Mechanical Simulations of Proton Transfer in DNA.

PubMed

Das, Susanta; Nam, Kwangho; Major, Dan Thomas

2018-03-13

In recent years, a number of quantum mechanical-molecular mechanical (QM/MM) enzyme studies have investigated the dependence of reaction energetics on the size of the QM region using energy and free energy calculations. In this study, we revisit the question of QM region size dependence in QM/MM simulations within the context of energy and free energy calculations using a proton transfer in a DNA base pair as a test case. In the simulations, the QM region was treated with a dispersion-corrected AM1/d-PhoT Hamiltonian, which was developed to accurately describe phosphoryl and proton transfer reactions, in conjunction with an electrostatic embedding scheme using the particle-mesh Ewald summation method. With this rigorous QM/MM potential, we performed rather extensive QM/MM sampling, and found that the free energy reaction profiles converge rapidly with respect to the QM region size within ca. ±1 kcal/mol. This finding suggests that the strategy of QM/MM simulations with reasonably sized and selected QM regions, which has been employed for over four decades, is a valid approach for modeling complex biomolecular systems. We point to possible causes for the sensitivity of the energy and free energy calculations to the size of the QM region, and potential implications.

Molecular Mechanism of Active Zone Organization at Vertebrate Neuromuscular Junctions

PubMed Central

Nishimune, Hiroshi

2013-01-01

Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic molecular mechanism that organizes the active zones by connecting the pre- and the postsynaptic specialization. The presynaptic component of this trans-synaptic mechanism is comprised of cytosolic active zone proteins bound to the cytosolic domains of voltage-dependent calcium channels (P/Q-, N-, and L-type) on the presynaptic membrane. The postsynaptic component of this mechanism is the synapse organizer (laminin β2) that is expressed by the postsynaptic cell and accumulates specifically on top of the postsynaptic specialization. The pre- and the postsynaptic components interact directly between the extracellular domains of calcium channels and laminin β2 to anchor the presynaptic protein complex in front of the postsynaptic specialization. Hence, the presynaptic calcium channel functions as a scaffolding protein for active zone organization and as an ion-conducting channel for synaptic transmission. In contrast to the requirement of calcium influx for synaptic transmission, the formation of the active zone does not require the calcium influx through the calcium channels. Importantly, the active zones of adult synapses are not stable structures and require maintenance for their integrity. Furthermore, aging or diseases of the central and peripheral nervous system impair the active zones. This review will focus on the molecular mechanisms that organize the presynaptic active zones and summarize recent findings at the neuromuscular junctions and other synapses. PMID:22135013

Investigation of molecular mechanisms and regulatory pathways of pro-angiogenic nanorods

NASA Astrophysics Data System (ADS)

Nethi, Susheel Kumar; Veeriah, Vimal; Barui, Ayan Kumar; Rajendran, Saranya; Mattapally, Saidulu; Misra, Sanjay; Chatterjee, Suvro; Patra, Chitta Ranjan

2015-05-01

Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [EuIII(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular mechanisms and signaling pathways in order to develop the most efficient and effective alternative treatment strategy for CVDs. However, the exact underlying mechanism and cascade signaling pathways behind the pro-angiogenic properties exhibited by EHNs still remain unclear. Herein, we report for the first time that the hydrogen peroxide (H2O2), a redox signaling molecule, generated by these EHNs activates the endothelial nitric oxide synthase (eNOS) that promotes the nitric oxide (NO) production in a PI3K (phosphoinositide 3-kinase)/Akt dependent manner, eventually triggering angiogenesis. We intensely believe that the investigation and understanding of the in-depth molecular mechanism and signaling pathways of EHNs induced angiogenesis will help us in developing an effective alternative treatment strategy for cardiovascular related and ischemic diseases where angiogenesis plays an important role.Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [EuIII(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular

The archetype-genome exemplar in molecular dynamics and continuum mechanics

NASA Astrophysics Data System (ADS)

Greene, M. Steven; Li, Ying; Chen, Wei; Liu, Wing Kam

2014-04-01

We argue that mechanics and physics of solids rely on a fundamental exemplar: the apparent properties of a system depend on the building blocks that comprise it. Building blocks are referred to as archetypes and apparent system properties as the system genome. Three entities are of importance: the archetype properties, the conformation of archetypes, and the properties of interactions activated by that conformation. The combination of these entities into the system genome is called assembly. To show the utility of the archetype-genome exemplar, this work presents the mathematical ingredients and computational implementation of theories in solid mechanics that are (1) molecular and (2) continuum manifestations of the assembly process. Both coarse-grained molecular dynamics (CGMD) and the archetype-blending continuum (ABC) theories are formulated then applied to polymer nanocomposites (PNCs) to demonstrate the impact the components of the assembly triplet have on a material genome. CGMD simulations demonstrate the sensitivity of nanocomposite viscosities and diffusion coefficients to polymer chain types (archetype), polymer-nanoparticle interaction potentials (interaction), and the structural configuration (conformation) of dispersed nanoparticles. ABC simulations show the contributions of bulk polymer (archetype) properties, occluded region of bound rubber (interaction) properties, and microstructural binary images (conformation) to predictions of linear damping properties, the Payne effect, and localization/size effects in the same class of PNC material. The paper is light on mathematics. Instead, the focus is on the usefulness of the archetype-genome exemplar to predict system behavior inaccessible to classical theories by transitioning mechanics away from heuristic laws to mechanism-based ones. There are two core contributions of this research: (1) presentation of a fundamental axiom—the archetype-genome exemplar—to guide theory development in computational

Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach.

PubMed

Guttikonda, Satish K; Marri, Pradeep; Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P

2016-01-01

Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions.

Elucidating the thermal, chemical, and mechanical mechanisms of ultraviolet ablation in poly(methyl methacrylate) via molecular dynamics simulations.

PubMed

Conforti, Patrick F; Prasad, Manish; Garrison, Barbara J

2008-08-01

[Figure: see text]. Laser ablation harnesses photon energy to remove material from a surface. Although applications such as laser-assisted in situ keratomileusis (LASIK) surgery, lithography, and nanoscale device fabrication take advantage of this process, a better understanding the underlying mechanism of ablation in polymeric materials remains much sought after. Molecular simulation is a particularly attractive technique to study the basic aspects of ablation because it allows control over specific process parameters and enables observation of microscopic mechanistic details. This Account describes a hybrid molecular dynamics-Monte Carlo technique to simulate laser ablation in poly(methyl methacrylate) (PMMA). It also discusses the impact of thermal and chemical excitation on the ensuing ejection processes. We used molecular dynamics simulation to study the molecular interactions in a coarse-grained PMMA substrate following photon absorption. To ascertain the role of chemistry in initiating ablation, we embedded a Monte Carlo protocol within the simulation framework. These calculations permit chemical reactions to occur probabilistically during the molecular dynamics calculation using predetermined reaction pathways and Arrhenius rates. With this hybrid scheme, we can examine thermal and chemical pathways of decomposition separately. In the simulations, we observed distinct mechanisms of ablation for each type of photoexcitation pathway. Ablation via thermal processes is governed by a critical number of bond breaks following the deposition of energy. For the case in which an absorbed photon directly causes a bond scission, ablation occurs following the rapid chemical decomposition of material. A detailed analysis of the processes shows that a critical energy for ablation can describe this complex series of events. The simulations show a decrease in the critical energy with a greater amount of photochemistry. Additionally, the simulations demonstrate the effects

Molecular mechanisms of cognitive dysfunction following traumatic brain injury

PubMed Central

Walker, Kendall R.; Tesco, Giuseppina

2013-01-01

Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration. PMID:23847533

Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery.

