Development of a Data-Driven Integrative Model of a Bacterial Chromosome

Abstract

The chromosome of archetypal bacteria E. coli is known for a complex topology with a 4.6 × 10 6 base pairs (bp) long sequence of nucleotides packed within a micrometer-sized cellular 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 multiresolution genome-wide experimentally measured data within a framework of polymer based architecture. In particular the model is informed with an intragenome contact probability map at 5000 bp resolution derived via the Hi-C experiment and RNA-sequencing data at 500 bp resolution. Via dynamical simulations, this data-driven polymer based model generates an appropriate conformational ensemble commensurate with chromosome architectures that E. coli adopts. As a key hallmark of the E. coli chromosome the model spontaneously self-organizes into a set of nonoverlapping 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 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

“…The details of the data-integrated chromosome model have been reported by us in a recent article. Here, we first provide a brief description of the chromosome model, the details of which have been published in a recent article . Then, we describe our modeling approach for ribosomes.…”

“…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 study and in Supporting Information Methods. We then perform molecular dynamics simulations, as described in a later section, to obtain an ensemble to conformations.…”

“…In reality, when considering all-atom descriptions of DNA, mRNA-bound 70S ribosomes, and free (30S/50S) ribosomes, there are numerous sites where electrostatic and van der Waals interactions can occur. 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) …”

“…coli through molecular biology techniques, − microscopy studies, − chromosome conformation capture methods, − ChIP-Seq analyses, , and RNA-Seq investigations . These rapidly advancing data sets, coupled with computational models, have facilitated the elucidation of the architectural characteristics of the chromosome at increasingly higher resolutions, leading to a better understanding of its spatial organization. − A majority of these studies delve into the architecture of the chromosome and compaction mechanisms driven by various nucleoid-binding proteins.…”

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