Sloppiness, Modeling, and Evolution in Biochemical Networks

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The wonderful complexity of livings cells cannot be understood solely by studying one gene or protein at a time. Instead, we must consider their interactions and study the complex biochemical networks they function in. Quantitative computational models are important tools for understanding the dynamics of such biochemical networks, and we begin in Chapter 2 by showing that the sensitivities of such models to parameter changes are generically `sloppy', with eigenvalues roughly evenly spaced over many decades. This sloppiness has practical consequences for the modeling process. In particular, we argue that if one's goal is to make experimentally testable predictions, sloppiness suggests that collectively fitting model parameters to system-level data will often be much more efficient that directly measuring them. In Chapter 3 we apply some of the lessons of sloppiness to a specific modeling project involving in vitro experiments on the activation of the heterotrimeric G protein transducin. We explore how well time-series activation experiments can constrain model parameters, and we show quantitatively that the T177A mutant of transducin exhibits a much slower rate of rhodopsin-mediated activation than the wild-type. All the preceding biochemical modeling work is performed using the SloppyCell modeling environment, and Chapter 4 briefly introduces SloppyCell and some of the analyses it implements. Additionally, the two appendices of this thesis contain preliminary user and developer documentation for SloppyCell. Modelers tweak network parameters with their computers, and nature tweaks such parameters through evolution. We study evolution in Chapter 5 using a version of Fisher's geometrical model with minimal pleiotropy, appropriate for the evolution of biochemical parameters. The model predicts a striking pattern of cusps in the distribution of fitness effects of fixed mutations, and using extreme value theory we show that the consequences of these cusps should be observable in feasible experiments. Finally, this thesis closes in Chapter 6 by briefly considering several topics: sloppiness in two non-biochemical models, two technical issues with building models, and the effect of sloppiness on evolution beyond the first fixed mutation.
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uncertainties; transducin; SloppyCell; geometrical model
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dissertation or thesis
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