Bulletin of the American Physical Society
2007 APS March Meeting
Volume 52, Number 1
Monday–Friday, March 5–9, 2007; Denver, Colorado
Session X35: Focus Session: Nucleic Acid Protein Interaction |
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Sponsoring Units: DBP Chair: Dean Astumian, University of Maine Room: Colorado Convention Center 405 |
Friday, March 9, 2007 8:00AM - 8:36AM |
X35.00001: Accuracy of Localization Methods for Individual Fluorescent Probes Invited Speaker: Recent technological developments have made light microscopy of single molecules possible. The limited number of photons available from a single fluorescent molecule makes image analysis a statistical analysis. Consequently, optimal data analysis is as important to experimental resolution as improved experimental conditions, such as photobleaching rates of fluorescent probes. The simple case of \textit{localization accuracy} provides a pertinent example. In theory, conventional lens-based light microscopy can determine the position of a point-like object with an accuracy that increases infinitely with the number of photons producing it. In practice, a finite signal-to-noise ratio limits localization accuracy and so may the choice of statistical estimator. Some estimators are easier to apply than others, but their relative virtues in regards to accuracy is unclear, or only known numerically for specific cases. We analyze three popular estimators under ideal conditions, find exact analytical results for their accuracy, and clear up a confusion in the literature. Next we test our results for accuracies against ideal real data, and find results that change our view of these estimators for practical use. [Preview Abstract] |
Friday, March 9, 2007 8:36AM - 8:48AM |
X35.00002: Phenotypic consequences of promoter-mediated transcriptional noise: Experiment and computational modeling Gabor Balazsi, William Blake, Michael Kohanski, Kevin Murphy, James Collins A more complete understanding of the causes and effects of gene expression noise is needed to elucidate whether the resulting phenotypes are disadvantageous or confer some adaptive advantage. We introduce mutations within the promoter region of an engineered, repressible \textit{Saccharomyces cerevisiae} GAL1 promoter to show that the level of gene expression noise is affected by the sequence of the TATA box. Through computer simulations, we identify transcription scaffold stability as a critical noise-mediating factor. We demonstrate that TATA box-dependent, increased gene expression noise can be beneficial after an acute change in environmental conditions. First, we illustrate computationally how a stable transcription scaffold can enable increased cell-cell variability at steady state. Second, we experimentally verify our computational prediction that the increased gene expression noise enabled by TATA-containing promoters confers a clear benefit in the face of an acute environmental stress. [Preview Abstract] |
Friday, March 9, 2007 8:48AM - 9:00AM |
X35.00003: Role of boundary constrains in DNA looping problem. Alexei Tkachenko We present a theoretical study of the effects of boundary constrains on DNA looping. The developed Effective Hamiltonian description enables one to calculate the looping probability density (so called J-factor), in a much simpler way than by traditional methods. Our approach is applicable to a variety of in-vitro and in-vivo problems, ranging from DNA cyclization, to protein-mediated DNA looping. In particular, it will be demonstrated that the existing controversy between various DNA cyclization experiments can be attributed to the variation in the boundary conditions. [Preview Abstract] |
Friday, March 9, 2007 9:00AM - 9:12AM |
X35.00004: Kinetic Accessibility of Buried DNA Sites in Nucleosomes Wolfram M\"obius, Richard A. Neher, Ulrich Gerland Motivated by recent experiments on nucleosome accessibility [1,2] we study the transient exposure of protein-binding DNA sites within nucleosomes using a theoretical model for spontaneous partial DNA unwrapping from histones. We focus on the functional dependence of the rates for site exposure and re-burial on the site position, which is pertinent to gene regulation. We find the dependence to be roughly described by a random walker model. Close inspection however reveals a surprising dependence of the re-burial rates on the length of unwrapped DNA. We show that this corresponds to a physical effect of flexibility-assisted barrier crossing, which we characterize within a toy model, the {\it semiflexible Brownian rotor}.\newline [1] G. Li, M. Levitus, C. Bustamante, and J. Widom, Nat. Struct. Biol. {\bf 12}, 46 (2005)\newline [2] M. Tomschik, H. Zheng, K. van Holde, J. Zlatanova, and S. Leuba, Proc. Natl. Acad. Sci. U.S.A. {\bf 102}, 3278 (2005)\newline [3] W. M\"obius, R.A. Neher, and U. Gerland, Phys. Rev. Lett. {\bf 97}, 208102 (2006) [Preview Abstract] |
Friday, March 9, 2007 9:12AM - 9:24AM |
