I will provide an overview of our work on the interplay between large-scale conformational changes, dimerization, and lipidmembrane binding in guanylate binding proteins (GBPs) and a bacterial dynamin-like protein (BDLP). Using various molecular dynamics (MD) simulations, protein-protein docking techniques, and free energy calculations, we interpret our findings in conjunction with experimental data whenever possible. GTP binding induces hinge motions in GBPs and BDLP, transitioning their conformations from closed to open states. For BDLP, we show that GTP binding initiates an allosteric pathway, creating a new salt-bridge pattern that lowers the energy barrier for this motion. Although the open state is less stable, it can be stabilized by membrane binding and polymerization—critical for their biological function in membrane remodeling. We also explored the oligomerization and structural dynamics of human GBP1 and murine GBPs 2 and 7, providing new dimer models consistent with experimental data. While mGBP2 behaves similarly to hGBP1, mGBP7 displays distinct dimerization and motion, with an elongated C-terminus that takes over membrane binding, as confirmed by experiments. The biological relevance of these findings will be discussed.

Jennifer Loschwitz¹, Bastian Bundschuh^1,2, Wibke Schumann¹ & Birgit Strodel^1,2

Computational Biochemistry Group @ ¹ Institute of Theoretical and Computational Chemistry, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany & ² Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich,
Germany