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Theory of Conformational Transitions in Biological Macromolecules: From Unifying Principles to Testable Predictions

  • Author(s): Pierse, Christopher Albert
  • Advisor(s): Dudko, Olga K
  • et al.
Abstract

In this dissertation, we develop quantitative approaches, rooted in statistical mechanics, to understand the principles that govern the conformational dynamics of biomolecules.

We derive analytical expressions that are directly applicable to modern single-molecule experiments. First, we focus on two types of biomolecular transitions that are fundamental to virtually every living process -- folding and binding.Derived herein are analytical expressions suitable for fitting the major experimental outputs from single-molecule folding and binding experiments to enable their analysis and interpretation. The fit yields the key determinants of the folding and binding processes: the intrinsic on-rate and the location and height of the activation barrier. Then, we shift our focus to the experimental identification and functional advantages of multiple reaction pathways in biomolecular transitions. We establish model-free, experimentally observable signatures in the response of macromolecules to force that unambiguously identify the presence of multiple pathways -- even when the pathways themselves cannot be resolved in experiment. The unified analytical description reveals that multiple reaction pathways can shape the response of molecules to external forces in diverse ways, resulting in a rich design space for tailored biological function already at the single molecule level.

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