Yannick G. Spill

Restraint‐based three‐dimensional modeling of genomes and genomic domains

Chromosomes are large polymer molecules composed of nucleotides. In some species, such as humans, this polymer can sum up to meters long and still be properly folded within the nuclear space of few microns in size. The exact mechanisms of how the meters long DNA is folded into the nucleus, as well as how the regulatory machinery can access it, is to a large extend still a mystery. However, and thanks to newly developed molecular, genomic and computational approaches based on the Chromosome Conformation Capture (3C) technology, we are now obtaining insight on how genomes are spatially organized. Here we review a new family of computational approaches that aim at using 3C‐based data to obtain spatial restraints for modeling genomes and genomic domains.

Impact of Thermostats on Folding and Aggregation Properties of Peptides Using the Optimized Potential for Efficient Structure Prediction Coarse-Grained Model.

The simulation of amyloid fibril formation is impossible if one takes into account all chemical details of the amino acids and their detailed interactions with the solvent. We investigate the folding and aggregation of two model peptides using the optimized potential for efficient structure prediction (OPEP) coarse-grained model and replica exchange molecular dynamics (REMD) simulations coupled with either the Langevin or the Berendsen thermostat. For both the monomer of blocked penta-alanine and the trimer of the 25-35 fragment of the Alzheimers amyloid β protein, we find little variations in the equilibrium structures and heat capacity curves using the two thermostats. Despite this high similarity, we detect significant differences in the populations of the dominant conformations at low temperatures, whereas the configurational distributions remain the same in proximity of the melting temperature. Aβ25-35 trimers at 300 K have an averaged β-sheet content of 12% and are primarily characterized by fully disordered peptides or a small curved two-stranded β-sheet stabilized by a disordered peptide. In addition, OPEP molecular dynamics simulations of Aβ25-35 hexamers at 300 K with a small curved six-stranded antiparallel β-sheet do not show any extension of the β-sheet content. These data support the idea that the mechanism of Aβ25-35 amyloid formation does not result from a high fraction of extended β-sheet-rich trimers and hexamers.

A convective replica‐exchange method for sampling new energy basins

Replica‐exchange is a powerful simulation method for sampling the basins of a rugged energy landscape. The replica‐exchange methods sampling is efficient because it allows replicas to perform round trips in temperature space, thereby visiting both low and high temperatures in the same simulation. However, replicas have a diffusive walk in temperature space, and the round trip rate decreases significantly with the system size. These drawbacks make convergence of the simulation even more difficult than it already is when bigger systems are tackled. Here, we present a simple modification of the exchange method. In this method, one of the replicas steadily raises or lowers its temperature. We tested the convective replica‐exchange method on three systems of varying complexity: the alanine dipeptide in implicit solvent, the GB1 β‐hairpin in explicit solvent and the Aβ25–35 homotrimer in a coarse grained representation. For the highly frustrated Aβ25–35 homotrimer, the proposed “convective” replica‐exchange method is twice as fast as the standard method. It discovered 24 out of 27 free‐energy basins in less than 500 ns. It also prevented the formation of groups of replicas that usually form on either side of an exchange bottleneck, leading to a more efficient sampling of new energy basins than in the standard method.

On the demultiplexing of chromosome capture conformation data.

How to describe the multiple chromosome structures that underlie interactions among genome loci and how to quantify the occurrence of these structures in a cell population remain important challenges to solve, which can be addressed via a proper demultiplexing of chromosome capture conformation related data. Here, we first aim to review two main methodologies that have been proposed to tackle this problem: restrained‐based methods, in which the resulting chromosome structures stem from the multiple solutions of a distance satisfaction problem; and thermodynamic‐based methods, in which the structures stem from the simulation of polymer models. Next, we propose a novel demultiplexing method based on a matrix decomposition of contact maps. To this end, we extend the notion of topologically associated domains (TADs) by introducing that of statistical interaction domains (SIDs). SIDs can overlap and occur in a cell population at certain frequencies, and we propose a simple method to estimate these frequency values. As an application, we show that SIDs that measure 100 kb to tens of Mb long occur both frequently and specifically in the human genome.

