  One of the main concerns of Anfinsen was to reveal the connection between the
amino acid sequence and their biologically active conformation. This search
gave rise to two crucial questions in structural biology, namely, why the
proteins fold and how a sequence encodes its folding. As to the why, he
proposes a plausible answer, namely, at a given milieu a protein folds into its
functional form -- native state -- because such structure represents the lowest
free-energy minimum among all feasible conformations -- the thermodynamic
hypothesis or Anfinsen dogma. As to the how, this remains as an unsolved
challenge and, hence, this inquiry is examined here from a new perspective of
protein folding, namely, as an analytic whole -- a notion proposed by Leibnitz
and Kant. This new perspective forces us to discuss in detail why the
theoretical force-field-based approaches have failed in both their ability to
predict the three-dimensional structure of a protein accurately and in their
capacity to answer one of the most critical questions in structural biology:
how a sequence encodes its folding.
