Search for folding nuclei in three-dimensional protein structures

This paper presents the results of three new approaches to the problem of f inding the folding nucleus in the given 3D protein structure. The first, si mple phenomenological approach is based on involvement of various protein c hain residues in the protein core and secondary structure. It is shown that this approach demonstrates rather modest correlation with experiment. Two other, more complicated, but physically more grounded approaches are based on the search for the saddle points of the free energy landscape on the net work of protein folding/unfolding pathways. To this end, one of these appro aches employs the branch-and-bound technique, and the other makes use of dy namic programming. These approaches, and especially the latter, give better correlation with experiment, and the estimated free energies of the saddle points (i.e., of the folding/unfolding nuclei) are consistent with the exp erimentally observed rapid (within a fraction of a second) folding and unfo lding of small proteins.