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Leucine takes us to the membrane. And it deserves very loud applauses. We now take it for granted, but originally, entering the membrane hydrophobic core for life was likeÖ like for us would be colonizing Moon or Mars. Leucine made it possible, isnít it amazing?

We now enjoy a large variety of membrane proteins, which are absolutely essential for sustaining life. It is also the membrane, which allows cells create chemiosmotic gradients, and subsequently, generate ATP. The membrane proteins basically define what goes in, and what goes out, they sort what should be kept and what should be discarded, released, produced or exchanged by a cell. The cell itself is defined through the membrane and membrane proteins. But how did nature transverse this medium in the first place, how did it overcome the hydrophobic core, which is essentially an oil? Nucleic acids are too polar to enter it. Peptides are polar too, owning to the high polarity of the amide-based backbone. Yet, nature entered the membrane with the α-helix due to the recruitment of leucine to the canonical repertoire.

The structure of the leucine side-chain starts with a CH2-group, and this rather compact linker allows packing of this residue in the crowded context of an α-helix, full of other side-chains. Next, there is an iso-propyl attached to the linker, and this moiety forms a hydrophobic exterior. Thatís it. You donít even need a poly-leucine sequence, just leucine-rich shall be enough to form a hydrophobic α-helix.

Next effect occurs when this comes into the membrane, into the hydrophobic core, which is non-polar. This environment has a very little dielectric constant (ε ~ 2) in comparison to well insulating water (ε ~ 80), thereby strengthening the polar interactions of the backbone. Not only the α-helix becomes compatible with a hydrophobic medium, but also this structure becomes enormously strong.

Integral membrane proteins are most commonly made by motifs called α-bundles, and these allow formation of ion-channels, receptors, transporters and more, all possible functions.

Interesting readings:

- Pace, C. N. and Scholtz, J. M. A Helix Propensity Scale Based on Experimental Studies of Peptides and Proteins. Biophys. J., 75, 1998, 422-427, doi: 10.1016/S0006-3495(98)77529-0

A useful survey of α-helix propensity scales for amino acid.

- Holt, A. and Killian, J. A. Orientation and dynamics of transmembrane peptides: the power of simple models. Eur. Biophys. J., 39, 2010, 609-621, doi: 10.1007/s00249-009-0567-1

A recent review about the iron-sulfur clusters.

WALP and KALP peptides are common biophysical models for studying transmembrane helices. These are having repetitive (LeuAla)n stretches as the hydrophobic core spanning sequences. A review discusses some findings made with these models in a recent decade.

- Lee, B. D. et al. Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease. Trends Pharmacol. Sci., 33, 2012, 365-373, doi: 10.1016/

Leucine-rich repeat is a common motif in protein-protein interactions, related to a variety of diseases. An example is inherited Parkinson disease, and the review describes possible development of therapeutics targeting this motif.