STRUCTURE-BASED PREDICTION OF THE STABILITY OF TRANSMEMBRANE HELIX-HELIX INTERACTIONS - THE SEQUENCE DEPENDENCE OF GLYCOPHORIN-A DIMERIZATION

The ability to predict the effects of point mutations on the interacti on of alpha-helices within membranes would represent a significant ste p toward understanding the folding and stability of membrane proteins, We use structure-based empirical parameters representing steric clash es, favorable van der Waals interactions, and restrictions of sidechai n rotamer freedom to explain the relative dimerization propensities of 105 hydrophobic single-point mutants of the glycophorin A (GpA) trans membrane domain. Although the structure at the dimer interface is crit ical to our model, changes in side-chain hydrophobicity are uncorrelat ed with dimer stability, indicating that the hydrophobic effect does n ot influence transmembrane helix-helix association, Our model provides insights into the compensatory effects of multiple mutations and show s that helix-helix interactions dominate the formation of specific str uctures.