The Levinthal paradox of protein folding is commonly
perceived as a statement about the impossibility of folding
by a completely random conformational search. Often missed
in such narratives is the fact that the question raised by
Levinthal was in response to the experimental discovery of
two-state, switch-like cooperative folding in the late
1960s, rather than to the problem of conformational search
per se. The implication of this understanding on the notion
of a funnel-like energy landscape will be discussed.
Comparisons between theory and experiment on cooperative
folding indicate a prominent role of desolvation barriers,
which contribute to an apparent general organizing principle
entailing a coupling between local conformational
preferences and nonlocal packing interactions.
Investigations into the role of desolvation in protein
folding also resolves an apparent inconsistency between
experimental observations of enthalpic folding barriers and
the theoretical funnel picture of folding. Examples will be
given to illustrate how important folding principles have
been gleaned from studies using native-centric models and
how nonnative interactions may be treated perturbatively in
essentially the same conceptual framework.