Department of Systems and Computational Biology

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    A conceptual review on systems biology in health and diseases: From biological networks to modern therapeutics
    ( 2014-03-01) Somvanshi, Pramod Rajaram ; Venkatesh, K. V.
    Human physiology is an ensemble of various biological processes spanning from intracellular molecular interactions to the whole body phenotypic response. Systems biology endures to decipher these multi-scale biological networks and bridge the link between genotype to phenotype. The structure and dynamic properties of these networks are responsible for controlling and deciding the phenotypic state of a cell. Several cells and various tissues coordinate together to generate an organ level response which further regulates the ultimate physiological state. The overall network embeds a hierarchical regulatory structure, which when unusually perturbed can lead to undesirable physiological state termed as disease. Here, we treat a disease diagnosis problem analogous to a fault diagnosis problem in engineering systems. Accordingly we review the application of engineering methodologies to address human diseases from systems biological perspective. The review highlights potential networks and modeling approaches used for analyzing human diseases. The application of such analysis is illustrated in the case of cancer and diabetes. We put forth a concept of cell-to-human framework comprising of five modules (data mining, networking, modeling, experimental and validation) for addressing human physiology and diseases based on a paradigm of system level analysis. The review overtly emphasizes on the importance of multi-scale biological networks and subsequent modeling and analysis for drug target identification and designing efficient therapies. © 2013 Springer Science+Business Media Dordrecht.
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    A founder ectodysplasin A receptor (EDAR) mutation results in a high frequency of the autosomal recessive form of hypohidrotic ectodermal dysplasia in India
    ( 2012-04-01) Bashyam, M. D. ; Chaudhary, A. K. ; Reddy, E. C. ; Reddy, V. ; Acharya, V. ; Nagarajaram, H. A. ; Devi, A. R.R. ; Bashyam, L. ; Dalal, A. B. ; Gupta, N. ; Kabra, M. ; Agarwal, M. ; Phadke, S. R. ; Tainwala, R. ; Kumar, R. ; Hariharan, S. V.
    Background Hypohidrotic/anhidrotic ectodermal dysplasia (HED) is a rare Mendelian disorder affecting ectodermal tissues. The disease is primarily caused by inactivation of any one of three genes, namely ectodysplasin A1 (EDA-A1), which encodes a ligand belonging to the tumour necrosis factor (TNF) superfamily; ectodysplasin A receptor (EDAR), encoding the EDA-A1 receptor and ectodysplasin A receptor-associated death domain (EDARADD), encoding an adaptor protein. X-linked recessive (EDA-A1), the predominant form of HED, as well as autosomal recessive and dominant (EDAR and EDARADD) inheritance patterns have been identified in affected families. Objectives To determine the common genes causing HED in India. Methods We performed mutation analysis on 26 HED families from India (including 30 patients). In addition, we carried out sequence and structural analysis of missense/nonsense and insertion/deletion mutations. Results Among the 26 families analysed, disease-causing EDAR mutations were identified in 12 (46%) while EDA-A1 mutations were detected in 11 (42%). Four novel mutations in EDAR and five in EDA-A1 were identified. More importantly, a possible founder EDAR mutation, namely c.1144G > A, was identified in five independent families, thus accounting for about one-fifth of affected families in whom mutation was detected. A majority of EDA-A1 mutations localized to the TNF-like domain while the location of EDAR mutations was more widespread. Conclusions This is the first report of a founder EDAR mutation and of a significantly high frequency of autosomal recessive HED. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.
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    A hierarchical approach to protein fold prediction.
