  Understanding how monomeric proteins fold under in vitro conditions is
crucial to describing their functions in the cellular context. Significant
advances both in theory and experiments have resulted in a conceptual framework
for describing the folding mechanisms of globular proteins. The experimental
data and theoretical methods have revealed the multifaceted character of
proteins. Proteins exhibit universal features that can be determined using only
the number of amino acid residues (N) and polymer concepts. The sizes of
proteins in the denatured and folded states, cooperativity of the folding
transition, dispersions in the melting temperatures at the residue level, and
time scales of folding are to a large extent determined by N. The consequences
of finite N especially on how individual residues order upon folding depends on
the topology of the folded states. Such intricate details can be predicted
using the Molecular Transfer Model that combines simulations with measured
transfer free energies of protein building blocks from water to the desired
concentration of the denaturant. By watching one molecule fold at a time, using
single molecule methods, the validity of the theoretically anticipated
heterogeneity in the folding routes, and the N-dependent time scales for the
three stages in the approach to the native state have been established. Despite
the successes of theory, of which only a few examples are documented here, we
conclude that much remains to be done to solve the "protein folding problem" in
the broadest sense.
