Date of Graduation
5-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry (PhD)
Degree Level
Graduate
Department
Chemistry & Biochemistry
Advisor/Mentor
Mahmoud Moradi
Committee Member
Colin D. Heyes
Second Committee Member
Paul D. Adams
Third Committee Member
Suresh Thallapuranam
Keywords
CB1; cholesterol; Class C GPCR; G-protein coupled receptors; mGluR1; molecular dynamics simulation
Abstract
Proteins are not static entities; rather, they are dynamic macromolecules that undergo conformational changes to perform their biological functions. These structural transitions are often coupled to chemical events such as lipid interactions, or changes in the cellular environment. Understanding the intricate interplay between chemical perturbations and the resulting mechanical response is crucial for elucidating the activation mechanisms of proteins. This dissertation aims to characterize the role of chemo-mechanical couplings in the activation process of two G protein-coupled receptors (GPCRs): Cannabinoid Receptor 1 (CB1) and Metabotropic Glutamate Receptor 1 (mGluR1). We employ molecular dynamics simulations to investigate the conformational landscapes of CB1 and mGluR1. By studying the active and inactive states of apo CB1, we uncover distinct conformational dynamics between these states. Our results reveal that the inactive state of CB1 explores a wider conformational space compared to the more restricted active state. We identify key structural features and residues, such as the pivotal role of transmembrane helix 7 (TM7), that mediate the state-dependent conformational changes in CB1. Furthermore, we investigate the role of cholesterol in modulating the conformational dynamics of mGluR1. Our simulations show that cholesterol influences the conformational changes of the receptor, particularly in the TM1 and TM2 regions that form the dimeric interface. Intriguingly, we find that low cholesterol concentrations induce more significant conformational changes in mGluR1 compared to higher cholesterol levels or the absence of cholesterol. Our findings highlight the importance of considering the dynamic nature of proteins, rather than just their static structures, in understanding activation mechanisms. The activation process of CB1 and mGluR1 involves a complex network of dynamic conformational changes that are coupled to chemical perturbations. These results not only advance our understanding of GPCR activation but also underscore the necessity of incorporating protein dynamics into the development and refinement of therapeutic agents targeting these receptors. The knowledge gained from this dissertation could provide a framework for structure-based drug discovery that targets the state-specific conformational dynamics of CB1, mGluR1 and GPCRs at large. Our findings have potential applications in drug discovery, biotechnology, and precision medicine, where a detailed understanding of protein dynamics is essential for developing effective and selective treatments.
Citation
Isu, U. (2024). Characterizing the Role of Chemo-Mechanical Couplings in the Activation Process of Proteins that Undergo Conformational Changes. Graduate Theses and Dissertations Retrieved from https://scholarworks.uark.edu/etd/5272