Protein-Protein Interaction Modeling and Inhibition: The TAU Bioinfo3D Perspective

Protein-protein interactions are central to cell function. In order to fully understand these interactions, one has to elucidate the three-dimensional structures of the underlying complexes. While experimental methods have advanced significantly in the last decade, there are still few structures of protein complexes in the Protein Data Bank. Reliable computational techniques are required to fill in this gap. Better understanding of protein-protein interactions has also opened a large number of potential targets for the pharmaceutical industry, which previously viewed these interactions as “undruggable”. In this review, we focus on the algorithms developed by the Tel Aviv University Structural Bioinformatics (Bioinfo3D) Lab to model protein-protein interactions, and on a preliminary attempt to search for peptide inhibitors for these interactions. All the algorithms presented are among the fastest available today and can be accessed via the group web server.     

Prevalence and determinants of carotid atherosclerosis in healthy postmenopausal women

Fecal incontinence is an under-reported complication of scleroderma. Ten incontinent patients with scleroderma were evaluated through anorectal manometry and compared with 20 incontinent patients without scleroderma who were matched for age and sex as controls. The scleroderma patients had a higher voluntary external anal squeeze pressure, whereas the resting internal anal sphincter pressure was similar to that of the control group. The threshold for rectal sensation in the scleroderma group was significantly less than that in controls. Episodes of fecal incontinence, anal canal length, and maximal tolerable volume were not significantly different between the study groups. The rectoanal inhibitory response was abnormal in 80% of patients with systemic sclerosis but was normal in 70% of the controls. Stool consistency was significantly looser in the scleroderma patients. Treatment of fecal incontinence in scleroderma patients may be successful in many patients using a combination of dietary and pharmacologic manipulation because diarrhea is an important etiologic cofactor superimposed on reduced internal anal sphincter pressure.     

Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme

Tumor necrosis factor-alpha (TNFalpha) is a cytokine that induces protective inflammatory reactions and kills tumor cells but also causes severe damage when produced in excess, as in rheumatoid arthritis and septic shock. Soluble TNFalpha is released from its membrane-bound precursor by a membrane-anchored proteinase, recently identified as a multidomain metalloproteinase called TNFalpha-converting enzyme or TACE. We have cocrystallized the catalytic domain of TACE with a hydroxamic acid inhibitor and have solved its 2.0 A crystal structure. This structure reveals a polypeptide fold and a catalytic zinc environment resembling that of the snake venom metalloproteinases, identifying TACE as a member of the adamalysin/ADAM family. However, a number of large insertion loops generate unique surface features. The pro-TNFalpha cleavage site fits to the active site of TACE but seems also to be determined by its position relative to the base of the compact trimeric TNFalpha cone. The active-site cleft of TACE shares properties with the matrix metalloproteinases but exhibits unique features such as a deep S3' pocket merging with the S1' specificity pocket below the surface. The structure thus opens a different approach toward the design of specific synthetic TACE inhibitors, which could act as effective therapeutic agents in vivo to modulate TNFalpha-induced pathophysiological effects, and might also help to control related shedding processes.     

Sleep schedules and daytime functioning in adolescents

Sleep and waking behaviors change significantly during the adolescent years. The objective of this study was to describe the relation between adolescents' sleep/wake habits, characteristics of students (age, sex, school), and daytime functioning (mood, school performance, and behavior). A Sleep Habits Survey was administered in homeroom classes to 3,120 high school students at 4 public high schools from 3 Rhode Island school districts. Self-reported total sleep times (school and weekend nights) decreased by 40-50 min across ages 13-19, ps < .001. The sleep loss was due to increasingly later bedtimes, whereas rise times were more consistent across ages. Students who described themselves as struggling or failing school (C's, D's/F's) reported that on school nights they obtain about 25 min less sleep and go to bed an average of 40 min later than A and B students, ps < .001. In addition, students with worse grades reported greater weekend delays of sleep schedule than did those with better grades. Furthermore, this study examined a priori defined adequate sleep habit groups versus less than adequate sleep habit groups on their daytime functioning. Students in the short school-night total sleep group (< 6 hr 45 min) and/or large weekend bedtime delay group (> 120 min) reported increased daytime sleepiness, depressive mood, and sleep/wake behavior problems, ps < .05, versus those sleeping longer than 8 hr 15 min with less than 60 min weekend delay. Altogether, most of the adolescents surveyed do not get enough sleep, and their sleep loss interferes with daytime functioning.     

