Understanding the structure-function relationship of proteins such as G protein-coupled receptors (GPCRs) requires detailed information on their three-dimensional (3D) structure and dynamics. Recent progress in the structural elucidation of receptor-G protein or -arrestin complexes yields valuable starting points to studying their function and dynamics. I investigated the dynamic process of β2 adrenergic receptor-G protein recognition and binding using molecular dynamics (MD) simulations. MD simulation is a well-established technique to monitor the time-resolved motions of proteins and is used to investigate the dynamics of GPCRs. In order to start MD simulations, the structures that are often incompletely resolved have to be further completed. Finally, the results from computational analysis have to be subjected to experimental validation. To promote broad applicability of that workflow, I automated critical steps such as modeling of missing segments or interactive analysis and visualization of the results of MD simulations.
Web-tools allow researchers besides different methodological expertise to apply unfamiliar techniques on their biological systems of interest without the need to download software or databases. To facilitate usage, I included visualization allowing intuitive understanding and analysis. We developed the NGL molecular web-viewer, which accesses hardware-accelerated graphics through WebGL. This and other recent developments, reviewed by Mwalongo and others, opened up new possibilities for web molecular graphics and render- ing techniques, superseding plugin- and Java-based viewers and making them comparable with desktop tools, such as PyMOL, VMD, or UCSF Chimera.
Here, I implemented and applied tools for interactive modeling of missing segments into single-particle cryo-electron microscopy (cryo-EM) density maps, for interactive analysis of structure-functional dynamics, and more general to promote interdisciplinary research. To allow non-expert users access to bioinformatics methods and biophysical techniques, all tools were generated as web-services allowing interactive analysis and visualization.:Introduction
1 GPCRs as a prime example in structural and pharmaceutical biology
2 Modeling missing segments into cryo-EM density maps
3 Research goal I: Web service for modeling of missing segments into cryo-EM
density maps
4 From static to dynamics to investigate GPCR function
5 The complexity of sharing MD simulations
6 Research goal II: Interactive visual sharing of MD simulations
Manuscripts
1 FragFit: a web-application for interactive modeling of protein segments into cryo-EM density maps
2 MDsrv: viewing and sharing molecular dynamics simulations on the web.
3 Bringing Molecular Dynamics Simulation Data into View
Summary
1 Modeling of missing fragments into cryo-EM density maps
2 InteractiveanalysisofMDsimulationsontheweb . . . . . .
References
Appendix A Additional Manuscripts
1 SL2: an interactive webtool for modeling of missing segments in proteins
2 GPCR-SSFE 2.0-a fragment-based molecular modeling web tool for Class A G-protein coupled receptors.
3 A fragment based method for modeling of protein segments into cryo-EM density maps
4 Structural Insights into the Process of GPCR-G Protein Complex Formation
5 Sharing Data from Molecular Simulations
Appendix B
Darstellung des eigenen Beitrags
Selbständigkeitserklärung
Curriculumvitae & Publikationen
Danksagung
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:72400 |
| Date | 09 October 2020 |
| Creators | Tiemann, Johanna Katarina Sofie |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/updatedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.1093/nar/gky424, 10.1038/nmeth.4497, 10.1016/j.tibs.2019.06.004, 10.1093/nar/gkw297, 10.1093/nar/gkx399, 10.1186/s12859-017-1904-5, 10.1016/j.cell.2019.04.021, 10.1021/acs.jcim.9b00665 |
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