    ( 2011-01-01) Mohammad, Tabrez Anwar Shamim ; Nagarajaram, Hampapathalu Adimurthy
    Fold recognition, assigning novel proteins to known structures, forms an important component of the overall protein structure discovery process. The available methods for protein fold recognition are limited by the low fold-coverage and/or low prediction accuracies. We describe here a new Support Vector Machine (SVM)-based method for protein fold prediction with high prediction accuracy and high fold-coverage. The new method of fold prediction with high fold-coverage was developed by training and testing on a large number of folds in order to make the method suitable for large scale fold predictions. However, presence of large number of folds in the training set made the classification task difficult as a consequence of increased complexity involved in binary classifications of SVMs. In order to overcome this complexity we adopted a hierarchical approach where fold-prediction is made in two steps. At the first step structural class of the query is predicted and at the second step fold is predicted within the predicted structural class. This decreased the complexity of the classification problem and also improved the overall fold prediction accuracy. To the best of our knowledge this is the first taxonomic fold recognition method to cover over 700 protein-folds and gives prediction accuracy of around 70% on a benchmark dataset. Since the new method gives rise to state of the art prediction performance and hence can be very useful for structural characterization of proteins discovered in various genomes.
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    A Human Tyrosine Phosphatase Interactome Mapped by Proteomic Profiling
    ( 2017-08-04) Kumar, Parveen ; Munnangi, Prathyusha ; Chowdary, Kvs Rammohan ; Shah, Varun J. ; Shinde, Swapnil R. ; Kolli, Nanci R. ; Halehalli, Rachita R. ; Nagarajaram, Hampapathalu A. ; Maddika, Subbareddy
    Tyrosine phosphatases play a critical role in many cellular processes and pathogenesis, yet comprehensive analysis of their functional interacting proteins in the cell is limited. By utilizing a proteomic approach, here we present an interaction network of 81 human tyrosine phosphatases built on 1884 high-confidence interactions of which 85% are unreported. Our analysis has linked several phosphatases with new cellular processes and unveiled protein interactions genetically linked to various human diseases including cancer. We validated the functional importance of an identified interaction network by characterizing a distinct novel interaction between PTPN5 and Mob1a. PTPN5 dephosphorylates Mob1a at Y26 residue. Further, we identify that PTPN5 is required for proper midbody abscission during cytokinesis through regulation of Mob1a dephosphorylation. In conclusion, our study provides a valuable resource of tyrosine phosphatase interactions, which can be further utilized to dissect novel cellular functions of these enzymes.
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    A low CO < inf > 2 < /inf > -responsive mutant of Setaria viridis reveals that reduced carbonic anhydrase limits C < inf > 4 < /inf > photosynthesis
    ( 2021-04-02) Chatterjee, Jolly ; Coe, Robert A. ; Acebron, Kelvin ; Thakur, Vivek ; Yennamalli, Ragothaman M. ; Danila, Florence ; Lin, Hsiang Chun ; Balahadia, Christian Paolo ; Bagunu, Efren ; Padhma, Preiya P.O.S. ; Bala, Soumi ; Yin, Xiaojia ; Rizal, Govinda ; Dionora, Jacqueline ; Furbank, Robert T. ; Von Caemmerer, Susanne ; Quick, William Paul
    In C4 species, β-carbonic anhydrase (CA), localized to the cytosol of the mesophyll cells, accelerates the interconversion of CO2 to HCO3-, the substrate used by phosphoenolpyruvate carboxylase (PEPC) in the first step of C4 photosynthesis. Here we describe the identification and characterization of low CO2-responsive mutant 1 (lcr1) isolated from an N-nitroso-N-methylurea-(NMU) treated Setaria viridis mutant population. Forward genetic investigation revealed that the mutated gene Sevir.5G247800 of lcr1 possessed a single nucleotide transition from cytosine to thymine in a β-CA gene causing an amino acid change from leucine to phenylalanine. This resulted in severe reduction in growth and photosynthesis in the mutant. Both the CO2 compensation point and carbon isotope discrimination values of the mutant were significantly increased. Growth of the mutants was stunted when grown under ambient pCO2 but recovered at elevated pCO2. Further bioinformatics analyses revealed that the mutation has led to functional changes in one of the conserved residues of the protein, situated near the catalytic site. CA transcript accumulation in the mutant was 80% lower, CA protein accumulation 30% lower, and CA activity ∼98% lower compared with the wild type. Changes in the abundance of other primary C4 pathway enzymes were observed; accumulation of PEPC protein was significantly increased and accumulation of malate dehydrogenase and malic enzyme decreased. The reduction of CA protein activity and abundance in lcr1 restricts the supply of bicarbonate to PEPC, limiting C4 photosynthesis and growth. This study establishes Sevir.5G247800 as the major CA allele in Setaria for C4 photosynthesis and provides important insights into the function of CA in C4 photosynthesis that would be required to generate a rice plant with a functional C4 biochemical pathway.
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    A low prevalence of MYH7/MYBPC3 mutations among Familial Hypertrophic Cardiomyopathy patients in India
    ( 2012-01-01) Bashyam, Murali D. ; Purushotham, Guroji ; Chaudhary, Ajay K. ; Rao, Katika Madhumohan ; Acharya, Vishal ; Mohammad, Tabrez A. ; Nagarajaram, Hampapathalu A. ; Hariram, Vuppaladadhiam ; Narasimhan, Calambur
    Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disorder affecting the cardiac muscle and exhibits varied clinical symptoms because of genetic heterogeneity. Several disease causing genes have been identified and most code for sarcomere proteins. In the current study, we have carried out clinical and molecular analysis of FHC patients from India. FHC was detected using echocardiography and by analysis of clinical symptoms and family history. Disease causing mutations in the β-cardiac myosin heavy chain (MYH7) and Myosin binding protein C3 (MYBPC3) genes were identified using Polymerase Chain Reaction-Deoxyribose Nucleic Acid (PCR-DNA) sequencing. Of the 55 patient samples screened, mutations were detected in only nineteen in the two genes; MYBPC3 mutations were identified in 12 patients while MYH7 mutations were identified in five, two patients exhibited double heterozygosity. All four MYH7 mutations were missense mutations, whereas only 3/9 MYPBC3 mutations were missense mutations. Four novel mutations in MYBPC3 viz. c.456delC, c.2128G > A (p.E710K), c.3641G > A (p.W1214X), and c.3656T > C (p.L1219P) and one in MYH7 viz. c.965C > T (p.S322F) were identified. A majority of missense mutations affected conserved amino acid residues and were predicted to alter the structure of the corresponding mutant proteins. The study has revealed a greater frequency of occurrence of MYBPC3 mutations when compared to MYH7 mutations. © 2011 Springer Science+Business Media, LLC.
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    A non-invasive approach to explore the discriminatory potential of the urinary volatilome of invasive ductal carcinoma of the breast
    ( 2018-01-01) Taunk, Khushman ; Taware, Ravindra ; More, Tushar H. ; Porto-Figueira, Priscilla ; Pereira, Jorge A.M. ; Mohapatra, Rajkishore ; Soneji, Dharmesh ; Câmara, José S. ; Nagarajaram, H. A. ; Rapole, Srikanth
    Worldwide, breast invasive ductal carcinoma (IDC) accounts for the majority of the reported cases of this form of cancer. IDC effective management, as for any form of cancer, would greatly benefit from early diagnosis. This, however, due to various socio-economic reasons, is very far for the reality in developing countries like India, where cancer diagnosis is often carried out at late stages when disease management is troublesome. With the present work, we aim to evaluate a simple analytical methodology to identify a set of volatile organic compounds (VOCs) in urine samples, as a biosignature for IDC. Using solid-phase microextraction followed by gas chromatography/mass spectrometry, a panel of 14 urinary VOCs was found to discriminate IDC (n = 65) from a healthy control (HC) group (n = 70) through multivariate statistical treatments. Furthermore, metabolic pathway analysis revealed various dysregulated pathways involved in IDC patients hinting that their detailed investigations could lead to novel mechanistic insights into the disease pathophysiology. In addition, we validated the expression pattern of five of these VOCs namely 2-ethyl-1-hexanol, isolongifolenone, furan, dodecanoic acid, 2-methoxy-phenol in another external cohort of 59 urinary samples (IDC = 32 and HC = 27) and found their expression pattern to be consistent with the primary sample set. To our knowledge, this is the first study exploring breast IDC volatome alterations in Indian patients.
