Investigation of routes and funnels in protein folding by free energy   functional methods
  We use a free energy functional theory to elucidate general properties of heterogeneously ordering, fast folding proteins, and we test our conclusions with lattice simulations. We find that both structural and energetic heterogeneity can lower the free energy barrier to folding. Correlating stronger contact energies with entropically likely contacts of a given native structure lowers the barrier, and anticorrelating the energies has the reverse effect. Designing in relatively mild energetic heterogeneity can eliminate the barrier completely at the transition temperature. Sequences with native energies tuned to fold uniformly, as well as sequences tuned to fold by a single or a few routes, are rare. Sequences with weak native energetic heterogeneity are more common; their folding kinetics is more strongly determined by properties of the native structure. Sequences with different distributions of stability throughout the protein may still be good folders to the same structure. A measure of folding route narrowness is introduced which correlates with rate, and which can give information about the intrinsic biases in ordering due to native topology. This theoretical framework allows us to systematically investigate the coupled effects of energy and topology in protein folding, and to interpret recent experiments which investigate these effects. 
Steven S. Plotkin and Jose N. Onuchic