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Elucidating protein-protein interactions that regulate the structure of bacterial protein assemblies using multiscale modeling methods
Halingstad, Ethan Vebjorn
Halingstad, Ethan Vebjorn
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2023
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2024-11-29
Abstract
Self-assembling protein structures have a wide range of functions in many bacterial species. In the spore-forming bacterial pathogen Bacillus anthracis, a protective paracrystalline monolayer composed of the surface layer protein Sap is an important virulence factor that enables the spread of the disease anthrax. In many bacterial species such as Haliangium ochraceum, self-assembling bacterial microcompartments compartmentalize enzymes that aid in the energy production and metabolism of the organism.
The understanding of the mechanisms of assembly of both complexes has important implications for therapeutic and metabolic engineering. In vivo, nanobody-mediated disruption of the B. anthracis surface layer attenuated bacterial growth and prevented lethality. Revealing the mechanism of self-assembly may provide insight into the design of protein therapeutics with increased affinity and effectiveness. Metabolic engineers are also interested in repurposing bacterial microcompartments for non-native functions. Identifying molecular driving forces and assembly conditions that direct the morphology and cargo of bacterial microcompartment shells can guide the engineering of novel microcompartment shells to encapsulate non-endogenous enzymes and expand the range of metabolic activity.
Here, I propose the use of multiscale modelling to highlight the effect of protein flexibility on the exposure of key protein-protein interfaces in these self-assembling proteins. By generating and validating an atomistic model of the Sap protein lattice, I aim to identify the interactions responsible for lattice assembly to guide future nanobody design. I also provide a framework for the coarse-grained modeling of a hexameric H. ochraceum microcompartment subunit. The ability of this model to accurately capture the morphologies observed in in vivo and in vitro experiments will enable the in silico modeling of other microcompartment subunits that can be used collectively to explore the morphological landscape of microcompartment assemblies, further leading to the engineering of microcompartments that expand the range of microbial metabolism.
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