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    A procedure for the prediction of temperature-sensitive mutants of a globular protein based solely on the amino acid sequence
    ( 1996-11-26) Varadarajan, R. ; Nagarajaram, H. A. ; Ramakrishnan, C.
    Temperature-sensitive (Ts) mutants of a protein are an extremely powerful tool for studying protein function in vivo and in cell culture. We have devised a method to predict those residues in a protein sequence that, when appropriately mutated, are most likely to give rise to a Ts phenotype. Since substitutions of buried hydrophobic residues often result in significant destabilization of the protein, our method predicts those residues in the sequence that are likely to be buried in the protein structure. We also indicate a set of amino acid substitutions, which should be made to generate a Ts mutant of the protein. This method requires only the protein sequence. No structural information or homologous sequence information is required. This method was applied to a test data set of 30 nonhomologous protein structures from the Protein Data Bank. All of the residues predicted by the method to be ≤95% buried were, in fact, buried in the protein crystal structure. In contrast, only 50% of all hydrophobic residues in this data set were ≤95% buried. This method successfully predicts several known Ts and partially active mutants of T4 lysozyme, λ repressor, gene V protein, and staphylococcal nuclease. This method also correctly predicts residues that form part of the hydrophobic cores of λ repressor, myoglobin, and cytochrome b562.
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    A Prognostic Signature for Lower Grade Gliomas Based on Expression of Long Non-Coding RNAs
    ( 2019-07-01) Kiran, Manjari ; Chatrath, Ajay ; Tang, Xiwei ; Keenan, Daniel Macrae ; Dutta, Anindya
    Diffuse low-grade and intermediate-grade gliomas (together known as lower grade gliomas, WHO grade II and III) develop in the supporting glial cells of brain and are the most common types of primary brain tumor. Despite a better prognosis for lower grade gliomas, 70% of patients undergo high-grade transformation within 10 years, stressing the importance of better prognosis. Long non-coding RNAs (lncRNAs) are gaining attention as potential biomarkers for cancer diagnosis and prognosis. We have developed a computational model, UVA8, for prognosis of lower grade gliomas by combining lncRNA expression, Cox regression, and L1-LASSO penalization. The model was trained on a subset of patients in TCGA. Patients in TCGA, as well as a completely independent validation set (CGGA) could be dichotomized based on their risk score, a linear combination of the level of each prognostic lncRNA weighted by its multivariable Cox regression coefficient. UVA8 is an independent predictor of survival and outperforms standard epidemiological approaches and previous published lncRNA-based predictors as a survival model. Guilt-by-association studies of the lncRNAs in UVA8, all of which predict good outcome, suggest they have a role in suppressing interferon-stimulated response and epithelial to mesenchymal transition. The expression levels of eight lncRNAs can be combined to produce a prognostic tool applicable to diverse populations of glioma patients. The 8 lncRNA (UVA8) based score can identify grade II and grade III glioma patients with poor outcome, and thus identify patients who should receive more aggressive therapy at the outset.
