The relationship between classification of multi-domain proteins using an alignment-free approach and their functions: a case study with immunoglobulins

Establishing functional relationships between multi-domain protein sequences is a non-trivial task. Traditionally, delineating functional assignment and relationships of proteins requires domain assignments as a prerequisite. This process is sensitive to alignment quality and domain definitions. In multi-domain proteins due to multiple reasons, the quality of alignments is poor. We report the correspondence between the classification of proteins represented as full-length gene products and their functions. Our approach differs fundamentally from traditional methods in not performing the classification at the level of domains. Our method is based on an alignment free local matching scores (LMS) computation at the amino-acid sequence level followed by hierarchical clustering. As there are no gold standards for full-length protein sequence classification, we resorted to Gene Ontology and domain-architecture based similarity measures to assess our classification. The final clusters obtained using LMS show high functional and domain architectural similarities. Comparison of the current method with alignment based approaches at both domain and full-length protein showed superiority of the LMS scores. Using this method we have recreated objective relationships among different protein kinase sub-families and also classified immunoglobulin containing proteins where sub-family definitions do not exist currently. This method can be applied to any set of protein sequences and hence will be instrumental in analysis of large numbers of full-length protein sequences.

CLAP: A web-server for automatic classification of proteins with special reference to multi-domain proteins

Background: The function of a protein can be deciphered with higher accuracy from its structure than from its amino acid sequence. Due to the huge gap in the available protein sequence and structural space, tools that can generate functionally homogeneous clusters using only the sequence information, hold great importance. For this, traditional alignment-based tools work well in most cases and clustering is performed on the basis of sequence similarity. But, in the case of multi-domain proteins, the alignment quality might be poor due to varied lengths of the proteins, domain shuffling or circular permutations. Multi-domain proteins are ubiquitous in nature, hence alignment-free tools, which overcome the shortcomings of alignment-based protein comparison methods, are required. Further, existing tools classify proteins using only domain-level information and hence miss out on the information encoded in the tethered regions or accessory domains. Our method, on the other hand, takes into account the full-length sequence of a protein, consolidating the complete sequence information to understand a given protein better. Results: Our web-server, CLAP (Classification of Proteins), is one such alignment-free software for automatic classification of protein sequences. It utilizes a pattern-matching algorithm that assigns local matching scores (LMS) to residues that are a part of the matched patterns between two sequences being compared. CLAP works on full-length sequences and does not require prior domain definitions. Pilot studies undertaken previously on protein kinases and immunoglobulins have shown that CLAP yields clusters, which have high functional and domain architectural similarity. Moreover, parsing at a statistically determined cut-off resulted in clusters that corroborated with the sub-family level classification of that particular domain family. Conclusions: CLAP is a useful protein-clustering tool, independent of domain assignment, domain order, sequence length and domain diversity. Our method can be used for any set of protein sequences, yielding functionally relevant clusters with high domain architectural homogeneity. The CLAP web server is freely available for academic use at http://nslab.mbu.iisc.ernet.in/clap/.

A System-C based Micro architectural Exploration Framework for Latency, Power and Performance Trade-offs of On-Chip Interconnection

We describe a System-C based framework we are developing, to explore the impact of various architectural and microarchitectural level parameters of the on-chip interconnection network elements on its power and performance. The framework enables one to choose from a variety of architectural options like topology, routing policy, etc., as well as allows experimentation with various microarchitectural options for the individual links like length, wire width, pitch, pipelining, supply voltage and frequency. The framework also supports a flexible traffic generation and communication model. We provide preliminary results of using this framework to study the power, latency and throughput of a 4x4 multi-core processing array using mesh, torus and folded torus, for two different communication patterns of dense and sparse linear algebra. The traffic consists of both Request-Response messages (mimicing cache accesses)and One-Way messages. We find that the average latency can be reduced by increasing the pipeline depth, as it enables higher link frequencies. We also find that there exists an optimum degree of pipelining which minimizes energy-delay product.

