Universality and diversity of the protein folding scenarios: a comprehensive analysis with the aid of a lattice model.
BACKGROUND
The role of intermediates in protein folding has been a matter of great controversy. Although it was widely believed that intermediates play a key role in minimizing the search problem associated with the Levinthal paradox, experimental evidence has been accumulating that small proteins fold fast without any detectable intermediates.


RESULTS
We study the thermodynamics and kinetics of folding using a simple lattice model. Two folding sequences obtained by the design procedure exhibit different folding scenarios. The first sequence folds fast to the native state and does not exhibit any populated intermediates during folding. In contrast, the second sequence folds much slower, often being trapped in misfolded low-energy conformations. However, a small fraction of folding molecules for the second sequence fold on a fast track avoiding misfolded traps. In equilibrium at the same temperature the second sequence has a highly populated intermediate with structure similar to that of the kinetics intermediate.


CONCLUSIONS
Our analysis suggests that intermediates may often destabilize native conformations and derail the folding process leading it to traps. Less-optimized sequences fold via parallel pathways involving misfolded intermediates. A better designed sequence is more stable in the native state and folds fast without intermediates in a two-state process.
Mirny
L A
LA
Harvard University, Department of Chemistry, Cambridge, MA 02138, USA.
Abkevich
V
V
Shakhnovich
E I
EI
D000595:Amino Acid Sequence; D015195:Drug Design; D004355:Drug Stability; D007700:Kinetics; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry; D013816:Thermodynamics
D011506:Proteins