Robustness And Evolvability In Systems Biology And Plectoneme Formation In Dna Supercoiling
This thesis consists of two parts: (1) an exploration of robustness and evolvability in systems biology and how they are informed by recent developments in the study of parameter sensitivity in large multiparameter models, and (2) a study of the sudden formation of plectonemes (supercoiled structures) in DNA using an elastic rod model. Robustness and evolvability are important ideas in systems biology, representing the surprising resilience and adaptability of living organisms. The study of "sloppy models" describes the degree to which changes in parameters change the behavior of complex models, and thus has implications for how robust or evolvable a model may be with regard to perturbations in parameters. We study these connections, finding that sloppiness provides a framework for understanding why multiparameter models often seem so robust. It also explains how robustness to external conditions can be more easily arranged than one might naively expect, and allows for diversity that could increase the evolvability of a population. When overtwisted, DNA wraps around itself (supercoils) much like a garden hose or rubber band. As a single molecule of DNA is twisted, discontinuities have recently been experimentally observed for the first time that correspond to the sudden formation of a single supercoiled structure called a plectoneme. We study the sizes of these discontinuities with an elastic rod model and a simplified phenomenological model. We use these models to make predictions about a torque jump and length dependence that have been experimentally verified. Experiments also observe thermal hopping at the transition between states with and without a plectoneme. We then investigate the dynamics of this plectoneme nucleation, using transition state theory and the elastic rod model to predict the rate of hopping. We obtain a rate about 1000 times faster than found in experiments, and attribute the discrepancy to a slow timescale introduced by the large bead used to manipulate the DNA. Finally, we review numerical methods used to implement the elastic rod model for DNA.
dissertation or thesis