Development of a Data-driven Integrative Model of Bacterial Chromosome

Abstract

The chromosome of archetypal bacteria E. coli is known for a complex topology with 4.6 X 106base pairs (bp) long sequence of nucleotide packed within a micrometer-sized celllular confinement. The inherent organization underlying this chromosome eludes general consensus due to the lack of a high-resolution picture of its conformation. Here we present our development of an integrative model of E. coli at a 500 bp resolution (https://github.com/JMLab-tifrh/ecoli_finer), which optimally combines a set of multi-resolution genome-wide experimentally measured data within a framework of polymer based architecture. In particular the model is informed with intra-genome contact probability map at 5000 bp resolution derived via Hi-C experiment and RNA-sequencing data at 500 bp resolution. Via dynamical simulations, this data-driven polymer based model generates appropriate conformational ensemble commensurate with chromosome architectures that E. coli adopts. As a key hallmark, the model chromosome spontaneously self-organizes into a set of non-overlapping macrodomains and suitably locates plectonemic loops near the cell membrane. As novel extensions, it predicts a contact probability map simulated at a higher resolution than precedent experiments and can demonstrate segregation of chromosomes in a partially replicating cell. Finally, the modular nature of the model helps us to devise control simulations to quantify the individual role of key features in hierarchical organization of the bacterial chromosome.

Elucidation of Spatial Positioning of Ribosomes around Chromosome in Escherichia coli Cytoplasm via a Data-Informed Polymer-Based Model

“…This serves as an initial configuration for molecular dynamics. We next add Hi-C contact probabilities into the chromosome architecture as distance restraints maintained using harmonic springs as described in a previous The Journal of Physical Chemistry B study 18 and in Supporting Information Methods. We then perform molecular dynamics simulations, as described in a later section, to obtain an ensemble to conformations.…”

“…Here, we first provide a brief description of the chromosome model, the details of which have been published in a recent article. 18 Then, we describe our modeling approach for ribosomes.…”

“…We determined the labels by using RNA-Seq signals 12 and that in a genome equivalent of DNA there should be 43 ± 10 PARs as described in detail in a previous study. 18 Using the labels, we generate a hyperbranched polymer with a circular backbone. We then confine the initial conformation in a capsule whose cell dimensions are equivalent to experimentally observed cell dimensions: 3.05 μm in length and 0.82 μm in diameter.…”

“…Nevertheless, in this coarse-grained model, these forces have been substituted with their effective representations using the Lennard-Jones potentials that were previously developed in our study (Wasim et al, 2023). 18 Next, the Hi-C contact probabilities have been integrated into the model by first converting them into distances using…”

“…In this study, we utilize a recently developed integrated model of the E. coli cytoplasm, 18 which integrates Hi-C-derived data and RNA-seq data to obtain a hyperbranched computer model of the chromosome, as shown in Figure 1b. We optimize the chromosome−ribosome interactions to reproduce experimentally reported chromosome and ribosome axial densities.…”