Fig. 3

The protein folding landscape of a protein that is metastable in its native conformation. The native fold of this protein occupies a metastable local free energy minimum shown as a mountainside lake, and it is higher than the free energy of the majority of its denatured conformations. This protein can only be folded in vivo, and the folding must start from a higher energy state, at the top of the mountain. The entropy of the nascent peptide is reduced and the backbone conformational strain is introduced by the motions of the ribosome/chaperone complex in the process that is described in [67, 68] and in the text. Yellow arrow shows fast folding pathway in vivo. Many of the denatured forms of this protein have lower Gibbs free energy than the native conformation, and their spontaneous unassisted refolding is not possible. Reversibly and irreversibly denatured forms of the protein occupy multiple positions down the mountain slope