||Gilad Lerman Defining functional distance using manifold embeddings of gene ontology annotations
|Abstract: Although rigorous
measures of similarity for sequence and
structure are now well established, the problem of defining
has been particularly daunting. Here, we present several
embedding techniques to compute distances between Gene
functional annotations and consequently estimate functional
between protein domains. To evaluate accuracy, we correlate
functional distance to the well established measures of
structural, and phylogenetic similarities. Finally, we show
classification of structures into folds and superfamilies is
proximity in the newly defined function space. We show how
distances place structure-function relationships in biological
resulting in insight into divergent and convergent evolution.
and results can be readily generalized and applied to a wide
biologically relevant investigations, such as accuracy of
transference, the relationship between sequence, structure,
or coherence of expression modules.
This work is joint work Boris Shakhnovich and described in
|Victor Barocas (University of Minnesota)
||Multiscale mechanical modeling of bioartificial tissues
|Abstract: As biopolymer-based tissue engineering matures as a discipline, we are faced with a fundamental challenge: we understand to a degree how changes in fabrication and culture conditions can affect the structure and composition of the final model tissue, but we do not understand how those changes determine the mechanical properties. The problem is further complicated by the fact that the structural scale of the network is in microns (or tens of microns), but the functional scale is millimeters to centimeters. Our group uses volume averaging theory to develop models of bioartificial tissue mechanics based on a microscopic-scale network model coupled to a macroscopic-scale continuum model. The model has been applied to collagen gels, and also to a simplified model of arterial tissue. The talk will present the model as well as some more recent work on a biphasic formulation (accounting for interstitial flow) and on an extension to migrating cells.
|Jean Bergeron (Alpha-Zoulou Films)
||Math Matters public lecture: U.S. premier screening of the film
"Achieving the unachievable" with the film's writer/director
|Abstract: M.C. Escher is among the most mathematical of artists. In 1956 he challenged the laws of perspective with his graphic Print Gallery, and found himself trapped by an impossible barrier. His uncompleted master-piece quickly became the most puzzling enigma of modern art, for both artists and scientists. Half a century later, mathematician Hendrik Lenstra took everyone by surprise by drawing a fantastic bridge between the intuition of the artist and his own, and completed Escher's work mathematically. This story is presented in the 52 minute film Achieving the Unachievable by documentary filmmaker Jean Bergeron. After the screening, the film's U.S. premier, Bergeron will be available to answer questions.
|Balaji Gopalakrishnan (SAS Institute Inc.)
|Abstract: All marketing organizations — including the successful ones — are under increased pressure to do more with less. Throughout the marketing and fulfillment delivery chain marketers face competing business goals, multiple marketing programs and constraints like channel capacity, budget and customer contact policies. Typically it is required to maximize/minimize an objective such as the return on investment while satisfying these marketing goals/constraints. In this talk we will discuss the formulation of this problem as a binary integer programming model and outline the computational challenges involved in solving the model to optimality. We will also present an overview of the methodology used by the SAS Marketing Optimization software followed by some computational results.
|Tan Inoue (Kyoto University)
||RNA / RNP synthetic biology
|Abstract: In general, molecular design of RNA is difficult at the 3D level because of its highly complicated folding process. In the 1990s, biochemical and structural analyses revealed that many functional noncoding natural RNAs are organized into modules and fold into defined 3D structures. Moreover, several commonly used RNA–RNA binding motifs in these RNAs were identified by phylogenetic comparison and high-resolution structural analyses. Consequently, it has become possible to design self-folding RNAs precisely by employing such motifs and mimicking the modular organization of natural RNAs. As one such example, we have investigated the design and construction of a self-folding RNA scaffold consisting of standard doublestranded helices connected by the two RNA–RNA binding motifs. Results indicated that the constructed RNA folds compactly into the designed 3D structure. We have also reported the synthesis and development of an artificial RNA enzyme by installing a reaction site and a catalytic site into the designed RNA scaffold. For medical and biological applications, the goals of our current project are 1) to establish multifunctional RNP molecules with tumor seeking sensors, imaging agents and toxins that kill target cells, and 2) to establish artificial signal transduction systems for regulating function of a cell by employing designed RNA and RNP molecules. The strategy may be applicable to the synthesis and development of a variety of nonnatural functional RNAs with defined 3D structures.
