Multi-nucleation and vectorial folding pathways of large helix protein

At present we have already had the detailed knowledge of the folding of small model proteins, but a unified picture of how large proteins fold is still absent. We simulated the folding of a large eight-helix-bundle protein with a length of 145 amino acids by using a united-residue protein model. We observed a multiple nucleation folding pathway: the formation of secondary structures was followed by the nucleation of helices at the two terminal parts and also at the middle of the chain, and then the nuclei grew and combined with each other to form the tertiary structure. Surprisingly, we also found a vectorial folding pathway that was shown recently for co-translational folding in the ribosome exit tunnel. Furthermore, we found that all three-helix subunits in the chain can fold into native-like conformations independently, especially those at the two terminal parts and the middle of the chain, which may be responsible for the nucleation's. These results may be helpful to understand the folding mechanism of large repeat helical proteins.

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