X35.00005: Coarse-Grained Modeling of Molecular Machines in AAA+ Family Kenji Yoshimoto, Charles L. Brooks III We present a new coarse-grained model of the large protein complexes which belong to AAA+ (ATPase associated with diverse cellular activities) family. The AAA+ proteins are highly efficient molecular machines driven by the ATP (adenosine triphosphate) binding and hydrolysis and are involved in various cellular events. While a number of groups are developing various coarse-grained models for different AAA+ proteins, the molecular details of ATP binding and hydrolysis are often neglected. In this study, we provide a robust approach to coarse-graining both the AAA+ protein and the ATP (or ADP) molecules. By imposing the distance restraints between the phosphates of the ATP and the neighboring $C_{\alpha}$ of the proteins, which are used to conserve a typical motif of ATP binding pocket, we are able to predict large conformational changes of the AAA+ proteins, such as replicative hexameric helicases. In the case of the hexameric LTag (large tumor antigen), the backbone RMSD between the predicted ATP-bound structure and the X-ray structure is 1.2 $\AA$, and the RMSD between the predicted ADP-bound structure and the X-ray structure is 1.5 $\AA$. Using the same approach, we also investigate conformational changes in the hexameric E1 protein, whose X-ray structure was recently solved with ssDNA, and give some insights into the molecular mechanisms of DNA translocation. [Preview Abstract] |
Friday, March 9, 2007 9:24AM - 9:36AM |
X35.00006: A Simple Model of Nucleosome Localization David Schwab, Robijn Bruinsma It has recently been shown that nucleosomes localize to preferred locations along DNA. This localization is a result of the sequence dependent bending stiffness of dsDNA, which must be wrapped around a histone protein to form a nucleosome. As a simple model of nucleosome localization, we study a one-dimensional hard-core gas in a random potential. We numerically solve for the density profile and other thermodynamic quantities using as input both randomly generated potential profiles and experimental energy landscapes. We compare with the annealed average, inspired by the Random Energy Model, and find that the quenched and annealed averages differ significantly above the localization temperature, implying sequence induced structural organization long before the system has frozen. Although information about the ground state is preserved at higher temperatures, there exist massive structural reorganizations at fixed temperature when the chemical potential is lowered. This offers another perspective on why different cells, with different chemical potentials, have different gene expression. [Preview Abstract] |
Friday, March 9, 2007 9:36AM - 9:48AM |
X35.00007: Dynamics of assembly of proteins along a stretched DNA Ranjith Padinhateeri, John Marko We study the dynamics of filling of a one-dimensional lattice by k-site-long hard particles. We show that a model with adsorption, desorption and diffusion of k-mer particles can mimic in vitro experiments involving assembly of proteins along a stretched DNA. We study the dependence of force on the protein assembly dynamics and final filling. We also show that in a regime when adsorption rate is much larger than desorption rate, and no diffusion, one gets a power-law-like filling dynamics soon after jamming. [Preview Abstract] |
Friday, March 9, 2007 9:48AM - 10:00AM |
X35.00008: Hidden Markov Analysis of Tethered Particle Motion Phil Nelson, John Beausang Tethered particle experiments use light microscopy to measure the position of a micrometer-sized bead tethered to a microscope slide via a ~micrometer length polymer, in order to learn about the behavior of the invisible polymer. Currently, this method is being used to measure rate constants of DNA loop formation and breakdown mediated by repressor protein that binds to the DNA. We report a new technique for measuring these rates using a modified hidden Markov analysis that directly incorporates the diffusive motion of the bead, which is an inherent complication of tethered particle motion because it occurs on a time scale between the sampling frequency and the looping time. We compare the looping lifetimes found with our method, which are consistent over a range of sampling frequencies, to the lifetimes obtained via the traditional threshold-crossing analysis, which vary depending on how the raw data are filtered. Our method does not involve filtering, and so is able to detect short-lived looping events and sudden changes in looping behavior. [Preview Abstract] |
Friday, March 9, 2007 10:00AM - 10:12AM |
