We have developed an algorithm to assess the folding complexity in terms of the concept of sequential folding. A scenario that most proteins synthesized in eukaryotic cell might fold sequentially has been suggested recently in several experiments with distinctive mechanisms. This proposed folding mechanism in vivo significantly reduced the possibility of misfolding while the help of chaperone is excluded. Given a native protein 3-D structure, its folding complexity can be analyzed either based on the results of the structure being cut into hydrophobic folding units, or based on a set of hypothetical, transient, highly populated, contiguous fragments (or simply named as "building blocks" of the given structure). With the identification of building blocks at hand, the definition of sequential folding simply is a continuation of interactions between building blocks, which prevails sequentially along the sequence from N terminus to C terminus of a polypeptide chain. Via our automatic assessment of folding complexity, we give not only a clear indication of sequential folding of a given protein but also might provide some insight regarding its likelihood of misfolding and its kinetic folding rate. In terms of the funnel free energy landscape theory, a protein that truly follows the mechanism of sequential folding, in principle, encounters less rough free energy barrier. A simple sequentially folded protein should, therefore, folds less error-prone and folds faster than protein with a complex folding pattern.
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