  A general theoretical framework is developed using free energy functional
methods to understand the effects of heterogeneity in the folding of a
well-designed protein. Native energetic heterogeneity arising from
non-uniformity in native stability, as well as entropic heterogeneity intrinsic
to the topology of the native structure are both investigated as to their
impact on the folding free energy landscape and resulting folding mechanism.
Given a minimally frustrated protein, both structural and energetic
heterogeneity lower the thermodynamic barrier to folding, and designing in
sufficient heterogeneity can eliminate the barrier at the folding transition
temperature. Sequences with different distributions of stability throughout the
protein and correspondingly different folding mechanisms may still be good
folders to the same structure. This theoretical framework allows for a
systematic study of the coupled effects of energetics and topology in protein
folding, and provides interpretations and predictions for future experiments
which may investigate these effects.
