Understanding the folding and stability of a zinc finger-based full sequence design protein with replica exchange molecular dynamics simulations

ABSTRACT Full sequence design protein FSD-1 is a designed protein based on the motif of zinc finger protein. In this work, its folding mecha-nism and thermal stability are investigated using the replica exchange molecular dynamics model with the water molecules being treated explicitly. The results show that the folding of the FSD-1 is ini-tiated by the hydrophobic collapse, which is accom-panied with the formation of the C-terminal a-he-lix. Then the folding proceeds with the formation of the b-hairpin and the further package of the hydro-phobic core. Compared with the b-hairpin, the a-helix has much higher stability. It is also found that the N-capping motif adopted by the FSD-1 con-tributes to the stability of the a-helix dramatically. The hydrophobic contacts made by the side chain of Tyr3 in the native state are essential for the sta-bilization of the b-hairpin. It is also found that the folding of the N-terminal b-hairpin and the C-termi-nal a-helix exhibits weak cooperativity, which is consistent with the experimental data. Meanwhile, the folding pathway is compared between the FSD-1 and the target zinc finger peptide, and the possi-ble role of the zinc ion on the folding pathway of zinc finger is proposed. Proteins 2007;67:338