Essential dynamics of reversible peptide folding: Memory-free conformational dynamics governed by internal hydrogen bonds

A principal component analysis has been applied on equilibrium simulations of a beta -heptapeptide that shows reversible folding in a methanol solutio n. The analysis shows that the configurational space contains only three de nse sub-states. These states of relatively low free energy correspond to th e "native" left-handed helix, a partly helical intermediate, and a hairpin- like structure. The collection of unfolded conformations form a relatively diffuse cloud with little substructure, Internal hydrogen-bonding energies were found to correlate well with the degree of folding. The native helical structure folds from the N terminus; the transition from the major folding intermediate to the native helical structure involves the formation of the two most C-terminal backbone hydrogen bonds. A four-state Markov model was found to describe transition frequencies between the conformational states within error limits, indicating that memory-effects are negligible beyond the nanosecond time-scale. The dominant native state fluctuations were foun d to be very similar to unfolding motions, suggesting that unfolding pathwa ys can be inferred from fluctuations in the native state. The low-dimension al essential subspace, describing 69% of the collective atomic fluctuations , was found to converge at time-scales of the order of one nanosecond at al l temperatures investigated, whereas folding/unfolding takes place at signi ficantly longer time-scales, even above the melting temperature. (C) 2001 A cademic Press.