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 interaction of alpha-helices within membranes would represent a significant step toward understanding the folding and stability of membrane proteins. We use structure-based empirical parameters representing steric clashes, favorable van der Waals interactions, and restrictions of side-chain rotamer freedom to explain the relative dimerization propensities of 105 hydrophobic single-point mutants of the glycophorin A (GpA) transmembrane domain. Although the structure at the dimer interface is critical to our model, changes in side-chain hydrophobicity are uncorrelated with dimer stability, indicating that the hydrophobic effect does not influence transmembrane helix-helix association. Our model provides insights into the compensatory effects of multiple mutations and shows that helix-helix interactions dominate the formation of specific structures.
MacKenzie
K R
KR
Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., New Haven, CT 06520, USA.
Engelman
D M
DM
D000595:Amino Acid Sequence; D000818:Animals; D004910:Erythrocyte Membrane / Q000737:chemistry* / Q000378:metabolism; D006021:Glycophorins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D017354:Point Mutation; D017510:Protein Folding; D017421:Sequence Analysis; D013329:Structure-Activity Relationship
D006021:Glycophorins