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.

[1]  T C Terwilliger,et al.  Influence of interior packing and hydrophobicity on the stability of a protein. , 1989, Science.

[2]  W. DeGrado,et al.  A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids. , 1990, Science.

[3]  P. Argos,et al.  Rotamers: to be or not to be? An analysis of amino acid side-chain conformations in globular proteins. , 1993, Journal of molecular biology.

[4]  T. Steitz,et al.  Identifying nonpolar transbilayer helices in amino acid sequences of membrane proteins. , 1986, Annual review of biophysics and biophysical chemistry.

[5]  M. Saraste,et al.  Engineering membrane proteins. , 1995, Current opinion in biotechnology.

[6]  W. DeGrado,et al.  Protein Design: A Hierarchic Approach , 1995, Science.

[7]  K. P. Murphy,et al.  Solid model compounds and the thermodynamics of protein unfolding. , 1991, Journal of molecular biology.

[8]  A. Doig,et al.  Free energies of amino acid side-chain rotamers in alpha-helices, beta-sheets and alpha-helix N-caps. , 1997, Journal of molecular biology.

[9]  M. Kurpiewski,et al.  The energetic basis of specificity in the Eco RI endonuclease--DNA interaction. , 1990, Science.

[10]  G. von Heijne,et al.  Helix-helix packing in a membrane-like environment. , 1997, Journal of molecular biology.

[11]  G. Heijne.  Membrane protein structure prediction. Hydrophobicity analysis and the positive-inside rule. , 1992, Journal of molecular biology.

[12]  B. Wallace,et al.  Slow alpha helix formation during folding of a membrane protein. , 1997, Biochemistry.

[13]  James H. Prestegard,et al.  A Transmembrane Helix Dimer: Structure and Implications , 1997, Science.

[14]  D. Engelman,et al.  A dimerization motif for transmembrane α–helices , 1994, Nature Structural Biology.

[15]  M J Sternberg,et al.  Empirical scale of side-chain conformational entropy in protein folding. , 1993, Journal of molecular biology.

[16]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[17]  B. Matthews,et al.  Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. , 1992, Science.

[18]  W. Lim,et al.  The role of internal packing interactions in determining the structure and stability of a protein. , 1991, Journal of molecular biology.

[19]  D. Engelman,et al.  The effect of point mutations on the free energy of transmembrane alpha-helix dimerization. , 1997, Journal of molecular biology.

[20]  J. Ponder,et al.  Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes. , 1987, Journal of molecular biology.

[21]  D. Engelman,et al.  Sequence specificity in the dimerization of transmembrane alpha-helices. , 1992, Biochemistry.

[22]  V. Muñoz,et al.  Intrinsic secondary structure propensities of the amino acids, using statistical ϕ–ψ matrices: Comparison with experimental scales , 1994 .

[23]  G. Heijne,et al.  Ala‐insertion scanning mutagenesis of the glycophorin a transmembrane helix: A rapid way to map helix‐helix interactions in integral membrane proteins , 1996, Protein science : a publication of the Protein Society.

[24]  D. Engelman,et al.  Membrane protein folding and oligomerization: the two-stage model. , 1990, Biochemistry.

[25]  G von Heijne,et al.  Membrane proteins: from sequence to structure. , 1990, Protein engineering.

[26]  M. Levitt,et al.  Energy refinement of hen egg-white lysozyme. , 1974, Journal of molecular biology.

[27]  C. Tribet,et al.  Amphipols: polymers that keep membrane proteins soluble in aqueous solutions. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Roland L. Dunbrack,et al.  Backbone-dependent rotamer library for proteins. Application to side-chain prediction. , 1993, Journal of molecular biology.