“Many naturally-occurring proteins fold reliably and quickly to their native state despite the astronomical number of possible configurations. In nature, proteins apparently do not sample all of these possible configurations since they fold in a few seconds, and even postulating minimum time for going from one conformation to another, the proteins would have time to try on the order of 108 different conformations at most before reaching their final state.
We feel that protein folding is speeded and guided by the rapid formation of local interactions which then determine the further folding of the peptide. This suggests local amino acid sequences which form stable interactions and serve as nucleation points in the folding process.”
-C. Levinthal, Journal de Chimie Physique et de Physico-Chimie Biologique, 1968, 65, 44–45