PubMed

Roth, Bryan L; Lopez, Estela; Beischel, Scott; Westkaemper, Richard B; Evans, Jon M

2004-05-01

Because psychoactive plants exert profound effects on human perception, emotion, and cognition, discovering the molecular mechanisms responsible for psychoactive plant actions will likely yield insights into the molecular underpinnings of human consciousness. Additionally, it is likely that elucidation of the molecular targets responsible for psychoactive drug actions will yield validated targets for CNS drug discovery. This review article focuses on an unbiased, discovery-based approach aimed at uncovering the molecular targets responsible for psychoactive drug actions wherein the main active ingredients of psychoactive plants are screened at the "receptorome" (that portion of the proteome encoding receptors). An overview of the receptorome is given and various in silico, public-domain resources are described. Newly developed tools for the in silico mining of data derived from the National Institute of Mental Health Psychoactive Drug Screening Program's (NIMH-PDSP) K(i) Database (K(i) DB) are described in detail. Additionally, three case studies aimed at discovering the molecular targets responsible for Hypericum perforatum, Salvia divinorum, and Ephedra sinica actions are presented. Finally, recommendations are made for future studies.

Conduction mechanism of nitronyl-nitroxide molecular magnetic compounds

NASA Astrophysics Data System (ADS)

Dotti, N.; Heintze, E.; Slota, M.; Hübner, R.; Wang, F.; Nuss, J.; Dressel, M.; Bogani, L.

2016-04-01

We investigate the conduction mechanisms of nitronyl-nitroxide (NIT) molecular radicals, as useful for the creation of nanoscopic molecular spintronic devices, finding that it does not correspond to standard Mott behavior, as previously postulated. We provide a complete investigation using transport measurements, low-energy, sub-THz spectroscopy and introducing differently substituted phenyl appendages. We show that a nontrivial surface-charge-limited regime is present in addition to the standard low-voltage Ohmic conductance. Scaling analysis allows one to determine all the main transport parameters for the compounds and highlights the presence of charge-trapping effects. Comparison among the different compounds shows the relevance of intermolecular stacking between the aromatic ring of the phenyl appendix and the NIT motif in the creation of useful electron transport channels. The importance of intermolecular pathways is further highlighted by electronic structure calculations, which clarify the nature of the electronic channels and their effect on the Mott character of the compounds.

Calcium Biofortification: Three Pronged Molecular Approaches for Dissecting Complex Trait of Calcium Nutrition in Finger Millet (Eleusine coracana) for Devising Strategies of Enrichment of Food Crops

PubMed Central

Sharma, Divya; Jamra, Gautam; Singh, Uma M.; Sood, Salej; Kumar, Anil

2017-01-01

Calcium is an essential macronutrient for plants and animals and plays an indispensable role in structure and signaling. Low dietary intake of calcium in humans has been epidemiologically linked to various diseases which can have serious health consequences over time. Major staple food-grains are poor source of calcium, however, finger millet [Eleusine coracana (L.) Gaertn.], an orphan crop has an immense potential as a nutritional security crop due to its exceptionally high calcium content. Understanding the existing genetic variation as well as molecular mechanisms underlying the uptake, transport, accumulation of calcium ions (Ca2+) in grains is of utmost importance for development of calcium bio-fortified crops. In this review, we have discussed molecular mechanisms involved in calcium accumulation and transport thoroughly, emphasized the role of molecular breeding, functional genomics and transgenic approaches to understand the intricate mechanism of calcium nutrition in finger millet. The objective is to provide a comprehensive up to date account of molecular mechanisms regulating calcium nutrition and highlight the significance of bio-fortification through identification of potential candidate genes and regulatory elements from finger millet to alleviate calcium malnutrition. Hence, finger millet could be used as a model system for explaining the mechanism of elevated calcium (Ca2+) accumulation in its grains and could pave way for development of nutraceuticals or designer crops. PMID:28144246

Calcium Biofortification: Three Pronged Molecular Approaches for Dissecting Complex Trait of Calcium Nutrition in Finger Millet (Eleusine coracana) for Devising Strategies of Enrichment of Food Crops.

PubMed

Sharma, Divya; Jamra, Gautam; Singh, Uma M; Sood, Salej; Kumar, Anil

2016-01-01

Calcium is an essential macronutrient for plants and animals and plays an indispensable role in structure and signaling. Low dietary intake of calcium in humans has been epidemiologically linked to various diseases which can have serious health consequences over time. Major staple food-grains are poor source of calcium, however, finger millet [ Eleusine coracana (L.) Gaertn.], an orphan crop has an immense potential as a nutritional security crop due to its exceptionally high calcium content. Understanding the existing genetic variation as well as molecular mechanisms underlying the uptake, transport, accumulation of calcium ions (Ca 2+ ) in grains is of utmost importance for development of calcium bio-fortified crops. In this review, we have discussed molecular mechanisms involved in calcium accumulation and transport thoroughly, emphasized the role of molecular breeding, functional genomics and transgenic approaches to understand the intricate mechanism of calcium nutrition in finger millet. The objective is to provide a comprehensive up to date account of molecular mechanisms regulating calcium nutrition and highlight the significance of bio-fortification through identification of potential candidate genes and regulatory elements from finger millet to alleviate calcium malnutrition. Hence, finger millet could be used as a model system for explaining the mechanism of elevated calcium (Ca 2+ ) accumulation in its grains and could pave way for development of nutraceuticals or designer crops.

Investigations on the antiretroviral activity of carbon nanotubes using computational molecular approach.

PubMed

Krishnaraj, R Navanietha; Chandran, Saravanan; Pal, Parimal; Berchmans, Sheela

2014-01-01

Carbon nanotubes are the interesting class of materials with wide range of applications. They have excellent physical, chemical and electrical properties. Numerous reports were made on the antiviral activities of carbon nanotubes. However the mechanism of antiviral action is still in infancy. Herein we report, our recent novel findings on the molecular interactions of carbon nanotubes with the three key target proteins of HIV using computational chemistry approach. Armchair, chiral and zigzag CNTs were modeled and used as ligands for the interaction studies. The structure of the key proteins involved in HIV mediated infection namely HIV- Vpr, Nef and Gag proteins were collected from the PDB database. The docking studies were performed to quantify the interaction of the CNT with the three different disease targets. Results showed that the carbon nanotubes had high binding affinity to these proteins which confirms the antagonistic molecular interaction of carbon nanotubes to the disease targets. The modeled armchair carbon nanotubes had the binding affinities of -12.4 Kcal/mole, -20 Kcal/mole and -11.7 Kcal/mole with the Vpr, Nef and Gag proteins of HIV. Chiral CNTs also had the maximum affinity of -16.4 Kcal/mole to Nef. The binding affinity of chiral CNTs to Vpr and Gag was found to be -10.9 Kcal/mole and -10.3 Kcal/mole respectively. The zigzag CNTs had the binding affinity of -11.1 Kcal/mole with Vpr, -18.3 Kcal/mole with Nef and -10.9 with Gag respectively. The strong molecular interactions suggest the efficacy of CNTs for targeting the HIV mediated retroviral infections.