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    A single-step low cost detection of ground water Hg < sup > 2+ < /sup > using mercaptosuccinic acid functionalised silver nanoprism
    ( 2022-05-01) Banerjee, Swagata ; Shyamsundar, Katha ; Saharay, Moumita ; Roy, Shibsekhar
    We are reporting a rapid, highly sensitive, specific and cost-effective detection platform for Mercuric Ion (Hg2+) present in ground water using the dipole sensitive spectroscopic properties of Silver nanoprism (AgNPR). We synthesised AgNPR incorporating Bovine serum albumin (BSA) within its interstitial crystal planes to enhance solution stability and shelf-life. AgNPR was functionalised with mercaptosuccinic acid for Hg2+ specific interactions. The Dipole resonance peak (D-peak) of AgNPR exhibited 30 nm shift towards shorter wavelength in the presence of 1 µM Hg2+, accompanied with a change in colour from blue to purple. The interaction was highly specific for Hg2+ with a limit of detection (LOD) of 8.13 nM (1.62 ppb) that is much within United States Environment Protection Agency (EPA) and World Health Organization (WHO) recommended range. Transmission electron microscopy (TEM) demonstrated, at lower concentrations of Hg2+ (≤0.1 µM), the spectral changes are consistent with Hg2+ induced displacement of (Mercaptopropyl Succinic Acid) MSA from AgNPR surface and subsequent etching of AgNPR vertices by Cl- ions. Fringe length analysis performed on the high resolution TEM images of AgNPR indicated formation of Ag-Hg amalgam at higher concentrations of HgCl2 (1.0 µM). X-Ray diffraction (XRD) study also supported the mechanism. Density Functional Theory (DFT) calculations substanciated the selective interaction between MSA-AgNPR and Hg2+. We have tested real water sample spiked with Hg2+ by our method and found excellent recovery result comparable with the gold standard of ICP-MS measurement.
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    A sorghum (Sorghum bicolor) mutant with altered carbon isotope ratio
    ( 2017-06-01) Rizal, Govinda ; Karki, Shanta ; Thakur, Vivek ; Wanchana, Samart ; Alonso-Cantabrana, Hugo ; Dionora, Jacque ; Sheehy, John E. ; Furbank, Robert ; Von Caemmerer, Susanne ; Quick, William Paul
    Recent efforts to engineer C4 photosynthetic traits into C3 plants such as rice demand an understanding of the genetic elements that enable C4 plants to outperform C3 plants. As a part of the C4 Rice Consortium's efforts to identify genes needed to support C4 photosynthesis, EMS mutagenized sorghum populations were generated and screened to identify genes that cause a loss of C4 function. Stable carbon isotope ratio (δ13C) of leaf dry matter has been used to distinguishspecies with C3 and C4 photosynthetic pathways. Here, we report the identification of a sorghum (Sorghum bicolor) mutant with a low δ13C characteristic. A mutant (named Mut33) with a pale phenotype and stunted growth was identified from an EMS treated sorghum M2 population. The stable carbon isotope analysis of the mutants showed a decrease of 13C uptake capacity. The noise of random mutation was reduced by crossing the mutant and its wildtype (WT). The back-cross (BC1F1) progenies were like the WT parent in terms of 13C values and plant phenotypes. All the BC1F2 plants with low δ13C died before they produced their 6th leaf. Gas exchange measurements of the low δ13C sorghum mutants showed a higher CO2 compensation point (25.24 μmol CO2.mol-1air) and the maximum rate of photosynthesis was less than 5μmol.m-2.s-1. To identify the genetic determinant of this trait, four DNA pools were isolated; two each from normal and low δ13C BC1F2 mutant plants. These were sequenced using an Illumina platform. Comparison of allele frequency of the single nucleotide polymorphisms (SNPs) between the pools with contrasting phenotype showed that a locus in Chromosome 10 between 57,941,104 and 59,985,708 bps had an allele frequency of 1. There were 211 mutations and 37 genes in the locus, out of which mutations in 9 genes showed non-synonymous changes. This finding is expected to contribute to future research on the identification of the causal factor differentiating C4 from C3 species that can be used in the transformation of C3 to C4 plants.
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    A study on mutational dynamics of simple sequence repeats in relation to mismatch repair system in prokaryotic genomes
    ( 2012-04-01) Kumar, Pankaj ; Nagarajaram, H. A.
