ORCID
https://orcid.org/0000-0001-6511-5480
Date of Award
12-20-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Intrinsically disordered regions (IDRs) are protein domains or regions that lack a fixed three- dimensional structure. Within IDRs, regions and residues can engage in intramolecular interactions with other parts of the same polypeptide or intermolecular interactions with other biomolecules. This dissertation focuses on how the “context” of an IDR can influence the interactions it can undergo. Specifically, how the identity, chemistry, and position of interacting residues in IDRs tune IDR conformational behavior, the propensity of IDRs to self-assemble via phase separation, and how these three properties are tuned by the solution environment. These concepts are explored through a combination of bioinformatic sequence analysis, all-atom (CAMPARI) and coarse grain (PIMMS + LAMMPS) simulations, and through integral wet lab collaborations. Following an initial introduction of IDRs and the possible interactions they can undergo, explored are four key themes: Chapter 3-6 explore new bioinformatic methods for analyzing and characterizing IDRs enabling a more accessible and contextualized understanding of IDR conformational properties. Subsequently, the idea of sequence “context” is then explored through a set of collaborations showing how the distributions and clustering of amino acids can affect IDR conformation and condensate properties. The chemical solution “context” of an IDR is then introduced via a method for quantifying the sensitivity of IDR, and is explored through a discussion on how the solution environment of an IDR affects its conformational behavior and capacity undergo phase separation. Finally, Chapters 9 & 10 present mechanisms for identifying amino acid sequence features that delineate the presence of interacting residues in an IDR sequence and then also explores the idea of “context” relative to how IDR interactions with other proteins and RNA can promote phase separation.
Language
English (en)
Chair and Committee
Alex Holehouse
Recommended Citation
Ginell, Garrett, "Understanding the Chemical Context of Interactions in Intrinsically Disordered Proteins" (2023). Arts & Sciences Electronic Theses and Dissertations. 3213.
https://openscholarship.wustl.edu/art_sci_etds/3213