Folding with a protein's native shortcut network.

A complex network approach to protein folding is proposed, wherein a protein's contact map is reconceptualized as a network of shortcut edges, and folding is steered by a structural characteristic of this network. Shortcut networks are generated by a known message passing algorithm operating on protein residue networks. It is found that the shortcut networks of native structures (SCN0s) are relevant graph objects with which to study protein folding at a formal level. The logarithm form of their contact order (SCN0_lnCO) correlates significantly with folding rate of two-state and nontwo-state proteins. The clustering coefficient of SCN0s (C ) correlates significantly with folding rate, transition-state placement and stability of two-state folders. Reasonable folding pathways for several model proteins are produced when C is used to combine protein segments incrementally to form the native structure. The folding bias captured by C is detectable in non-native structures, as evidenced by Molecular Dynamics simulation generated configurations for the fast folding Villin-headpiece peptide. These results support the use of shortcut networks to investigate the role protein geometry plays in the folding of both small and large globular proteins, and have implications for the design of multibody interaction schemes in folding models. One facet of this geometry is the set of native shortcut triangles, whose attributes are found to be well-suited to identify dehydrated intraprotein areas in tight turns, or at the interface of different secondary structure elements.