The problem of protein folding is that how proteins acquire their native unique three-dimensional structure in the physiological milieu. To solve the problem, the following key questions should be answered: do proteins fold co-or post-translationally, i.e. during or after biosynthesis, what is the mechanism of protein folding, and what is the explanation for fast folding of proteins? The two first questions are discussed in the current review. The general lines are to show that the opinion, that proteins fold after they are synthesized is hardly substantiated and suitable for solving the problem of protein folding and why proteins should fold cotranslationally. A possible tentative model for the mechanism of protein folding is also suggested. To this end, a thorough analysis is made of the biosynthesis, delivery to the folding compartments, and the rates of the biosynthesis, translocation and folding of proteins. A cursory attention is assigned to the role of GroEL/ES-like chaperonins in protein folding.

In many studies on the protein folding problem it is assumed that the internal rotational barriers about NC(α) and C(α)C backbone bonds in unfolded polypeptides are quite small, around 0.7 kcal/mol, of an order comparable to the energy of kT at normal temperature (where k is Boltzmann's constant and T is the temperature in K) and hence that rotations about these bonds occur almost freely. Here it is highlighted that such consideration is an unfortunate mistake. Approximate values for the rotational barriers of NC(α) and C(α)C bonds are suggested from computations of U(ϕ, ψ) potential energy surface (PES) maps of a number of oligopeptides by a semiempirical method for conformational analysis. The proposed values are about 16 kcal/mol for NC(α) bonds and 6 kcal/mol for C(α)C bonds. The values of the same barriers estimated from some ab initio quantum-mechanical PES maps for several dipeptides available in literature are also highlighted.

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