Powder extrusion: Fundamentals and different applications

We propose a novel polymer extrusion process, known as the solid state shear extrusion pulverization and modification (SSSE process), based on the simultaneous action of shear deformation and pressure at selected temperatures. This process can be used for continuous pulverization and copulverization of various polymers. Including different blends, filled materials, thermoplastics, vulcanized rubbers, crosslinked polymers, polymer composites, and natural polymers. Various aspects of this process are considered, including unusual microstructure and properties of powders, low energy consumption, and mechanochemical effects. Possible applications of SSSE to polymer/rubber recycling and to obtaining advanced polymer powders and modified powders are considered, together with scaling-up problems of equipment suitable for industrial application.     

Molecular shape comparisons in searches for active sites and functional similarity

Here we examine the reliability of surface comparisons in searches for active sites in proteins. Detection of a patch of surface on one protein which is similar to an active site in another, may suggest similarities in enzymatic mechanisms, in enzyme functions and implicate a potential target for ligand/inhibitor design. Specifically, we compare the efficacy of molecular surface comparisons with comparisons of surface atoms and of C(alpha) backbone atoms. We further investigate comparisons of specific atoms, belonging to a predefined pattern of catalytic residues versus comparisons of molecular surfaces and, separately, of surface atoms. This aspect is particularly relevant, as catalytic residues may be (partially) buried. We also explore active site comparisons versus comparisons in which the entire molecular surfaces are scanned. While here we focus on the geometrical aspect of the problem, we also investigate the effect of adding residue labels in these comparisons. Our extensive studies cover the serine proteases, containing the highly conserved triad motif, and the chorismate mutases. Since such active site comparisons entail comparisons between unconnected points in 3D space, an order-independent comparison technique is necessary. The geometric hashing algorithm is ideally suited to handling such a task. It can perform both global shape matching for the whole surfaces of large protein molecules and searching for local shape similarities for small surface motifs. Our results show that molecular surface comparisons work best when the similarity is high. As the similarity deteriorates, the number of potential solutions increases rapidly, making their ranking difficult, particularly when scanning entire molecular surfaces. Utilizing atomic coordinates directly appears more adequate under such circumstances.      

Parallel and distributed processing of rules by data-reduction

The parallel evaluation of datalog rule programs, mainly by processors that are interconnected by a communication network, is discussed. Data-reduction, a paradigm for the parallel evaluation of a datalog program, is introduced. Parallelization is accomplished by partitioning the rule-instantiations among the processors. After presenting the paradigm, its implementation with seminaive evaluation, its communication overhead, and its application to stratified-negation datalog programs are discussed. It is proven that decomposability, a related concept introduced in previous works, is undecidable     

Creating tobacco control policy at the local level: implementation of a direct action organizing approach

This article describes the community activation and policy change process in seven Minnesota communities involved in the Tobacco Policy Options for Prevention (TPOP) study. The study's intervention employed a direct action organizing model, which relies on mobilizing large numbers of people to alter decision making and leverage the power of elites. As part of the organizing process, TPOP organizers and teams made 1,319 personal contacts with community members, generated 309 media stories, and initiated 445 public events related to tobacco use. These actions resulted in the establishment of comprehensive tobacco ordinances in all seven communities. The authors discuss the goals, training, activities and political factors relevant to four phases of the TPOP intervention: information gathering and team recruitment, community awareness building and ordinance development, preparing for city council, and ordinance establishment and enforcement. Included are suggestions for practitioners interested in using policy change and community-based advocacy to resolve public health problems.     

Investigation of the enzymatic mechanism of the yeast chorismate mutase by docking a transition state analog

The structure of the complex of the chorismate mutase from the yeast Saccharomyces cerevisiae with a transition state analog is constructed using a suite of docking tools. The construction finds the best location for the active site in the enzyme, and the best orientation of the analog compound in the active site. The resulting complex shows extensive salt links and hydrogen bonds between the enzyme and the compound, including those mediated by water molecules. A network of polar interactions between amino acid residues is found to solidify the active site of the enzyme. The enzymatic mechanism suggested for a bacterial chorismate mutase, that the active site is by design capable of selecting an active conformer of the substrate, and of stabilizing the transition state, is apparently intact in the yeast enzyme. No direct evidence is found to support an alternative mechanism which involves specific catalytic groups, although the possibility is not eliminated. This finding reinforces the notion of a function being evolutionarily conserved via a common mechanism, rather than via sequential or structural homology.