RosettaDock in CAPRI rounds 6-12

A challenge in protein-protein docking is to account for the conformational changes in the monomers that occur upon binding. The RosettaDock method, which incorporates sidechain flexibility but keeps the backbone fixed, was found in previous CAPRI rounds (4 and 5) to generate docking models with atomic accuracy, provided that conformational changes were mainly restricted to protein sidechains. In the recent rounds of CAPRI (6-12), large backbone conformational changes occur upon binding for several target complexes. To address these challenges, we explicitly introduced backbone flexibility in our modeling procedures by combining rigid-body docking with protein structure prediction techniques such as modeling variable loops and building homology models. Encouragingly, using this approach we were able to correctly predict a significant backbone conformational change of an interface loop for Target 20 (12 A rmsd between those in the unbound monomer and complex structures), but accounting for backbone flexibility in protein-protein docking is still very challenging because of the significantly larger conformational space, which must be surveyed. Motivated by these CAPRI challenges, we have made progress in reformulating RosettaDock using a "fold-tree" representation, which provides a general framework for treating a wide variety of flexible-backbone docking problems.     

The targets of CAPRI rounds 6-12

Six protein-protein complexes and two homodimeric proteins involved in a variety of biological processes were offered as targets to CAPRI by crystallographers in Rounds 6-12. CAPRI predictor groups had to predict their structure by docking the free proteins, which they did with a degree of success that depended largely on the amplitude of the conformation changes. In one case at least, the prediction pointed to alternative possibilities of interactions in the crystal of a complex, showing that docking methods have value even when there is an experimental structure.     

CONTENTS of Vol. 12(1-6), 2002

REVIEWNo.1Telomere and telomerase in oncology…………………………………..Jiao MU,Li Xin WEI(1)MAPK signal pathways in the regulation of cell proliferation in mammalian cells..................... ………………….……………..….....…....….……..…..Wei ZHANG,Hui Tu LIU(9)Structure and function of aggrecan.................................................................. .…….………..Chris KIANI,Liwen CHEN,Yao Jiong WU,Albert J YEE,Burton B YANG(19)REGULAR ARTICLESId…     

BMP-2、-3、-6和-12在骨肉瘤细胞株中的表达

目的研究骨形态发生蛋白(bone morphogenetic protein,BMP)-2、-3、-6和-12在骨肉瘤细胞株中的表达,为下一步研究BMPs在骨肉瘤发生发展中的作用奠定基础。方法利用免疫细胞化学法和Western blot法检测BMP-2、-3、-6和-12在人骨肉瘤细胞株MG63、U2OS和大鼠骨肉瘤细胞株UMR106中的内源性表达。结果在MG63、U2OS和UMR106细胞中,BMP-2、-3和-6均呈不同程度的阳性表达;而BMP-12在这3株骨肉瘤细胞中则均为阴性,并且两种检测方法所得结果完全一致。结论BMP-2、-3和-6在人骨肉瘤细胞株MG63、U2OS和大鼠骨肉瘤细胞株UMR106中均有内源性表达;而这3株骨肉瘤细胞中均未检出BMP-12的表达。     

Electron microscopic characterization of Rhizobium bacteriophage 16-6-12 and its isolated deoxyribonucleic acid.

Bacteriophage 16-6-12 of Rhizobium lupini has a long, non-contractile tail and a head which is hexagonal in outline. The tail is 140 nm in length, 11 nm in diameter, and carries a short term fiber. Analysis of the tail structure by optical diffraction indicates that it is of the helical "stacked disc" type. After phenol-extraction from purified particles, the DNA of phage 16-6-12 can circularize in vitro. No significant difference in contour length was observed between the linear (14.34 plus or minus 0.28 mum) and circular (14.44 plus or minus 0.24 mum) forms of molecules. After partial denaturation with alkali an AT-GC-map was constructed, which shows an asymmetric distribution of AT- and GC-rich regions. It is concluded that this phage DNA can circularize due to the presence of cohesive ends and that it is not circularly permuted.     

Effects of cyclic 12-, 8-, and 6-carbon compounds on glutathione S-transferase activity

The effects of feeding $\text{ICR}\text{Ha}$ mice cyclic 12-, 8-, and 6-carbon compounds on glutathione S-transferase (GST) activity in the liver, intestinal mucosa, and the forestomach were determined. The compounds used for this study were 1,5,9-trans,trans,cis-cyclododecatriene, 1,2-trans-5,6-trans-9,10-cis-cyclododecatriene-1,2-oxide, cyclododecanol, cyclododecene oxide, cyclododecane, 1,5-cyclooctadiene, cyclooctene oxide, cyclohexene, and cyclohexene oxide. The unsaturated cyclic 12-carbon compounds elicited the greatest increase in GST activity. Thus, feeding 1,5,9-trans,trans,cis-cyclododecatriene increased this activity almost 4-fold in the livers and the intestinal mucosa of experimental animals. Cyclic 8-carbon compounds were less effective and feeding the cyclic 6-carbon compounds did not result in any significant increase in GST activity. None of the compounds elicited increased GST activity in the fore-stomach. Previous studies have shown that compounds inducing increased GST activity can protect against chemical carcinogens. It remains to be determined whether the compounds identified in the present investigation as inducers of this enzyme system will have such protective capacities.     

