Local energy approach to the dynamic glass transition

We propose a new class of phenomenological models for dynamic glass transitions. The system consists of an ensemble of mesoscopic regions to which local energies are allocated. At each time step, a region is randomly chosen and a new local energy is drawn from a distribution that self-consistently depends on the global energy of the system. Then, the transition is accepted or not according to the Metropolis rule. Within this scheme, we model an energy threshold leading to a mode-coupling glass transition as in the p-spin model. The glassy dynamics is characterized by a two-step relaxation of the energy autocorrelation function. The aging scaling is fully determined by the evolution of the global energy and linear violations of the fluctuation dissipation relation are found for observables uncorrelated with the energies. Interestingly, our mean-field approach has a natural extension to finite dimension, that we briefly discuss.Comment: 4 pages, 5 figure

Single-domain protein folding: a multi-faceted problem

We review theoretical approaches, experiments and numerical simulations that have been recently proposed to investigate the folding problem in single-domain proteins. From a theoretical point of view, we emphasize the energy landscape approach. As far as experiments are concerned, we focus on the recent development of single-molecule techniques. In particular, we compare the results obtained with two main techniques: single protein force measurements with optical tweezers and single-molecule fluorescence in studies on the same protein (RNase H). This allows us to point out some controversial issues such as the nature of the denatured and intermediate states and possible folding pathways. After reviewing the various numerical simulation techniques, we show that on-lattice protein-like models can help to understand many controversial issues.Comment: 26 pages, AIP Conference Proceeding

Requirements for DNA-bridging proteins to act as topological barriers of the bacterial genome

Bacterial genomes have been shown to be partitioned into several kilobases long chromosomal domains that are topologically independent from each other, meaning that change of DNA superhelicity in one domain does not propagate to neighbors. Both in vivo and in vitro experiments have been performed to question the nature of the topological barriers at play, leading to several predictions on possible molecular actors. Here, we address the question of topological barriers using polymer models of supercoiled DNA chains. More specifically, we determine under which conditions DNA-bridging proteins may act as topological barriers. To this end, we developed a coarse-grained bead-and-spring model and investigated its properties through Brownian dynamics simulations. As a result, we find that DNA-bridging proteins must exert rather strong constraints on their binding sites: they must block the diffusion of the excess of twist through the two binding sites on the DNA molecule and, simultaneously, prevent the rotation of one DNA segment relative to the other one. Importantly, not all DNA-bridging proteins satisfy this second condition. For example, single bridges formed by proteins that bind DNA non-specifically, like H-NS dimers, are expected to fail with this respect. Our findings might also explain, in the case of specific DNA-bridging proteins like LacI, why multiple bridges are required to create stable independent topological domains. Strikingly, when the relative rotation of the DNA segments is not prevented, relaxation results in complex intrication of the two domains. Moreover, while the value of the torsional stress in each domain may vary, their differential is preserved. Our work also predicts that nucleoid associated proteins known to wrap DNA must form higher protein-DNA complexes to efficiently work as topological barriers.Comment: Accepted for publication in the Biophysical Journa

Periodic pattern detection in sparse boolean sequences

<p>Abstract</p> <p>Background</p> <p>The specific position of functionally related genes along the DNA has been shown to reflect the interplay between chromosome structure and genetic regulation. By investigating the statistical properties of the distances separating such genes, several studies have highlighted various periodic trends. In many cases, however, groups built up from co-functional or co-regulated genes are small and contain wrong information (data contamination) so that the statistics is poorly exploitable. In addition, gene positions are not expected to satisfy a perfectly ordered pattern along the DNA. Within this scope, we present an algorithm that aims to highlight periodic patterns in sparse boolean sequences, i.e. sequences of the type 010011011010... where the ratio of the number of 1's (denoting here the transcription start of a gene) to 0's is small.</p> <p>Results</p> <p>The algorithm is particularly robust with respect to strong signal distortions such as the addition of 1's at arbitrary positions (contaminated data), the deletion of existing 1's in the sequence (missing data) and the presence of disorder in the position of the 1's (noise). This robustness property stems from an appropriate exploitation of the remarkable alignment properties of periodic points in solenoidal coordinates.</p> <p>Conclusions</p> <p>The efficiency of the algorithm is demonstrated in situations where standard Fourier-based spectral methods are poorly adapted. We also show how the proposed framework allows to identify the 1's that participate in the periodic trends, i.e. how the framework allows to allocate a <it>positional score </it>to genes, in the same spirit of the sequence score. The software is available for public use at <url>http://www.issb.genopole.fr/MEGA/Softwares/iSSB_SolenoidalApplication.zip</url>.</p

DNA supercoiling in bacteria: state of play and challenges from a viewpoint of physics based modeling

