Dissertation
COARSE-GRAINED MOLECULAR SIMULATIONS FOR CONFORMATIONAL CHANGES OF TRANSMEMBRANE AND MEMBRANE TRAFFICKING PROTEINS
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2022
DOI:
https://doi.org/10.7273/000004388
Handle:
https://hdl.handle.net/2376/119020
Abstract
Observation of protein conformational change has been a great challenge in biomolecular research. From the efflux pumping mechanism of the multidrug-resistant protein in gram-negative bacteria to the membrane-bending ability of the C2-domain protein for endothelial exocytosis of drug carrier vesicles across the blood-brain barrier (BBB), operational conformational changes of those proteins are still unclear. Conventional molecular dynamics (MD) simulation can capture interaction details of small molecule groups. However, obtaining conformational change for a big protein system or exceeding simulation time to microseconds is difficult. To maintain the accuracy of all-atom MD simulation and capture a longer dynamic, we use a specific MD simulation combining united-atom proteins and coarse-grained (CG) ambiances to examine the aforementioned antiport efflux pumping and membrane-bending procedures. Simulations for each system are conducted for up to two microseconds. Our results indicate that the conformational change for drug pumping of the multidrug-resistant protein Acriflavine resistance B (AcrB) could be obstructed by a strongly binding inhibitor. By the protonation at transmembrane helices, the binding-state of AcrB porter transits to the extrusion-state to expel the antibiotic drugs or natural substrates. However, the inhibitor-like drug chlorpromazine can interfere with the state transition by binding with a hydrophobic trap inside the distal binding pocket to consequently disrupt the operation of the protonated transmembrane helices. Our research suggests that finding inhibitor-like drugs is an efficient way to fight gram-negative bacteria. In the second study, we found that the C2-domain protein named synaptotagmin-like protein is important for the membrane pre-fusion stage of vesicular exocytosis in the BBB. In more detail, when calcium ions occupy C2-domains’ calcium-binding sites, the protein connects to lipid membranes stronger such that its lipid-binding parts observe a greater abundance of lipid contact. The more synaptotagmin-like proteins surrounding the SNARE complex in the system, the better the membranes significantly bend. The bending causes lipid disorders on both membranes and supports the fusion between them. Thus, synaptotagmin-like protein is found as an important trigger for membrane fusion during vesicular exocytosis in the BBB.
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Details
- Title
- COARSE-GRAINED MOLECULAR SIMULATIONS FOR CONFORMATIONAL CHANGES OF TRANSMEMBRANE AND MEMBRANE TRAFFICKING PROTEINS
- Creators
- Quyen Van Dinh
- Contributors
- Prashanta Dutta (Advisor)Jin Liu (Committee Member)Soumik Banerjee (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Mechanical and Materials Engineering, School of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 140
- Identifiers
- 99900883136201842
- Language
- English
- Resource Type
- Dissertation