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

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

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

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

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

An acyclic vertex coloring of a graph is a proper vertex coloring such that there are no bichromatic cycles. The acyclic chromatic number of G, denoted a (G), is the minimum number of colors required for acyclic vertex coloring of graph G. For a family F of graphs, the acyclic chromatic number of F, denoted by a (F), is defined as the maximum a (G) over all the graphs G∈ F. In this paper we show that a (F)= 8 where F is the family of graphs of maximum degree 5 and give a linear time algorithm to achieve this bound.

Abstract

General purpose programming on the graphics processing units(GPGPU) has received a lot of attention in the parallel computing community as it promises to offer a large computational power at a very low price. GPGPU is best suited for regular data parallel algorithms. They are not directly amenable for algorithms which have irregular data access patterns such as convex hull, list ranking etc. In this paper, we present a GPU-optimized implementation for finding the convex hull of a two dimensional point set. Our implementation tries to minimize the impact of irregular data access patterns. Our implementation can find the convex hull of 10 million random points in less than 0.2 seconds and achieves a speedup of up to 14 over the standard sequential CPU implementation. We also discuss some of the practical issues relating to the implementation of convex hull algorithms on massively multi-threaded architectures like that of the GPU.

Abstract

Graphics Processing Units provide a large computational power at a very low price which position them as an ubiquitous accelerator. GPGPU is accelerating general purpose computations using GPU's. GPU's have been used to accelerate many Linear Algebra routines and Numerical Methods. Lanczos is an iterative method well suited for finding the extreme eigenvalues and the corresponding eigenvectors of large sparse symmetric matrices. In this paper, we present an implementation of Lanczos Algorithm on GPU using the CUDA programming model and apply it to two important problems : graph bisection using spectral methods, and image segmentation. Our GPU implementation of spectral bisection performs better when compared to both an Intel Math Kernel Library implementation and a Matlab implementation. Our GPU implementation shows a speedup up to 97.3 times over Matlab Implementation and 2.89 times over the Intel Math Kernel Library implementation on a Intel Core i7 920 Processor, which is a quad-core CPU. Similarly, our image segmentation implementation achieves a speed up of 3.27 compared to a multicore CPU based implementation using Intel Math Kernel Library and OpenMP. Through this work, we therefore wish to establish that the GPU may still be a better platform for also highly irregular and computationally intensive applications.

Abstract

This paper considers the question of how many colors a distributed graph coloring algorithm would need to use if it had only k rounds available, for any positive integer k. In our main result, we present an algorithm that runs in O(k) rounds for any k bounded below by ©(log log n) and bounded above by O(√log n), and uses O(a Å n1/k) colors to color a graph with arboricity a. This result is optimal since the palette size matches the lower bound of Barenboim and Elkin (PODC 2008). This result is achieved via the use of several new results developed in this paper on coloring graphs whose edges have been acyclically oriented. For example, suppose that G is an n-vertex, acyclically oriented graph with maximum out-degree Δo. We present an algorithm that, for any k ≥ 2 loglog n, runs in O(k) rounds on G to produce an (i) O(Δo)-coloring when Δo Δ ©(maxkn2/k2log1+1/kn, 2k) and an (ii) O(Δo Å n2/k2)-coloring when Δo ∈ Ω(maxk log1+1/kn, 2k). These results are useful in any setting where it is possible to efficiently compute acyclic orientations of a graph with Δo << Δ. We derive non-trivial bounds on the palette size even when k < 2 loglog n. Our main technical contributions can be summarized as: (i) developing a k-round version of the algorithm of Kothapalli et al. (IPDPS 2006) which computes an O(?)-coloring of a graph in O(√log n) rounds, and (ii) developing an oriented version of the Brooks-Vizing coloring result of Grable and Panconesi (SODA 1998).

Abstract

We consider the dominating point set reporting problem in two-dimension. We propose a data structure for finding the set of dominating points inside a given orthogonal query rectangle. Given a set of n points in the plane, it supports 4-sided queries in O (log n+ k), where k is size of the output, using O (n log n) space. This work can be of application when range queries are generated using mobile devices with limited display capacity.