Postsynthetic Exterior Decoration of an Organic Cage by Copper(I)-Catalysed A(3)-Coupling and Detection of Nitroaromatics

A new synthetic protocol based on one-pot, copper(I)-catalysed multicomponent reaction of formaldehyde, secondary amine and terminal alkyne has been employed to postsynthetically modify a self-assembled nanoscopic organic cage. By employing this synthetic strategy, three new cages appended with phenyl-, xylyl-and naphthyl-acetylene moieties have been synthesised. The resulting modified cages were characterised by using a range of spectroscopic techniques. The synthesised cages were fluorescent and thus one of them was tested to explore the potential use of such compounds as chemosensors for the detection of nitroaromatics. Experimental findings suggest a high selective quenching of initial fluorescence intensity in the presence of nitroaromatic compounds. Furthermore, it has been observed that among the various nitroaromatics tested, nitrophenolic compounds have better quenching ability.

Embryogenesis in flowering plants: Recent approaches and prospects

The overall architectural pattern of the mature plant is established during embryogenesis. Very little is known about the molecular processes that underlie embryo morphogenesis. Last decade has, nevertheless, seen a burst of information on the subject. The synchronous somatic embryogenesis system of carrot is largely being used as the experimental system. Information on the molecular regulation of embryogenesis obtained with carrot somatic embryos as well as observations on sandalwood embryogenic system developed in our laboratory are summarized in this review. The basic experimental strategy of molecular analysis mostly relied on a comparison between genes and proteins being expressed in embryogenic and non-embryogenic cells as well as in the different stages of embryogenesis. Events such as expression of totipotency of cells and establishment of polarity which are so critical for embryo development have been characterized using the strategy, Several genes have been identified and cloned from the carrot system, These include sequences that encode certain extracellular proteins (EPs) that influence cell proliferation and embryogenesis in specific ways and sequences of the abscisic acid (ABA) inducible late embryogenesis abundant (LEA) proteins which are most abundant and differentially expressed mRNAs in somatic embryos. That LEAs are expressed in the somatic embryos of a tree flora also is evidenced from studies on sandalwood Several undescribed or novel sequences that are enhanced in embryos were identified. A sequence of this nature exists in sandalwood embryos was demonstrated using a Cuscuta haustorial (organ-specific) cDNA probe. Somatic embryogenesis systems have been used to assess the expression of genes isolated from non-embryogenic tissues. Particular attention has been focused on both cell cycle and histone genes.

Construction and use of linear regression models for processor performance analysis

Processor architects have a challenging task of evaluating a large design space consisting of several interacting parameters and optimizations. In order to assist architects in making crucial design decisions, we build linear regression models that relate Processor performance to micro-architecture parameters, using simulation based experiments. We obtain good approximate models using an iterative process in which Akaike's information criteria is used to extract a good linear model from a small set of simulations, and limited further simulation is guided by the model using D-optimal experimental designs. The iterative process is repeated until desired error bounds are achieved. We used this procedure to establish the relationship of the CPI performance response to 26 key micro-architectural parameters using a detailed cycle-by-cycle superscalar processor simulator The resulting models provide a significance ordering on all micro-architectural parameters and their interactions, and explain the performance variations of micro-architectural techniques.

Mapping adaptive resonance theory onto ring and mesh architectures

In recent years, parallel computers have been attracting attention for simulating artificial neural networks (ANN). This is due to the inherent parallelism in ANN. This work is aimed at studying ways of parallelizing adaptive resonance theory (ART), a popular neural network algorithm. The core computations of ART are separated and different strategies of parallelizing ART are discussed. We present mapping strategies for ART 2-A neural network onto ring and mesh architectures. The required parallel architecture is simulated using a parallel architectural simulator, PROTEUS and parallel programs are written using a superset of C for the algorithms presented. A simulation-based scalability study of the algorithm-architecture match is carried out. The various overheads are identified in order to suggest ways of improving the performance. Our main objective is to find out the performance of the ART2-A network on different parallel architectures. (C) 1999 Elsevier Science B.V. All rights reserved.

On the utility of an instrumented impact set-up to characterise the response of discontinuous buffer strips in carbon–epoxy systems in dry and wet conditions

The use of an instrumented impact test set-up to evaluate the influence of water ingress on the impact response of a carbon–epoxy (C–E) laminated composite system containing discontinuous buffer strips (BS) has been examined. The data on the BS-free C–E sample in dry conditions are used as reference to compare with the data derived from those immersed in water. The work demonstrated the utility of an instrumented impact test set-up in characterising the response, first owing to the architectural difference due to introduction of buffer strips and then due to the presence of an additional phase in the form of water ingressed into the sample. The presence of water was found to enhance the energy absorption characteristics of the C–E system with BS insertions. It was also noticed that with an increasing number of BS layer insertions, the load–time plots displayed characteristic changes. The ductility indices (DI) were found to display a lower value for the water immersed samples compared to the dry ones.

