A Molecular View of Kinetic Pathways

Two short pathways that link the a-helical and /3-hairpin macrostates without making use of microstates with an instantaneous temperature above 488K are shown in Fig.5.1. The path shown in Fig.5.1 (upper) involves the unwinding of both ends of the helix, leaving approximately one turn of helix in the middle of the molecule. This turn then serves as a nucleation point for the formation of the /3-turn, which is stabilized by hydrophobic interactions between the side chains of Y45 and F52. The native hydrogen bonds nearest to the turn then form, after which the remainder of the native hairpin structure forms. This pathway is similar to previously proposed mechanisms for the folding of the G-peptide /3-hairpin from a coil state, which emphasize the formation of hydrophobic contacts before hydrogen bond formation [17,18, 140-143] and the persistence of the /3-turn even in the unfolded state [143]. 

The novel aspect of the path shown in Fig. 5.1 (upper) is the preformation of the /3-turn from a residual turn in an otherwise unfolded a-helix. 

An alternative pathway (Fig. 5.1 Lower) involves the unwinding of the C-terminal half of the a-helix, which then loops back so as to be nearly parallel to the remaining helix. This proximity allows for the possibility of side-chain interactions between the helix and the C-terminal half of the molecule, including hydrophobic interactions between F52 in the helix and either W43 or Y45. This pathway is very similar to the one previously identified by us on the basis of the analysis of the potential of mean force for the G-peptide along two principle component degrees of freedom [144], In both pathways, it is clear that formation of native /3-hairpin contacts can occur without the complete loss of helical secondary structure, making the idea of the a-helix as an on-path intermediate in the formation of the /3-hairpin physically plausible [100], 

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