Molecular Evolution Activities

This is a comprehensive bibliography (under construction) of primary and secondary sources on the neutral theory of molecular evolution. It currently covers the period 1973-2001.

Author :

Pielak, G. J.;Auld, D. S.;Beasley, J. R.;Betz, S. F.;Cohen, D. S.;Doyle, D. F.;Finger, S. A.;Fredericks, Z. L.;Hilgenwillis, S.;Saunders, A. J.;Trojak, S. K.

Year :


Title :

Protein Thermal-Denaturation, Side-Chain Models, and Evolution - Amino-Acid Substitutions at a Conserved Helix-Helix Interface

Journal :


Volume :


Issue :


Pages :


Date :

Mar 14

Short Title :

Protein Thermal-Denaturation, Side-Chain Models, and Evolution - Amino-Acid Substitutions at a Conse

Alternate Journal :


Custom 2 :


Abstract :

Random mutant libraries with substitutions at the interface between the N- and C-terminal helices of Saccharomyces cerevisiae iso-1-cytochrome c were screened. All residue combinations that have been identified in naturally occurring cytochrome c sequences are found in the libraries. Mutants with these combinations are biologically functional. Enthalpies, heat capacities, and midpoint temperatures of denaturation are used to determine the entropy and Gibbs free energy of denaturation (Delta G(D)) for the ferri form of the wild-type protein and 13 interface variants. Changes in Delta G(D) cannot be allocated solely to enthalpic or entropic effects, but there is no evidence of enthalpy-entropy compensation. The lack of additivity of Delta G(D) values for single versus multiple amino acid substitutions indicates that the helices interact thermodynamically. Changes in Delta G(D) are not in accord with helix propensities, indicating that interactions between the helices and the rest of the protein outweigh helix propensity. Comparison of Delta G(D) values for the interface variants and nearly 90 non-cytochrome c variants to side-chain model data leads to several conclusions. First, hydrocarbon side chains react to burial-like transfer from water to cyclohexane, but even weakly polar side chains respond differently. Second, despite octanol being a poor model for protein interiors, octanol-to-water transfer free energies are useful stability predictors for changing large hydrocarbon side chains to smaller ones. Third, unlike cyclohexane and octanol, the Dayhoff mutation matrix predicts stability changes for a variety of substitutions, even at interacting sites. Furthermore, a correlation is observed between stability changes and the growth rates of yeast harboring the variants. In relation to protein evolution, interface variants possessing residue combinations found in naturally occurring cytochrome c sequences are the most stable, and the data support the neutral theory of macromolecular evolution.

Notes :

Times Cited: 22 QM333 BIOCHEMISTRY-USA
 -- contributed by John Beatty, March 29, 2002