Membrane proteins present a significant challenge to structural biology. Although more than 30% of the human genome encodes membrane proteins and about 60% of drugs target them, relatively few structures have been determined, highlighting the need for developing new approaches. An environment suitable for studying membrane proteins requires the presence of lipid molecules to solubilize the proteins, making it difficult to form a suitable crystal or produce resonance signals with narrow linewidths. Also, in most cases, the lack of long-range distance information obtained from NOE measurements prevents defining the global fold of α-helical membrane proteins.

In this Thesis, methodological developments to determine membrane protein structures using solution NMR spectroscopy and results on proteins with single and multiple hydrophobic trans-membrane domains and amphipathic in-plane helices are described. Measurements of weak anisotropic interactions provide unique structural information that can complement distance information. The potential of the developed methods for high-throughput applications to structural genomics of membrane proteins is tested.