On the Prediction of the Enantioselectivity of Candida rugosa Lipase by Comparative Molecular Field Analysis

Comparative molecular field analysis (CoMFA) was used to derive a quantitative substrate model for the enzymatic resolution of norbornanol esters by the lipase of Candida rugosa. Within these calculations, the steric and electrostatic interactions of both enantiomers and the differences in the corresponding two fields were used for the correlation of the substrate structure with the enantioselectivity of the hydrolysis. Different alignments of the molecules were used to improve the model.     

Three-Dimension Quantitative Structure-Activity Relationship Analysis of Some Cinnamamides Using Comparative Molecular Similarity Indices Analysis (CoMSIA)

Comparative molecular similarity indices analysis (CoMSIA) has been applied to a data set of cinnamamides. Five different properties: steric, electrostatic, hydrophobic, H-bond donor and H-bond acceptor, assumed to cover the major contributions to ligand binding, were used to generate the 3D-QSAR model. A significant cross-validated correlation coefficient q ² (0.691) was obtained, indicating the statistical significance of the model for untested compounds of this class. The model was used to predict the anticonvulsant activities of five test-set compounds, and the predicted values were in good agreement with the experimental results. Moreover, from the contour maps, the key features vital to ligand binding have been identified, which are important for us to trace the important properties and gain insight into the potential mechanisms of intermolecular interactions between ligand and receptor.Electronic Supplementary Material available.     

Taboo-based Monte Carlo Search as a Method to Improve Sampling Efficiency

Abstract

Taboo-based Monte Carlo search which restricts the sampling of the region near an old configuration, is developed. In this procedure, Monte Carlo simulation and random search method are combined to improve the sampling efficiency. The feasibility of this method is tested on global optimization of a continuous model function, melting of the 256 Lennard-Jones particles at T? = 0.680 and ρ? = 0.850 and polypeptides (alanine dipeptide and Metenkephalin). From the comparison of results for the model function between our method and other methods, we find the increase of convergence rate and the high possibility of escaping from the local energy minima. The results of the Lennard-Jones solids and polypeptides show that the convergence property to reach the equilibrium state is better than that of others. It is also found that no significant bias in ensemble distribution is detected, though taboo-based Monte Carlo search does not sample the correct ensemble distribution owing to the restriction of the sampling of the region near an old configuration.     

Search and Analysis of Identical Reverse Octapeptides in Unrelated Proteins

For the past few decades, intensive studies have been carried out in an attempt to understand how the amino acid sequences of proteins encode their three dimensional structures to perform their specific functions. In order to understand the sequence-structure relationship of proteins, several sub-sequence search studies in non-redundant sequence-structure databases have been undertaken which have given some fruitful clues. In our earlier work, we analyzed a set of 3124 non-redundant protein sequences from the Protein Data Bank (PDB) and retrieved 30 identical octapeptides having different secondary structures. These octapeptides were characterized by using different computational procedures. This prompted us to explore the presence of octapeptides with reverse sequences and to analyze whether these octapeptides would adopt similar structures as that of their parent octapeptides. Our identical reverse octapeptide search resulted in the finding of eight octapeptide pairs (octapeptide and reverse octapeptide) with similar secondary structure and 23 octapeptide pairs with different secondary structures. In the present work, the geometrical and biophysical characteristics of identical reverse octapeptides were explored and compared with unrelated octapeptide pairs by using various computational tools. We thus conclude that proteins containing identical reverse octapeptides are not very abundant and residues in the octapeptide pairs do not contribute to the stability of the protein. Furthermore, compared to unrelated octapeptides, identical reverse octapeptides do not show certain biophysical and geometrical properties.     

Comparative QSAR studies on peptide deformylase inhibitors

Comparative quantitative structure–activity relationship (QSAR) analyses of peptide deformylase (PDF) inhibitors were performed with a series of previously published (British Biotech Pharmaceuticals, Oxford, UK) reverse hydroxamate derivatives having antibacterial activity against Escherichia coli PDF, using 2D and 3D QSAR methods, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR). Statistically reliable models with good predictive power were generated from all three methods (CoMFA r ² = 0.957, q ² = 0.569; CoMSIA r ² = 0.924, q ² = 0.520; HQSAR r ² = 0.860, q ² = 0.578). The predictive capability of these models was validated by a set of compounds that were not included in the training set. The models based on CoMFA and CoMSIA gave satisfactory predictive r ² values of 0.687 and 0.505, respectively. The model derived from the HQSAR method showed a low predictability of 0.178 for the test set. In this study, 3D prediction models showed better predictive power than 2D models for the test set. This might be because 3D information is more important in the case of datasets containing compounds with similar skeletons. Superimposition of CoMFA contour maps in the active site of the PDF crystal structure showed a meaningful correlation between receptor–ligand binding and biological activity. The final QSAR models, along with information gathered from 3D contour and 2D contribution maps, could be useful for the design of novel active inhibitors of PDF. Figure Superimposition of comparative molecular field analysis (CoMFA) contour plot in the active site of peptide deformylase (PDF)     

