Bulletin of the American Physical Society
2007 APS March Meeting
Volume 52, Number 1
Monday–Friday, March 5–9, 2007; Denver, Colorado
Session Y35: DNA/RNA in vivo |
Hide Abstracts |
Sponsoring Units: DBP Chair: John Bechoefer, Simon Fraser University Room: Colorado Convention Center 405 |
Friday, March 9, 2007 11:15AM - 11:27AM |
Y35.00001: Designability as a Selection Force? An Analysis of the Yeast Cell Cycle Dynamics. Yigal Nochomovitz, Surya Ganguli, Hao Li The concept of designability may play a role in the evolution of biological phenotypes. We define ``designability'' generally as the number of genotypes that encode a particular phenotype. For networks, the designability of a dynamical phenotype is the number of topologies that encode a particular ordering of dynamical states. By analyzing ensembles of simplified models of topologies and dynamics (Nochomovitz, Y.D. {\&} Li, H. PNAS 103, 2006.) we have begun to explore the validity of the designability hypothesis at an abstract level. We have discovered from these exploratory studies that certain dynamical signals are highly designable, indicating that some dynamical signals can be realized by many different topological connections. To test the designability hypothesis on a real biological system, we analyze the dynamics of the budding yeast cell cycle. We compute the designability of the yeast cell cycle phenotype and the designabilities of $\sim $ 1000 weakly perturbed variants of the yeast cell cycle phenotype. A comparison of the designability of the true yeast cell cycle phenotype with the designabilities of the pool of perturbed phenotypes reveals that the designability of the budding yeast cell cycle dynamics is near-optimal. This finding provides some evidence for the hypothesis that designability, as an ``entropic'' force, may couple with the traditional fitness landscape to influence the evolution of biological phenotypes. [Preview Abstract] |
Friday, March 9, 2007 11:27AM - 11:39AM |
Y35.00002: Fine tuning by miRNAs in development Peter McHale, Erel Levine, Herbert Levine The unique role played by microRNA in a developing embryo is a topic of much current research interest. One possibility is that microRNA diffuse within a developing tissue, acting as communicators between different cells. Here we pursue this possibility in two different contexts. The first case occurs when the transcription profiles of the microRNA and its target are spatially anticorrelated, as for example is the case in the iab4-Ubx system in fly. Conversely, in the second context the two transcription profiles are correlated in space, as may be the case for the mir10-Hoxb4 system in mouse. In each context we identify a major function for a mobile miRNA. In the first, miRNA serve to induce an all-or-nothing response of the mRNA profile to its morphogen by generating a sharp boundary between domains of high and (ultimately) low target expression. In the second, miRNA amplify polarity in the target expression pattern by removing residual mRNAs. Importantly, our model predicts that these two functions require very different type of diffusion. While our results are highly quantitative, we propose ways of realizing them in experiments, taking into account limitations of standard experimental techniques. [Preview Abstract] |
Friday, March 9, 2007 11:39AM - 11:51AM |
Y35.00003: Modeling the dynamics of the nucleosome at various levels. Alexey Onufriev, Andrew Fenley, Jory Zmuda-Ruscio, David Adams The primary level of DNA compaction in eukaryotic organisms is the nucleosome, yet details of its dynamics are not fully understood. While the whole nucleosome must be highly stable, protective of its genetic material, at the same time its tightly wrapped DNA should be highly accessible, easily revealing its information content. A combination of atom-level classical molecular dynamics and a course-grained continuum description provide insights into the functioning of the system. In particular, the nucleosomal DNA appears to be considerably more flexible than what can be expected based on its canonical persistence length. A coarse-grained electrostatic model of the nucleosome explains how its stability can be modulated with small environmental changes as well as post-translational modifications. Implications for the nucleosome assembly process in \textit{vivo} are discussed. [Preview Abstract] |
Friday, March 9, 2007 11:51AM - 12:03PM |
