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Graph Representations of Oxidative Folding
Pathways
Vilmos ÁGOSTON 1 , Masa CEMAZAR 2,3 and Sándor PONGOR 2
1
Bioinformatics Group, Biological Research Center, Hungarian Academy of Sciences,
Temesvári krt. 626726 Szeged, Hungary
2
Protein Structure and Bioinformatics Group, International Centre for Genetic
Engineering and Biotechnology, Area Science Park, 34012 Trieste, Italy
3
Current address: Institute for Molecular Bioscience, University of Queensland, St. Lucia
4072, QLD, Australia
Abstract. Oxidative folding combines the formation of native disulfide bond with
the conformational folding resulting in the native three-dimensional fold. Oxidative
folding pathways can be described in terms of disulfide intermediate species (DIS)
containing a varying number of disulfide bonds and free cysteine residues, which
can also be - as opposed to the majority of protein folding states -isolated and
experimentally studied. Each DIS corresponds to a family of folding states
(conformations) that the given DIS can adopt in three dimensions. The oxidative
folding space can be represented as a network of DIS states interconnected by
disulfide interchange reactions reactions that can either create/abolish or rearrange
disulfide bridges. Such networks can be used to visualize folding pathways in terms
of the experimentally observed intermediates. In a number of experimentally studied
cases, the observed intermediates appear as part of contiguous oxidative folding
pathways.
Introduction
Levinthal's paradox, introduced in 1968 [1], stated that the folding of a protein would last
more than the age of the universe, if it went through looking for the native conformation by
adapting every single conformation possible. There have been many propositions regarding
how the conformational space is restricted so that the folding time is reduced to the
experimental range. We know today that most single domain proteins are able to fold
effectively in vitro to their native folds within seconds. The obvious flaw in stating the
paradox itself is actually the fact that the search for the native conformation is unbiased
with no stabilisation of particular conformations. Today it has been widely accepted that the
native state is the energetically most favourable one on the potential energy surface .
Actually, each conformational state of the protein assumes a certain position on this
surface, which means that not all states are equal in free energy and hence the search for the
native fold cannot be unbiased. The way this view has evolved to form theories about
folding pathways is the following. Already Levinthal stated that there exist specific
pathways for folding. By restricting the molecules to those pathways the polypeptide chain
does not need to undergo an extensive search of all the conformational space. In 1973
Anfinsen proposed that the information coded in the amino acid sequence of a protein
completely determines its folded structure and that the native state is the global minimum
of the free energy [2]. Later, a variety of theories emerged, for example the framework
model, the diffusion-collision model, the nucleation model, the hydrophobic-collapse
model and the jigsaw model. The hydrophobic-collapse and the framework models were
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