Locomotion-related oscillatory body movements at 6-12 Hz modulate the hippocampal theta rhythm

The hippocampal theta rhythm is required for accurate navigation and spatial memory but its relation to the dynamics of locomotion is poorly understood. We used miniature accelerometers to quantify with high temporal and spatial resolution the oscillatory movements associated with running in rats. Simultaneously, we recorded local field potentials in the CA1 area of the hippocampus. We report that when rats run their heads display prominent vertical oscillations with frequencies in the same range as the hippocampal theta rhythm (i.e., 6-12 Hz). In our behavioral set-up, rats run mainly with speeds between 50 and 100 cm/s. In this range of speeds, both the amplitude and frequency of the "theta" head oscillations were increasing functions of running speed, demonstrating that the head oscillations are part of the locomotion dynamics. We found evidence that these rhythmical locomotor dynamics interact with the neuronal activity in the hippocampus. The amplitude of the hippocampal theta rhythm depended on the relative phase shift with the head oscillations, being maximal when the two signals were in phase. Despite similarity in frequency, the head movements and LFP oscillations only displayed weak phase and frequency locking. Our results are consistent with that neurons in the CA1 region receive inputs that are phase locked to the head acceleration signal and that these inputs are integrated with the ongoing theta rhythm.     

Incorporating biochemical information and backbone flexibility in RosettaDock for CAPRI rounds 6-12

In CAPRI rounds 6-12, RosettaDock successfully predicted 2 of 5 unbound-unbound targets to medium accuracy. Improvement over the previous method was achieved with computational mutagenesis to select decoys that match the energetics of experimentally determined hot spots. In the case of Target 21, Orc1/Sir1, this resulted in a successful docking prediction where RosettaDock alone or with simple site constraints failed. Experimental information also helped limit the interacting region of TolB/Pal, producing a successful prediction of Target 26. In addition, we docked multiple loop conformations for Target 20, and we developed a novel flexible docking algorithm to simultaneously optimize backbone conformation and rigid-body orientation to generate a wide diversity of conformations for Target 24. Continued challenges included docking of homology targets that differ substantially from their template (sequence identity <50%) and accounting for large conformational changes upon binding. Despite a larger number of unbound-unbound and homology model binding targets, Rounds 6-12 reinforced that RosettaDock is a powerful algorithm for predicting bound complex structures, especially when combined with experimental data.     

Seroprevalence of T. cruzi infection in 6- and 12- year-old school children from three Uruguayan endemic departments

The last national survey on seroprevalence of T. cruzi human infection in Uruguay, showed a 3.4% in adults from endemic areas. Since 1983, antivectorial actions of the control program have been carried out continually. In consequence, household infestation by Triatoma infestan, the main vector of T. cruzi in Uruguay, decreased in all endemic areas and was completely eliminated in some of them. The objectives of the present work are to evaluate the new seroepidemiological situation. A representative sampling of rural and urban population was undertaken, to include six and twelve year-old school children from three departments: Artigas, Rivera and Tacuarembo. The whole sample included 4,722 school children, evaluated by the indirect immunofluorescence (IFI) test for Chaga? disease. The seroprevalence of T. cruzi infection in the six year-old group was 0.3% in Artigas, 0.6% in Rivera and 1.0% in Tacuarembo. The seropositive children with seropositive mothers support the possible congenital transmission.     

Editorial board page for “Molecular Simulation”, Volume 12, Number 3-6

Abstract

This is a scanned image of the original Editorial Board page(s) for this issue.     

The entrainment of caecotrophy-rhythm of the rabbit following 6- and 12-h phase-shifts of the Zeitgeber

By means of automatic registration of hard faeces excretion the caecotrophy-rhythm of 10 rabbits was monitored. In the animals a negative phase angle difference existed between 'lights on' and the start of caecotrophy in LD 12:12. Five rabbits practised caecotrophy once and 5 rabbits twice/24 h. Following 6-h phase-shifts of the LD-regimen the caecotrophy-rhythm was shifted in the same direction as the Zeitgeber. The time of re-entrainment for advance shifts of caecotrophy is significantly longer than for delay shifts. The inversion of the Zeitgeber causes caecotrophy to be delay-shifted in all animals.     

Biophysical characterization of complexation of DNA with oppositely charged Gemini surfactant 12-3-12

The interaction between DNA and cationic gemini surfactant trimethylene-1, 3-bis (dodecyldimethylammonium bromide) (12-3-12) has been investigated by the measurements of fluorescence, surface tension, UV spectrum and circular dichroism (CD). Micelle-like structure of 12-3-12 induced by DNA appears at critical aggregation concentration (CAC), which is much lower than critical micelle concentration (CMC) of 12-3-12 in DNA-free solution. CAC is independent of DNA concentration, but the CMC of the mixed solutions of DNA and 12-3-12(CMC(mix)) increases with the increasing of DNA concentration. The surface tensions of the mixed system are higher than that of the pure surfactant solution, much different from the so-called synergistic lowering of the surface tension for other polymer-surfactant systems. Phase separation occurs after the neutralization point and the precipitate redissolves with superfluous 12-3-12. Cationic surfactant 12-3-12 can exclude ethidium bromide (EB) from the DNA/EB complex, and this process does not depend on the DNA concentration but on the charge ratio of 12-3-12 to DNA. The binding constant of EB to DNA decreases sharply at the charge ratio from 0.5 to 1.0. Circular dichroism (CD) spectra show that DNA undergoes a conformational transition from native B-form to chiral psi-phase with increasing of 12-3-12.