DNA supercoiling is central to fundamental processes of living organisms. Its average level along the chromosome and over time reflects the dynamic equilibrium of opposite activities of topoisomerases, which are required to relax mechanical stresses that are inevitably produced during DNA replication and gene transcription. Supercoiling affects all scales of the spatio-temporal organization of bacterial DNA, from the base pair to the large scale chromosome conformation. Highlighted in vitro and in vivo in the 1960s and 1970s, respectively, the first physical models were proposed concomitantly in order to predict the deformation properties of the double helix. About fifteen years later, polymer physics models demonstrated on larger scales the plectonemic nature and the tree-like organization of supercoiled DNA. Since then, many works have tried to establish a better understanding of the multiple structuring and physiological properties of bacterial DNA in thermodynamic equilibrium and far from equilibrium. The purpose of this essay is to address upcoming challenges by thoroughly exploring the relevance, predictive capacity, and limitations of current physical models, with a specific focus on structural properties beyond the scale of the double helix. We discuss more particularly the problem of DNA conformations, the interplay between DNA supercoiling with gene transcription and DNA replication, its role on nucleoid formation and, finally, the problem of scaling up models. Our primary objective is to foster increased collaboration between physicists and biologists. To achieve this, we have reduced the respective jargon to a minimum and we provide some explanatory background material for the two communities.Comment: 11 figure

Recovery of free energy branches in single molecule experiments

We present a method for determining the free energy of coexisting states from irreversible work measurements. Our approach is based on a fluctuation relation that is valid for dissipative transformations in partially equilibrated systems. To illustrate the validity and usefulness of the approach, we use optical tweezers to determine the free energy branches of the native and unfolded states of a two-state molecule as a function of the pulling control parameter. We determine, within 0.6 kT accuracy, the transition point where the free energies of the native and the unfolded states are equal.Comment: To appear in Phys. Rev. Lett. 4 pages + Supp. Mat. (6 pages

Parallel stepwise stochastic simulation: Harnessing GPUs to Explore Possible Futures States of a Chromosome Folding Model Thanks to the Possible Futures Algorithm (PFA)

International audienceFor the sake of software compatibility, simulations are often parallelized withoutmuch code rewriting. Performances can be further improved by optimizing codes so that to use themaximum power offered by parallel architectures. While this approach can provide some speed-up,performance of parallelized codes can be strongly limited a priori because traditional algorithmshave been designed for sequential technologies. Thus, additional increase of performance shouldultimately rely on some redesign of algorithms.Here, we redesign an algorithm that has traditionally been used to simulate the folding proper-ties of polymers. We address the issue of performance in the context of biological applications,more particularly in the active field of chromosome modelling. Due to the strong confinementof chromosomes in the cells, simulation of their motion is slowed down by the laborious searchfor the next valid states to progress. Our redesign, that we call the Possible Futures Algorithm(PFA), relies on the parallel computation of possible evolutions of the same state, which effectivelyincreases the probability to obtain a valid state at each step. We apply PFA on a GPU-basedarchitecture, allowing us to optimally reduce the latency induced by the computation overhead ofpossible futures. We show that compared to the initial sequential model the acceptance rate of newstates significantly increases without impacting the execution time. In particular, the stronger theconfinement of the chromosome, the more efficient PFA becomes, making our approach appealingfor biological applications.While most of our results were obtained using Fermi architecture GPUs from NVIDIA, we highlightimproved performance on the cutting-edge Kepler architecture K20 GPUs

CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the {\beta}-globin locus

The principles underlying the architectural landscape of chromatin beyond the nucleosome level in living cells remains largely unknown despite its potential to play a role in mammalian gene regulation. We investigated the 3-dimensional folding of a 1 Mbp region of human chromosome 11 containing the {\beta}-globin genes by integrating looping interactions of the insulator protein CTCF determined comprehensively by chromosome conformation capture (3C) into a polymer model of chromatin. We find that CTCF-mediated cell type specific interactions in erythroid cells are organized to favor contacts known to occur in vivo between the {\beta}-globin locus control region (LCR) and genes. In these cells, the modeled {\beta}-globin domain folds into a globule with the LCR and the active globin genes on the periphery. By contrast, in non-erythroid cells, the globule is less compact with few but dominant CTCF interactions driving the genes away from the LCR. This leads to a decrease in contact frequencies that can exceed 1000-fold depending on the stiffness of the chromatin and the exact positioning of the genes. Our findings show that an ensemble of CTCF contacts functionally affects spatial distances between control elements and target genes contributing to chromosomal organization required for transcription.Comment: Full article, including Supp. Mat., is available at Nucleic Acids Research, doi: 10.1093/nar/gks53