Biology Reference
In-Depth Information
Chapter 11
Subcellular Systems
11.1 Protein Folding and “Info-statistical Mechanics”
The field of protein folding appears to have gone through a paradigm shift around
1995, largely due to the work of Wolynes and his group (Wolynes et al. 1995; Dill
and Chan 1997; Harrison and Durbin 1985). The paradigm shift involves replacing
the idea of
folding pathways
with the so-called folding funnel. In other words, the
earlier notion of a denatured protein folding to its final native conformation through
a series of distinct intermediate conformational states has been replaced by a new
view, according to which an ensemble of conformational isomers (often called
“conformers,” not to be confused with “conformons”; a conformer can carry many
conformons in it; see Sect.
11.3.2
) of a denatured protein undergoes a transition to a
final native conformation through a series of “ensembles” of conformational
intermediates, each intermediate following a unique folding path to the final
common native structure. In short, the paradigm shift is from
individual intermedi-
ate conformational isomers
of a protein to an
ensemble of the conformational
isomers
, on the one hand, and from a
single folding pathway
to an
ensemble of
folding pathways
(down the folding funnel), on the other.
Leopold et al. (1992) characterize the “protein folding funnel” as follows:
...
a kinetic mechanism for understanding the self-organizing principle of the sequence-
structure relationship. This concept follows from a few general considerations. (i) Proteins
fold from a random state by collapsing and reconfiguring [i.e., mainly conformationally
rearranging polypeptides without breaking or forming covalent bonds:
my addition
],
(ii) reconfiguration occurs diffusively [i.e., as a consequence of Brownian motions of
proteins:
my addition
] and follows a general drift from higher energy to lower energy
conformations, and (iii) reconfiguration occurs between conformations that are geometri-
cally similar - i.e., global interconversions are energetically prohibitive after collapse - so
local interconversions alone are considered. We define the folding funnel as a collection of
geometrically similar collapsed structures, one of which is thermodynamically stable with
respect to the rest, though not necessarily with respect to the whole conformation space
...
.
Just as water flows down a funnel, higher energy conformers (i.e., conforma-
tional isomers) of a denatured protein are thought to “flow” down the folding funnel
