Abstract
Leucine and Isoleucine are two amino acids that differ only by the
positioning of one methyl group. This small difference has however
important consequences in α-helices, as the β-branching of Ile results
in helix destabilization. We set out to investigate whether there are
general trends for the occurrences of Leu and Ile residues in structures
and sequences of class A GPCRs (G protein-coupled receptors). GPCRs are
integral membrane proteins in which α-helices span the plasma membrane
seven times and which play a crucial role in signal transmission into
the cell. We found that Leu side chains are generally present in less
densely packed regions and are more protein-surface exposed than Ile
side chains. We explored whether this difference might be attributed to
different functions of the two amino acids and tested if Leu adjusts the
hydrophobicity of the transmembrane domain based on the Wimley-White
whole-residue hydrophobicity scales. In class A GPCRs, Leu decreases the
variation in hydropathy between receptors and Leu content correlates
positively with hydropathy calculated without Leu. Both measures
indicate that hydropathy is tuned by Leu. To test this idea further, we
generated protein sequences with random amino acid compositions using a
simple numerical model, in which hydropathy was tuned by adjusting the
number of Leu residues. The model was able to replicate the observations
made with class A GPCR sequences. We speculate that Leu tunes the
hydropathy of the transmembrane domain of class A GPCRs to facilitate
correct insertion into membranes and/or for stability within them.