  The Levinthal paradox exposes many critical questions on the protein folding
problem, among which we could point out why proteins can reach their native
state in a biologically reasonable time. A proper answer to this question is of
foremost importance for evolutive biology since it enables us to understand
life as we know it. Preliminary results, based on the upper bound protein
marginal-stability limit, together with transition state theory arguments, lead
us to show that two-state proteins must reach their native state in, at most,
seconds rather than ($\sim 10^{27}$) years -- as indicated by a naive solution
of the Levinthal paradox. This outcome -- added to the amide hydrogen-exchange
protection factors analysis -- makes it possible for us to suggest how a
protein point mutations and/or post-translational modifications impact its
folding time scales but not its upper bound limit that obeys the physics ruling
the process. Noteworthy for almost 50 years, the protein folding problem --mas
the Levinthal paradox -- has been a topic of passionate debate because
Anfinsen's challenge -- how a sequence encodes its folding -- remains unsolved
despite the smashing success of accurately predicting the protein
tridimensional structures by state-of-the-art numerical-methods. Aimed to
unlock this long-standing challenge, we propose a new perspective of protein
folding, specifically, as a problem that should be devised as an 'analytic
whole' -- a Leibniz & Kant's notion. This viewpoint might help us decode
Anfinsen's challenge and, thus, open new avenues for future research in the
protein folding field.