Y35.00004: How frog embryos replicate their DNA reliably John Bechhoefer, Brandon Marshall Frog embryos contain three billion base pairs of DNA. In early embryos (cycles 2-12), DNA replication is extremely rapid, about 20 min., and the entire cell cycle lasts only 25 min., meaning that mitosis (cell division) takes place in about 5 min. In this stripped-down cell cycle, there are no efficient checkpoints to prevent the cell from dividing before its DNA has finished replication - a disastrous scenario. Even worse, the many origins of replication are laid down stochastically and are also initiated stochastically throughout the replication process. Despite the very tight time constraints and despite the randomness introduced by origin stochasticity, replication is extremely reliable, with cell division failing no more than once in 10,000 tries. We discuss a recent model of DNA replication that is drawn from condensed-matter theories of 1d nucleation and growth. Using our model, we discuss different strategies of replication: should one initiate all origins as early as possible, or is it better to hold back and initiate some later on? Using concepts from extreme-value statistics, we derive the distribution of replication times given a particular scenario for the initiation of origins. We show that the experimentally observed initiation strategy for frog embryos meets the reliability constraint and is close to the one that requires the fewest resources of a cell. [Preview Abstract] |
Friday, March 9, 2007 12:03PM - 12:15PM |
Y35.00005: Modeling the Forced Extension of Nicked DNA Alexander Balaeff, Stephen Craig, David Beratan The design and study of DNA-based nanodevices has been a topic of considerable interest in the last decade. While the applications of classical continuous DNA structures have been thoroughly studied, nicked DNA structures, i.e., ones that contains breaks (``nicks'') in one or both DNA backbone chains, have received much less attention. Recently, Kersey et al. (JACS, 2004) reported the force spectroscopy of long DNA chains with periodic nicks, self-assembled from short DNA oligomers. We attempt to model the experimental force-extension profiles in a series of steered molecular dynamics simulations. The simulated all-atom model of a basic unit of the long self-assembled chain, a 16bp-long DNA segment with a nick in the middle of one strand, is extended by applying either a constant force or a moving harmonic potential to the DNA ends. The computed force-extension profiles are compared to those for a non-nicked DNA; the dynamics of structural changes in the nicked DNA during the forced extension is discussed. A theoretical framework is established to link the extension and rupture in the simulated basic unit to the corresponding events in the long self-assembled chain. [Preview Abstract] |
Friday, March 9, 2007 12:15PM - 12:27PM |
Y35.00006: Single-Molecule Studies of the Temperature Dependence of Viral DNA Packaging Motors Michael White, Dorian Raymer, Peter Rickgauer, Derek Fuller, Shelley Grimes, Paul Jardine, Dwight Anderson, Doug Smith A key step in the assembly of many viruses is the packaging of dsDNA into a preformed capsid by the action of a portal molecular motor complex. ~We have developed methods for directly measuring viral DNA translocation at the single molecule level using optical tweezers and applied these methods to study bacteriophages $\Phi $29, lambda, and T4. Our previous measurements with $\Phi $29 were performed at room temperature. ~Here we report that the rate of DNA translocation is strongly temperature dependent. ~Preliminary measurements indicate that the motor velocity increases $\sim $2-fold, to $\sim $250-300 bp/s when the temperature is increased from $\sim $20 to 30 degrees C. ~As the viral packaging motors are enzymes that catalyze ATP hydrolysis, such a trend with increasing temperature is to be expected, at least up to the point where the motor complex is thermally dissociated or denatured. ~However, the detailed form of the temperature dependence is difficult to quantify using standard bulk assay methods. ~We have installed a heating/cooling system in our optical tweezers instrument that allows us to precisely control the temperature in our sample chamber. ~This system allows us to systematically study the temperature dependence of the DNA translocation rate. [Preview Abstract] |
Friday, March 9, 2007 12:27PM - 12:39PM |
Y35.00007: Identifying Dyads and their conservation in Drosphila. Debasis Dan Core promoter regions in Drosophila are enriched with binding sites like TATA, Inr, DPE, MTE, etc. They have very strict spacing between each other in promoters where they occur together. For example, in Drosophila melanogaster TATA-Inr has a spacing of 25-30 bp. Our aim in this work is to identify all such pair of motifs having strict positional constraint in the core promoters of all Drosophila species. We discover how these motifs and the spacing between them evolve within Drosophila species. For this we analyze 700 bp upstream and 300 bp downstream of TSS in D. melanogaster and the corresponding orthologous region in other Drosophila species. For each species, this 1000 bp region is searched for statistically over-represented compound words of the form W1N{L}W2, where L is the spacing between words W1 and W2. These compound words are systematically clustered for further analysis. [Preview Abstract] |
