Molecular biology: silencing unlimited

Heterochromatin domains are essential for normal chromosome functions. The Eri1 ribonuclease is a negative regulator of the RNA interference machinery; recent studies have shown that, in fission yeast lacking Eri1, heterochromatin formation is more promiscuous.     

Fold helical proteins by energy minimization in dihedral space and a DFIRE-based statistical energy function

Statistical energy functions are discrete (or stepwise) energy functions that lack van der Waals repulsion. As a result, they are often applied directly to a given structure (native or decoy) without further energy minimization being performed to the structure. However, the full benefit (or hidden defect) of an energy function cannot be revealed without energy minimization. This paper tests a recently developed, all-atom statistical energy function by energy minimization with a fixed secondary helical structure in dihedral space. This is accomplished by combining the statistical energy function based on a distance-scaled finite ideal-gas reference (DFIRE) state with a simple repulsive interaction and an improper torsion energy function. The energy function was used to minimize 2000 random initial structures of 41 small and medium-sized helical proteins in a dihedral space with a fixed helical region. Results indicate that near-native structures for most studied proteins can be obtained by minimization alone. The average minimum root-mean-squared distance (rmsd) from the native structure for all 41 proteins is 4.1 A. The energy function (together with a simple clustering of similar structures) also makes a reasonable selection of near-native structures from minimized structures. The average rmsd value and the average rank for the best structure in the top five is 6.8 A and 2.4, respectively. The accuracy of the structures sampled and the structure selections can be improved significantly with the removal of flexible terminal regions in rmsd calculations and in minimization and with the increase in the number of minimizations. The minimized structures form an excellent decoy set for testing other energy functions because most structures are well-packed with minimum hard-core overlaps with correct hydrophobic/hydrophilic partitioning. They are available online at http://theory.med.buffalo.edu.     

Tissue culture: the unlimited potential

Lack of tissue-specific differentiated functions of cells in tissue culture, once thought to be due to “dedifferentiation”, was shown to be due to selective overgrowth of fibroblasts by a series of simple experiments that challenged the prevailing dogma. Following this insight, enrichment culture techniques (alternate animal and culture passage) were designed to give functionally differentiated tumor cells selective advantage over the fibroblasts. These experiments resulted in the derivation of a large number of functionally differentiated clonal strains of a range of cell types, providing the final point of destruction of the dogma of “dedifferentiation.” Instead, the hypothesis was proposed that cells in culture accurately represent cells in vivo, but without the complex in vivo environment. With the development of hormonally defined media and its combination with functionally differentiated clonal cell lines, this concept has been strengthened and the potential of tissue culture studies has been greatly augmented. Hormonally defined media allow the culture of cell types that cannot be grown in conventional, serum-supplemented media. These approaches demonstrate that hormonal responses and dependencies can be discovered in culture. Following this thinking and the discovery of hormonal dependencies of cancer cells has led to a new rationale for therapy. Tissue culture and cell technology continue to play an important role in solving human health problems.     

