Abstract
This Perspective is intended to raise questions about the conventional
interpretation of protein folding. According to the conventional
interpretation, developed over many decades, a protein population can
visit a vast number of conformations under unfolding conditions, but a
single dominant native population emerges under folding conditions.
Accordingly, folding comes with a substantial loss of conformational
entropy. How is this price paid? The conventional answer is that
favorable interactions between and among the side chains can compensate
for entropy loss, and moreover, these interactions are responsible for
the structural particulars of the native conformation. Challenging this
interpretation, the Perspective introduces a proposal that high energy
(i.e., unfavorable) excluding interactions winnow the accessible
population substantially under physical-chemical conditions that favor
folding. Both steric clash and unsatisfied hydrogen bond donors and
acceptors are classified as excluding interactions, so called because
conformers with such disfavored interactions will be largely excluded
from the thermodynamic population. Both excluding interactions and
solvent factors that induce compactness are somewhat non-specific, yet
together they promote substantial chain organization. Moreover, proteins
are built on a backbone scaffold consisting of a-helices and strands of
b sheet, where the number of hydrogen bond donors and acceptors is
exactly balanced. These repetitive secondary structural elements are the
only two conformers that can be both completely hydrogen-bond satisfied
and extended indefinitely without encountering a steric clash. Putting
the “bottom line” at the top: it is likely that hydrogen-bond
satisfaction represents a largely overlooked parameter in protein
folding models.