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Title:From metabolites to macromolecules: Computational models of the E. coli and H. sapiens cytoplasms
Author(s):Rickard, Meredith
Director of Research:Gruebele, Martin H; Pogorelov, Taras V
Doctoral Committee Chair(s):Gruebele, Martin H
Doctoral Committee Member(s):Luthey-Schulten, Zaida; van der Donk, Wilfred
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Molecular Dynamics
Protein Dynamics
Protein Folding
Abstract:In recent years, there has been an increasing emphasis on the impact of the cellular environment on biomolecular dynamics. In particular, there is growing evidence that the cell’s environment is finely tuned to modulate the stability, kinetics, binding, and activity of proteins within it. This thesis uses computational techniques to better understand the atomistic mechanisms underlying these impacts on protein dynamics. I begin by describing the motivation and challenges of simulating biomolecules in-cell. In Chapter 1, I discuss the in-cell environment and introduce crowding, sticking, and quinary interactions, the basic interactions that affect protein-dynamics in-cell. I briefly highlight several experimental studies that have demonstrated the impact of the cellular environment on protein dynamics over the last fifteen years. Then, I discuss the history and current landscape of simulating biomolecules in cellular conditions, including notable studies and ongoing challenges. In Chapter 2, I describe the design, construction, and simulation of my contribution to this landscape—several ~200,000 atom models that depict small sections of the E. coli and H. sapiens cytoplasm in atomistic detail. Then, I move into the results of these cytosolic simulations, including the effect of the cellular environment on ATP (Chapter 3), the partial folding of a small, fast-folding WW domain in the E. coli models (Chapter 4), and the nonspecific protein-protein sticking observed throughout my simulations (Chapter 5). Additionally, I present preliminary results from the H. sapiens cytoplasm simulations, including partial folding of another fast-folding construct and quinary interactions between two enzymes (Chapter 6). Finally, I describe the results of a collaboration between the Gruebele group, the Pogorelov group, Professor Stephen Taylor (UIUC Department of Music), Kurt Hebel, and Carla Scaletti (both of the sound design software company Symbolic Sound). Together, we have developed data sonification techniques to use sound as a teaching tool and data analysis aid in protein folding research (Chapter 7).
Issue Date:2021-12-03
Rights Information:Copyright 2021 Meredith Rickard
Date Available in IDEALS:2022-04-29
Date Deposited:2021-12

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