Molecular mechanisms of induced pluripotency.

PubMed

Kulcenty, Katarzyna; Wróblewska, Joanna; Mazurek, Sylwia; Liszewska, Ewa; Jaworski, Jacek

2015-01-01

Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types.

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

NASA Astrophysics Data System (ADS)

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

2004-11-01

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

Molecular Mechanisms of Ethanol-associated Oro-esophageal Squamous Cell Carcinoma

PubMed Central

Liu, Yao; Chen, Hao; Sun, Zheng; Chen, Xiaoxin

2016-01-01

Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC. PMID:25766659

[Pharmacodynamic evaluation and molecular mechanism research of Huanshao capsule on irregular menstruation].

PubMed

Sun, Jian-Hui; Huo, Hai-Ru; Li, Xiao-Qin; Li, Hong-Mei; Qin, De-Huai; Wu, Chun

2018-04-01

Huanshao capsule is widely used in irregular menstruation and has achieved a good effect. Huanshao capsule can promote gonad development in mice, significantly improve the ovarian index in mice, increase estrogen level and reduce FSH level in rats, inhibit the pain response induced by oxytocin and estrogen, inhibit writhing reaction induced by acetic acid pain in mice. Due to the complexity of traditional Chinese medical formula, the pharmacological mechanism of the treatment on the irregular menstruation of the Huanshao capsule is unclear. In this study, the internet-based computation platform (www.tcmip.cn）was used to explore the molecular mechanism of Huanshao capsule on the menstrual. The aim of this study was to find the molecular mechanism of Huanshao capsule in treating menstrual. In the study of the molecular mechanism of Huanshao capsule in the treatment of menstrual by using the internet-based computation platform, Huanshao capsule maybe treat the menstrual by the pathway of endocrine system, GnRH signal transduction pathway, estrogen signal transduction pathway, oxytocin signaling pathway, thyroid hormone signaling pathway, VEGF signaling pathway, FCεRI signaling pathway and purine metabolism and nucleotide metabolism. The early pharmacological study confirmed Huanshao capsule could increase the serum estradiol level and decrease follicle stimulating hormone level and the traditional Chinese medicine pharmacology coincide with the prediction result of internet-based computation platform which roles as the pathway of GnRH signaling pathway and estrogen signal transduction pathway. Other pathway needs further experimental verification. Copyright© by the Chinese Pharmaceutical Association.

A model of how different biology experts explain molecular and cellular mechanisms.

PubMed

Trujillo, Caleb M; Anderson, Trevor R; Pelaez, Nancy J

2015-01-01

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular mechanism of their choice. Data were collected from interviews, artifacts, and drawings, and then subjected to thematic analysis. We found that biologists explained the specific activities and organization of entities of the mechanism. In addition, they contextualized explanations according to their biological and social significance; integrated explanations with methods, instruments, and measurements; and used analogies and narrated stories. The derived methods, analogies, context, and how themes informed the development of our final MACH model of mechanistic explanations. Future research will test the potential of the MACH model as a guiding framework for instruction to enhance the quality of student explanations. © 2015 C. M. Trujillo et al. CBE—Life Sciences Education © 2015 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Bayesian approach to inverse statistical mechanics.

PubMed

Habeck, Michael

2014-05-01

Inverse statistical mechanics aims to determine particle interactions from ensemble properties. This article looks at this inverse problem from a Bayesian perspective and discusses several statistical estimators to solve it. In addition, a sequential Monte Carlo algorithm is proposed that draws the interaction parameters from their posterior probability distribution. The posterior probability involves an intractable partition function that is estimated along with the interactions. The method is illustrated for inverse problems of varying complexity, including the estimation of a temperature, the inverse Ising problem, maximum entropy fitting, and the reconstruction of molecular interaction potentials.

Bayesian approach to inverse statistical mechanics

NASA Astrophysics Data System (ADS)

Habeck, Michael

2014-05-01

Inverse statistical mechanics aims to determine particle interactions from ensemble properties. This article looks at this inverse problem from a Bayesian perspective and discusses several statistical estimators to solve it. In addition, a sequential Monte Carlo algorithm is proposed that draws the interaction parameters from their posterior probability distribution. The posterior probability involves an intractable partition function that is estimated along with the interactions. The method is illustrated for inverse problems of varying complexity, including the estimation of a temperature, the inverse Ising problem, maximum entropy fitting, and the reconstruction of molecular interaction potentials.

Small-Molecule Hormones: Molecular Mechanisms of Action

PubMed Central

Budzińska, Monika

2013-01-01

Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes. PMID:23533406

Evaluation of a grid based molecular dynamics approach for polypeptide simulations.

PubMed

Merelli, Ivan; Morra, Giulia; Milanesi, Luciano

2007-09-01

Molecular dynamics is very important for biomedical research because it makes possible simulation of the behavior of a biological macromolecule in silico. However, molecular dynamics is computationally rather expensive: the simulation of some nanoseconds of dynamics for a large macromolecule such as a protein takes very long time, due to the high number of operations that are needed for solving the Newton's equations in the case of a system of thousands of atoms. In order to obtain biologically significant data, it is desirable to use high-performance computation resources to perform these simulations. Recently, a distributed computing approach based on replacing a single long simulation with many independent short trajectories has been introduced, which in many cases provides valuable results. This study concerns the development of an infrastructure to run molecular dynamics simulations on a grid platform in a distributed way. The implemented software allows the parallel submission of different simulations that are singularly short but together bring important biological information. Moreover, each simulation is divided into a chain of jobs to avoid data loss in case of system failure and to contain the dimension of each data transfer from the grid. The results confirm that the distributed approach on grid computing is particularly suitable for molecular dynamics simulations thanks to the elevated scalability.

Possible molecular mechanisms linking air pollution and asthma in children.

