Why does a protein fold?

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With the help of lattice Monte Carlo modelling of heteropolymers, we show that the necessary condition for a protein to fold on short call is to proceed through partially folded intermediates. These elementary structures are formed at an early stage in the folding process and contain, at the local level, essentially all of the amino acids found in the folding core (transition state) of the protein, providing the local guidance for its formation. The sufficient condition for the protein to fold is that the designed sequence has an energy, in the native conformation, below Ec (the lowest energy of the structurally dissimilar compact conformations) where it has not to compete with the bulk of misfolded conformations. Sequences with energy close to Ec can display prion--like behaviour, folding to two structurally dissimilar conformations, one of them being the native.