Molecular modeling and simulation of bacterial chemosensory arrays

Cassidy, C. Keith

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Description

Title

Molecular modeling and simulation of bacterial chemosensory arrays

Author(s)

Cassidy, C. Keith

Issue Date

2017-01-10

Director of Research (if dissertation) or Advisor (if thesis)

Schulten, Klaus

Doctoral Committee Chair(s)

Chemla, Yann R.

Committee Member(s)

• Luthey-Schulten, Zaida
• Cooper, S. Lance
• Stack, John D.

Department of Study

Physics

Discipline

Physics

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Bacterial chemotaxis
• Chemosensory array
• Chemoreceptor
• Molecular dynamics
• Molecular modeling
• Multi-protein complex

Abstract

The movement of an organism in response to environmental chemical cues is known as chemotaxis. Motile bacteria use chemotaxis to navigate through their environments, enabling cells to efficiently locate favorable growing conditions while avoiding harmful ones. Central to this ability, bacteria posses a universally conserved sensory apparatus, known as the chemosensory array, which involves the clustering of thousands of proteins into a highly cooperative signaling network. The present dissertation will present my work using techniques in computational modeling and simulation to investigate the molecular structure and function of the bacterial chemosensory array. A brief overview of each chapter follows. Chapter 1 provides an introduction to the systems-level features of chemotaxis in the model organism Escherichia coli as well as an overview of the molecular organization and function of the chemosensory array. Chapter 2 gives an outline of the core methodologies used in my work, specifically all-atom molecular dynamics (MD) simulation and Molecular Dynamics Flexible Fitting (MDFF). In addition, two of the primary techniques used to analyze the MD simulations presented in this dissertation are sketched out, namely structural clustering based on root- mean-square displacement (RMSD) and Principal Component Analysis (PCA). Chapter 3 reports my work, in collaboration with Peijun Zhang’s Lab, to investigate the structural and dynamical features of the extended chemosensory array. Using computational techniques to synthesize multi-scale structural data from X-ray crystallography and cryo-electron tomography (cryo-ET), an atomic model of the cytoplasmic portion of the chemosensory array from Thermotoga maritima is constructed and refined. Through the use of large-scale MD simulations, a novel conformational change in a key signaling protein is identified and subsequently shown to be critical for chemotaxis signaling in live E. coli cells. Chapter 4 details the construction of an atomic model of a complete, transmembrane (TM) chemoreceptor. In particular, I use homology modeling and MD simulations, in- formed by biochemical and X-ray crystallographic data, to derive a model of the E. coli serine receptor (Tsr), including the previously uncharacterized TM four-helix bundle and HAMP domains. In addition, I report a series of MD simulations of a fragment of the resulting Tsr model, investigating the structural and dynamical effects of mutations on a key control cable residue. Preliminary MD simulations of the intact Tsr model are also presented. Chapter 5 reports work in collaboration with Michael Eisenbach’s Lab at the Weizmann Institute, exploring the role of acetylation on CheY activation and the generation of clockwise (CW) flagellar motor rotation. Specifically, I present a series of MD simulations that investigate the effect of a hyperactivating mutation at a key acetylation site and offer a molecular explanation of acetylation-dependent generation of CW flagellar motor rotation. I conclude with a brief description of recent work, expanding upon the results of the previous chapters, which has resulted in the first atomically resolved model of the E. coli transmembrane chemosensory array.

Graduation Semester

2017-05

Type of Resource

text

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Copyright and License Information

Copyright 2017 C. Keith Cassidy

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