Physically resolved Whole-Cell Colloidal Modeling of Escherichia coli Reveals Growth-Dependent Nucleoid Organization

The spatial organization of macromolecules within Escherichia coli plays a critical role in coordinating transcriptional activity and gene expression. Recent studies suggest that, at faster growth rates, E. coli may sequester RNA polymerase (RNAP) to improve ribosomal RNA transcription. In this work, we build an efficient, colloidal-scale, dynamical whole-cell model of E. coli with explicit representation of biomolecules using a systematic refinement pipeline to map molecular and genomic details onto colloid surfaces. Using a sequence-specific E. coli chromosome and a physiologically accurate representation of biomolecules, we investigate how cytoplasmic crowding, polydispersity, and protein interactions influence nucleoid compaction and the distribution of macromolecules, such as ribosomes, nucleoid-associated proteins (NAPs), transcription factors, and RNAPs, within the crowded bacterial cell. We further characterize how these effects influence nucleoid mesh size and transcriptional accessibility. Our results predict growth-dependent transcription initiation and provide insight into the physical determinants that affect RNAP accessibility, which can inform the design of antibacterial drugs targeting the transcriptional machinery.