UC San Diego

Due to the relative prevalence and centrality of the proteome, it is unsurprising that a great number of environmental stressors exert pressure on the cell via impacting proteome function. Whether it be in a global sense, as in temperature or pH destabilizing large fractions of the proteome, or in a more local sense, as in the targeting of one or a handful of proteins by an inhibitory compound, it is not possible to understand physicochemical pressures on the cellular system without considering properties of the proteome. This thesis aims to enable the analysis and simulation of such physicochemical constraints upon the cellular system through integration of systems biology with protein structural data and computational methods. This is the approach of the emerging field of structural systems biology. This work demonstrates examples of interrogating physicochemical stress imposed upon metabolic systems by exposure to exogenous chemicals and non-optimal temperatures. An extensive data resource was developed to capture biologically-relevant protein structural states to be integrated with the genome-scale metabolic model of the bacterium Escherichia coli. The primary results include 1) prediction of causal drug off-targets to explain a lethal but poorly understood drug side effect in humans, 2) establishing metabolic activities as growth-rate limiting under heat shock conditions and discovering specific bottlenecks such stress creates in the metabolic system of E. coli, and 3) analysis of antibacterial mechanisms of both well- and poorly-understood compounds and drug design via protein targeting. Thus, through the integration of structural and systems biology, new insights are provided about the impact of physicochemical stress on complex biological systems