|Luc Jaeger (University of California)
||RNA tertiary structure as a proto-language for nano-construction
|Abstract: Common occurrence of many small structural motifs in natural RNA molecules suggests that nature utilize s a vocabulary of sequence patterns to compose structural molecules with sophisticated topologies such as the ribosome and large ribozymes. By careful analysis of sequences and tertiary structures of natural RNAs, 3D RNA modules and their folding and assembly principles are presently gathered for generating the syntax of a proto-language for rational design and prediction of RNA 3D shapes. RNA architectonics refers to the creation of this proto-language and to its use to build new RNAs with self-assembly properties. Recently, RNA architectonics led to the reliable prediction and design of the tertiary structure of several artificial RNA building blocks able to form programmable filaments and 2D RNA arrays at the nano-scale level. As a proof of concept, we also demonstrated that structurally complex RNAs based on a syntax involving a repertoire of several different RNA motifs can self-assemble into complex supra-molecular 3D nano-particles. This studies show that RNA architectonics can be used as a tool to explore and compare the biophysical properties of various RNA tertiary structure motifs that would be otherwise more difficult to investigate in isolation or within their natural context. It also demonstrates that RNA is an ideal medium for sculpting addressable and responsive self-assembling architectures of any desired shapes in the 20 to 50 nm scale. Moreover, it suggests that RNA supra-molecular assembly can potentially lead to the development of highly sophisticated therapeutic nano-devices for biological and medical applications.
1. Jaeger, L. & Chworos, A. (2006) The Architectonics of Programmable RNA and DNA Nanostructures. Current Opinion in Structural Biology, 16, 531-543.
2. Chworos, A, Severcan, I., Koyfman, A. Y., Wienkam, P., Oroudjev, E., Hansma, H. G. & Jaeger, L. (2004). Building programmable jigsaw puzzles with RNA. Science 306, 2068-2072.
3. Nasalean, L., Baudrey, S., Leontis, N.B. & Jaeger, L. (2006) Controlling RNA self-assembly to form filaments. Nucleic Acids Res. 34, 1381-1392
4. Bates, A.D., Callen B.P., Cooper J.M., Cosstick, R., Geary, C., Glidle, A., Jaeger, L., Pearson, J.L., Proupín-Pérez, M., Xu, C., & Cumming, D.R. S. (2006) Construction and characterization of a gold nanoparticle wire assembled using Mg2+-dependent RNA-RNA interactions. Nanoletters 6, 445-448.
|Debra Knisley (East Tennessee State University)
||Graphical invariants and topological indices as biomolecular descriptors
|Abstract: A number of molecular descriptors of small molecules are derived from graphical representations of the molecule. These descriptors, sometimes called topological indices, are used to identify or relate the structure of a molecular with expected bioactivity and they are an essential tool in the drug design industry. It is generally accepted that these molecular descriptors are not applicable to macromolecules. However, topological indices are equivalent to graphical invariants in graph theory. Graph theory offers a wealth of graphical invariants annotated with structural implications, primarily for large graphs. Thus we consider applying known graphical measures to quantify macromolecules, including secondary RNA structures, amino acids and several families of proteins.
|David M.J. Lilley (University of Dundee)
||Structure, dynamics and catalytic mechanisms of two ribozymes
|Abstract: CR-UK Nucleic Acid Structure Group, MSI/WTB complex, University of Dundee, Dundee DD1 5EH, UK firstname.lastname@example.org
The nucleolytic ribozymes are catalytic RNA molecules that generate site-specific cleavage by means of a transesterification reaction involving the 2’ and 5’ O atoms. We have made a study of two of these, the hairpin and VS ribozymes.
