@article{bibcite_191,
  keywords = {Kinetics, Peptides, Protein Folding, Protein Structure, Secondary, Thermodynamics, Amino Acid Sequence, Isotopes, Photochemistry, Spectroscopy, Fourier Transform Infrared},
  author = {J. A. Ihalainen and B. Paoli and S. Muff and E. H. G. Backus and J. Bredenbeck and G. A. Woolley and A. Caflisch and P. Hamm},
  title = {Alpha-Helix folding in the presence of structural constraints},
  abstract = {<p>We have investigated the site-specific folding kinetics of a photoswitchable cross-linked \&alpha;-helical peptide by using single <sup>13</sup>C=<sup>18</sup>O isotope labeling together with time-resolved IR spectroscopy. We observe that the folding times differ from site to site by a factor of eight at low temperatures (6 \&deg;C), whereas at high temperatures (45 \&deg;C), the spread is considerably smaller. The trivial sum of the site signals coincides with the overall folding signal of the unlabeled peptide, and different sites fold in a noncooperative manner. Moreover, one of the sites exhibits a decrease of hydrogen bonding upon folding, implying that the unfolded state at low temperature is not unstructured. Molecular dynamics simulations at low temperature reveal a stretched-exponential behavior which originates from parallel folding routes that start from a kinetically partitioned unfolded ensemble. Different metastable structures (<i>i.e.</i>, traps) in the unfolded ensemble have a different ratio of loop and helical content. Control simulations of the peptide at high temperature, as well as without the cross-linker at low temperature, show faster and simpler (<i>i.e.</i>, single-exponential) folding kinetics. The experimental and simulation results together provide strong evidence that the rate-limiting step in formation of a structurally constrained \&alpha;-helix is the escape from heterogeneous traps rather than the nucleation rate. This conclusion has important implications for an \&alpha;-helical segment within a protein, rather than an isolated \&alpha;-helix, because the cross-linker is a structural constraint similar to those present during the folding of a globular protein.</p>},
  year = {2008},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  volume = {105},
  pages = {9588-9593},
  month = {2008 Jul 15},
  issn = {1091-6490},
  doi = {10.1073/pnas.0712099105},
  language = {eng},
}