SAXS Merge: an automated statistical method to merge SAXS profiles using Gaussian processes.

A statistical method to merge SAXS profiles using Gaussian processes is presented.

SAS profile correlations reveal SAS hierarchical nature and information content

In structural biology, Small-Angle Scattering experiments (SAS) are unique, because although they provide low resolution data, they can be performed in closer-to-native conditions than those arising in X-Ray crystallography. A number of questions on SAS, however, remain unsolved, particularly in the light of modelling ensembles of conformers in solution. In this article, we study the ensemble average and covariance of SAS profiles analytically. Using this ensemble covariance, we demonstrate the hierarchical nature of SAS profiles. Furthermore, we show that the information content is not uniform and reaches its maximum in the intermediate q range. The arguments are generalized using microsecond-scale molecular dynamics trajectories of the lysozyme and on an ensemble of the intrinsically disordered protein p15PAF. We show that for highly flexible systems, the SAS profile is a representation of the ensemble of conformers in solution, and not that of one conformer in particular.

Binless normalization of Hi-C data provides significant interaction and difference detection independently of resolution

3C-like experiments, such as 4C or Hi-C, have been fundamental in understanding genome organization. Thanks to these technologies, it is now known, for example, that Topologically Associating Domains (TADs) and chromatin loops are implicated in the dynamic interplay of gene activation and repression, and their disruption can have dramatic effects on embryonic development. To make their detection easier, scientists have endeavored into deeper sequencing to mechanically increase the chances to detect weaker signals such as chromatin loops. Part of this mindset can be attributed to the limitations of existing software: the analysis of Hi-C experiments is both statistically and computationally demanding. Here, we devise a new way to represent Hi-C data, which leads to a more detailed classification of paired-end reads and, ultimately, to a new normalization and interaction detection method. Unlike any other, Binless is resolution-agnostic, and adapts to the quality and quantity of available data. We demonstrate its capacities to call interactions and differences and make the software freely available.

Convective Replica-Exchange in Ergodic Regimes.

In a recent article (J. Comput. Chem. 2013, 34, 132-140), convective replica-exchange (convective-RE) has been presented as an alternative to the standard even-odd transition scheme. Computations on systems of various complexity have shown that convective-RE may increase the number of replica round-trips in temperature space with respect to the standard exchange scheme, leading to a more effective sampling of energy basins. Moreover, it has been shown that the method may prevent the formation of bottlenecks in the diffusive walk of replicas through the space of temperature states. By using an ideal temperature-RE model and a classical harmonic-oscillator RE scheme, we study the performances of convective-RE when ergodicity is not broken and convergence of acceptance probabilities is attained. In this dynamic regime, the round-trip ratio between convective and standard-RE is at maximum ∼ 1.5, a value much smaller than that observed in nonergodic simulations. For large acceptance probabilities, the standard-RE outperforms convective-RE. Our observations suggest that convective-RE can safely be used in either ergodic or non-ergodic regimes; however, convective-RE is advantageous only when bottlenecks occur in the state-space diffusion of replicas, or when acceptance probabilities are globally low. We also show that decoupling of the state-space dynamics of the stick replica from the dynamics of the remaining replicas improves the efficiency of convective-RE at low acceptance probability regimes.

Promoter bivalency favors an open chromatin architecture in embryonic stem cells

In embryonic stem cells (ESCs), developmental gene promoters are characterized by their bivalent chromatin state, with simultaneous modification by MLL2 and Polycomb complexes. Although essential for embryogenesis, bivalency is functionally not well understood. Here, we show that MLL2 plays a central role in ESC genome organization. We generate a catalog of bona fide bivalent genes in ESCs and demonstrate that loss of MLL2 leads to increased Polycomb occupancy. Consequently, promoters lose accessibility, long-range interactions are redistributed, and ESCs fail to differentiate. We pose that bivalency balances accessibility and long-range connectivity of promoters, allowing developmental gene expression to be properly modulated.Analysis of bivalent promoters in embryonic stem cells (ESCs) shows that deletion of MLL2 in ESCs leads to increased Polycomb occupancy, reduced promoter accessibility, redistribution of long-range chromatin interactions, and failure to differentiate.