X35.00009: Model for the simultaneous evolution of protein sequences and conformations Longhua Hu, Alexander Grosberg Protein molecule folds because its sequence is quenched while its conformation dynamically evolves governed by the quenched sequence. Sequence design procedures known in the literature usually operate by computationally annealing the sequence on the background of properly quenched conformation. There are suggestions in the literature to invigorate both the sequence design and the computational folding algorithms by considering the simultaneous evolution of both sequence and conformation, assuming that these two sets of degrees of freedom interact with thermostats of two different temperatures. To examine this procedure, we study the model of random walks on the graph in which each vertex represents the state of a protein, including both sequence and conformation. The graph has bonds of two sorts, some represent change of conformation (physical motion), while others represent change of sequence (`mutation'). We show that when sequence and conformation dynamics are governed by different temperatures, there cannot be any equilibrium, and we analyze the stationary currents in the system which are realized by never stopping cascade of sequence rearrangements followed by conformational moves followed by sequence moves and so on, ad infinum. [Preview Abstract] |
Friday, March 9, 2007 10:12AM - 10:24AM |
X35.00010: Unwinding of double-stranded DNA and branch migration of Holliday junctions by hexameric motor proteins Noah Ribeck, Omar A. Saleh Ring-shaped hexameric helicases are critical components of the DNA replication machinery in eukaryotes and bacteria. It has been shown that in vitro, certain hexameric helicases such as Mcm4,6,7 from eukaryotes, and DnaB from E. coli can translocate while encircling either single-stranded DNA (while opening a DNA fork in advance of the protein) or while encircling double-stranded DNA. Further, the latter translocation mode can drive branch migration of Holliday junctions. Using magnetic tweezers, we have performed single-molecule measurements of the activity of DnaB and the Mcm complex during both fork-opening and branch migration. We will report on progress of measurements of velocity of these motors in each mode, and relate the results to theoretical models of active and passive unwinding. [Preview Abstract] |
Friday, March 9, 2007 10:24AM - 10:36AM |
X35.00011: How cells decide between life and death: predictions from stochastic simulation Subhadip Raychaudhuri, Eric Willgohs, Thuc-Nghi Nguyen Recent experiments show that cells experiencing oxidative stress conditions trigger both apoptotic (programmed cell death) and survival pathways. Cross-talk between those two complex signal transduction networks, in turn, crucially decides between life and death of a cell. We have developed a Monte Carlo stochastic simulation method that can predict the outcomes of cellular decision-making (between life and death) under oxidative stress in a probabilistic manner. Even under identical cellular conditions our stochastic simulations can lead to differential cellular response as observed in recent in vitro experiments. Interestingly, our numerical experiments indicate that spatial heterogeneity and localization of signaling molecules, in addition to the structure of the signaling networks, are crucial to such a stochastic outcome of cell signaling. By performing sensitivity analyses under a variety of physiological conditions we are able to identify some of the critical regulators of apoptotic cell death signaling under oxidative stress. [Preview Abstract] |
Friday, March 9, 2007 10:36AM - 10:48AM |
X35.00012: Evolution of codes, crosstalk, and sequence niches in biomolecular signaling Christopher Myers Signaling and regulation in cellular networks is mediated through biomolecular interactions, which can be somewhat promiscuous, involving the molecular recognition of broad sets of binding targets. This leads to some basic questions concerning crosstalk among similar sets of biomolecules: does it occur, to what extent can it be avoided, how can phenotypic errors due to crosstalk be minimized, and when might crosstalk be advantageous? Beyond biology, questions of this sort have connections to phase transitions in constraint satisfaction problems, and to the theory of message coding in noisy channels. Expanding upon my previous work exploring the nature of the satisfiability (SAT-UNSAT) transition in a simple model of protein-protein interactions, this talk will investigate the role of sequence evolution in shaping high-dimensional sequence niches and biomolecular codes. [Preview Abstract] |
Friday, March 9, 2007 10:48AM - 11:00AM |
X35.00013: Transcriptional Interference: A quantitative approach to in vivo dynamics of RNAP on DNA. Kim Sneppen We present a mathematical model for transcriptional interference by RNA polymerase traffic in Escherichia coli. The model deals with the interference between the two promoters pA and pS. The RNAPs are injected onto the DNA through binding and formation of sitting duck complexes at the respective promoters, followed by subsequent formation of elongating complexes. Finally we discuss a combination of modeling and in vivo-experiments can be used to infer the interference-recruitment game that govern the core of the genetic switch in the temperate bacteriophages 186.\\ K. Sneppen, I.B. Dodd, K.E. Shearwin, A.C. Palmer, R.A. Schubert, B.P. Callen, and J.B. Egan. J. Mol. Biol. 346:399 (2005) [Preview Abstract] |
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