    Mutational bias toward expansion or contraction of simple sequence repeats (SSRs) is referred to as directionality of SSR evolution. In this communication, we report the mutational bias exhibited by mononucleotide SSRs occurring in the non-coding regions of several prokaryotic genomes. Our investigations revealed that the strains or species lacking mismatch repair (MMR) system generally show higher number of polymorphic SSRs than those species/strains having MMR system. An exception to this observation was seen in the mycobacterial genomes that are MMR deficient where only a few SSR tracts were seen with mutations. This low incidence of SSR mutations even in the MMR-deficient background could be attributed to the high fidelity of the DNA polymerases as a consequence of high generation time of the mycobacteria. MMR system-deficient species generally did not show any bias toward mononucleotide SSR expansions or contractions indicating a neutral evolution of SSRs in these species. The MMR-proficient species in which the observed mutations correspond to secondary mutations showed bias toward contraction of polymononucleotide tracts, perhaps, indicating low efficiency of MMR system to repair SSR-induced slippage errors on template strands. This bias toward deletion in the mononucleotide SSR tracts might be a probable reason behind scarcity for long poly A|T and G|C tracts in prokaryotic systems which are mostly MMR proficient. In conclusion, our study clearly demonstrates mutational dynamics of SSRs in relation to the presence/absence of MMR system in the prokaryotic system. © 2012 Springer Science+Business Media, LLC.
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    Ab initio and metadynamics studies on the role of essential functional groups in biomineralization of calcium carbonate and environmental situations
    ( 2014-11-19) Saharay, Moumita ; Kirkpatrick, R. James
    The interactions of proteins, polysaccharides and other biomolecules with Ca2+, CO32-, and water are central to the understanding of biomineralization and crystallization of calcium carbonate (CaCO3), and their association with the natural organic matter (NOM) in the environment. A molecular-level investigation of how such interactions and thermodynamic forces drive the nucleation and growth of crystalline CaCO3 in living organisms remains elusive. This paper presents ab initio and metadynamics studies of the interactions of Ca2+, CO32-, and water with the essential amino acids/functional groups, e.g. arginine/NH2+, aspartate or glutamate/COO-, aspartic or glutamic acid/COOH, and serine/OH, of protein/organic molecules that are likely to be critical to the biomineralization of CaCO3. These functional groups were modeled as guanidinium (Gdm+), acetate (AcO-), acetic acid (AcOH), and ethanol (EtOH) molecules, respectively. The Gdm+-Ca2+-CO32- and AcO--Ca2+-CO32- systems were found to form stable ion-complexes irrespective of the presence of near neighbor water molecules. The strong electrostatic interactions of these functional groups with their counter-ions significantly affect the fundamental vibrational frequencies of the functional groups, mainly the NH2 stretching (str.) and degenerate (deg.) scissors modes of Gdm+ and -C=OO, CC, and CO str. modes of AcO-. The free-energy calculations reveal that EtOH forms weakly bound molecular complexes with the Ca2+-CO32- ion pairs in water. However, the interaction strength of EtOH with crystalline CaCO3 can increase significantly due to combined effect of H-bond and electron donor acceptor (EDA) type of interactions. These results indicate that -NH2+ and -COO- bearing molecules serve as potential nucleation sites promoting crystallization of CaCO3 phases while -OH bearing molecules are likely to control the morphology of the crystalline phases by attaching to the growing crystal surfaces. © the Owner Societies.
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    Ab initio molecular dynamics investigations of structural, electronic and dynamical properties of water in supercritical carbon dioxide
    ( 2009-01-22) Saharay, Moumita ; Balasubramanian, Sundaram
    Ab initio molecular dynamics simulations of a solitary perdeuterated water molecule solvated in supercritical carbon dioxide have been performed along an isotherm at three different densities. Electron donoracceptor interactions between the oxygen atom of water and the carbon atom of CO2 as well as hydrogen bonded interactions between the two molecules have been shown to play a dominant role in the solvation. The mean dipole moment of the water molecule increases with the density of the solution, from a value of 1.85 D at low density to around 2.15 D at the highest density. The increase in the solvent density causes the water molecule to exhibit a range of behavior, from a free molecule to one that interacts strongly with CO2. A blue shift in the bending mode of water has been observed with increasing solvent density. The carbon dioxide molecules which are present in the first neighbor shell of water are found to exhibit larger propensity to deviate from a linear geometry in their instantaneous configurations. © 2009 IACS.
