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1.
Nitric oxide reductase (Nor), a member of the cytochrome P450 superfamily, takes part in the denitrification process of fungi by reducing NO to N(2)O. Evidence indicates that Nor binds NADH, source of the reducing equivalents of the reaction, within its large hydrophilic ligand binding cavity on the distal side of heme and receives electrons directly from the cofactor. Here we present a binding mode analysis of the structure of the Nor-NO-NADH complex, performed in three steps. The NADH cofactor was first docked into the enzyme interior using the Monte Carlo multiple minimum algorithm, refined by low-mode conformational search and the final arrangement was obtained in a 5ns NPT molecular dynamics simulation. The NADH cofactor, in our results, is positioned--by Arg174, Lys291, Asp393 and several water molecules--within reactive distance of the NO binding spot suggesting a direct hydride shift mechanism between the two. The catalytically required water molecule is captured by NADH and the cofactor not only retains the suggested H-bonded proton transfer pathway between the active site and the solvent, but provides structural restraint for its members. We also found that direct interaction is formed between the cofactor and propionate A of the heme group, which flips from the proximal to the distal side of the heme plane in order to become an H-bonding partner of NADH. The role of Arg64 and Glu71 was suggested to be fixing the residues of the translocated helix B' to their new position.  相似文献   

2.
Mycobacterium tuberculosis (Mtb) is a successful pathogen that overcomes the numerous challenges presented by the immune system of the host. In the last 40 years few anti-TB drugs have been developed, while the drug-resistance problem is increasing; there is thus a pressing need to develop new anti-TB drugs active against both the acute and chronic growth phases of the mycobacterium. Methionine S-adenosyltransferase (MAT) is an enzyme involved in the synthesis of S-adenosylmethionine (SAM), a methyl donor essential for mycolipid biosynthesis. As an anti-TB drug target, Mtb-MAT has been well validated. A homology model of MAT has been constructed using the X-ray structures of E. coli MAT (PDB code: 1MXA) and rat MAT (PDB code: 1QM4) as templates, by comparative protein modeling principles. The resulting model has the correct stereochemistry as gauged from the Ramachandran plot and good three-dimensional (3D) structure compatibility as assessed by the Profiles-3D score. The structurally and functionally important residues (active site) of Mtb-MAT have been identified using the E. coli and rat MAT crystal structures and the reported point mutation data. The homology model conserves the topological and active site features of the MAT family of proteins. The differences in the molecular electrostatic potentials (MEP) of Mtb and human MAT provide evidences that selective and specific Mtb-MAT inhibitors can be designed using the homology model, by the structure-based drug design approaches.  相似文献   

3.
The response of a noninteracting population of identical neurons to a step change in steady synaptic input can be analytically calculated exactly from the dynamical equation that describes the population's evolution in time. Here, for model integrate-and-fire neurons that undergo a fixed finite upward shift in voltage in response to each synaptic event, we compare the theoretical prediction with the result of a direct simulation of 90,000 model neurons. The degree of agreement supports the applicability of the population dynamics equation. The theoretical prediction is in the form of a series. Convergence is rapid, so that the full result is well approximated by a few terms.  相似文献   

4.
Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen. PknI is one of the 11 functional Serine/Threonine Protein Kinases which is predicted to regulate the cell division of M. tuberculosis. In order to find newer drugs and vaccine we need to understand the pathogenesis of the disease. We have used the bioinformatics approach to identify the functionally active residues of PknI and to confirm the same with wet lab experiments. In the current study, we have created homology model for PknI and have done comparative structural analysis of PknI with other kinases. Molecular docking studies were done with a library of kinase inhibitors and T95 was found as the potent inhibitor for PknI. Based on structure based pharmacophore analysis of kinase substrate complexes, Lys 41 along with Asp90, Val92 and Asp96 were identified as functionally important residues. Further, we used site directed mutagenesis technique to mutate Lys 41 to Met resulting in defective cell division of Mycobacterium smegmatis mc2. Overall, the proposed model together with its binding features gained from pharmacophore docking studies helped in identifying ligand inhibitor specific to PknI which was confirmed by laboratory experiments.  相似文献   

5.
Owing to the rapid development and advancements in the field of networks and communication, sharing of multimedia contents over insecure networks has becom  相似文献   

6.
The graphical characterisation of many important structural properties, such as controllability, observability, diagnosability of many kinds of structured systems, uses mainly four types of elementary graphical conditions: connectivity, complete matching, linking and distance conditions. Since structural properties depend on different associations of elementary conditions, it is interesting to study elementary conditions. This paper is the first part of this global approach based on elementary graphical conditions and we choose to study the so-called connectivity and complete matching conditions. Starting from the graphical representation associated with a system, the paper provides Boolean expressions of the connectivity and complete matching conditions based on the edges validity, which can be linked to the physical components operating state. These expressions can then be used to define and compute the reliability of a structural property knowing the reliability of the system physical components. This knowledge can be important during both conception and exploitation stages. The proposed methods are quite intuitive and simple to implement and have basically polynomial complexity orders. This makes our approach well suited to analyse large-scale systems.  相似文献   