Gulf societies and the image of unlimited good

Conclusion In conclusion, a number of theoretical points need to be made. The first relates to the question of the primacy of the economic infrastructure in determining the shape of social institutions and the direction of social change in society. We accept this theoretical position, but still one may ask, why then in the case of Kuwait is it the state which is now dominant in affecting sociocultural life? While appreciating the analytical value of the Marxist thesis which sees that it is the material economic base which in the final instance determines the evolution of society, at the same time we see that this does not mean that the material infrastructural base will also by necessity dominate society. For our purposes here Godelier's analytical distinction between what he terms infrastructural determination and superstructural domination is quite useful, and provides an adequate explanation as to why the state has come to be dominant in Gulf societies. Godelier argues that in both historical and contemporary comparative cases where superstructures (kinship, religion, the state, etc.) appeared to be dominant in society, such superstructures always functioned as a relation of production. For a social institution and/or an activity to play a dominant role in the functioning and evolution of society, it must necessarily, in addition to its own ostensible purpose and explicit functions, function directly and internally as a relation of production. Godelier's proposed hypothesis turns the analytical focus not so much on what the social relations or institutions are, but rather on what they do, or better, make people do. It is evident in the discussion above that the state structure in Kuwait, due to the peculiarities of the oil economy and other social factors, has come to play (in addition to its explicit political functions) a very important and again explicit economic role. The oil state controls not only the means of production and allocation of wealth, but simultaneously functions as a controller of the relations of production in society.The second point relates to an earlier reference made about George Foster's conceptualization of the image of limited good. Unlike the cognitive conceptual formulation made by Foster two decades ago about peasant society, our argument in this paper emphasizes that the image of the unlimited good is a derivative social and psychocultural phenomenon resulting from the impact of broader economic and historical transformations which have been taking place in recent years in the oil-rich Arab Gulf countries. The major shortcoming in Foster's analysis of the peasants' image of limited good is that he relies only on cognitive formulation and does not go beyond the limitations of derivative analysis.The third point ties in with our note on Foster's formulation. It emphasizes the fact that it is the broader impersonal socioeconomic conditions that in the final analysis produce certain images in a given society at a given time. These conditions also determine, but may not necessarily dominate, the forms and other cultural peculiarities these images may take. In fact, it has recently become noticeable that the image of the unlimited good has begun to shrink in people's minds, especially after the 1982–83 Al-Manakh stock market crash in Kuwait and the recent dramatic downfall in oil prices.Since we are using a Marxist socioeconomic perspective in our analysis one may ask whether there are no contradictions in this Kuwaiti image of the unlimited good. I believe that the absence of discussion on contradictions does not create an analytical gap. We have shown in the preceding discussion that the emergence of the oil welfare state with its tremendous capacities to dominate society as a result of its lavish wealthfarism and its role as a controller of wealth in society has enabled it to accomodate for the rising needs and expectations of a small society. In addition, the existence of other socioeconomic and political conditions and variables—such as smallness, expatriate labor force, national and ethnic loyalties still overshadowing real class loyalties, the short historical period for this social experiment of oil wealth, and so on — has helped in repressing the rise of contradictions along class lines.Moreover, a discourse which shows how it is possible for new socioeconomic conditions to arrest, at least for a given time period, the development of contradictions can competently follow a Marxist mode of analysis. I see, therefore, no analytical disjunction arising from the fact that a Marxist perspective has been used while at the same time we have tried to elucidate the nature of the forces and conditions which have brought about harmony epitomized by the image of the unlimited good. Such an elucidation has also aided us in seeing why it is satisfaction and acceptance of the economicopolitical system, and not contradictions, that have come to prevail in modern Kuwait.We also note at the end of our discussion how change in the larger impersonal socioeconomic conditions since 1984 has begun generating not only new perceptions away from the image of the umlimited good but also immature class contradictions and consciousness expressing themselves in mystified forms of envy of the super-rich or rivalry with expatriates.The last important fact is that perceptions, images and worldviews do not have a functional autonomy of their own. Images always need to be grounded.Dr. Sulayman N. Khalaf is Visiting Assistant Professor of Anthropology in the Department of Sociology and Social Work, the Faculty of Arts, United Arab Emirates University.

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Fold recognition without folds

Fold recognition predicts protein three-dimensional structure by establishing relationships between a protein sequence and known protein structures. Most methods explicitly use information derived from the secondary and tertiary structure of the templates. Here we show that rigorous application of a sequence search method (PSI-BLAST) with no reference to secondary or tertiary structure information is able to perform as well as traditional fold recognition methods. Since the method, SENSER, does not require knowledge of the three-dimensional structure, it can be used to infer relationships that are not tractable by methods dependent on structural templates.     

Proteins will Fold Anyway!!

Abstract

In order to investigate the environmental conditions of amino acid residues in protein molecules, four kinds of packing studies (atomic, geometric, hydrophobic and hydration) were formulated and tested on two proteins; bovine pancreatic trypsin inhibitor (BPTI) and bovine pancreatic ribonuclease S (RNase S). The inter-relationship of these packings on the fluctuations of amino acid residues was analysed by comparing the packing results with the dynamical studies, such as the root-mean-square-deviation values of atomic displacements obtained from the trajectories of molecular dynamics simulation, temperature factor information from crystal structures and residue fluctuations in proteins from continuum model. These analyses yield information about the most fluctuating and most stabilizing residue sites. Comparison of the results obtained by these methods indicate a good agreement, specifying an inverse correlation between the residue packing and fluctuations. This kind of study is helpful in identifying the specific residue sites such as nucleation, receptor binding and antigenic determining sites which in a way indirectly correlates with the functional residues in protein molecules.     

Fold recognition with minimal gaps

Here we present a simplified form of threading that uses only a 20 x 20 two-body residue-based potential and restricted number of gaps. Despite its simplicity and transparency the Monte Carlo-based threading algorithm performs very well in a rigorous test of fold recognition. The results suggest that by simplifying and constraining the decoy space, one can achieve better fold recognition. Fold recognition results are compared with and supplemented by a PSI-BLAST search. The statistical significance of threading results is rigorously evaluated from statistics of extremes by comparison with optimal alignments of a large set of randomly shuffled sequences. The statistical theory, based on the Random Energy Model, yields a cumulative statistical parameter, epsilon, that attests to the likelihood of correct fold recognition. A large epsilon indicates a significant energy gap between the optimal alignment and decoy alignments and, consequently, a high probability that the fold is correctly recognized. For a particular number of gaps, the epsilon parameter reaches its maximal value, and the fold is recognized. As the number of gaps further increases, the likelihood of correct fold recognition drops off. This is because the decoy space is small when gaps are restricted to a small number, but the native alignment is still well approximated, whereas unrestricted increase of the number of gaps leads to rapid growth of the number of decoys and their statistical dominance over the correct alignment. It is shown that best results are obtained when a combination of one-, two-, and three-gap threading is used. To this end, use of the epsilon parameter is crucial for rigorous comparison of results across the different decoy spaces belonging to a different number of gaps.     

