Understanding the mechanisms of multidrug transport proteins

• Applicant: Professor Dr. Lars Schäfer
• Subject Area: Biophysics
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 212212136

Multidrug transport proteins pump a wide range of compounds across the cell membrane and play an important role in cancer chemotherapy and the treatment of infectious diseases. The goal of this project is to unravel the structure-function relationships underlying the mechanisms of two multidrug transporters, the small multidrug resistance (SMR) protein EmrE and the ATP-binding cassette (ABC) transporter Sav1866. Specific aims for EmrE are to map the substrate recognition and transport pathways, and to understand the energetic and structural basis for the coupling between substrate and proton transport. Furthermore, I will probe how protein-lipid interactions influence the structure and dynamics of EmrE, and investigate the functional role of the protein oligomeric state. Ultimately, I aim at steering the structure and oligomeric state – and thereby the function – of EmrE through photoswitchable lipids. For Sav1866, the goal is to characterize the transition between the inward- and outward-facing conformations, and to study substrate recognition and translocation. To reach these aims, I will use molecular dynamics (MD) type computer simulations and closely collaborate with experimental groups. In addition to the application of conventional all-atom MD simulations, efficient multiscale models will be developed to access the required spatial and temporal scales. Successful application of the outlined approach will foster future mechanistic studies of membrane protein – lipid complexes, and ultimately enable to directly simulate the dynamic interplay of lipids and proteins in small but functional cellular units, such as small vesicles.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: Cluster