7.
In this paper we present Top Tom, a digital platform whose goal is to provide analytical and visual solutions for the exploration of a dynamic corpus of user‐generated messages and media articles, with the aim of i) distilling the information from thousands of documents in a low‐dimensional space of explainable topics, ii) cluster them in a hierarchical fashion while allowing to drill down to details and stories as constituents of the topics, iii) spotting trends and anomalies. Top Tom implements a batch processing pipeline able to run both in near‐real time with time stamped data from streaming sources and on historical data with a temporal dimension in a cold start mode. The resulting output unfolds along three main axes: time, volume and semantic similarity (i.e. topic hierarchical aggregation). To allow the browsing of data in a multiscale fashion and the identification of anomalous behaviors, three visual metaphors were adopted from biological and medical fields to design visualizations, i.e. the flowing of particles in a coherent stream, tomographic cross sectioning and contrast‐like analysis of biological tissues. The platform interface is composed by three main visualizations with coherent and smooth navigation interactions: calendar view, flow view, and temporal cut view. The integration of these three visual models with the multiscale analytic pipeline proposes a novel system for the identification and exploration of topics from unstructured texts. We evaluated the system using a collection of documents about the emerging opioid epidemics in the United States.  相似文献   

8.
The present work combines molecular docking calculations, 3D-QSAR, molecular dynamics simulations and free binding energy calculations (MM/PBSA and MM/GBSA) in a set of 28 structural analogues of acyl homoserine lactones with Quorum Sensing antagonist activity. The aim of this work is to understand how ligand binds and is affected by the molecular microenvironment in the active site of the LasR receptor for pseudomonas aeruginosa. We also study the stability of the interaction to find key structural characteristics that explain the antagonist activities of this set of ligands. This information is relevant for the rational modification or design of molecules and their identification as powerful LasR modulators.The analysis of molecular docking simulations shows that the 28 analogues have a similar binding mode compared to the native ligand. The carbonyl groups belonging to the lactone ring and the amide group of the acyl chain are oriented towards the amino acids forming hydrogen bond like interactions. The difference in antagonist activity is due to location and orientation of the LasR side chains within the hydrophobic pocket in its binding site. Additionally, we carried out molecular dynamics simulations to understand the conformational changes in the ligand-receptor interaction and the stability of each complex. Results show a direct relationship among the interaction energies of the ligands and the activities as an antagonist of the LasR receptor.  相似文献   

9.
A theoretical study at the level of density functional theory (DFT) was performed to characterize noncovalent intermolecular interactions, especially hydrogen bond interactions, in the active site of enzyme human androsterone sulphotransferase (SULT2A1/ADT). Geometry optimization, interaction energy, 2H, 14N, and 17O electric field gradient (EFG) tensors, 1H, 13C, 17O, and 15N chemical shielding (CS) tensors, Natural Bonding Orbital (NBO) analysis, and quantum theory of atoms in molecules (QTAIM) analysis of this active site were investigated. It was found that androsterone (ADT) is able to form hydrogen bonds with residues Ser80, Ile82, and His99 of the active site. The interaction energy calculations and NBO analysis revealed that the ADT molecule forms the strongest hydrogen bond with Ser80. Results revealed that ADT interacts with the other residues through electrostatic and Van der Waals interactions. Results showed that these hydrogen bonds influence on the calculated 2H, 14N, and 17O quadrupole coupling constants (QCCs), as well as 1H, 13C, 17O, and 15N CS tensors. The magnitude of the QCC and CS changes at each nucleus depends directly on its amount of contribution to the hydrogen bond interaction.  相似文献   

10.
One of the key technologies related to knowledge and data engineering is the acquisition of knowledge and data in the development and utilization of information system and the strategies to capture new knowledge and data. Actually, millions of documents, including technical reports, government files, newspapers, books, magazines, letters, bank checks, etc., have to be processed every day, and knowledge has to be acquired from them. This paper presents a new approach to document analysis for automatic knowledge acquisition. The traditional approaches have two major disadvantages: (1) They are not effective for processing documents with high geometrical complexity. Specially, the top-down approach can process only the simple documents which have specific format or contain some a priori information. (2) The top-down approach needs to split large components into small ones iteratively, while the bottom-up approach needs to merge small components into large ones iteratively. They are time consuming. This new approach is based on modified fractal signature. It can overcome the above weaknesses  相似文献   

11.
Summary The methods of improving LR(k) parsers proposed by DeRemer and Korenjak are shown to be based on a single concept — that of modifying the contextual information on which parsing decisions are made. This concept is then used to derive a straightforward algorithm for eliminating unit productions from an LR parser.  相似文献   

12.
This paper presents a model of (en)action from a conceptual and theoretical point of view. This model is used to provide solid bases to overcome the complexity of designing virtual environments for learning (VEL). It provides a common grounding for trans-disciplinary collaborations where embodiment can be perceived as the cornerstone of the project. Where virtual environments are concerned, both computer scientists and educationalists have to deal with the learner/user’s body; therefore the model provides tools with which to approach both human actions and learning processes within a threefold model. It is mainly based on neuroscientific research, including enaction and the neurophysiology of action.  相似文献   