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    Ab initio molecular-dynamics study of supercritical carbon dioxide
    ( 2004-05-22) Saharay, Moumita ; Balasubramanian, Sundaram
    The microscopic structure and dynamics of supercritical carbon dioxide was studied using Car-Parrinello molecular dynamics simulations. The reorientational dynamics of carbon dioxide molecules was investigated through first- and second-order time correlation functions. The intramolecular vibrations of carbon dioxide were examined through an analysis of the velocity autocorrelation function of the atoms. The results indicate that in the supercritical state the carbon dioxide molecule is marginally nonlinear, and thus possesses a dipole moment.
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    Ab initio studies on [bmim] [PF < inf > 6 < /inf > ]-CO < inf > 2 < /inf > mixture and CO < inf > 2 < /inf > clusters
    ( 2008-06-01) Bhargava, B. L. ; Saharay, M. ; Balasubramanian, S.
    Ab initio molecular dynamics studies have been carried out on the room temperature ionic liquid, 1, n-butyl,3-methylimidazolium hexafluorophosphate ([bmim][PF6]) and supercritical carbon dioxide mixture at room temperature and experimental density. Partial radial distribution functions (RDF) for different sites have been computed to see the organization of CO 2 molecules around the ionic liquid. Several partial RDFs around the carbon atom of CO2 molecule are compared to find out that the CO 2 has specific interaction with a carbon atom present in the imidazolium ring. The CO2 is also found to be very well organized around the terminal carbon atom of the butyl chain. The partial RDFs for the oxygen atoms around oxygen and carbon atoms of the CO2 suggests that there is very good organization of CO2 molecules around themselves even in the [bmim] [PF6] - CO2 mixture. The instantaneous quadrupole moment tensor has been calculated for the anion and the cation. The ensemble average of diagonal components of quadrupole moment tensor of the cation have finite values, whereas the off-diagonal components of the cation and both the diagonal and off-diagonal components of the anion have the value of zero with a large standard deviation. The CPMD studies performed on CO 2 clusters reveals the greater tendency of the clusters with more CO2 units, to deviate from the linear geometry. © Indian Academy of Sciences.
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    Amino acid substitution scoring matrices specific to intrinsically disordered regions in proteins
    ( 2019-12-01) Trivedi, Rakesh ; Nagarajaram, Hampapathalu Adimurthy
    An amino acid substitution scoring matrix encapsulates the rates at which various amino acid residues in proteins are substituted by other amino acid residues, over time. Database search methods make use of substitution scoring matrices to identify sequences with homologous relationships. However, widely used substitution scoring matrices, such as BLOSUM series, have been developed using aligned blocks that are mostly devoid of disordered regions in proteins. Hence, these substitution-scoring matrices are mostly inappropriate for homology searches involving proteins enriched with disordered regions as the disordered regions have distinct amino acid compositional bias, and therefore expected to have undergone amino acid substitutions that are distinct from those in the ordered regions. We, therefore, developed a novel series of substitution scoring matrices referred to as EDSSMat by exclusively considering the substitution frequencies of amino acids in the disordered regions of the eukaryotic proteins. The newly developed matrices were tested for their ability to detect homologs of proteins enriched with disordered regions by means of SSEARCH tool. The results unequivocally demonstrate that EDSSMat matrices detect more number of homologs than the widely used BLOSUM, PAM and other standard matrices, indicating their utility value for homology searches of intrinsically disordered proteins.