PubMed

Esposito, Susanna; Tenconi, Rossana; Lelii, Mara; Preti, Valentina; Nazzari, Erica; Consolo, Silvia; Patria, Maria Francesca

2014-03-01

Air pollution has many effects on the health of both adults and children, but children's vulnerability is unique. The aim of this review is to discuss the possible molecular mechanisms linking air pollution and asthma in children, also taking into account their genetic and epigenetic characteristics. Air pollutants appear able to induce airway inflammation and increase asthma morbidity in children. A better definition of mechanisms related to pollution-induced airway inflammation in asthmatic children is needed in order to find new clinical and therapeutic strategies for preventing the exacerbation of asthma. Moreover, reducing pollution-induced oxidative stress and consequent lung injury could decrease children's susceptibility to air pollution. This would be extremely useful not only for the asthmatic children who seem to have a genetic susceptibility to oxidative stress, but also for the healthy population. In addition, epigenetics seems to have a role in the lung damage induced by air pollution. Finally, a number of epidemiological studies have demonstrated that exposure to common air pollutants plays a role in the susceptibility to, and severity of respiratory infections. Air pollution has many negative effects on pediatric health and it is recognised as a serious health hazard. There seems to be an association of air pollution with an increased risk of asthma exacerbations and acute respiratory infections. However, further studies are needed in order to clarify the specific mechanism of action of different air pollutants, identify genetic polymorphisms that modify airway responses to pollution, and investigate the effectiveness of new preventive and/or therapeutic approaches for subjects with low antioxidant enzyme levels. Moreover, as that epigenetic changes are inheritable during cell division and may be transmitted to subsequent generations, it is very important to clarify the role of epigenetics in the relationship between air pollution and lung disease

Deformation-mechanism map for nanocrystalline metals by molecular-dynamics simulation.

PubMed

Yamakov, V; Wolf, D; Phillpot, S R; Mukherjee, A K; Gleiter, H

2004-01-01

Molecular-dynamics simulations have recently been used to elucidate the transition with decreasing grain size from a dislocation-based to a grain-boundary-based deformation mechanism in nanocrystalline f.c.c. metals. This transition in the deformation mechanism results in a maximum yield strength at a grain size (the 'strongest size') that depends strongly on the stacking-fault energy, the elastic properties of the metal, and the magnitude of the applied stress. Here, by exploring the role of the stacking-fault energy in this crossover, we elucidate how the size of the extended dislocations nucleated from the grain boundaries affects the mechanical behaviour. Building on the fundamental physics of deformation as exposed by these simulations, we propose a two-dimensional stress-grain size deformation-mechanism map for the mechanical behaviour of nanocrystalline f.c.c. metals at low temperature. The map captures this transition in both the deformation mechanism and the related mechanical behaviour with decreasing grain size, as well as its dependence on the stacking-fault energy, the elastic properties of the material, and the applied stress level.

Amino acid analogues bind to carbon nanotube via π-π interactions: Comparison of molecular mechanical and quantum mechanical calculations

NASA Astrophysics Data System (ADS)

Yang, Zaixing; Wang, Zhigang; Tian, Xingling; Xiu, Peng; Zhou, Ruhong

2012-01-01

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.

Amino acid analogues bind to carbon nanotube via π-π interactions: comparison of molecular mechanical and quantum mechanical calculations.

PubMed

Yang, Zaixing; Wang, Zhigang; Tian, Xingling; Xiu, Peng; Zhou, Ruhong

2012-01-14

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.

Ginger (Zingiber officinale) phytochemicals-gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches.

PubMed

Rampogu, Shailima; Baek, Ayoung; Gajula, Rajesh Goud; Zeb, Amir; Bavi, Rohit S; Kumar, Raj; Kim, Yongseong; Kwon, Yong Jung; Lee, Keun Woo

2018-04-02

Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported. Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis. Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package. Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used

Understanding the influence of buckwheat bran on wheat dough baking performance: Mechanistic insights from molecular and material science approaches.

PubMed

Zanoletti, Miriam; Marti, Alessandra; Marengo, Mauro; Iametti, Stefania; Pagani, M Ambrogina; Renzetti, Stefano

2017-12-01

A molecular and material science approach is used to describe the influence of coarse and fine buckwheat bran on wheat dough properties and bread textural quality. Focus is given on (i) gluten solvation and structural arrangements in presence of bran as studied by front-face fluorescence; (ii) thermo-mechanical behavior of dough during heating studied by dynamic mechanical thermal analysis and (iii) texture of bread crumb analyzed in terms of a cellular solid. The thermo-mechanical behavior of dough was found to be largely related to starch phase transitions during heating. The use of thermodynamic approaches to biopolymer melting revealed that key transitions such as the onset of starch gelatinization were function of the interplay of water and bran volume fractions in the dough. Front-face fluorescence studies in wheat dough revealed that gluten solvation and structural arrangements were delayed by increasing bran addition level and reduction in particle size, as indicated by the drastic decrease in the protein surface hydrophobicity index. Variations in gluten structure could be strongly related to dough baking performance, i.e. specific volume. With regards to texture, the approach revealed that crumb texture was controlled by variations in density, moisture and bran volume fractions. Overall, this study elucidates a number of physical mechanisms describing the influence of buckwheat bran addition to dough and bread quality. These mechanisms strongly pointed at the influence of bran on water partitioning among the main polymeric components. In the future, these mechanisms should be investigated with bran material of varying source, composition and structure. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bioinformatics analysis on molecular mechanism of rheum officinale in treatment of jaundice

NASA Astrophysics Data System (ADS)

Shan, Si; Tu, Jun; Nie, Peng; Yan, Xiaojun

2017-01-01

Objective: To study the molecular mechanism of Rheum officinale in the treatment of Jaundice by building molecular networks and comparing canonical pathways. Methods: Target proteins of Rheum officinale and related genes of Jaundice were searched from Pubchem and Gene databases online respectively. Molecular networks and canonical pathways comparison analyses were performed by Ingenuity Pathway Analysis (IPA). Results: The molecular networks of Rheum officinale and Jaundice were complex and multifunctional. The 40 target proteins of Rheum officinale and 33 Homo sapiens genes of Jaundice were found in databases. There were 19 common pathways both related networks. Rheum officinale could regulate endothelial differentiation, Interleukin-1B (IL-1B) and Tumor Necrosis Factor (TNF) in these pathways. Conclusions: Rheum officinale treat Jaundice by regulating many effective nodes of Apoptotic pathway and cellular immunity related pathways.

Deep insights into the mode of ATP-binding mechanism in Zebrafish cyclin-dependent protein kinase-like 1 (zCDKL1): A molecular dynamics approach.

PubMed

Rout, Ajaya Kumar; Dehury, Budheswar; Maharana, Jitendra; Nayak, Chirasmita; Baisvar, Vishwamitra Singh; Behera, Bijay Kumar; Das, Basanta Kumar

2018-05-01

In eukaryotes, the serine/threonine kinases (STKs) belonging to cyclin-dependent protein kinases (CDKs) play significant role in control of cell division and curb transcription in response to several extra and intra-cellular signals indispensable for enzymatic activity. The zebrafish cyclin-dependent protein kinase-like 1 protein (zCDKL1) shares a high degree of sequence and structural similarity with mammalian orthologs and express in brain, ovary, testis, and low levels in other tissues. Regardless of its importance in the developmental process, the structure, function and mode of ATP recognition have not been investigated yet due to lack of experimental data. Henceforth, to gain atomistic insights in to the structural dynamics and mode of ATP binding, a series of computational techniques involving theoretical modeling, docking, molecular dynamics (MD) simulations and MM/PBSA binding free energies were employed. The modeled bi-lobed zCDKL1 shares a high degree of secondary structure topology with human orthologs where ATP prefers to lie in the central cavity of the bi-lobed catalytic domain enclosed by strong hydrogen bonding, electrostatic and hydrophobic contacts. Long range MD simulation portrayed that catalytic domain of zCDKL1 to be highly rigid in nature as compared to the complex (zCDKL1-ATP) form. Comparative analysis with its orthologs revealed that conserved amino acids i.e., Ile10, Gly11, Glu12, Val18, Arg31, Phe80, Glu 130, Cys143 and Asp144 were crucial for ATP binding mechanism, which needs further investigation for legitimacy. MM/PBSA method revealed that van der Waals, electrostatic and polar solvation energy mostly contributes towards negative free energy. The implications of ATP binding mechanism inferred through these structural bioinformatics approaches will help in understanding the catalytic mechanisms of important STKs in eukaryotic system. Copyright © 2018. Published by Elsevier Inc.