The hairpin ribozyme folds to generate an intimate loop-loop interaction to create the local environment in which catalysis can proceed. By means of FRET we can observe individual hairpin ribozyme molecules as they undergo multiple cycles of cleavage and ligation, and measure the rates of the internal reactions. On average, the cleaved ribozyme undergoes several docking-undocking events before a ligation reaction occurs. On the basis of these experiments, we have explored the role of the nucleobases G8 and A38 in the catalysis. Both cleavage and ligation reactions are pH dependent, corresponding to the titration of a group with pKA = 6.2. We have used a novel ribonucleoside in which these bases are replaced by imidazole to investigate the role of acid-base catalysis in this ribozyme. We observe significant rates of cleavage and ligation, and a bell-shaped pH dependence for both.
The VS ribozyme is the largest of the nucleolytic ribozymes, and the only one for which there is no crystal structure. The ribozyme consists of five helical sections organised by two three-way junctions, each of which undergo metal ion-induced folding. Using a ‘divide and conquer’ approach based principally on the analysis of component junctions by FRET, we deduced the global structure of the ribozyme. We have now solved the structure of the complete ribozyme at low resolution using small-angle X-ray scattering in solution.
The binding of the substrate stem-loop generates a catalytically-productive interaction with the A730 loop active site. We have identified two critical nucleotides in the catalytic process; A756 within the A730 loop, and G638 in the substrate internal loop. Mutation or functional group substitution of either nucleobase leads to > 1,000-fold impairment of catalytic activity, while leaving the structure and binding to the ribozyme unaltered. The pH dependencies of the rate of cleavage of substrate with guanine, adenine, 2,6-diaminopurine or inosine at position 638 are fully consistent with a mechanism in which G638 and A756 act in concert in general acid-base catalysis.
The proposed mechanism of the VS and hairpin ribozymes, together with the manner of the generation of the active sitea and their topology, are strikingly similar each other. This has probably arisen by convergent evolution.
M.K. Nahas, T.J. Wilson, S. Hohng, K. Jarvie, D.M.J. Lilley and T. Ha Observation of internal cleavage and ligation reactions of a ribozyme Nature Struct. Molec. Biol. 11, 1107-1113 (2004).
Z. Zhao, A. McLeod, S. Harusawa, L. Araki, M. Yamaguchi, T. Kurihara and D. M. J. Lilley Nucleobase participation in ribozyme catalysis. J. Amer. Chem. Soc. 127, 5026-5027 (2005).
T. J. Wilson, J. Ouellet, Z. Zhao, S. Harusawa, L. Araki, T. Kurihara and D. M. J. Lilley Nucleobase catalysis in the hairpin ribozyme. RNA 12, 980-987 (2006).
T. J. Wilson, A. C. McLeod and D. M. J. Lilley A guanine nucleobase important for catalysis by the VS ribozyme EMBO J. 26, 2489-2500 (2007).
|Timothy Newman (Arizona State University)
||Strong fluctuations and cycling in biological systems
|Abstract: In this talk I describe a mechanism for generating cycles in a large
class of "mesoscale" biological populations (meaning populations
composed of thousands to tens of thousands of units). Cycles are caused
by a resonant amplification of the system dynamics triggered by internal
noise. I will discuss this mechanism in the context of two classes of
simple systems: ecological (e.g. predator-prey, host- pathogen) and
biochemical (e.g. small gene regulation networks,
modules of metabolic processes)
|Henri Orland (Commissariat à l'Énergie Atomique Saclay (CEA))
||A topological classification of RNA folds
|Abstract: After reviewing some elementary properties of RNA, we show how the RNA
folding problem can be formulated exactly in terms of an NxN matrix
field theory. This formulation introduces a classification of RNA structures
according to their topological genus.
The large N limit of this theory generates the secondary structures of RNA
(planar graphs), whereas 1/N corrections are identified as pseudo-knots. We
show how the RNA structures can be analyzed in terms of primitive pseudo
knots of low genus and how this concept can be included in Monte Carlo
calculations to actually predict RNA folds.
|Randy C. Paffenroth (Numerica Corporation)
||Networked target tracking architectures
|Abstract: The coordinated use of multiple distributed sensors by network
communication has the potential to substantially improve estimates of
target positions, features, and attributes. This improvement is
primarily due to geometric diversity, complementary sensor
information, and different coverage areas. Unfortunately, sensor
networks are not without their challenges. In particular, there is a
balance between network bandwidth constraints and the maintenance of a
consistent picture of the scenario across the network participants.