Structural Bridges through Fold Space

Several protein structure classification schemes exist that partition the protein universe into structural units called folds. Yet these schemes do not discuss how these units sit relative to each other in a global structure space. In this paper we construct networks that describe such global relationships between folds in the form of structural bridges. We generate these networks using four different structural alignment methods across multiple score thresholds. The networks constructed using the different methods remain a similar distance apart regardless of the probability threshold defining a structural bridge. This suggests that at least some structural bridges are method specific and that any attempt to build a picture of structural space should not be reliant on a single structural superposition method. Despite these differences all representations agree on an organisation of fold space into five principal community structures: all-α, all-β sandwiches, all-β barrels, α/β and α + β. We project estimated fold ages onto the networks and find that not only are the pairings of unconnected folds associated with higher age differences than bridged folds, but this difference increases with the number of networks displaying an edge. We also examine different centrality measures for folds within the networks and how these relate to fold age. While these measures interpret the central core of fold space in varied ways they all identify the disposition of ancestral folds to fall within this core and that of the more recently evolved structures to provide the peripheral landscape. These findings suggest that evolutionary information is encoded along these structural bridges. Finally, we identify four highly central pivotal folds representing dominant topological features which act as key attractors within our landscapes.     

Globin-like蛋白质折叠类型识别

蛋白质折叠类型识别是蛋白质结构研究的重要内容.以SCOP中的Globin-like折叠为研究对象,选择其中序列同一性小于25%的17个代表性蛋白质为训练集,采用机器和人工结合的办法进行结构比对,产生序列排比,经过训练得到了适合Globin-like折叠的概形隐马尔科夫模型(profile HMM)用于该折叠类型的识别.以Astrall.65中的68057个结构域样本进行检验,识别敏感度为99.64%,特异性100%.在折叠类型水平上,与Pfam和SUPERFAMILY单纯使用序列比对构建的HMM相比,所用模型由多于100个归为一个,仍然保持了很高的识别效果.结果表明:对序列相似度很低但具有相同折叠类型的蛋白质,可以通过引入结构比对的方法建立统一的HMM模型,实现高准确率的折叠类型识别.     

Fold predictions for bacterial genomes

Fold assignments for newly sequenced genomes belong to the most important and interesting applications of the booming field of protein structure prediction. We present a brief survey and a discussion of such assignments completed to date, using as an example several fold assignment projects for proteins from the Escherichia coli genome. This review focuses on steps that are necessary to go beyond the simple assignment projects and into the development of tools extending our understanding of functions of proteins in newly sequenced genomes. This paper also discusses several problems seldom addressed in the literature, such as the problem of domain prediction and complementary predictions (e.g., transmembrane regions and flexible regions) and cross-correlation of predictions from different servers. The influence of sequence and structure database growth on prediction success is also addressed. Finally, we discuss the perspectives of the field in the context of massive sequence and structure determination projects, as well as the development of novel prediction methods.     

Fold recognition via a tree.

Recently, we developed a pairwise structural alignment algorithm using realistic structural and environmental information (SAUCE). In this paper, we at first present an automatic fold hierarchical classification based on SAUCE alignments. This classification enables us to build a fold tree containing different levels of multiple structural profiles. Then a tree-based fold search algorithm is described. We applied this method to a group of structures with sequence identity less than 35% and did a series of leave one out tests. These tests are approximately comparable to fold recognition tests on superfamily level. Results show that fold recognition via a fold tree can be faster and better at detecting distant homologues than classic fold recognition methods.     

Fold recognition by predicted alignment accuracy

One of the key components in protein structure prediction by protein threading technique is to choose the best overall template for a given target sequence after all the optimal sequence-template alignments are generated. The chosen template should have the best alignment with the target sequence since the three-dimensional structure of the target sequence is built on the sequence-template alignment. The traditional method for template selection is called Z-score, which uses a statistical test to rank all the sequence-template alignments and then chooses the first-ranked template for the sequence. However, the calculation of Z-score is time-consuming and not suitable for genome-scale structure prediction. Z-scores are also hard to interpret when the threading scoring function is the weighted sum of several energy items of different physical meanings. This paper presents a support vector machine (SVM) regression approach to directly predict the alignment accuracy of a sequence-template alignment, which is used to rank all the templates for a specific target sequence. Experimental results on a large-scale benchmark demonstrate that SVM regression performs much better than the composition-corrected Z-score method. SVM regression also runs much faster than the Z-score method.