Computational Study Of Lipid-Destabilizing Protein Fragments: Towards A Comprehensive View Of Tilted Peptides

Tilted peptides are short sequence fragments (10-20 residues long) that possess
an asymmetric hydrophobicity gradient along their sequence when they are helical.
Due to this gradient, they adopt a tilted orientation towards a single
lipid/water interface and destabilize the lipids. We have detected those peptides
in many different proteins with various functions. While being all
tilted-oriented at a single lipid/water interface, no consensus sequence can be
evidenced. In order to better understand the relationships between their
lipid-destabilizing activity and their properties, we used IMPALA to classify the
tilted peptides. This method allows the study of interactions between a peptide
and a modeled lipid bilayer using simple restraint functions designed to mimic
some of the membrane properties. We predict that tilted peptides have access to a
wide conformational space in membranes, in contrast to transmembrane and
amphipathic helices. In agreement with previous studies, we suggest that those
metastable configurations could lead to the perturbation of the acyl chains
organization and could be a general mechanism for lipid destabilization. Our
results further suggest that tilted peptides fall into two classes: those from
proteins acting on membrane behave differently than destabilizing fragments from
interfacial proteins. While the former have equal access to the two layers of the
membrane, the latter are confined within a single lipid layer. This could be in
relation with the organization of lipid substrate on which the peptides
physiologically act.