Complete atomistic model of a bacterial cytoplasm for integrating physics, biochemistry, and systems biology

Abstract

A model for the cytoplasm of Mycoplasma genitalium is presented that integrates data from a variety of sources into a physically and biochemically consistent model. Based on gene annotations, core genes expected to be present in the cytoplasm were determined and a metabolic reaction network was reconstructed. The set of cytoplasmic genes and metabolites from the predicted reactions were assembled into a comprehensive atomistic model consisting of proteins with predicted structures, RNA, protein/RNA complexes, metabolites, ions, and solvent. The resulting model bridges between atomistic and cellular scales, between physical and biochemical aspects, and between structural and systems views of cellular systems and is meant as a starting point for a variety of simulation studies.

Molecular dynamics simulations of large macromolecular complexes

“…Future physics-based multi-scale models, incorporating biochemical information and systems biology will enable the study of cellular-scale processes involving thousands of proteins, as exemplified by the pioneering work of Feig et. al, related to the atomistic description of the bacterial cytoplasm [5]. …”

“…As illustrated in Figure 1, the rise of scientific supercomputing has allowed for the study of the living cell in unparalleled detail, from the scale of the atom [1, 2] to a whole organism [3, 4, 5] and at all levels in between [6]. In particular, the past three decades have witnessed the evolution of molecular dynamics (MD) simulations as a “computational microscope” [7], which has provided a unique framework for the study of the phenomena of cell biology in atomic (or near-atomic) detail.…”

Advances in free-energy-based simulations of protein folding and ligand binding

“…As the time and length scales that can be simulated continue to grow, so does our ability to tackle more challenging problems. The current frontier includes modeling protein-protein and protein-DNA binding affinities, the behavior of ATPases [69-71], aggregation and amyloid formation [72], and the cytoplasm of a bacterium cell [73]. …”

Protein folding/unfolding in the presence of interacting macromolecular crowders

“…Their simulated system contained 1000 macromolecules of 50 types (proteins and RNAs), with a composition reflecting that in the cytoplasm of Escherichia Coli bacteria. Recently, Feig et al presented a detailed and extensive model for another bacterial cytoplasm, that of Mycoplasma genitalium, which may serve as a starting point for simulations [63,64]. The model includes proteins, RNAs, protein/RNA complexes, metabolites, ions as well as explicit solvent molecules.…”