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    AmpliBASE MT™: A Mycobacterium tuberculosis diversity knowledgebase
    ( 2004-04-12) Majeed, Ahmed A. ; Ahmed, Niyaz ; Rao, K. Rajender ; Ghousunnissa, S. ; Kauser, Farhana ; Bose, Buddhaditta ; Nagarajaram, H. A. ; Katoch, V. M. ; Cousins, Debby V. ; Sechi, Leonardo A. ; Gilman, Robert H. ; Hasnain, Seyed E.
    Summary: AmpliBASE MT™ is an online databank of high-resolution DNA fingerprints representing fluorescent amplified fragment length polymorphism (FAFLP) profiles or amplitypes developed for the Mycobacterium tuberculosis complex strains from 48 different countries. AmpliBASE MT™ is based on a relational database management system that is hyperlinked to visualize genotyping results in the form of DNA fingerprint images for individual strains. A flexible search system based on systematic comparisons of fragment sizes in base pairs allows inter-laboratory comparison of FAFLP profiles. Besides this, the database also displays previously published data on IS6110 profiles, spoligotypes, MIRU-VNTRs and large sequence polymorphisms along with the FAFLP records that will give the overall comparisons. Being the first of its kind, AmpliBASE MT™ is expected to be a very helpful tool in strengthening the concept of'geographic genomics'and will be very helpful to molecular epidemiologists and those interested in diagnostic development for tuberculosis. © Oxford University Press 2004; all rights reserved.
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    An iterative structure-assisted approach to sequence alignment and comparative modeling
    ( 1999-01-01) Burke, David F. ; Deane, Charlotte M. ; Nagarajaram, Hampapathalu A. ; Campillo, Nuria ; Martin-Martinez, Mercedes ; Mendes, Joaquim ; Molina, Franck ; Perry, Jeff ; Reddy, B. V.B. ; Soares, Claudio M. ; Steward, Robert E. ; Williams, Mark ; Carrondo, Maria Armenia ; Blundell, Tom L. ; Mizuguchi, Kenji
    Correct alignment of the sequence of a target protein with those of homologues of known three-dimensional structure is a key step in comparative modeling. Usually an iterative approach that takes account of the local and overall structural features is required. We describe such an approach that exploits databases of structural alignments of homologous proteins (HOMSTRAD, http://www-cryst.bioc.cam.ac.uk/homstrad) and protein superfamilies (CAMPASS, http://www-cryst.bioc.cam.ac.uk/campass), in which structure-based alignments are analyzed and formatted with the program JOY (http://www- cryst.bioc.cam.ac.uk/joy) to reveal conserved local structural features. The databases facilitate the recognition of a family or superfamily, they assist in the selection of useful parent structures, they are helpful in alignment of the target sequences with the parent set, and are useful for deriving relationships that can be used in validating models. In the iterative approach, a model is constructed on the basis of the proposed sequence alignment and this is then reexpressed in the JOY format and realigned with the parent set. This is repeated until the model and sequence alignment is optimized. We examine the case for comparison and use of multiple structures of family members, rather than a single parent structure. We use the targets attempted by our group in CASP3 to assess the value of such procedures.
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    Analysis and prediction of inter-strand packing distances between β-sheets of globular proteins
    ( 1999-01-01) Nagarajaram, Hampapathalu A. ; Reddy, Boojala V.B. ; Blundell, Tom L.
    Any two β-strands belonging to two different β-sheets in a protein structure are considered to pack interactively if each β-strand has at least one residue that undergoes a loss of one tenth or more of its solvent contact surface area upon packing. A data set of protein 3-D structures (determined at 2.5 Å resolution or better), corresponding to 428 protein chains, contains 1986 non-identical pairs of β-strands involved in interactive packing. The inter-axial distance between these is significantly correlated to the weighted sum of the volumes of the interacting residues at the packing interface. This correlation can be used to predict the changes in the inter-sheet distances in equivalent β-sheets in homologous proteins and, therefore, is of-value in comparative modelling of proteins.