Kinetics of Folding
Levinthal’s Paradox: A protein would essentially never find its native fold by sampling all possible conformations: to sample the 3^100 combinations of a 100 amino acid-long protein would take longer than the age of universe (assuming it folds at the rate of 1 fold/picosecond). YET it does. A protein’s ability to quickly home in on its native fold led to two models.
Diffusion-Collision Model: folds occur in a stepwise manner that collaboratively grow secondary structure elements into tertiary structures. Secondary structures form first, followed by formation of tertiary structure.
Nucleation-Condensation Model: the formation of hydrophobic interactions that stabilize otherwise weak secondary structures. In NCM, the core forms first, followed by the secondary structure. The cores collapse in a relatively random way, allowing secondary structure to form because residues are in close proximity.
Experimental evidence suggests both may occur depending on the primary sequence.