While a wealth of information has poured forth for water soluble proteins, membrane protein investigation has lagged severely and many of their unique features remain to be discovered. This disparity is clearly seen in the PDB where membrane protein structures constitute less than 1% of the available structures. By contrast, across species membrane proteins constitute 25% to 30% of the total number of genes.

The practical importance of membrane proteins is underscored by medicine, where they constitute the majority of drug targets, and the GPCR family itself is the target of almost 50% of available drugs. This is all the more notable considering there are approximately 800 GPCR family genes in humans, which amounts to less than 2.5% of genes in the human genome.

This thesis attempts to further characterize membrane proteins from extant knowledge of their sequence and structure. The first chapter explores fold diversity in membrane proteins, driving the structural genomics effort to reveal all unique folds in the protein universe, and finds a very limited diversity compared to water soluble proteins. In the context of limited fold diversity, the strong preference of membrane proteins to oligomerize rather than evolve via recombination of domains, helps to explain diversity of function despite slower evolutionary rates of transmembrane regions.

Chapter two describes our discovery of a common motif in membrane proteins, the glycine zipper, the significance of which is demonstrated by its role in disease etiology, with implications in the formation of amyloid channels and prion disease.

The final chapter illustrates the broad biological implications of understanding the forces that drive protein folding, which goes hand in hand with the ability to view high resolution structures. Clearly, the membrane environment imposes very different requirements on a protein sequence than water. We find significant differences in the degree of residue burial between proteins in the membrane and water soluble environments, which can explain the difference in evolutionary rates between these environments. The results suggest a unique mechanism for optimizing van der waal's forces and folding and stability of proteins in the membrane region, which lacks the solvophobic contribution to folding. Moreover, our finding that evolutionary divergence rates of residues with similar levels of burial in either environment is very similar on average, makes it unlikely that another factor might explain the difference in evolutionary rates. The significance of increased structural sensitivity in the membrane region is emphasized by a strong correlation between burial and the structural location of deleterious nsSNP's.