Stabilities of leucine zipper dimers estimated by an empirical free energy method.
The leucine zipper motif is a characteristic amino acid sequence found in dimeric DNA-binding proteins. Computer-generated models for leucine zippers were constructed as alpha-helical coiled dimers with leucine repeated every seventh residue. An empirical Gibbs free energy, delta G, function which incorporates hydrophobic force, electrostatic interactions, and conformational entropy loss as the major intermolecular interactions was used to estimate the delta G of dimer formation in fos, jun, and GCN4 zipper sequences. The calculations showed that complexes known to form stable homo- or heterodimers have favorable (negative) delta G, while other less stable complexes have unfavorable (positive) delta G. Leucines in position d of the coiled coil contribute large hydrophobic stabilization energies while residues in the a position contribute less to dimer stability. Hydrophobic contributions show little sequence specificity, however, and do not contribute significantly to homo/heterodimer preference. Charged residues in the e and g positions, on the other hand, determine homo/heterodimer specificity. In GCN4 homodimers, residues GLU el, Glu b2, Lys g2, and Lys e4 greatly contribute to dimer stability. The preferential stability of fos-jun heterodimer over the jun-jun and fos-fos homodimers is primarily due to the side chains Asp b1, Glu g1, Asp b2, Glu e2, Glu g2, Glu g3, and Lys a5 of the fos helix, and Arg c1, Lys g1, Lys b2, Lys e2, Arg e4, and Glu g4 of the jun helix.
Krystek
S R
SR
Department of Macromolecular Modeling, Bristol-Myers Squibb Research Institute, Princeton, NJ.
Bruccoleri
R E
RE
Novotny
J
J
D016350:Leucine Zippers; D046911:Macromolecular Substances; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry
D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos