Looping and Clustering: a statistical physics approach to protein-DNA complexes in bacteria

International audienceThe DNA shows a high degree of spatial and dynamical organization over a broad range of length scales. It interacts with different populations of proteins and can form protein-DNA complexes that underlie various biological processes, including chromosome segregation. A prominent example is the large ParB-DNA complex, an essential component of a widely spread mechanism for DNA segregation in bacteria. Recent studies suggest that DNA-bound ParB proteins interact with each other and condense into large clusters with multiple extruding DNA-loops. In my talk, I present the Looping and Clustering model [1], a simple statistical physics approach to describe how proteins assemble into a protein-DNA cluster with multiple loops. Our analytic model predicts binding profiles of ParB proteins in good agreement with data from high precision ChIP-sequencing – a biochemical technique to analyze the interaction between DNA and proteins at the level of the genome. The Looping and Clustering framework provides a quantitative tool that could be exploited to interpret further experimental results of ParB-like protein complexes and gain some new insights into the organization of DNA.[1] Walter, J.-C., Walliser, N.-O., ... & Broedersz, C. P., New J. Phys. 20, 035002 (2018)

Restrictions on infinite sequences of type IIB vacua

Ashok and Douglas have shown that infinite sequences of type IIB flux vacua with imaginary self-dual flux can only occur in so-called D-limits, corresponding to singular points in complex structure moduli space. In this work we refine this no-go result by demonstrating that there are no infinite sequences accumulating to the large complex structure point of a certain class of one-parameter Calabi-Yau manifolds. We perform a similar analysis for conifold points and for the decoupling limit, obtaining identical results. Furthermore, we establish the absence of infinite sequences in a D-limit corresponding to the large complex structure limit of a two-parameter Calabi-Yau. In particular, our results demonstrate analytically that the series of vacua recently discovered by Ahlqvist et al., seemingly accumulating to the large complex structure point, are finite. We perform a numerical study of these series close to the large complex structure point using appropriate approximations for the period functions. This analysis reveals that the series bounce out from the large complex structure point, and that the flux eventually ceases to be imaginary self-dual. Finally, we study D-limits for F-theory compactifications on K3\times K3 for which the finiteness of supersymmetric vacua is already established. We do find infinite sequences of flux vacua which are, however, identified by automorphisms of K3.Comment: 35 pages. v2. Typos corrected, ref. added. Matches published versio

PALP - a User Manual

This article provides a complete user's guide to version 2.1 of the toric geometry package PALP by Maximilian Kreuzer and others. In particular, previously undocumented applications such as the program nef.x are discussed in detail. New features of PALP 2.1 include an extension of the program mori.x which can now compute Mori cones and intersection rings of arbitrary dimension and can also take specific triangulations of reflexive polytopes as input. Furthermore, the program nef.x is enhanced by an option that allows the user to enter reflexive Gorenstein cones as input. The present documentation is complemented by a Wiki which is available online.Comment: 71 pages, to appear in "Strings, Gauge Fields, and the Geometry Behind - The Legacy of Maximilian Kreuzer". PALP Wiki available at http://palp.itp.tuwien.ac.at/wiki/index.php/Main_Pag

Signature of (anti)cooperativity in the stochastic fluctuations of small systems: application to the bacterial flagellar motor

The cooperative binding of molecular agents onto a substrate is pervasive in living systems. To study whether a system shows cooperativity, one can rely on a fluctuation analysis of quantities such as the number of substrate-bound units and the residence time in an occupancy state. Since the relative standard deviation from the statistical mean monotonically decreases with the number of binding sites, these techniques are only suitable for small enough systems, such as those implicated in stochastic processes inside cells. Here, we present a general-purpose grand canonical Hamiltonian description of a small one-dimensional (1D) lattice gas with either nearest-neighbor or long-range interactions as prototypical examples of cooperativity-influenced adsorption processes. First, we elucidate how the strength and sign of the interaction potential between neighboring bound particles on the lattice determine the intensity of the fluctuations of the mean occupancy. We then employ this relationship to compare the theoretical predictions of our model to data from single molecule experiments on bacterial flagellar motors (BFM) of E. coli. In this way, we find evidence that cooperativity controls the mechano-sensitive dynamical assembly of the torque-generating units, the so-called stator units, onto the BFM. Furthermore, in an attempt to quantify fluctuations and the adaptability of the BFM, we estimate the stator-stator interaction potential. Finally, we conclude that the system resides in a sweet spot of the parameter space (phase diagram) suitable for a smoothly adaptive system while minimizing fluctuations.Comment: 35 pages, 18 figures, 4 table

