Understanding Vesicle Budding: A Computational Multi-scale Approach

• Applicant: Dr. Korbinian Liebl
• Subject Area: Theoretical Chemistry: Molecules, Materials, Surfaces
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505618855

Vesicle budding plays a central role in the trafficking of proteins within eukaryotic cells and is hence of outmost biological relevance. This process is driven by coat protein complexes (e.g., COP1 or COP2) which bind to and subsequently remodel the target lipid membrane. Over the past years, our understanding of these complexes has grown due to experimental studies which have resolved structural models for building blocks of COP1/COP2 but also even entirely coated membranes using cryo-electron microscopy (cryo-EM), for instance. From the physical point of view, however, vesicle budding has remained poorly understood: How coatomers are recruited to the membrane, how the building blocks assemble and how the kinetics of membrane coating can be described is still unanswered.In this project, we seek to clarify these questions and reveal the dynamics of membrane coating by the COP1 system. To this purpose, we will use all-atom Molecular Dynamics (MD) simulations to quantify the underlying protein-protein and protein-lipid interactions. Subsequently, we will derive coarse-grained (CG) models from the atomistic data based on the Ultra Coarse-graining (UCG) and Multi-Configurational Coarse-graining (MCCG) techniques. Employing these techniques will allow us to better capture conformational transitions due to chemical changes. The Arf1 GTPase, for example, is an essential component in the COP1 system and undergoes essential structural changes upon exchange of GDP for GTP.Moreover, we will combine the UCG representation with the Green's Function Reaction Dynamics (GFRD) method. In this way, we will link the microscopic and mesoscopic scales and are thus able to realistically simulate large-scale multi-protein structure formation processes at the required time scale. Based on the novel UCG/GFRD simulations, we will characterize the recruitment and assembly processes of COP1, determine to which extent the chemical state of the ARF1 GTPase (bound by GDP or GTP) regulates the kinetics of membrane coating and explore the interplay between membrane bending and protein binding.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Gregory A. Voth