Graph-representation of oxidative folding pathways

The oxidative folding space can be represented as a network of DIS states interconnected by disulfide interchange reactions that can either create/abolish or rearrange disulfide bridges. We propose a simple 3D representation wherein the states having the same number of disulfide bridges are placed on separate planes. In this representation, the shuffling transitions are within the planes, and the redox edges connect adjacent planes. In a number of experimentally studied cases (bovine pancreatic trypsin inhibitor, insulin-like growth factor and epidermal growth factor), the observed intermediates appear as part of contiguous oxidative folding pathways.Such networks can be used to visualize folding pathways in terms of the experimentally observed intermediates. A simple visualization template written for the Tulip package http://www.tulip-software.org/ webcite can be obtained from V.A.The process of protein folding whereby a linear polypeptide chain reaches its native structure has been one of the most intensely studied biomolecular problems over the past 50 years (for current reviews see [1-3]). Folding of a protein is usually pictured as a search for the native conformation within the conformational space of all possible conformational states, each characterized by a set of parameters. Even though most of the conformational states are not accessible to experiment, graphic representations of the potential energy surface have played pivotal roles in explaining how the conformational space is gradually restricted during the process folding [4]. Key concepts such as folding pathways [5] are also best explained by graphic representations.The particular kind of folding that this article is concerned with is oxidative folding, which is the fusion of native disulfide bond formation with conformational folding [6-8]. This complex process is guided by two types of interactions: first, non-covalent interactions giving rise to secondary and tertiary structure, and second, coval