An Analysis of Field Potentials During Different Tailflip Behaviours in Crayfish

Crayfish tailflips have been intensively studied to reveal the decision-making processes and neural organisation underlying a stereotyped escape behaviour. Three behaviours mediated by different neural pathways have been well described: medial giant, lateral giant and non-giant tailflips. It has proved difficult to distinguish between the three without invasive or restrictive experimental manipulation. We report unambiguous differences between the signals generated by the crayfish Cherax destructor during the three types of tailflip when recorded by bath electrodes placed in the holding aquarium. Using our ability to distinguish between the different behaviours in freely moving animals we examined the relationship between the type of tailflip evoked by stimulation to different parts of the body. The transition zone between medial and lateral giant tailflips is the thoracic-abdominal border but it is not absolute and some stimuli produce responses that cannot be unambiguously assigned to either behavioural category. We examined the latency between stimulation at different points down the length of the body and the appearance of the electrical signal accompanying escape for both medial and lateral tailflips. We used two methods to estimate the proportion of the latency accounted for by giant fibre conduction velocity. The results support current views of the differences between the activation sites of the two giant fibre systems and suggest why stimulation in the transition zone results in ambiguous outcomes.     

Comparative Molecular Analysis of Endoevaporitic Microbial Communities

A phylogenetic comparison of microbial communities in hypersaline evaporites was conducted on crusts from Guerrero Negro, Mexico, and Lindsey Lake, New Mexico, using culture-independent rRNA gene sequence analysis. Many sequences were shared between evaporites, which suggests that similar environments select for specific microbial lineages from a global metacommunity.     

Construction of a Quantitative Three-dimensional Model for Odor Quality using Comparative Molecular Field Analysis (CoMFA)

A quantitative structure-activity relationship (QSAR) studyof odorants was performed taking an odor as an activity. Asan example, we took the ‘green odor of pyrazine derivatives’as an activity. Conformational analysis of the pyrazine derivativeswas performed, and conformers were selected using the longestside-length of a circumscribed box (LLCB) as a criterion. Comparativemolecular field analysis (CoMFA) was used to elucidate the three-dimensional(3D) structural features of the derivatives. As a result, itwas found that the steric and electrostatic features of thederivatives were correlated with human olfactory detection thresholdvalues. We constructed a quantitative 3D model using the graphicviews of CoMFA and partial structures of the derivatives. Theprediction of human olfactory detection threshold values ofother pyrazine derivatives with green odor was possible by usingthe 3D model. As another example, we took the ‘sweet odorof compounds with various structures’ as an activity.A quantitative 3D model for sweet odor was constructed in thesame manner. Analysing the structural features of odorants byCoMFA and constructing 3D models for several important odorqualities would help to (i) explain or predict human olfactorydetection threshold values of interesting odorants, (ii) designnew odorants by suggesting the steric and electrostatic requirements,and (iii) elucidate the mechanism of odorant-receptor interaction.Chem Senses 21: 201–210, 1996.     

Efficient Test Molecule Sampling in Molecular Simulation

Abstract

Excluded volume map sampling (EVMS) is a particularly efficient means of performing test molecule sampling to estimate or impose chemical potential in molecular simulations. This paper discusses the motivation and applications of excluded volume map sampling, presents computer code demonstrating its implementation, and gives an example of its application.     