Looping and clustering model for the organization of protein-DNA complexes on the bacterial genome

The bacterial genome is organized by a variety of associated proteins inside a structure called the nucleoid. These proteins can form complexes on DNA that play a central role in various biological processes, including chromosome segregation. A prominent example is the large ParB-DNA complex, which forms an essential component of the segregation machinery in many bacteria. ChIP-Seq experiments show that ParB proteins localize around centromere-like parS sites on the DNA to which ParB binds specifically, and spreads from there over large sections of the chromosome. Recent theoretical and experimental studies suggest that DNA-bound ParB proteins can interact with each other to condense into a coherent 3D complex on the DNA. However, the structural organization of this protein-DNA complex remains unclear, and a predictive quantitative theory for the distribution of ParB proteins on DNA is lacking. Here, we propose the looping and clustering model, which employs a statistical physics approach to describe protein-DNA complexes. The looping and clustering model accounts for the extrusion of DNA loops from a cluster of interacting DNA-bound proteins that is organized around a single high-affinity binding site. Conceptually, the structure of the protein-DNA complex is determined by a competition between attractive protein interactions and loop closure entropy of this protein-DNA cluster on the one hand, and the positional entropy for placing loops within the cluster on the other. Indeed, we show that the protein interaction strength determines the 'tightness' of the loopy protein-DNA complex. Thus, our model provides a theoretical framework for quantitatively computing the binding profiles of ParB-like proteins around a cognate (parS) binding site

Four-modulus "Swiss Cheese" chiral models

We study the 'Large Volume Scenario' on explicit, new, compact, four-modulus Calabi-Yau manifolds. We pay special attention to the chirality problem pointed out by Blumenhagen, Moster and Plauschinn. Namely, we thoroughly analyze the possibility of generating neutral, non-perturbative superpotentials from Euclidean D3-branes in the presence of chirally intersecting D7-branes. We find that taking proper account of the Freed-Witten anomaly on non-spin cycles and of the Kaehler cone conditions imposes severe constraints on the models. Nevertheless, we are able to create setups where the constraints are solved, and up to three moduli are stabilized.Comment: 40 pages, 10 figures, clarifying comments added, minor mistakes correcte

Toric Construction of Global F-Theory GUTs

We systematically construct a large number of compact Calabi-Yau fourfolds which are suitable for F-theory model building. These elliptically fibered Calabi-Yaus are complete intersections of two hypersurfaces in a six dimensional ambient space. We first construct three-dimensional base manifolds that are hypersurfaces in a toric ambient space. We search for divisors which can support an F-theory GUT. The fourfolds are obtained as elliptic fibrations over these base manifolds. We find that elementary conditions which are motivated by F-theory GUTs lead to strong constraints on the geometry, which significantly reduce the number of suitable models. The complete database of models is available at http://hep.itp.tuwien.ac.at/f-theory/. We work out several examples in more detail.Comment: 35 pages, references adde

Looping and Clustering model for the organization of protein-DNA complexes on the bacterial genome

The bacterial genome is organized by a variety of associated proteins inside a structure called the nucleoid. These proteins can form complexes on DNA that play a central role in various biological processes, including chromosome segregation. A prominent example is the large ParB-DNA complex, which forms an essential component of the segregation machinery in many bacteria. ChIP-Seq experiments show that ParB proteins localize around centromere-like parS sites on the DNA to which ParB binds specifically, and spreads from there over large sections of the chromosome. Recent theoretical and experimental studies suggest that DNA-bound ParB proteins can interact with each other to condense into a coherent 3D complex on the DNA. However, the structural organization of this protein-DNA complex remains unclear, and a predictive quantitative theory for the distribution of ParB proteins on DNA is lacking. Here, we propose the Looping and Clustering (LC) model, which employs a statistical physics approach to describe protein-DNA complexes. The LC model accounts for the extrusion of DNA loops from a cluster of interacting DNA-bound proteins that is organized around a single high-affinity binding site. Conceptually, the structure of the protein-DNA complex is determined by a competition between attractive protein interactions and the configurational and loop entropy of this protein-DNA cluster. Indeed, we show that the protein interaction strength determines the "tightness" of the loopy protein-DNA complex. Thus, our model provides a theoretical framework to quantitatively compute the binding profiles of ParB-like proteins around a cognate parS binding site