Study of the villin headpiece folding dynamics by combining coarse-grained Monte Carlo evolution and all-atom molecular dynamics

The folding mechanism of the Villin headpiece (HP36) is studied by means
of a novel approach which entails an initial coarse-grained Monte Carlo
(MC) scheme followed by all-atom molecular dynamics (MD) simulations in
explicit solvent. The MC evolution occurs in a simplified free-energy
landscape and allows an efficient selection of marginally-compact
structures which are taken as viable initial conformations for the MD.
The coarse-grained MC structural representation is connected to the one
with atomic resolution through a ``fine-graining'' reconstruction
algorithm. This two-stage strategy is used to select and follow the
dynamics of seven different unrelated conformations of HP36. In a
notable case the MD trajectory rapidly evolves towards the folded state,
yielding a typical root-mean-square deviation (RMSD) of the core region
of only 2.4 Angstrom from the closest NMR model (the typical RMSD over
the whole structure being 4.0 Angstrom). The analysis of the various
MC-MD trajectories provides valuable insight into the details of the
folding and mis-folding mechanisms and particularly about the delicate
influence of local and nonlocal interactions in steering the folding
process. (C) 2004Wiley-Liss, Inc.