Folding with a protein's native shortcut network

Abstract: A complex network approach to protein folding is proposed. The graph object is the network of shortcut edges present in a native-state protein (SCN0). Although SCN0s are found via an intuitive message passing algorithm (S. Milgram, Psychology Today, May 1967 pp. 61-67), they are meaningful enough that the logarithm form of their contact order (SCN0_lnCO) correlates significantly with protein kinetic rates, regardless of protein size. Further, the clustering coefficient of a SCN0 (CSCN0) can be used to combine protein segments iteratively within the Restricted Binary Collision model to form the whole native structure. This simple yet surprisingly effective strategy identified reasonable folding pathways for 12 small single-domain two-state folders, and three non-canonical proteins: ACBP (non-two-state), Top7 (non-cooperative) and DHFR (non-single-domain, > 100 residues). For two-state folders, CSCN0 is relatable to folding rates, transition-state placement and stability. The influence of CSCN0 on folding extends to non-native structures. Moreover, SCN analysis of non-native structures could suggest three fold success factors for the fast folding Villin headpiece peptide. These results support the view of protein folding as a bottom-up hierarchical process guided from above by native-state topology, and could facilitate future constructive demonstrations of this long held hypothesis for larger proteins.