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Karim Fahmy has his expertise in the field of spectroscopic investigations of membrane proteins. As an infrared spectroscopist, he has contributed to the understanding of fundamental molecular mechanisms of GPCR activation, using the visual photoreceptor, bovine rhodopsin, as a model system. His interest focuses on the functional role of the water/lipid/protein interface in GPCRs and other membrane proteins. Presently, he addresses the properties of water within membrane proteins and the linkage of membrane hydration to the protonation state of membrane protein side chains at the membrane interface. 


Statement of the Problem: The active transport of ions across biological membranes requires their hydration shell to interact with the interior of membrane proteins. Although restricted to the membrane protein surface, lipid protein interactions markedly affect transport rates of metals through P-type ATPases. However, the influence of the external lipid phase on internal dielectric dynamics is hard to access by experiment. Methodology & Theoretical Orientation:  Using the octahelical transmembrane architecture of the copper-transporting P1B-type ATPase from Legionella pneumophila as a model structure, we have established the site-specific labeling of internal cysteines with 6-bromoacetyl-2-dimethylaminonaphthalene (BADAN), a polarity-sensitive fluorophore. This enabled dipolar relaxation studies in a solubilized form of the membrane protein and in its lipid-embedded state in nanodiscs. The latter provide a native-like lipid environment but facilitate spectroscopic studies due to their lower scattering in the UV-vis as compared to vesicles.  Conclusion & Significance: Time-dependent fluorescence shifts of BADAN linked specifically to either of the conserved copper-binding active site cysteines, Cys382 and Cys384 revealed the local hydration and dipole mobility around the transmembrane ion-binding motif. At Cys382, both parameters were strongly reduced upon lipid insertion of the membrane protein. The environment of Cys384, although less than a helical turn apart, was little affected by the lipidic phase. Against expectation and differently from Cys382, dipole mobility increased around Cys384 in NDs as compared to the less constrained detergent-solubilized state. Thus, the distribution of hydration and dipole mobility is shaped significantly and independently of each other by membrane lateral pressure. Vice versa, the lipidic phase may exert restoring forces on water-mediated H-bond networks around the conserved transmembrane ion-binding site for driving conformational changes during the catalytic transport cycle.