Pancreatic lipase is a soluble globular protein that must undergo structural modifications before it can hydrolyze oil droplets coated with bile salts. The binding of colipase and movement of the lipase lid open access to the active site. Mechanisms triggering lid mobility are unclear. The *KNILSQIVDIDGI* fragment of the lid of the human pancreatic lipase is predicted by molecular modeling to be a tilted peptide. Tilted peptides are hydrophobicity motifs involved in membrane fusion and more globally in perturbations of hydrophobic/hydrophilic interfaces. Analysis of this lid fragment predicts no clear consensus of secondary structure that suggests that its structure is not strongly sequence determined and could vary with environment. Point mutations were designed to modify the hydrophobicity profile of the [ 240 - 252] fragment and their consequences on the lipase-mediated catalysis were tested. Two mutants, in which the tilted peptide motif was lost, also have poor activity on bile saltcoated oil droplets and cannot be reactivated by colipase. Conversely, one mutant in which a different tilted peptide is created retains colipase dependence. These results suggest that the tilted hydrophobicity pattern of the [ 240 - 252] fragment is neither important for colipase binding to lipase, nor for interfacial binding but is important to trigger the maximal catalytic efficiency of lipase in the presence of bile salt.

Few structures of membrane proteins are known and their relationships with the membrane are unclear. In a previous report, 20 X-ray structures of transmembrane proteins were analyzed in silico for their orientation in a 36A-thick membrane [J. Mol. Graph. Model. 20 (2001) 235]. In this paper, we use the same approach to analyze how the insertion of the X-ray structures varies with the bilayer thickness. The protein structures are kept constant and, at each membrane thickness, the protein is allowed to tilt and rotate in order to accommodate at their best. The conditions are said to be optimal when the energy of insertion is minimal. The results show that most helix bundles require thicker membranes than porin barrels. Moreover, in a few instances, the ideal membrane thickness is unrealistic with respect to natural membranes supporting that the X-ray structure requires adaptation to stabilize in membrane. For instance, the squalene cyclase could adapt by bending the side chains of its ring of lysine and arginine in order to increase the hydrophobic surface in contact with membranes. We analyzed the distribution of amino acids in the water, interface and acyl chain layers of the membrane and compared with the literature.