  For the vast majority of naturally occurring, small, single domain proteins
folding is often described as a two-state process that lacks detectable
intermediates. This observation has often been rationalized on the basis of a
nucleation mechanism for protein folding whose basic premise is the idea that
after completion of a specific set of contacts forming the so-called folding
nucleus the native state is achieved promptly. Here we propose a methodology to
identify folding nuclei in small lattice polymers and apply it to the study of
protein molecules with chain length N=48. To investigate the extent to which
protein topology is a robust determinant of the nucleation mechanism we compare
the nucleation scenario of a native-centric model with that of a sequence
specific model sharing the same native fold. To evaluate the impact of the
sequence's finner details in the nucleation mechanism we consider the folding
of two non- homologous sequences. We conclude that in a sequence-specific model
the folding nucleus is, to some extent, formed by the most stable contacts in
the protein and that the less stable linkages in the folding nucleus are solely
determined by the fold's topology. We have also found that independently of
protein sequence the folding nucleus performs the same `topological' function.
This unifying feature of the nucleation mechanism results from the residues
forming the folding nucleus being distributed along the protein chain in a
similar and well-defined manner that is determined by the fold's topological
features.
