Abstract

Understanding protein folding thermodynamics and kinetics is a central issue in molecular biology. Molecular dynamics (MD) simulations are being extensively used for this purpose. However, direct comparison between simulations and experiments requires both, an accurate description of the system and extensive sampling of the conformational space. Variants of MD have been developed to overcome sampling issues. Here, we use umbrella sampling technique to quantitatively compute the differences in thermodynamic quantities of the unfolding process of Trp-cage miniprotein TC5b (PDB ID: 1L2Y) due to changes in temperature as well as the presence/absence of chemical denaturants. Urea at a concentration of 8M has been used as the chemical denaturant. WHAM was used to obtain the unbiased free energy profiles. The free energy profile can be categorised into three parts – the opening of the Trp-cage, separation of secondary structure elements and distortion of alpha-helix. An increase in temperature or presence of urea effects only the opening of the Trp-cage while the separation of the secondary structure elements and distortion of alpha-helix is independent of temperature and urea. Contour plots were constructed to substantiate the results obtained from free energy profiles.

Abstract

Ribonucleases act as biological counter weights by playing a major role in gene expression. Ribonuclease H is one of them which performs the endonucleotic cleaveage reaction of the 3'-O-P linkage of RNA strand of DNA/RNA hybrids. These enzymes show specificity towards DNA/RNA hybrids but not pure structures. One of the reason for this differentiation could be mixed A/Bconformation of hybrid compared to pure structures and there might be other reasons. There is a debate concerning the substrate recognition mechanism whether this is because of induced fit type mechanism or conformational rearrangement of monomers in order to come close or may be non bonded interactions which will put the enzyme and substrate together in order to perform the hydrolysis reaction. While the role of metal ions in the reaction has been recognised, the mechanism is not obvious. For differentating the structural changes, we performed long molecular dynamics (MD) simulations on ribonuclease H enzyme of B.halodurans with its substrate and their monomers. The calculations show that the large conformational changes in both the monomers favours the reaction. Since the protein hydrophobic core is very stable, these changes will take place at surface level. The principal component analysis also supports the large conformational changes in protein and hybrid. Apart form these changes, the protein binding increases the plasticity of the hybrids. Overall the calculations show that structural deformations in both hybrid and enzyme brings them close to each other. Free energy calculations have been performed to study the proteinhybrid interactions

Abstract

Transannular Diels Alder reaction (TADA), a combination of both intramolecular and Diels-Alder reactions, is a powerful synthetic organic reaction mechanism used in synthesizing polycyclic compounds with high degree of chemo-, regio- and stereospecificity. TADA reactions occur in (x+y+2)-membered triene macrocycles, which contain both the diene and the dienophile moieties, to form A.B.C[x+6+y] type tricyclic compounds. The TADA reactivity of a series of 14-membered macrocyclic rings have been studied using the density functional B3LYP level of theory. The reactants and the transition states are capable of existing in different conformations. The key conformers of the transition states were studied at the B3LYP level. We have done force field parameters for the trienes, and performed detailed replica exchange molecular dynamics simulations to identify all possible isomers of the reactants. We established a linear correlation between the activation energies and the extent of sampling of the reactants in certain conformational states. In this presentation, we also will present the effect of the lengths of the linkers (3 to 5 methylene units) connecting the diene and dienophile units on the TADA reactivities.

Abstract

Background: The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play an important role in cancer cell proliferation and survival. ERK1/2 proteins also are important for normal cell functions. Thus, anti-cancer therapies that block all ERK1/2 signaling may result in undesirable toxicity to normal cells. As an alternative, we have used computational and biological approaches to identify low-molecular weight compounds that have the potential to interact with unique ERK1/2 docking sites and selectively inhibit interactions with substrates involved in promoting cell proliferation. Methods: Colony formation and water soluble tetrazolium salt (WST) assays were used to determine the effects of test compounds on cell proliferation. Changes in phosphorylation and protein expression in response to test compound treatment were examined by immunoblotting and in vitro kinase assays. Apoptosis was determined with immunoblotting and caspase activity assays. Results: In silico modeling was used to identify compounds that were structurally similar to a previously identified parent compound, called 76. From this screen, several compounds, termed 76.2, 76.3, and 76.4 sharing a common thiazolidinedione core with an aminoethyl side group, inhibited proliferation and induced apoptosis of HeLa cells. However, the active compounds were less effective in inhibiting proliferation or inducing apoptosis in non-transformed epithelial cells. Induction of HeLa cell apoptosis appeared to be through intrinsic mechanisms involving caspase-9 activation and decreased phosphorylation of the pro-apoptotic Bad protein. Cell-based and in vitro kinase assays indicated that compounds 76.3 and 76.4 directly inhibited ERK-mediated phosphorylation of caspase-9 and the p90Rsk-1 kinase, which phosphorylates and inhibits Bad, more effectively than the parent compound 76. Further examination of the test compound’s mechanism of action showed little effects on related MAP kinases or other cell survival proteins. Conclusion: These findings support the identification of a class of ERK-targeted molecules that can induce apoptosis in transformed cells by inhibiting ERK-mediated phosphorylation and inactivation of pro-apoptoticproteins.