Molecular modelling studies on d-annulated benzazepinones as VEGF-R2 kinase inhibitors using docking and 3D-QSAR

Chemotypes comprising the d-annulated 1,3-dihydro-2H-1-benzazepin-2-one scaffold derived from the paullone structure were found to be potent vascular endothelial growth factor receptor 2 (VEGF-R2) kinase inhibitors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on a series of d-annulated benzazepinones with VEGF-R2 kinase inhibition activities. The comparative molecular field analysis and comparative molecular similarity indices analysis models using 32 molecules in the training set gave r²_cv values of 0.811 and 0.769, r² values of 0.962 and 0.953, respectively. 3D contour maps generated from the two models revealed that the electron-withdrawing groups at R₁ and the bulky, electron-withdrawing as well as hydrogen bond donor groups at R₂ position are favourable; the bulky, hydrogen bond acceptor substituent at R₃ and the minor groups at R₄ position may benefit the potency. We have designed a series of novel VEGF-R2 inhibitors by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results may aid in designing of potential VEGF-R2 inhibitors with better activities.     

量子化学在生物分子领域的研究进展

量子化学的方法对生物分子研究的发展提供了全新的思路和方法。本文介绍了量子化学的基本计算方法,并综述了近两年来量子化学方法在生物分子领域的研究进展。     

Search strategies of fruit flies in steady and shifting winds in the absence of food odours

Abstract. Flight behaviour by females of two species of fruit flies, Drosophila funebris and Drosophila immigrans , was videorecorded in a wind tunnel in still air and in wind with a constant or shifting direction. Flies which were deprived of food overnight took flight in the absence of food odours. Both species responded to the presented winds in agreement with two models that predict the shortest distance to an odour plume. According to these models, the shortest distance to an odour plume is travelled when insects fly at right angles to the wind with a steady direction. In winds shifting over more than 60, the shortest distance to an odour plume is achieved when insects fly parallel to the time-averaged wind direction. We propose a behavioural mechanism which accomplishes the observed flight directions taken by the two species of fruit flies in response to the tested wind regimes.     

分子生物学杂志文献搜索引擎开发研究

为了方便从事分子生物学研究人员快捷、准确地查阅相关杂志文献,开发和利用NCBI的Medline数据库的杂志文献资源。我们从Medline(PubMed)中检索并列出184种有关分子生物学的杂志名录,制作了每种杂志的超级链接及部分杂志年份相应的超级链接,组成一个有关分子生物学杂志文献的搜索引擎。此搜索引擎能快捷、准确、动态地检索184种分子生物学杂志全部文献题录及部分杂志各年的文献题录,并可在PubMed中进一步检索出文献的摘要和部分全文。     

Conformational Flexibility of Two RNA Trimers Explored by Computational Tools and Database Search

Abstract

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

Registry numbers:

adenylyl-(3′ →5′)-adenylyl-(3′ →5′)-adenosine [917-44-2]

adenylyl-(3′ →5′)-uridylyl-(3′ →5′)-guanosine [3494-35-7]     

The Genetic Algorithm and the Conformational Search of Polypeptides and Proteins

Abstract

The genetic algorithm is a technique of function optimization derived from the principles of evolutionary theory. We have adapted it to perform conformational search on polypeptides and proteins. The algorithm was first tested on several small polypeptides and the 46 amino acid protein crambin under the AMBER potential energy function. The probable global minimum conformations of the polypeptides were located 90% of the time and a non-native conformation of crambin was located that was 150kcal/mol lower in potential energy than the minimized crystal structure conformation. Next, we used a knowledge-based potential function to predict the structures of melittin, pancreatic polypeptide, and crambin. A 2.31 Å ΔRMS conformation of melittin and a 5.33 Å ΔRMS conformation of pancreatic polypeptide were located by genetic algorithm-based conformational search under the knowledge-based potential function. Although the ΔRMS of pancreatic polypeptide was somewhat high, most of the secondary structure was correct. The secondary structure of crambin was predicted correctly, but the potential failed to promote packing interactions. Finally, we tested the packing aspects of our potential function by attempting to predict the tertiary structure of cytochrome b ₅₆₂ given correct secondary structure as a constraint. The final predicted conformation of cytochrome b ₅₆₂ was an almost completely extended continuous helix which indicated that the knowledge-based potential was useless for tertiary structure prediction. This work serves as a warning against testing potential functions designed for tertiary structure prediction on small proteins.     