United polarizable multipole water model for molecular mechanics simulation

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

Qi, Rui; Wang, Qiantao; Ren, Pengyu, E-mail: pren@mail.utexas.edu

2015-07-07

We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3–5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interactionmore » site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.« less

Mechanism of Urea Crystal Dissolution in Water from Molecular Dynamics Simulation.

PubMed

Anand, Abhinav; Patey, G N

2018-01-25

Molecular dynamics simulations are used to determine the mechanism of urea crystal dissolution in water under sink conditions. Crystals of cubic and tablet shapes are considered, and results are reported for four commonly used water models. The dissolution rates for different water models can differ considerably, but the overall dissolution mechanism remains the same. Urea dissolution occurs in three stages: a relatively fast initial stage, a slower intermediate stage, and a final stage. We show that the long intermediate stage is well described by classical rate laws, which assume that the dissolution rate is proportional to the active surface area. By carrying out simulations at different temperatures, we show that urea dissolution is an activated process, with an activation energy of ∼32 kJ mol -1 . Our simulations give no indication of a significant diffusion layer, and we conclude that the detachment of molecules from the crystal is the rate-determining step for dissolution. The results we report for urea are consistent with earlier observations for the dissolution of NaCl crystals. This suggests that the three-stage mechanism and classical rate laws might apply to the dissolution of other ionic and molecular crystals.

Structural basis of Staphylococcus epidermidis biofilm formation: mechanisms and molecular interactions

PubMed Central

Büttner, Henning; Mack, Dietrich; Rohde, Holger

2015-01-01

Staphylococcus epidermidis is a usually harmless commensal bacterium highly abundant on the human skin. Under defined predisposing conditions, most importantly implantation of a medical device, S. epidermidis, however, can switch from a colonizing to an invasive life style. The emergence of S. epidermidis as an opportunistic pathogen is closely linked to the biofilm forming capability of the species. During the past decades, tremendous advance regarding our understanding of molecular mechanisms contributing to surface colonization has been made, and detailed information is available for several factors active during the primary attachment, accumulative or dispersal phase of biofilm formation. A picture evolved in which distinct factors, though appearing to be redundantly organized, take over specific and exclusive functions during biofilm development. In this review, these mechanisms are described in molecular detail, with a highlight on recent insights into multi-functional S. epidermidis cell surface proteins contributing to surface adherence and intercellular adhesion. The integration of distinct biofilm-promoting factors into regulatory networks is summarized, with an emphasis on mechanism that could allow S. epidermidis to flexibly adapt to changing environmental conditions present during colonizing or invasive life-styles. PMID:25741476

Molecular mechanisms underlying the actions of dietary factors on the skeleton

USDA-ARS?s Scientific Manuscript database

This book chapter summarizes the current state of knowledge on molecular mechanisms whereby nutritional status and dietary factors found in fruits, vegetables, and grains affect bone turnover and skeletal quality. The Wnt-beta catenin and bone morphogenic protein (BMP) pathways in osteoblast bone ce...

Molecular mechanisms of cisplatin resistance in cervical cancer

PubMed Central

Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

2016-01-01

Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. PMID:27354763

Molecular mechanisms of cisplatin resistance in cervical cancer.

PubMed

Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

2016-01-01

Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%-20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer.

Molecular Mechanism of Species-dependent Sweet Taste toward Artificial Sweeteners

PubMed Central

Liu, Bo; Ha, Matthew; Meng, Xuan-Yu; Kaur, Tanno; Khaleduzzaman, Mohammed; Zhang, Zhe; Jiang, Peihua; Li, Xia; Cui, Meng

2011-01-01

The heterodimer of Tas1R2 and Tas1R3 is a broadly acting sweet taste receptor, which mediates mammalian sweet taste toward natural and artificial sweeteners and sweet-tasting proteins. Perception of sweet taste is a species selective physiological process. For instance, artificial sweeteners aspartame and neotame taste sweet to humans, apes and Old World monkeys but not to New World monkeys and rodents. Although specific regions determining the activation of the receptors by these sweeteners have been identified, the molecular mechanism of species-dependent sweet taste remains elusive. Using human/squirrel monkey chimeras, mutagenesis and molecular modeling, we reveal that the different responses of mammalian species towards the artificial sweeteners aspartame and neotame are determined by the steric effect of a combination of a few residues in the ligand binding pocket. Residues S40 and D142 in the human Tas1R2, which correspond to residues T40 and E142 in the squirrel monkey Tas1R2, were found to be the critical residues for the species dependent difference in sweet taste. In addition, human Tas1R2 residue I67, which corresponds to S67 in squirrel monkey receptor, modulates the higher affinity of neotame than that of aspartame. Our studies not only shed light on the molecular mechanism of species dependent sweet taste toward artificial sweeteners, but also provide guidance for designing novel effective artificial sweet compounds. PMID:21795555

Molecular mechanism of species-dependent sweet taste toward artificial sweeteners.

PubMed

Liu, Bo; Ha, Matthew; Meng, Xuan-Yu; Kaur, Tanno; Khaleduzzaman, Mohammed; Zhang, Zhe; Jiang, Peihua; Li, Xia; Cui, Meng

2011-07-27

The heterodimer of Tas1R2 and Tas1R3 is a broadly acting sweet taste receptor, which mediates mammalian sweet taste toward natural and artificial sweeteners and sweet-tasting proteins. Perception of sweet taste is a species-selective physiological process. For instance, artificial sweeteners aspartame and neotame taste sweet to humans, apes, and Old World monkeys but not to New World monkeys and rodents. Although specific regions determining the activation of the receptors by these sweeteners have been identified, the molecular mechanism of species-dependent sweet taste remains elusive. Using human/squirrel monkey chimeras, mutagenesis, and molecular modeling, we reveal that the different responses of mammalian species toward the artificial sweeteners aspartame and neotame are determined by the steric effect of a combination of a few residues in the ligand binding pocket. Residues S40 and D142 in the human Tas1R2, which correspond to residues T40 and E142 in the squirrel monkey Tas1R2, were found to be the critical residues for the species-dependent difference in sweet taste. In addition, human Tas1R2 residue I67, which corresponds to S67 in squirrel monkey receptor, modulates the higher affinity of neotame than of aspartame. Our studies not only shed light on the molecular mechanism of species-dependent sweet taste toward artificial sweeteners, but also provide guidance for designing novel effective artificial sweet compounds.

Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells.

PubMed

Kumar, Sanjay; Tchounwou, Paul B

2015-12-01

Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in acute promyelocytic leukemia (APL) cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. We used the APL cell line as a model, and applied a variety of molecular tools to elucidate the cytotoxic mode of action of cisplatin. We found that cisplatin inhibited cell proliferation by a cytotoxicity, characterized by DNA damage and modulation of oxidative stress. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity. It also down regulated the p38MAPK pathway. Overall, this study highlights the molecular mechanisms that underline cisplatin toxicity to APL cells, and provides insights into selection of novel targets and/or design of therapeutic agents to treat APL.

Molecular mechanisms of foliar water uptake in a desert tree

PubMed Central

Yan, Xia; Zhou, Maoxian; Dong, Xicun; Zou, Songbing; Xiao, Honglang; Ma, Xiao-Fei

2015-01-01

Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants. PMID:26567212

Quantum wavepacket ab initio molecular dynamics: an approach for computing dynamically averaged vibrational spectra including critical nuclear quantum effects.

PubMed

Sumner, Isaiah; Iyengar, Srinivasan S

2007-10-18

We have introduced a computational methodology to study vibrational spectroscopy in clusters inclusive of critical nuclear quantum effects. This approach is based on the recently developed quantum wavepacket ab initio molecular dynamics method that combines quantum wavepacket dynamics with ab initio molecular dynamics. The computational efficiency of the dynamical procedure is drastically improved (by several orders of magnitude) through the utilization of wavelet-based techniques combined with the previously introduced time-dependent deterministic sampling procedure measure to achieve stable, picosecond length, quantum-classical dynamics of electrons and nuclei in clusters. The dynamical information is employed to construct a novel cumulative flux/velocity correlation function, where the wavepacket flux from the quantized particle is combined with classical nuclear velocities to obtain the vibrational density of states. The approach is demonstrated by computing the vibrational density of states of [Cl-H-Cl]-, inclusive of critical quantum nuclear effects, and our results are in good agreement with experiment. A general hierarchical procedure is also provided, based on electronic structure harmonic frequencies, classical ab initio molecular dynamics, computation of nuclear quantum-mechanical eigenstates, and employing quantum wavepacket ab initio dynamics to understand vibrational spectroscopy in hydrogen-bonded clusters that display large degrees of anharmonicities.

New Approaches to Sepsis: Molecular Diagnostics and Biomarkers

PubMed Central

Bauer, Michael; Riedemann, Niels C.; Hartog, Christiane S.

2012-01-01

Summary: Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies. PMID:23034322

Teaching Classical Statistical Mechanics: A Simulation Approach.

ERIC Educational Resources Information Center

Sauer, G.

1981-01-01

Describes a one-dimensional model for an ideal gas to study development of disordered motion in Newtonian mechanics. A Monte Carlo procedure for simulation of the statistical ensemble of an ideal gas with fixed total energy is developed. Compares both approaches for a pseudoexperimental foundation of statistical mechanics. (Author/JN)

Neural mechanisms of cue-approach training

PubMed Central

Bakkour, Akram; Lewis-Peacock, Jarrod A.; Poldrack, Russell A.; Schonberg, Tom

2016-01-01

Biasing choices may prove a useful way to implement behavior change. Previous work has shown that a simple training task (the cue-approach task), which does not rely on external reinforcement, can robustly influence choice behavior by biasing choice toward items that were targeted during training. In the current study, we replicate previous behavioral findings and explore the neural mechanisms underlying the shift in preferences following cue-approach training. Given recent successes in the development and application of machine learning techniques to task-based fMRI data, which have advanced understanding of the neural substrates of cognition, we sought to leverage the power of these techniques to better understand neural changes during cue-approach training that subsequently led to a shift in choice behavior. Contrary to our expectations, we found that machine learning techniques applied to fMRI data during non-reinforced training were unsuccessful in elucidating the neural mechanism underlying the behavioral effect. However, univariate analyses during training revealed that the relationship between BOLD and choices for Go items increases as training progresses compared to choices of NoGo items primarily in lateral prefrontal cortical areas. This new imaging finding suggests that preferences are shifted via differential engagement of task control networks that interact with value networks during cue-approach training. PMID:27677231

Advancing neuroscience through epigenetics: molecular mechanisms of learning and memory.

PubMed

Molfese, David L

2011-01-01

Humans share 96% of our 30,000 genes with Chimpanzees. The 1,200 genes that differ appear at first glance insufficient to describe what makes us human and them apes. However, we are now discovering that the mechanisms that regulate how genes are expressed tell a much richer story than our DNA alone. Sections of our DNA are constantly being turned on or off, marked for easy access, or secluded and hidden away, all in response to ongoing cellular activity. In the brain, neurons encode information-in effect memories-at the cellular level. Yet while memories may last a lifetime, neurons are dynamic structures. Every protein in the synapse undergoes some form of turnover, some with half-lives of only hours. How can a memory persist beyond the lifetimes of its constitutive molecular building blocks? Epigenetics-changes in gene expression that do not alter the underlying DNA sequence-may be the answer. In this article, epigenetic mechanisms including DNA methylation and acetylation or methylation of the histone proteins that package DNA are described in the context of animal learning. Through the interaction of these modifications a "histone code" is emerging wherein individual memories leave unique memory traces at the molecular level with distinct time courses. A better understanding of these mechanisms has implications for treatment of memory disorders caused by normal aging or diseases including schizophrenia, Alzheimer's, depression, and drug addiction.

Combined quantum-mechanics/molecular-mechanics dynamics simulation of A-DNA double strands irradiated by ultra-low-energy carbon ions

NASA Astrophysics Data System (ADS)

Ngaojampa, C.; Nimmanpipug, P.; Yu, L. D.; Anuntalabhochai, S.; Lee, V. S.

2011-02-01

In order to promote understanding of the fundamentals of ultra-low-energy ion interaction with DNA, molecular dynamics simulations using combined quantum-mechanics/molecular-mechanics of poly-AT and poly-GC A-DNA double strands irradiated by <200 eV carbon ions were performed to investigate the molecular implications of mutation bias. The simulations were focused on the responses of the DNA backbones and nitrogenous bases to irradiation. Analyses of the root mean square displacements of the backbones and non-hydrogen atoms of base rings of the simulated DNA structure after irradiation revealed a potential preference of DNA double strand separation, dependent on the irradiating energy. The results show that for the backbones, the large difference in the displacement between poly-GC and poly-AT in the initial time period could be the reason for the backbone breakage; for the nitrogenous base pairs, A-T is 30% more sensitive or vulnerable to ion irradiation than G-C, demonstrating a preferential, instead of random, effect of irradiation-induced mutation.

Unraveling the mechanism of molecular doping in organic semiconductors.