Friday, March 9, 2007 12:39PM - 12:51PM |
Y35.00008: Relating Promoter Sequences to the Proteins that Bind to Them: A Comparison Study. Kimberly Glass Chromatin Immunoprecipitation (ChIP-on-ChIP) microarray data reveals that the proteins H3K9dimethyl and RNA-Polymerase II are exclusive regarding their binding to the promoter region of genes. When comparing the base pair sequences of the promoters that bind to Pol2 versus H3K9, striking differences appear. The mononucleotides have fundamentally different behaviors in each group. In addition, motifs that cluster before the transcriptional start site also generally have a strong enrichment in one group compared to the other. Using this knowledge a model can be developed that allows one to calculate a probability that a promoter will bind to either H3K9 or Pol2 based on its base pair sequence. [Preview Abstract] |
Friday, March 9, 2007 12:51PM - 1:03PM |
Y35.00009: Studying Codon Usage: From sequence to function Terry Hwa, Stefan Klumpp, Jiajia Dong Protein coding sequences exhibit strong variances in the use of codons. Highly expressed genes such as those encoding ribosomal proteins use codons corresponding to the highly abundant tRNAs (``optimized codons''). High expression of heterologous genes also requires codon optimization, but even the codon usage of very weakly expressed genes tends to be far from random. To understand this biased choice of codon usage, we develop a theory based on the concept of ``ribosomal load.'' Ribosome is the key limiting commodity for rapidly growing organisms so that the use of ``non-optimal'' codons in any gene prolongs the translational elongation time, thus reducing the effective ribosome concentration. This presents a fitness cost, the magnitude of which depends on the amount of that protein being translated. We formulated and solved an evolution equation based on the above ingredients. This provides a quantitative relation between codon usage and protein abundance, which is found to be in good agreement with the available data for E.coli. This result suggests a convenient way to quantitatively predict protein abundances based on genome sequence data. [Preview Abstract] |
Friday, March 9, 2007 1:03PM - 1:15PM |
Y35.00010: A Model of Codon Usage Bias Morten Kloster, Chao Tang The genetic code is degenerate; most amino acids can be encoded by from two to as many as six different codons. While one might expect these codons to be used with equal frequency, this turns out not to be the case---not only are some codons favored over others, but their usage can vary significantly between different genes in the same organism. Known causes of codon bias include differences in mutation rates as well as selection pressure related to the expression level of a gene, but the standard analysis methods can explain only a fraction of the observed codon usage variation. We here introduce an explicit model of codon usage bias, inspired by statistical physics. Combining this model with a maximum likelihood approach, we are able to clearly identify up to four different sources of bias in various genomes. We have applied the algorithm to Saccharomyces cerevisiae as well as 325 bacterial genomes, and in most cases our model explains essentially all observed variance. [Preview Abstract] |
Friday, March 9, 2007 1:15PM - 1:27PM |
Y35.00011: Single Molecule Study of Metalloregulatory Protein-DNA Interactions Susanta Sarkar, Jaime Benitez, Zhengxi Huang, Qi Wang, Peng Chen Control of metal concentrations is essential for living body. Metalloregulatory proteins respond to metal concentrations by regulating transcriptions of metal resistance genes via protein-DNA interactions. It is thus necessary to understand interactions of metalloregulatory proteins with DNA. Ensemble measurements provide average behavior of a vast number of biomolecules. In contrast, single molecule spectroscopy can track single molecules individually and elucidate dynamics of processes of short time scales and intermediate structures not revealed by ensemble measurements. Here we present single molecule study of interactions between PbrR691, a MerR-family metalloregulatory protein and DNA. We presume that the dynamics of protein/DNA conformational changes and interactions are important for the transcription regulation and kinetics of these dynamic processes can provide useful information about the mechanisms of these metalloregulatory proteins. [Preview Abstract] |
Friday, March 9, 2007 1:27PM - 1:39PM |
