Aggregation, Protein
27
Native state
Unfolded state
Molten globule
states
Energy
Entropy
Q
Fig. 1
Schematic representation of the folding funnel. Q is the number of
native interactions.
through a complicated energy landscape.’’
Thus, a wide variety of folding behav-
iors emerge from the energy landscape,
depending on the energetic parameters
and conditions. The folding rate could be
slowed by ripples in the energy landscape
corresponding to local minima populated
by transiently stable intermediates. In a
rugged energy landscape with kinetic traps
formed by energy barriers, the folding will
be even slower. When local energy barriers
are high enough, protein molecules could
be trapped and possibly aggregate.
The new view has progressively replaced
the classical one of a unique sequential
pathway and is now quite generally ac-
cepted. It is similar to the jigsaw puzzle
model proposed in 1986 by Harrison and
Durbin, suggesting the possibility of mul-
tiple folding routes to reach a unique
solution. Many experimental results are
consistent with this view. There is an
increasing amount of evidence showing
that the extended polypeptide chain folds
through a heterogeneous population of
partially folded intermediates in fluctuat-
ing equilibrium. Several alternative folding
pathways have been observed for differ-
ent proteins. From the convergence of
theoretical and experimental studies, a
uni±ed view of the folding process has
progressively emerged, also providing an
explanation for the aggregation processes.
2.2
Detection of Aggregates during the
Refolding Process
2.2.1
Transient Aggregation
Several observations indicate that transient
aggregation could occur during
in vitro
protein refolding. Direct evidence for the
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