Date of Graduation
8-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Cell & Molecular Biology (PhD)
Degree Level
Graduate
Department
Cell & Molecular Biology
Advisor/Mentor
Moradi, Mahmoud
Committee Member
Sakon, Josh
Second Committee Member
Wang, Yong
Third Committee Member
Fan, Chenguang
Keywords
Molecular dynamics; Chemo-mechanical coupling; Influenza
Abstract
Proteins are dynamic entities that undergo conformational changes essential for their biological functions. These structural changes often correspond with chemical events such as lipid interactions or environmental changes like protonation or acidification. Understanding the complex relationship between these chemical perturbations and the resultant mechanical responses is crucial for elucidating protein mechanisms. This dissertation investigates the chemo-mechanical coupling in the conformational dynamics of the bacterial ABC transporter Sav1866 and the impact of protonation on the Influenza virus hemagglutinin HA0. Using molecular dynamics simulations, we explore the conformational landscapes of Sav1866 and HA0. Our study examines how varying lipid compositions affect the dynamics of Sav1866, revealing distinct conformational behaviors. Notably, Sav1866 demonstrates unique channel-like behavior in DMPC lipid environments, with both cytoplasmic and periplasmic gates open throughout the simulation, unlike the transition observed in POPE lipids. Specific lipid-protein interactions, including crucial hydrogen bonds, are shown to influence these conformational states, underscoring the lipid-dependent specificity in the function of ABC transporters. Furthermore, our research delves into the effects of protonation on HA0’s conformational dynamics, particularly focusing on the residue H106 in the HA2 region. Protonation at this site leads to significant conformational changes necessary for the fusion process, including the destabilization and opening of the S4 helix and the observation of FP release in the protonated systems. These findings illuminate the complex and detailed dynamics of Sav1866 and HA0. The insights gained could inform structure-based drug discovery, offering potential applications in drug design, biotechnology, and precision medicine where understanding protein dynamics is critical for developing effective and selective treatments.
Citation
Badiee, S. A. (2024). How Local Interactions Give Rise to Large-Scale Conformational Changes in Proteins: A Molecular Dynamics Study. Graduate Theses and Dissertations Retrieved from https://scholarworks.uark.edu/etd/5464