  Models of protein energetics which neglect interactions between amino acids
that are not adjacent in the native state, such as the Go model, encode or
underlie many influential ideas on protein folding. Implicit in this
simplification is a crucial assumption that has never been critically evaluated
in a broad context: Detailed mechanisms of protein folding are not biased by
non-native contacts, typically imagined as a consequence of sequence design
and/or topology. Here we present, using computer simulations of a well-studied
lattice heteropolymer model, the first systematic test of this oft-assumed
correspondence over the statistically significant range of hundreds of
thousands of amino acid sequences, and a concomitantly diverse set of folding
pathways. Enabled by a novel means of fingerprinting folding trajectories, our
study reveals a profound insensitivity of the order in which native contacts
accumulate to the omission of non-native interactions. Contrary to conventional
thinking, this robustness does not arise from topological restrictions and does
not depend on folding rate. We find instead that the crucial factor in
discriminating among topological pathways is the heterogeneity of native
contact energies. Our results challenge conventional thinking on the
relationship between sequence design and free energy landscapes for protein
folding, and help justify the widespread use of Go-like models to scrutinize
detailed folding mechanisms of real proteins.