Synergy between the N-terminal and C-terminal domains of Mycobacterium tuberculosis HupB is essential for high-affinity binding, DNA supercoiling and inhibition of RecA-promoted strand exchange

The occurrence of DNA architectural proteins containing two functional domains derived from two different architectural proteins is an interesting emerging research theme in the field of nucleoid structure and function. Mycobacterium tuberculosis HupB, unlike Escherichia coli HU, is a two-domain protein that, in the N-terminal region, shows broad sequence homology with bacterial HU. The long C-terminal extension, on the other hand, contains seven PAKK/KAAK motifs, which are characteristic of the histone H1/H5 family of proteins. In this article, we describe several aspects of HupB function, in comparison with its truncated derivatives lacking either the C-terminus or N-terminus. We found that HupB binds a variety of DNA repair and replication intermediates with K(d) values in the nanomolar range. By contrast, the N-terminal fragment of M. tuberculosis HupB (HupB(MtbN)) showed diminished DNA-binding activity, with K(d) values in the micromolar range, and the C-terminal domain was completely devoid of DNA-binding activity. Unlike HupB(MtbN), HupB was able to constrain DNA in negative supercoils and introduce negative superhelical turns into relaxed DNA. Similarly, HupB exerted a robust inhibitory effect on DNA strand exchange promoted by cognate and noncognate RecA proteins, whereas HupB(MtbN), even at a 50-fold molar excess, had no inhibitory effect. Considered together, these results suggest that synergy between the N-terminal and C-terminal domains of HupB is essential for its DNA-binding ability, and to modulate the topological features of DNA, which has implications for processes such as DNA compaction, gene regulation, homologous recombination, and DNA repair.

INTACTE: An Interconnect Area, Delay, and Energy Estimation Tool for Microarchitectural Explorations

Prior work on modeling interconnects has focused on optimizing the wire and repeater design for trading off energy and delay, and is largely based on low level circuit parameters. Hence these models are hard to use directly to make high level microarchitectural trade-offs in the initial exploration phase of a design. In this paper, we propose INTACTE, a tool that can be used by architects toget reasonably accurate interconnect area, delay, and power estimates based on a few architecture level parameters for the interconnect such as length, width (in number of bits), frequency, and latency for a specified technology and voltage. The tool uses well known models of interconnect delay and energy taking into account the wire pitch, repeater size, and spacing for a range of voltages and technologies.It then solves an optimization problem of finding the lowest energy interconnect design in terms of the low level circuit parameters, which meets the architectural constraintsgiven as inputs. In addition, the tool also provides the area, energy, and delay for a range of supply voltages and degrees of pipelining, which can be used for micro-architectural exploration of a chip. The delay and energy models used by the tool have been validated against low level circuit simulations. We discuss several potential applications of the tool and present an example of optimizing interconnect design in the context of clustered VLIW architectures. Copyright 2007 ACM.

Coordination-driven self-assembly of 2D-metallamacrocycles using a shape-selective Pt(2)(II)-organometallic 90 degrees acceptor: design, synthesis and sensing study

Synthesis of a series of two-dimensional metallamacrocycles via coordination-driven self-assembly of a shape-selective Pt(2)(II)-molecular building unit incorporating carbazole-ethynyl functionality is described. An equimolar (1 : 1) combination of a Pt(2)(II)-organometallic 90 degrees acceptor, 1, with rigid linear ditopic donors (L(a) and L(b)) afforded [4 + 4] self-assembled octanuclear molecular squares, 2 and 3, in quantitative yields, respectively [L(a) = 4,4'-bipyridine; L(b) = trans-1,2-bis(4-pyridyl)ethylene]. Conversely, a similar treatment of 1 with an amide-based unsymmetrical flexible ditopic donor, L(c), resulted in the formation of a [2 + 2] self-sorted molecular rhomboid (4a) as a single product [L(c) = N-(4-pyridyl)isonicotinamide]. Despite the possibility of several linkage isomeric macrocycles (rhomboid, triangle and square) due to the different connectivity of L(c), the formation of a single and symmetrical molecular rhomboid (4a) as the only product is an interesting observation. All the self-assembled macrocycles (2, 3 and 4a) were fully characterized by multinuclear NMR ((1)H and (31)P) and ESI-MS analysis. Further structural insights about the size and shape of the macrocycles were obtained through energy minimization using density functional theory (DFT) calculations. Decoration of the starting carbazole building unit with Pt-ethynyl functionality enriches the assemblies to be more p-electron rich and luminescent in nature. Macrocycles 2 and 3 could sense the presence of electron deficient nitroaromatics in solution by quenching of the initial intensity upon gradual addition of picric acid (PA). They exhibited the largest quenching response with high selectivity for nitroaromatics compared to several other electron deficient aromatics tested.

