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Center for the Study of Systems Biology

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    RNA Enzymes: From Folding to Function in Living Cells
    (Georgia Institute of Technology, 2008-03-25) Fedor, Martha J.
    Our research aims to generate fundamental insights into catalysis by RNA enzymes and into the pathways through which RNAs form specific functional structures. RNA catalysis remains an intriguing puzzle that has grown in significance since the recent discoveries that the ribosome itself is an RNA enzyme and that human and bacterial mRNAs contain self-cleaving ribozymes. The hairpin ribozyme catalyzes a reversible self-cleavage reaction in which nucleophilic attack of a ribose 2’ hydroxyl on an adjacent phosphorus proceeds through a trigonal bipyramidal trasition state that leads to the formation of 2’,3’-cyclic phosphate and 2’ hydroxyl termini. The metal cation independence of activity and the availability of high-resolution active site structures have made the hairpin ribozyme the prototype for nucleobase-mediated catalytic chemistry. A network of stacking and hydrogen bonding interactions align the reactive phosphate in the appropriate orientation for an SN2-type nucleophilic attack and orient nucleotide base functional groups near the reactive phosphate to facilitate catalytic chemistry. Two active site nucleobases, G8 and A38, adopt orientations reminiscent of the histidine residues that mediate general acid base catalysis in ribonuclease A, a protein enzyme that catalyzes the same phosphodiester cleavage chemistry. However, our biochemical experiments argue against analogous roles for G8 and A38 in hairpin ribozyme catalysis and suggest that these residues contribute to catalysis through positioning and orientation and electrostatic stabilization of the electronegative transition site. Ribozymes are useful model systems for investigation of RNA folding, since self-cleavage reflects the assembly of a precise functional structure. To learn how structure-function principles revealed through in vitro experiments translate to the behavior of RNA in living cells, we devised a way to evaluate RNA assembly in vivo using RNA self-cleavage rates to quantify assembly of functional RNA structures. Results of these studies show that intracellular RNA folding kinetics and equilibria are indistinguishable from RNA folding behavior in vitro, provided that in vitro folding reactions approximate the ionic conditions characteristic of an intracellular environment. These studies contribute basic knowledge of RNA structure and function and provide a framework for developing technical and therapeutic application involving RNAs as targets and reagents.
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    New RNA-binding peptidomimetic structures that repress HIV viral replication by specifically inhibiting transcriptional activation
    (Georgia Institute of Technology, 2008-03-18) Varani, Gabriele
    The Interaction between the human immunodeficiency virus (HIV-1) transactivator protein Tat and its response element TAR plays an essential role in viral replication by controlling HIV transcription. Previous attempts to inhibit this interaction have failed to yield molecules with sufficient potency and specificity to warrant pharmaceutical development. We have shown that comformationally constrained cyclic peptide structural mimics of Tat provide nM inhibitors of the Tat-TAR interaction. These peptidomimetics are proteolytically stable, penetrate cells efficiently and have no cytotoxicity. They specifically inhibit Tat-dependent activation of transcription in cells and repress replication of a wide variety of viral strains representing all the major HIV clades in primary human lymphocytes. The potency and selectivity observed for this family of peptides is unprecedented among Tat inhibitors and suggest that these types of compounds may be widely useful for the pharmacological inhibition of other protein-RNA interactions.
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    Positive Selection on Non-coding Sequences During Human Evolution: From Genome to Nucleotide
    (Georgia Institute of Technology, 2008-03-04) Wray, Gregory
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    Systems Biology and its Role in Predictive Health and Personalized Medicine
    (Georgia Institute of Technology, 2008-02-05) Voit, Eberhard O.
