Rate of β‐structure formation in polypeptides

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Abstract
An explanation is suggested for why a marginally stable β‐structure folds extremely slowly; it is predicted that even a small increase in stability drastically accelerates β‐folding. According to the theory, this folding is a first‐order phase transition, and the rate‐limiting step is nucleation. The rate‐determining “nucleus” (transition state) is the smallest β‐sheet that is sufficiently large to provide an overall free energy reduction during subsequent folding. If the stability of the β‐structure is low, the nucleus is large and possesses a high free energy due to having a large perimeter. When the net stability of the final β‐structure increases (due to either an increase of the β‐sheet stability or a decrease in stability of the competing structures, e.g., α‐helices), the size and energy of a nucleus decrease and the rate of folding increases exponentially. This must result in a fast folding of polypeptides enriched by β‐forming residues (e.g., protein chains). The theory is developed for intramolecular β‐structure, but it can also explain the overall features of intermolecular β‐folding; it is applicable both to antiparallel and parallel β‐sheets. The difference in folding of β‐sheets, α‐helices, and proteins is discussed.