Performance modeling and architecture exploration of network processors

This paper proposes a Petri net model for a commercial network processor (Intel iXP architecture) which is a multithreaded multiprocessor architecture. We consider and model three different applications viz., IPv4 forwarding, network address translation, and IP security running on IXP 2400/2850. A salient feature of the Petri net model is its ability to model the application, architecture and their interaction in great detail. The model is validated using the Intel proprietary tool (SDK 3.51 for IXP architecture) over a range of configurations. We conduct a detailed performance evaluation, identify the bottleneck resource, and propose a few architectural extensions and evaluate them in detail.

Relative roles of instruction count and cycles per instruction in WCET estimation

Most of the existing WCET estimation methods directly estimate execution time, ET, in cycles. We propose to study ET as a product of two factors, ET = IC * CPI, where IC is instruction count and CPI is cycles per instruction. Considering directly the estimation of ET may lead to a highly pessimistic estimate since implicitly these methods may be using worst case IC and worst case CPI. We hypothesize that there exists a functional relationship between CPI and IC such that CPI=f(IC). This is ascertained by computing the covariance matrix and studying the scatter plots of CPI versus IC. IC and CPI values are obtained by running benchmarks with a large number of inputs using the cycle accurate architectural simulator, Simplescalar on two different architectures. It is shown that the benchmarks can be grouped into different classes based on the CPI versus IC relationship. For some benchmarks like FFT, FIR etc., both IC and CPI are almost a constant irrespective of the input. There are other benchmarks that exhibit a direct or an inverse relationship between CPI and IC. In such a case, one can predict CPI for a given IC as CPI=f(IC). We derive the theoretical worst case IC for a program, denoted as SWIC, using integer linear programming(ILP) and estimate WCET as SWIC*f(SWIC). However, if CPI decreases sharply with IC then measured maximum cycles is observed to be a better estimate. For certain other benchmarks, it is observed that the CPI versus IC relationship is either random or CPI remains constant with varying IC. In such cases, WCET is estimated as the product of SWIC and measured maximum CPI. It is observed that use of the proposed method results in tighter WCET estimates than Chronos, a static WCET analyzer, for most benchmarks for the two architectures considered in this paper.

Architectural plan of transcriptional regulation in Mycobacterium tuberculosis

Transcriptional regulation enables adaptation in bacteria. Typically, only a few transcriptional events are well understood, leaving many others unidentified. The recent genome-wide identification of transcription factor binding sites in Mycobacterium tuberculosis has changed this by deciphering a molecular road-map of transcriptional control, indicating active events and their immediate downstream effects.

Iridium-decorated multiwall carbon nanotubes and its catalytic activity with Shell 405 in hydrazine decomposition

Iridium-functionalized multiwalled carbon nanotubes (Ir-MWNT) are the future catalyst support material for hydrazine fuel decomposition. The present work demonstrates decoration of iridium particle on iron-encapsulated multiwalled carbon nanotubes (MWNT) by wet impregnation method in the absence of any stabilizer. Electron microscopy studies reveal the coated iridium particle size in the range of 5-10 nm. Elemental analysis by energy dispersive X-ray diffraction confirms 21 wt% of Ir coated over MWNT. X-ray photoelectron spectroscopy (XPS) shows 4f(5/2) and 4f(7/2) lines of iridium and confirms the metallic nature. The catalytic activity of Ir-MWNT/Shell 405 combination is performed in 1 N hydrazine micro-thrusters. The thruster performance shows increase in chamber pressure and decrease in chamber temperature when compared to Shell 405 alone. This enhanced performance is due to high thermal conducting nature of MWNTs and the presence of Ir active sites over MWNTs.