The energy landscapes of metamorphic proteins

Seifi, Bahman (2023) The energy landscapes of metamorphic proteins. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Most proteins fold into a unique three-dimensional structure called the native state. Recently some examples have been found of so-called metamorphic proteins that undergo reversible large-scale structural transformations between different native states. In this thesis, we develop simulation methods and models to study the thermodynamics of these transformations, both at the coarse-grained and all-atom levels. Because our understanding of the physics fold switching is incomplete, our models utilize in part so-called structure-based or Gō-like potentials, which provide energetic bias towards one, or more, native states. We employ these computational methods to two different fold switch systems: the bacterial protein RfaH and the engineered fold switch system GA/GB. Our models are developed and tested on experimental data for these systems. We study both equilibrium properties, such as stability properties and the characteristics of their energy landscapes, and kinetic properties, such as the mechanism that trigger fold switching and molecular details of the fold switch process. We also study, for the GA/GB system, what role macromolecular crowding effects play for controlling which of the native states is most stable.

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