13.
14.
We tested a method for comparing ECG signals (P waves), in a sample of 10 normal males. In each subject, sets of 219 body surface ECGs were simultaneously recorded during tidal respiration. Only beats at end expiration and peak inspiration were considered. The beats of each group were subdivided into two subgroups of the same size (about 30 beats) and separately averaged. The two averaged beats at end expiration, assumed to be equal, were compared in order to estimate the noise variance (sigma2), i.e., the lowest value of variance at which the beats were statistically similar (P less than 0.05). At the same value of sigma2, the beat at end expiration significantly differed from that at peak inspiration. By considering the individual leads, significant differences were found in more than 50% of the 219 ECGs, in specific thoracic areas. The data indicated that the method can reveal differences between P waves occurring during tidal respiration and provide information on the topographical distribution of the differences.  相似文献   

15.
Robots are emerging in welfare services, and organizations require information on whether novel technologies are approved among staff. On the basis of technology acceptance theories, this study proposes a model that adds a principled approach to the intention to use care robots. Data of 544 professionals with care robot experience were collected. The use intention was predicted by usefulness, enjoyment, social influence, and attitude. Respondents who found robots useful and accepted by their colleagues were more likely to view robot use as consistent with their personal values. The care robot acceptance model supports consideration of the profession-specific context in robotization.  相似文献   

16.
《Ergonomics》2012,55(9):1134-1149
Abstract

Darknet markets provide an anonymous, online platform for users to trade illicit drugs, fraudulent identity data, and other commodities. Although law enforcement agencies have been successful in seising many markets, the Darknet is an agile and dynamic environment and market activities often persist and emerge in a new form. Given this constantly changing environment, new ways of disrupting darknet markets are required. This study used Event Analysis of Systemic Teamwork (EAST) to analyse market activity and understand vulnerabilities to disruption. This involved using the EAST broken-links approach to assess the effects of compromising the transmission of information between tasks and between agents. The analysis identified critical vulnerabilities in the system, which included information involved in registering, depositing funds, communicating listing details to buyers, and communicating dispute resolution messages. This study indicates that systems ergonomics methods—in particular, EAST—can provide insight into system vulnerabilities that might be targeted for disruption.

Practitioner summary

This study provides a conceptualisation of the processes, people, structures, and information involved in the buying and selling of goods on a darknet market. Law enforcement agencies may use broken-links analyses to systematically consider the effects of their interventions.  相似文献   

17.
The paper presents a general method to evaluate a masonry structure with a complex geometry and unknown material properties. This multidisciplinary approach integrates close range digital photogrammetry, ground probing radar (GPR) and finite elements analysis (FEM) to analyse a masonry bridge. The resulting information from photogrammetry and radar is applied to define a 3D model, which is then used to simulate the behaviour of the bridge using FEM. Two different approaches to model the internal composition of the bridge with finite elements are presented. Sensitivity analysis is applied to study the reasons of the structural damage.  相似文献   

18.
A real symmetric matrix is diagonalisable by a suitable orthonormal change of basis. The joint approximate diagonalisation problem is to find an orthonormal change of basis which simultaneously diagonalises, or approximately diagonalises, two or more real symmetric matrices. A number of important signal processing problems require the computation of a joint approximate diagonaliser. However, no algorithm to date is guaranteed to find the optimal diagonaliser. This paper reformulates the diagonalisation problem as a convex optimisation problem on a Riemannian manifold and is thus able to guarantee global convergence to the optimal diagonaliser.  相似文献   

19.
As the use of approximations is often the only way to deal with the optimization of complex structures, this paper discusses the use of Kalman filtering as a new approach for building global approximations. Basic ideas and procedures of Kalman filters are first recalled. Next, key elements of how to implement the method for design problems are described. Finally, in order to evaluate the performance of the approach, an inverse problem which consists in optimizing a warhead with respect to constraints on the resulting projectile is studied. It is shown that global approximations are convenient for the solution of complex optimization problems and that Kalman filtering techniques appear to be an interesting strategy for the construction of global approximations in structural optimization.  相似文献   

20.
An approach for the modeling and evaluation of reliability and availability of systems using the knowledge of the reliability growth of their components is presented. Detailed models of reliability and availability for single-component systems are derived under much weaker assumption than usually considered. These models, termed knowledge models, enable phenomena to be precisely characterized, and a number of properties to be deduced. Since the knowledge models are too complex to be applied in real life for performing predictions, simplified models for practical purposes (action models) are discussed. The hyperexponential model is presented and applied to field data of software and hardware failures. This model is shown to be comparable to other models as far as reliability of single-component systems is concerned: in addition, it enables estimating and predicting the reliability of multicomponent systems, as well as their availability. The transformation approach enables classical Markov models to be transformed into other Markov models which account for reliability growth. The application of the transformation to multicomponent systems is described  相似文献   

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