Kevin Drew, Dylan Chivian, and Richard Bonneau


The goal of de novo structure prediction is to predict the native structure of a protein given only its amino acid sequence. It is generally assumed that a protein sequence folds to a well-defined ensemble average commonly referred to as the native conformation or native ensemble of conformations. It is also commonly assumed that the native state is at or near the global free energy minimum and that this minimum is accessible, leading to folding rates spanning not longer than minutes (albeit spanning >6 orders of magnitude). Exciting exceptions to these assumptions exist, but these assumptions remain quite safe for a large majority of proteins. The problem of finding this native state can be broken into two smaller problems: first, developing an accurate potential and, second, developing an efficient method for searching the energy landscape arising from the potential.

Many methods that are today referred to as de novo have previously and/or alternately been referred to “new folds” or ab initio methods. For the purpose of this review, we will classify a method as de novo structure prediction if that method does not rely on homology between the query sequence and a sequence in the Protein Data Bank (PDB) to create a template for structure prediction. De novo methods, by this definition, are forced to consider much larger conformational landscapes than fold ...

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