Abstract

Here, we present an update of the CHARMM27 all-atom additive force field for nucleic acids that improves the treatment of RNA molecules. The original CHARMM27 force field parameters exhibit enhanced Watson-Crick base pair opening which is not consistent with experiment, whereas analysis of molecular dynamics (MD) simulations show the 2'-hydroxyl moiety to almost exclusively sample the O3' orientation. Quantum mechanical (QM) studies of RNA related model compounds indicate the energy minimum associated with the O3' orientation to be too favorable, consistent with the MD results. Optimization of the dihedral parameters dictating the energy of the 2'-hydroxyl proton targeting the QM data yielded several parameter sets, which sample both the base and O3' orientations of the 2'-hydroxyl to varying degrees. Selection of the final dihedral parameters was based on reproduction of hydration behavior as related to a survey of crystallographic data and better agreement with experimental NMR Jcoupling values. Application of the model, designated CHARMM36, to a collection of canonical and noncanonical RNA molecules reveals overall improved agreement with a range of experimental observables as compared to CHARMM27. The results also indicate the sensitivity of the conformational heterogeneity of RNA to the orientation of the 2'-hydroxyl moiety and support a model whereby the 2'- hydroxyl can enhance the probability of conformational transitions in RNA.

Abstract

t Tropical islands are special and sensitive ecosystems which are subjected to various disturbances imposed by human activities and natural disasters. A detailed study about the changing landscape scenarios of these fragile island systems induced by various driving factors could be used for setting up measurements in support of conservation and sustainable development projects. The current research is a meta-analysis of the studies carried out in Andaman and Nicobar islands which analyzed the impact of tsunami of 2004 using geospatial tools. Based on the analysis, it was observed that the Nicobar islands were more affected compared to the Andaman islands. The majority of the researchers used preand post-tsunami satellite imagery and adopted visual interpretation method to delineate the changed classes. The study infers uplift of land in Andaman (exposing) and subsidence in Nicobar islands (inundation) with severe damage to the coastal elements like mangroves, coral reefs, plantations and in few cases interior forest. The analysis showed there were no records of the damage for some small islands. Finally, it is concluded that utility of microwave satellite data for change analysis will prove better in regions like Andaman and Nicobar where it is difficult to get cloud free optical data because of the high monsoon periods in these islands. It is also suggested that future work utilizing suitable temporal satellite imagery should focus on the extent of recovery of vegetation and other coastal elements which suffer the impact of disaster.

Abstract

Hierarchical Ring Networks are widely used in communication systems, logistics and shared multiprocessors. It is hence imperative that efficient design of these structures has to be carried out, to reduce costs of their installation and help increase the ease of management. In this paper, we look at the problem of designing efficient 2- level Hierarchical Ring Networks, in the context of link costs optimization. 2-level HRNs only have two kinds of rings - local rings to connect disjoint sets of nodes and a global ring to interconnect all the local rings. We present an algorithm that is based on Simulated Annealing. We present results for scenarios containing upto 300 nodes. The results obtained from the algorithm are most encouraging.

Abstract

In this paper we consider range-aggregate query problems wherein we wish to preprocess a set S of geometric objects such that given a query orthogonal range q, a certain aggregation function on the objects S0 = S \ q can be answered eciently. Range-aggregate version of point enclosure queries, 1-d segment intersection, 2-d orthogonal seg- ment intersection (with/without distance constraint) are revisited and we improve the existing results for these problems. We also provide semi- dynamic (insertions) solutions to some of these problems. This paper is the rst attempt to provide dynamic solutions to problems involving geometric aggregation operations.

Abstract

Advances in sensing and data gathering technologies have resulted in an explosion in the volume of data that is being generated, processed, and archived. In particular, this information overload calls for new methods for querying large spatial datasets, since users are often not interested in merely retrieving a list of all data items satisfying a query, but would, instead, like a more informative \summary" of the retrieved items. An example is the so-called top-k problem, where the goal is to retrieve from a set of n weighted points in IRd the k most signicant points, ranked by their weights, that lie in an orthogonal query box in IRd (rather than get a list of all points lying in the query box). In this paper, ecient and output-sensitive solutions are presented for this problem in two settings. In the rst setting, the k points are reported in arbitrary order and the underlying set can be updated dynamically through insertions and deletions of points. In the second setting, the k points are reported in sorted order of their weights.

Abstract

Dipterocarpaceae is one of the important timber families of Andaman Islands whose members were largely exploited for their timber in the past. The current study discusses in detail about the family Dipterocarpaceae of North Andaman forest with reference to its species composition, population structure and other ecological entities. Data was analyzed using various ecological and statistical methods. Dipterocarps were encountered in 97 plots, occupying 80% of the sampled area with 68 stems ha-1 and basal area of 8.2 m2 ha-1. Dipterocarpaceae ranked 3rd with reference to stem density (11%) and 1st with respect to basal area (18%). The family showed five species viz., Dipterocarpus alatus, D. costatus, D. gracilis, D. grandiflorus and Hopea odorata compounded from two genera–