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    Mechanisms of Chromosomal Fragility and Rearrangements Triggered by Human Unstable Repeats
    (Georgia Institute of Technology, 2008-01-22) Lobachev, Kirill
    Research of my lab focuses on understanding how chromosomal rearrangements arise and lead to hereditary diseases and cancer. Chromosomes containing repeats that can adopt stable secondary structures are highly prone for double-strand breaks and various types of rearrangements. Molecular mechanisms for this type of genetic instability in eukaryotes are poorly understood. Using yeast, S. cerevisiae, we are investigating the chromosomal fragility mediated by two sequence motifs: cruciform-forming inverted repeats and H-DNA-forming GAA/TTC triplet repeats. Both types of repeats strongly induce breakage which results from the replication arrest by the secondary structures. However, genetic requirements for fragility, mode of breakage and consequences for the genome integrity are different for these two types of repeats. We propose that the nature of the secondary structure predisposes chromosomes for the specific pattern of gross chromosomal rearrangements. These rearrangements are strikingly similar to carcinogenic aberration suggesting that repeat-mediated instability might be a general phenomenon that operates not only in yeast but also in humans. I will present recent data from my lab on proteins that are involved into the fragility.
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    Interactome networks
    (Georgia Institute of Technology, 2007-11-27) Vidal, Marc
    For over half a century it has been conjectured that macromolecules form complex networks of functionally interacting components, and that the molecular mechanisms underlying most biological processes correspond to particular steady states adopted by such cellular networks. However, until recently, systems-level theoretical conjectures remained largely unappreciated, mainly because of lack of supporting experimental data. To generate the information necessary to eventually address how complex cellular networks relate to biology, we initiated, at the scale of the whole proteome, an integrated approach for modeling protein-protein interaction or "interactome" networks. Our main questions are: How are interactome networks organized at the scale of the whole cell? How can we uncover local and global features underlying this organization, and how are interactome networks modified in human disease, such as cancer?
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    From Systems Biology to Systems Analytics: Seeing More by Looking at Less
    (Georgia Institute of Technology, 2007-10-09) Mizaikoff, Boris
    Systematic analysis of interactions between molecules and biological entities requires the development and application of experimental tools and analytical methods to quantitatively measure and image molecular events, molecular pathways, and molecular signals at the level of individual cells, ensembles of small biological entities and entire organisms with the required molecular selectivity, sensitivity, and temporal/spatial resolution. While it is evident that current analytical techniques are frequently limited to averaged measurements or ex-situ analysis, the analytical challenges for in-situ multi-parametric characterization of living biological entities such as cells, microbes, bacteria or ensembles thereof remain significant. Hence, in analogy and complementary to Systems Biology concerned with deciphering complex molecular processes and their relation to biological functionalities, we view Systems Analytics as the toolbox enabling the quantitative determination of multiple molecular parameters to elucidate these interactions and relations. From the analytic chemistry point of view, we may describe individual cells as a measurement compartment with spatial/volume dimensions in the μm-nm/μL-nL range, and quantitative molecular dimensions in the mM-nM domain. The spatial dimensionality of molecular events within or at cellular compartments (e.g. vesicular processes) or at the cell surface (e.g. exo-or endocytosis) along with the magnitude of the local species concentration determine the need for quantitative analytical measurements at the micro- and nanoscale. We will discuss the diversity of measurement challenges at these compartments, which include the small dimensions of the involved samples and volumes, the complex and frequently changing background matrix, the sensitivity and/or discriminatory power of in-situ analytical techniques, and their temporal and/or spatial resolution to quantitatively monitor dynamic processes associated with cellular functions. In turn, individual optical/spectroscopic, electrochemical, and surface sensitive analytical techniques have already demonstrated their potential at the macro- and microscopic level, i.e. identifying which molecular species are present, their concentration, their location, and — ideally - the kinetics, dynamics of the involved molecular processes. In contrast to approaches utilizing individual analytical techniques, the development of generic multifunctional analytical platforms orchestrates a suite of complementary measurement techniques to cooperatively investigate complex biological systems, complemented by the development of (bio)sensing chemistries, synthetic molecular receptors, multivariate evaluation techniques, and micro/nanofabrication for functional system miniaturization. Thereby, we capitalize on the benefits of several analytical techniques addressing the conformational, electrochemical, and spectroscopic properties of the sample leading toward simultaneous rather than the classical sequential information acquisition process, aiming at maximizing the synchronicity between multiple methods in the temporal and spatial domain.