The GASright Motif in Membrane Protein Dimerization and Structural Prediction

The most common transmembrane proteins are the single-pass membrane proteins (SPMPs), which span the membrane by threading a single alpha-helix through the hydrophobic lipid bilayer. SPMPs are biologically important to the function of the cell. The function of many SPMPs involves the homo-dimerization of their TM domain. One sequence motif that has been shown to be important in SPMP homo-dimerization is the GxxxG motif, or two glycine residues spaced at i and i+4. This small residue motif is often found at the interface of the GASright TM dimer structural motif, the association of two parallel transmembrane helices at a right-handed crossing angle of around -40 degrees.;The small residues at the interface allow for the close approach between the two helices, and this tight packing allows for the formation of Calpha--H˙˙˙O=C bonds. Calpha--H˙˙˙O=C bonds form between the alpha-carbon hydrogen on one helix, and the carbonyl oxygen on the opposing helix. While the energetic contribution of these bonds is still a matter of debate, the bonds are commonly seen in GASright structures and are predicted to have a favorable contribution to protein folding.;Using computational modeling, I have discovered strong evidence suggesting that interhelical carbon hydrogen bonds which occur between Calpha--H donors and backbone carbonyl oxygen acceptors (Calpha--H˙˙˙O=C bonds) are an important force driving in the association of transmembrane proteins.;Using this knowledge, I was able to design an ab initio structural prediction algorithm (CATM) to correctly predict the known structures of transmembrane dimers. From this work, I predicted the structure of a protein whose transmembrane structure has not been solved---an important mitochondrial kinase involved in coenzyme Q biosynthesis.;Currently, I am working to further develop the CATM algorithm to predict the strength of transmembrane dimerization in bacterial membranes. To improve the prediction capability, I have been experimentally measuring GASright oligomerization on a large number of predicted sequences. The current model shows a strong correlation between the experimental strength of association and optimization of van der Waals packing and Calpha--H hydrogen bonding.