Computational studies of macromolecular crowding effects on proteins

Bazmi, Saman (2023) Computational studies of macromolecular crowding effects on proteins. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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The high concentration of macromolecules inside living cells leads to an effect called macromolecular crowding. One very basic consequence of crowding is a decrease in the volume physically available to the molecules in the solution. This consequence is called the excluded volume effect. It has been observed experimentally that the excluded volume effect impacts various processes in cells. In this thesis, we investigate the effect of macromolecular crowding on two different large-scale conformational transitions in proteins: folding, which is the process by which proteins become functional and achieve their native state; and fold switching, a process in which a protein exhibits two or more native states and reversibly interconverts between them. To address these issues, we develop and apply coarse-grained models at various levels of resolution. In particular, we use two different models. 1. A sequence-based model with 7 atoms per amino acid in which folding is driven by effective hydrophobic interactions and hydrogen bonding. 2. A model with one bead per amino acid, with a structure-based (G¯o-like) potential, which provides an energetic bias towards two or more native states. Sampling of conformational space is performed using Monte Carlo techniques and Langevin dynamics. A long standing assumption in the crowding field is that the excluded volume effect always stabilizes the native states of proteins. However, by using our sequence-based model, we find this crowding effect can be destabilizing in some cases depending on the protein and crowding condition. To study crowding effects on fold switching, which has not been done before, we focus on the GA/GB fold switch system based on the 56 amino acid binding domain of protein G. This system is a designed fold switch system in which amino acid mutations drive the switch between the two different folds adopted by GA and GB. We find that crowding impacts the population balance between the two different folds. Specifically, we find that crowding enhances the stability of GB relative to GA. Overall, this thesis provides insight into how crowding effects on proteins depend on factors such as protein fold, types of interactions between crowders and proteins, crowders concentration, and conformational landscape of the protein, further advancing our understanding of the intricate interplay between cellular environments and protein behavior.

Item Type: Thesis (Doctoral (PhD))
Item ID: 16215
Additional Information: Includes bibliographical references
Keywords: macromolecules proteins, crowders, fold switching, computational biophysics
Department(s): Science, Faculty of > Physics and Physical Oceanography
Date: October 2023
Date Type: Submission
Digital Object Identifier (DOI):
Library of Congress Subject Heading: Macromolecules; Computational biology; Protein folding

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