In this talk we will discuss pertinent issues including network
communication schemes, track initiation and maintenance, and bias
|Deena Schmidt (University of Minnesota)
||Waiting for k mutations: with applications to DNA regulatory sequence evolution and cancer
|Abstract: We consider the population genetics problem: How long does it take before some member of the population has k specified mutations? The case k=2 is relevant to the onset of cancer due to the inactivation of both copies of a tumor suppresor gene. Results of Nowak and collaborators give the waiting time distribution in this case and the time until the mutant phenotype becomes fixed in the population. Here we apply these results to obtain insights into regulatory sequence evolution in Drosophila and humans. In particular, we examine the waiting time for a pair of mutations, the first of which inactivates an existing transcription factor binding site and the second which creates a new one. Consistent with recent experimental observations for Drosophila, we find that a few million years is sufficient, but for humans with a much smaller effective population size, this type of change would take more than 100 million years. In addition, we'll discuss models for larger k, which are needed for colon cancer and other diseases where a sequence of mutations leads to cells with uncontrolled growth.
|Bruce A. Shapiro (National Cancer Institute)
||Computational approaches to RNA nanodesign
|Abstract: We have developed a number of computational tools that permit a user to design RNA based nano-particles with various functionalities. One of these tools is a newly developed relational database, RNAJunction, which contains structural and sequence information for all known RNA n-way junctions and kissing loop interactions. The database also contains the results from applying molecular mechanics and structural clustering techniques to the motifs. The database of motifs can be searched in a variety of ways and provide a source for further analysis and RNA nano building blocks. Another computational tool, NanoTiler, permits a user to interactively and automatically construct user specified RNA-based nano-scale shapes. The combination of the RNAJunction database, NanoTiler and other computational tools allows the rapid prototyping of designed RNA shapes. We discuss some of the principles involved in these design tools and show how the RNA nanodesign process can be accomplished with the use of these methodologies.
|Devarajan Thirumalai (University of Maryland)
||Exploring the energy landscape of RNA
|Abstract: Recent single molecule experiments and high-resolution temperature jump experiments show that the energy landscape of RNA is rugged. As a result, even the formation of a hairpin, exhibits all the signatures of folding (multiple pathways and complex kinetics) usually associated with self-assembly of ribozymes. I will describe the kinetics of hairpin formation, initiated by both temperature and force quench, using computations. The profound differences between the two methods will be illustrated in terms of the pathways to the native state. Analogies to folding of ribozymes will also be given.
|Zhian Wang (University of Minnesota)
||Models for mesenchymal motion in tissue
|Abstract: The interaction between cells and extracelluar matrix (ECM) is highly complex and many biological mechanisms have been identified, which provides significant insights of understanding cell invasion such as wound healing, cancer progression and so on. The cell migration using the two strategies, i.e., contact guidance and remodeling of matrix, is termed mesenchymal motion. The mathematical models of mesenchymal motion were developed by Thomas Hillen (2006) and numerical scheme was investigated by Painter (2007). In my talk, I will present the analytic results in addition to their works and explain the findings in the context of biological applications of cell movement in tissues.
|Sarah Woodson (Johns Hopkins University)
||How RNA tells right from wrong: base pairs, tertiary interactions, and counterions in RNA folding
|Abstract: RNAs must self-assemble into unique three-dimensional structures in the cell, yet how RNA molecules find their native structure in a short time is not well understood. This is a challenging problem, because RNA secondary structures are thermodynamically stable but not uniquely specified by the sequence, while tertiary interactions are specific but not very stable. Consequently, many RNAs become trapped in metastable, non-native intermediates. Recent footprinting and SAXS experiments on a bacterial ribozyme show that tertiary interactions make helix assembly more specific during the initial collapse transition. Specific collapse increases the flux through folding pathways that lead directly to the native structure. The stability of the folded RNA also depends on the charge density of the counterions; small multivalent counterions stabilize the RNA more than large monovalent ions. In low charge density counterions, the transition state ensemble becomes broader, accelerating the search for the native structure.