Y35.00012: A plausible model for the digital response of p53 to DNA damage Gustavo Stolovitzky, Lan Ma, John Wagner, J. Jeremy Rice, Hu Wenwei, Arnold Levine The single-cell response of p53 to ionizing radiation (IR) is such that the number of oscillations of p53 shows dependence on the radiation dose. We present a model of this phenomenon. In our model, double strand break (DSB) sites induced by IR interact with a limiting pool of DNA repair proteins, forming complexes that are sensed by ATM, a protein kinase that activates p53 once phosphorylated by DNA damage. The ATM sensing module switches on or off the downstream p53-mdm2 negative feedback loop. Our simulations show that by assuming stochasticity in the initial number of DSBs and the DNA repair process, p53 and Mdm2 exhibit a coordinated oscillatory dynamics upon IR stimulation in single cells, with a stochastic number of oscillations whose mean increases with IR dose. [Preview Abstract] |
Friday, March 9, 2007 1:39PM - 1:51PM |
Y35.00013: Transcription factor binding energy vs. biological function M. Djordjevic, E. Grotewold Transcription factors (TFs) are proteins that bind to DNA and regulate expression of genes. Identification of transcription factor binding sites within the regulatory segments of genomic DNA is an important step towards understanding of gene regulatory networks. Recent theoretical advances that we developed [1,2], allow us to infer TF-DNA interaction parameters from in-vitro selection experiments [3]. We use more than 6000 binding sequences [3], assembled under controlled conditions, to obtain protein-DNA interaction parameters for a mammalian TF with up to now unprecedented accuracy. Can one accurately identify biologically functional TF binding sites (i.e. the binding sites that regulate gene expression), even with the best possible protein-DNA interaction parameters? To address this issue we i) compare our prediction of protein binding with gene expression data, ii) use evolutionary comparison between related mammalian genomes. Our results strongly suggest that in a genome there exists a large number of randomly occurring high energy binding sites that are not biologically functional. [1] M Djordjevic, submitted to\textit{ Biomol. Eng.} [2] M. Djordjevic and A. M. Sengupta, \textit{Phys. Biol.} \textbf{3:} 13, 2006. [3] E. Roulet et al., \textit{Nature Biotech.} \textbf{20}: 831, 2002. [Preview Abstract] |
Friday, March 9, 2007 1:51PM - 2:03PM |
Y35.00014: Dynamics of DNA bending/unbending in complex with DNA-bending protein IHF Anjum Ansari, Paula Vivas, Serguei Kuznetsov Kinetics of conformational changes in proteins and DNA that lead to precise recognition of specific DNA binding sites are difficult to observe with the limited time-resolution of stop-flow and single-molecule techniques. Here we use a $\sim $10 ns laser T-jump apparatus to probe the kinetics of a $\sim $35-bp DNA substrate bound to \textit{E. coli} Integration Host Factor (IHF) and end-labeled with a FRET pair. These T-jump measurements, in combination with stop-flow, provide the first direct observation of the DNA bending/unbending kinetics in a protein-DNA complex (Sugimura and Crothers, PNAS, in press; Kuznetsov et al., PNAS, in press). The rates and activation energy of DNA bending are similar to that of a single A:T base pair opening inside uncomplexed DNA, suggesting that spontaneous thermal disruption in base-pairing nucleated at an A:T site may be sufficient to overcome the free energy barrier needed to partially bend/kink DNA. An unusual salt dependence of the binding affinity observed previously for IHF/DNA complex, and explained in terms of DNA binding coupled with disruption of a network of salt bridges within the protein (Holbrook et al., 2001, JMB, \textbf{310}, 379), is reflected in the salt dependence of the observed bending rates. These results suggest that salt-dependent protein conformational changes may be playing a role in the DNA bending process. [Preview Abstract] |
Friday, March 9, 2007 2:03PM - 2:15PM |
Y35.00015: HMGB binding to DNA: comparisons between single and double box motifs Micah J. McCauley, Jeff Zimmerman, L. James Maher III, Mark C. Williams High Mobility Group B (HMGB) proteins contain two HMG box domains known to bind non-sequence specifically into the DNA minor groove, slightly intercalating base pairs and producing a strong bend in the DNA backbone. These proteins are believed to alter DNA elasticity, making DNA more accessible for transcription in vivo. To probe the effects of HMG proteins on DNA elasticity, we use optical tweezers to measure the forces required to stretch single DNA molecules, alone and in the presence of HMGB proteins at varying solution conditions. Experiments quantify the binding constant of HMGB to DNA, as well as changes in the flexibility and stability of the double helix. Previous results from a protein fragment containing a single HMG box suggested significant flexibility changes in the double helix but did not show helix stabilization, while a double box protein from rat HMGB--1 appears to significantly stabilize the DNA helix. [Preview Abstract] |
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