Structure-based prediction of the stability of transmembrane helix-helix interactions: the sequence dependence of glycophorin A dimerization

Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3583-90. doi: 10.1073/pnas.95.7.3583.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Erythrocyte Membrane / chemistry*
  • Erythrocyte Membrane / metabolism
  • Glycophorins / chemistry*
  • Glycophorins / genetics
  • Glycophorins / metabolism
  • Humans
  • Models, Molecular*
  • Models, Theoretical*
  • Molecular Sequence Data
  • Point Mutation
  • Protein Folding*
  • Sequence Analysis
  • Structure-Activity Relationship


  • Glycophorins

Associated data

  • PDB/1AFO