Folding-unfolding thermodynamics of a beta-heptapeptide from equilibrium simulations

The thermodynamics of folding and unfolding of a beta-heptapeptide in metha nol solution has been studied at four different temperatures, 298 K, 340 K, 350 K, and 360 K, by molecular dynamics simulation. At each of these tempe ratures, the 50-ns simulations were sufficient to generate an equilibrium d istribution between a relatively small number of conformations (similar to 10(2)), showing that, even above the melting temperature (similar to 340 K) , the peptide does not randomly sample conformational space. The free energ y of folding and the free energy difference between pairs of conformations have been calculated from their relative populations. The experimentally de termined folded conformation at 298 K, a left-handed 3(1)-helix, is at each of the four temperatures the predominant conformation, with its probabilit y and average lifetime decreasing with increasing temperature. The most com mon intermediates of folding and unfolding are also the same at the four te mperatures, Paths and rates of interconversion between different conformati ons have been determined. It has been found that folding can occur through multiple pathways, not necessarily downhill in free energy, although the fi nal step involves a reduced number of intermediates. Proteins 1999;34:269-2 80. (C) 1999Wiley-Liss, Inc.