PubMed

Mityashin, Alexander; Olivier, Yoann; Van Regemorter, Tanguy; Rolin, Cedric; Verlaak, Stijn; Martinelli, Nicolas G; Beljonne, David; Cornil, Jérôme; Genoe, Jan; Heremans, Paul

2012-03-22

The mechanism by which molecular dopants donate free charge carriers to the host organic semiconductor is investigated and is found to be quite different from the one in inorganic semiconductors. In organics, a strong correlation between the doping concentration and its charge donation efficiency is demonstrated. Moreover, there is a threshold doping level below which doping simply has no electrical effect. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular Mechanisms of Prostate Cancer Progression

DTIC Science & Technology

2003-01-01

other drugs ( novobiocin and related hsp90 inhibitors have been shown to bind to the N-ter- coumarins) that are reported to target hsp90 are now be...undesirable for an indirect method of telomerase inhibition (data not shown). However, radicicol, which binds in the ATP- binding pocket of hsp90 and...compounds (e.g. novobiocin ) to block chaperone function using a totally different mechanism of hsp90 inhbition, as well as innovative genetic approaches

All-acrylic multigraft copolymers: Effect of side chain molecular weight and volume fraction on mechanical behavior

DOE PAGES

Goodwin, Andrew; Wang, Weiyu; Kang, Nam -Goo; ...

2015-08-21

We present in this paper the synthesis of poly(n-butyl acrylate)-g-poly(methyl methacrylate) (PnBA-g-PMMA) multigraft copolymers via a grafting-through (macromonomer) approach. The synthesis was performed using two controlled polymerization techniques. The PMMA macromonomer was obtained by high-vacuum anionic polymerization followed by the copolymerization of n-butyl acrylate and PMMA macromonomer using reversible addition–fragmentation chain transfer (RAFT) polymerization to yield the desired all-acrylic multigraft structures. The PnBA-g-PMMA multigraft structures exhibit randomly spaced branch points with various PMMA contents, ranging from 15 to 40 vol %, allowing an investigation into how physical properties vary with differences in the number of branch points and molecular weightmore » of grafted side chains. The determination of molecular weight and polydispersity indices of both the PMMA macromonomer and the graft copolymers was carried out using size exclusion chromatography with triple detection, and the structural characteristics of both the macromonomer and PnBA-g-PMMA graft materials were characterized by 1H and 13C NMR. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was employed for monitoring the macromonomer synthesis. Thermal characteristics of the materials were analyzed using differential scanning calorimetry and thermogravimetric analysis. The mechanical performance of the graft materials was characterized by rheology and dynamic mechanical analysis, revealing that samples with PMMA content of 25–40 vol % exhibit superior elastomeric properties as compared to materials containing short PMMA side chains or <25 vol % PMMA. In conclusion, atomic force microscopy showed a varying degree of microphase separation between the glassy and rubbery components that is strongly dependent on PMMA side chain molecular weight.« less

Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

PubMed Central

Próchnicki, Tomasz; Mangan, Matthew S.; Latz, Eicke

2016-01-01

Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K + efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca 2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

Molecular mechanisms influencing efficiency of RNA interference in insects.

PubMed

Cooper, Anastasia M W; Silver, Kristopher; Jianzhen, Zhang; Park, Yoonseong; Zhu, Kun Yan

2018-06-21

RNA interference (RNAi) is an endogenous, sequence-specific gene silencing mechanism elicited by small RNA molecules. RNAi is a powerful reverse genetic tool, and is currently being utilized for managing insects and viruses. Widespread implementation of RNAi-based pest management strategies is currently hindered by inefficient and highly variable results when different insect species, strains, developmental stages, tissues, and genes are targeted. Mechanistic studies have shown that double-stranded ribonucleases (dsRNases), endosomal entrapment, deficient function of the core machinery, and inadequate immune stimulation contribute to limited RNAi efficiency. However, a comprehensive understanding of the molecular mechanisms limiting RNAi efficiency remains elusive. The recent advances in dsRNA stability in physiological tissues, dsRNA internalization into cells, the composition and function of the core RNAi machinery, as well as small-interfering RNA/double-stranded RNA amplification and spreading mechanisms are reviewed to establish a global understanding of the obstacles impeding wider understanding of RNAi mechanisms in insects. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Precision medicine and molecular imaging: new targeted approaches toward cancer therapeutic and diagnosis.

PubMed

Ghasemi, Mojtaba; Nabipour, Iraj; Omrani, Abdolmajid; Alipour, Zeinab; Assadi, Majid

2016-01-01

This paper presents a review of the importance and role of precision medicine and molecular imaging technologies in cancer diagnosis with therapeutics and diagnostics purposes. Precision medicine is progressively becoming a hot topic in all disciplines related to biomedical investigation and has the capacity to become the paradigm for clinical practice. The future of medicine lies in early diagnosis and individually appropriate treatments, a concept that has been named precision medicine, i.e. delivering the right treatment to the right patient at the right time. Molecular imaging is quickly being recognized as a tool with the potential to ameliorate every aspect of cancer treatment. On the other hand, emerging high-throughput technologies such as omics techniques and systems approaches have generated a paradigm shift for biological systems in advanced life science research. In this review, we describe the precision medicine, difference between precision medicine and personalized medicine, precision medicine initiative, systems biology/medicine approaches (such as genomics, radiogenomics, transcriptomics, proteomics, and metabolomics), P4 medicine, relationship between systems biology/medicine approaches and precision medicine, and molecular imaging modalities and their utility in cancer treatment and diagnosis. Accordingly, the precision medicine and molecular imaging will enable us to accelerate and improve cancer management in future medicine.

Precision medicine and molecular imaging: new targeted approaches toward cancer therapeutic and diagnosis

PubMed Central

Ghasemi, Mojtaba; Nabipour, Iraj; Omrani, Abdolmajid; Alipour, Zeinab; Assadi, Majid

2016-01-01

This paper presents a review of the importance and role of precision medicine and molecular imaging technologies in cancer diagnosis with therapeutics and diagnostics purposes. Precision medicine is progressively becoming a hot topic in all disciplines related to biomedical investigation and has the capacity to become the paradigm for clinical practice. The future of medicine lies in early diagnosis and individually appropriate treatments, a concept that has been named precision medicine, i.e. delivering the right treatment to the right patient at the right time. Molecular imaging is quickly being recognized as a tool with the potential to ameliorate every aspect of cancer treatment. On the other hand, emerging high-throughput technologies such as omics techniques and systems approaches have generated a paradigm shift for biological systems in advanced life science research. In this review, we describe the precision medicine, difference between precision medicine and personalized medicine, precision medicine initiative, systems biology/medicine approaches (such as genomics, radiogenomics, transcriptomics, proteomics, and metabolomics), P4 medicine, relationship between systems biology/medicine approaches and precision medicine, and molecular imaging modalities and their utility in cancer treatment and diagnosis. Accordingly, the precision medicine and molecular imaging will enable us to accelerate and improve cancer management in future medicine. PMID:28078184

Void effect on mechanical properties of copper nanosheets under biaxial tension by molecular dynamics method

NASA Astrophysics Data System (ADS)

Yang, Zailin; Yang, Qinyou; Zhang, Guowei; Yang, Yong

2018-03-01

The relationship between void size/location and mechanical behavior under biaxial loading of copper nanosheets containing voids are investigated by molecular dynamics method. The void location and the void radius on the model are discussed in the paper. The main reason of break is discovered by the congruent relationship between the shear stress and its dislocations. Dislocations are nucleated at the corner of system and approached to the center of void with increased deformation. Here, a higher stress is required to fail the voided sheets when smaller voids are utilized. The void radius influences the time of destruction. The larger the void radius is, the lower the shear stress and the earlier the model breaks. The void location impacts the dislocation distribution.

Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review).

PubMed

Yan, Fenggen; Mo, Xiumei; Liu, Junfeng; Ye, Siqi; Zeng, Xing; Chen, Dacan

2017-11-01

The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics.

Catecholaminergic systems in stress: structural and molecular genetic approaches.

PubMed

Kvetnansky, Richard; Sabban, Esther L; Palkovits, Miklos

2009-04-01

Stressful stimuli evoke complex endocrine, autonomic, and behavioral responses that are extremely variable and specific depending on the type and nature of the stressors. We first provide a short overview of physiology, biochemistry, and molecular genetics of sympatho-adrenomedullary, sympatho-neural, and brain catecholaminergic systems. Important processes of catecholamine biosynthesis, storage, release, secretion, uptake, reuptake, degradation, and transporters in acutely or chronically stressed organisms are described. We emphasize the structural variability of catecholamine systems and the molecular genetics of enzymes involved in biosynthesis and degradation of catecholamines and transporters. Characterization of enzyme gene promoters, transcriptional and posttranscriptional mechanisms, transcription factors, gene expression and protein translation, as well as different phases of stress-activated transcription and quantitative determination of mRNA levels in stressed organisms are discussed. Data from catecholamine enzyme gene knockout mice are shown. Interaction of catecholaminergic systems with other neurotransmitter and hormonal systems are discussed. We describe the effects of homotypic and heterotypic stressors, adaptation and maladaptation of the organism, and the specificity of stressors (physical, emotional, metabolic, etc.) on activation of catecholaminergic systems at all levels from plasma catecholamines to gene expression of catecholamine enzymes. We also discuss cross-adaptation and the effect of novel heterotypic stressors on organisms adapted to long-term monotypic stressors. The extra-adrenal nonneuronal adrenergic system is described. Stress-related central neuronal regulatory circuits and central organization of responses to various stressors are presented with selected examples of regulatory molecular mechanisms. Data summarized here indicate that catecholaminergic systems are activated in different ways following exposure to distinct

An Approach with Hybrid Segmental Mechanics.

PubMed

Mishra, Harsh Ashok; Maurya, Raj Kumar

2016-06-01

Present case report provides an insight into the hybrid segmental mechanics with treatment of 13-year-old male, considering the side effects of sole continuous arch wire sliding mechanics. Patient was diagnosed as a case of skeletal class I jaw relationship, low mandibular plane angle, class II molar relation on right and class I molar relation on left side, anterior cross bite, crowding of 12mm in upper, 5mm in lower arch. He also had proclined upper and lower anteriors by 2mm, convex profile and incompetent lips. Total treatment duration was 20 months, during which segmental canine retraction was performed with TMA (Titanium, Molybdenum, Aluminum) 'T' loop retraction spring followed by consolidation of spaces with continuous arch mechanics. Most of the treatment objectives were met with good intraoral and facial results within reasonable framework of time. This approach used traditional twin brackets, which offered the versatility to use continuous arch-wire mechanics, segmental mechanics and hybrid sectional mechanics.

Gap compression/extension mechanism of bacterial flagellar hook as the molecular universal joint.

PubMed

Furuta, Tadaomi; Samatey, Fadel A; Matsunami, Hideyuki; Imada, Katsumi; Namba, Keiichi; Kitao, Akio

2007-03-01

Bacterial flagellar hook acts as a molecular universal joint, transmitting torque produced by the flagellar basal body, a rotary motor, to the flagellar filament. The hook forms polymorphic supercoil structures and can be considered as an assembly of 11 circularly arranged protofilaments. We investigated the molecular mechanism of the universal joint function of the hook by a approximately two-million-atom molecular dynamics simulation. On the inner side of the supercoil, protein subunits are highly packed along the protofilament and no gaps remain for further compression, whereas subunits are slightly separated and are hydrogen bonded through one layer of water molecules on the outer side. As for the intersubunit interactions between protofilaments, subunits are packed along the 6-start helix in a left-handed supercoil whereas they are highly packed along the 5-start helix in a right-handed supercoil. We conclude that the supercoiled structures of the hook in the left- and right-handed forms make maximal use of the gaps between subunits, which we call "gap compression/extension mechanism". Mutual sliding of subunits at the subunit interface accompanying rearrangements of intersubunit hydrogen bonds is interpreted as a mechanism to allow continuous structural change of the hook during flagellar rotation at low energy cost.

Quantum Mechanics/Molecular Mechanics Free Energy Maps and Nonadiabatic Simulations for a Photochemical Reaction in DNA: Cyclobutane Thymine Dimer.

PubMed

Mendieta-Moreno, Jesús I; Trabada, Daniel G; Mendieta, Jesús; Lewis, James P; Gómez-Puertas, Paulino; Ortega, José

2016-11-03

The absorption of ultraviolet radiation by DNA may result in harmful genetic lesions that affect DNA replication and transcription, ultimately causing mutations, cancer, and/or cell death. We analyze the most abundant photochemical reaction in DNA, the cyclobutane thymine dimer, using hybrid quantum mechanics/molecular mechanics (QM/MM) techniques and QM/MM nonadiabatic molecular dynamics. We find that, due to its double helix structure, DNA presents a free energy barrier between nonreactive and reactive conformations leading to the photolesion. Moreover, our nonadiabatic simulations show that most of the photoexcited reactive conformations return to standard B-DNA conformations after an ultrafast nonradiative decay to the ground state. This work highlights the importance of dynamical effects (free energy, excited-state dynamics) for the study of photochemical reactions in biological systems.

Mechanical Properties of LaRC(tm) SI Polymer for a Range of Molecular Weights

NASA Technical Reports Server (NTRS)

Whitley, Karen S.; Gates, Thomas S.; Hinkley, Jeffrey A.; Nicholson, Lee M.

2000-01-01

Mechanical testing of an advanced polyimide resin (LaRC(tm)-SI) with known variations in molecular weight was performed over a range of temperatures below the glass transition temperature. Elastic and inelastic properties were characterized as a function of molecular weight and test temperature. It was shown that notched tensile strength is a strong function of both temperature and molecular weight, whereas stiffness is only a strong function of temperature. The combined analysis of calculated yield stress and notched tensile strength indicated that low molecular weight materials tended to fail in a brittle manner, whereas high molecular weight materials exhibited ductile failure. The microphotographs of the failure surfaces also supported these findings.