Impact of local and non-local interactions on thermodynamics and kinetics of protein folding.

To address the question of how the geometry of a protein's native conformation affects its folding and stability, we studied three model 36-mers on a cubic lattice. The native structure of one of these model 36-mers consisted mostly of local contacts, while that of a second consisted mostly of non-local contacts. The third native structure had a typical compact native conformation, and served as our reference. For each protein, the amino acid sequence was designed to have a pronounced energy minimum at its native conformation. We observed dramatic differences in folding, dependent on the presence or absence of non-local contacts. For the proteins with a typical large number of non-local contacts, the folding transition was all-or-none, whereas for the one with mostly local contacts, it was not. Although the maximum rate of folding was similar for all three proteins, we found that under conditions at which each native conformation was stable, the structure with mostly non-local contacts folded two orders of magnitude faster than the one with mostly local contacts. The statistical analysis of protein structure agrees fully with the implications of the theory. We discuss the importance of cooperativity in protein folding for its stability.