Guidelines for membrane protein engineering derived from de novo designed model peptides.

Notwithstanding great advances in the engineering and structural analysis of globular proteins, relatively limited success has been achieved with membrane proteins--due largely to their intrinsic high insolubility and the concomitant difficulty in obtaining crystals. Progress with de novo synthesis of model membrane-interactive peptides presents an opportunity to construct simpler peptides with definable structures, and permits one to approach an understanding of the properties of the membrane proteins themselves. In the present article, we review how our laboratory and others have used peptide approaches to assess the detailed interactions of peptides with membranes, and primary folding at membrane surfaces and in membranes. Structural studies of model peptides identified the existence of a "threshold hydrophobicity," which controls spontaneous peptide insertion into membranes. Related studies of the relative helicity of peptides in organic media such as n-butanol indicate that the helical propensity of individual residues--not simply their hydrophobicity--may dictate the conformations of peptides in membranes. The overall experimental results provide fundamental guidelines for membrane protein engineering.