Interactions between Handler Well-Being and Canine Health and Behavior in Search and Rescue Teams

ABSTRACT

This study reports on three years of prospective, longitudinal data on the psychological well-being of the human handlers and the health and behavior of the search and rescue dogs deployed in New York City and Washington, DC in the aftermath of the terrorist attacks on September 11, 2001. Eighty-five human handlers (63 deployed and 22 controls) and ninetyfour dogs (66 deployed, 28 controls) were assessed at multiple time points including 6 months, 1 year, 2 years, and 3 years after the 9/11 attacks. Humans were assessed for psychological health by structured clinical interview and self-report. Dogs were assessed for physical health and behavior by veterinary records and handler report. For humans, deployment after 9/11 did indeed represent a relatively short-term risk factor for developing symptoms of depression and posttraumatic stress disorder (PTSD). By and large, however, the sample showed remarkable resilience as a whole, and overall rates of DSM-IV diagnoses were quite low. By year 3, 9/11 deployment no longer conferred any special risk. On the other hand, long-term employment in an emergency profession did emerge as a significant risk factor for symptoms of PTSD by year 3. With respect to the interaction between handler emotional well-being and canine health and behavior, we found that physical illness and/or death in the dog was prospectively associated with greater symptoms of depression in the handler. We also found that symptoms of depression and PTSD in the handlers prospectively predicted behavioral problems in the dogs over time. Separation anxiety, attachment/attention seeking, chasing, and excitability emerged in the dogs at 1 year. Behavioral problems escalated to aggression towards other dogs at year 2 and separation anxiety, aggression towards other dogs, and aggression towards strangers at year 3. Like any relationship, the partnership between a handler and his or her working dog can confer both protection—when the relationship is going well and both members are healthy—and vulnerability—when either member is physically ill or psychologically or behaviorally distressed.     

Comparative Estimation of Genetic Diversity in Population Studies using Molecular Sampling and Traditional Sampling Methods

Entomopathogenic nematodes (EPN) are efficient biological pest control agents. Population genetics studies on EPN are seldom known. Therefore, it is of interest to evaluate the significance of molecular sampling method (MSM) for accuracy, time needed, and cost effectiveness over traditional sampling method (TSM). The study was conducted at the Mohican Hills golf course at the state of Ohio where the EPN H. bacteriophora has been monitored for 18 years. The nematode population occupies an area of approximately 3700 m² with density range from 0.25-2 per gram soil. Genetic diversity of EPN was studied by molecular sampling method (MSM) and traditional sampling method (TSM) using the mitochondrial gene pcox1. The MSM picked 88% in compared to TSM with only 30% of sequenced cox 1 gene. All studied genetic polymorphism measures (sequence and haplotype) showed high levels of genetic diversity of MSM over TSM. MSM minimizes the chance of mitochondrial genes amplification from non target organisms (insect or other contaminating microorganisms). Moreover, it allows the sampling of more individuals with a reliable and credible representative sample size. Thus, we show that MSM supersedes TSM in labour intensity, time consumption and requirement of no special experience and efficiency.     

Molecular docking and 3D-QSAR on 2-(oxalylamino) benzoic acid and its analogues as protein tyrosine phosphatase 1B inhibitors

In this paper, molecular docking technique was used to investigate the binding conformation of twelve 2-(oxalylamino) benzoic acid (OBA) inhibitors in the active site of PTP1B. The predicted binding affinities are linearly correlated to the experimental values (r² = 0.859). Furthermore, comparative molecular field analysis (CoMFA) was conducted based on the binding conformation predicted by molecular docking. The predicted CoMFA model has satisfactory statistical significance and good actual predicted power. The information from molecular docking and CoMFA may give us some valuable hints to the optimization of lead compounds.     

Plant-parasitic Nematode Distributions in an Alfalfa Field

A 7-ha alfalfa field (Medicago saliva L. cv Mesa Sirsa) was sampled systematically on a 6 x 6-m grid by removing individual cores (2.54 cm diam) to a depth of 45 cm from each of the 1,936 grid intersections. The soil was mainly coarse-textured with a fine-textured streak running centrally, north to south. Nematodes were extracted by a semiautomatic elutriator and sugar flotation-sieving technique. Five plant-parasitic species were consistently present: Meloidogyne arenaria, Pratylenchus minyus, Merlinius brevidens, Helicotylenchus digonicus, and Paratrichodorus minor. All species had a highly skewed nonnormal frequency distribution that departed significantly from randontness. Goodness-of-fit tests on the distribution of five populations in the entire field showed that three (Meloidogyne, Merlinius, and Helicotylenchus) were described by a negative binomial. When the samples were categorized by soil texture (coarse vs. fine-textured), all populations in the fine-textured areas, and three populations (Meloidogyne, Pratylenchus, and Merlinius) in the coarse areas, fitted a negative binomial distribution. Nearly all populations titted a negative binomial when the frequency distributions from randomly located one-meter-square areas were examined for each species.