Molecular Simulation and Systems Biology - Systems Biology: Networks, Models, and Applications - page 83

showing three different representations of this peptide.) This structure
is stably folded on its own, and has emerged as one of the standard
model systems used to study protein folding mechanisms. A range
of experimental and computational approaches have been applied to
elucidate the thermodynamics and kinetics of folding in this system.
Experimental work on this beta hairpin was initiated by Blanco et al.
in 1994 [37]. They were the first to synthesize the 16-residue peptide
and demonstrate that it was folded in a beta hairpin structure by
NMR spectroscopy. The experimental study of the kinetics of folding
in this system was pioneered by Munoz et al., who determined the
folding time to be 6 s using a laser temperature-jump experiment [38].

They also suggested that folding proceeded by a “zipping” mechanism,
where the turn forms first, and then the beta-sheet hydrogen bonds
form outward from the turn. In this model, formation of native
hydrophobic contacts happens relatively late in the folding process.
This hydrogen-bond-centric view of folding was challenged by early
simulations of the folding thermodynamics of this system. Dinner et al.
studied the beta hairpin in implicit solvent using the CHARMm force
field [39]. Their simulations showed a folding mechanism that was
initiated by hydrophobic collapse. Following the formation of contacts
between the hydrophobic side chains, native-like hydrogen bonds
formed between those core residues and propagated outward toward
the turn and the termini.
Pande and Rokhsar simulated the unfolding and refolding of the
beta hairpin in water using an explicit solvent model [40]. Their
studies showed an unfolding process that proceeded by an initial
loss of hydrogen bonding, followed by dissolution of the hydrophobic
core. This suggested a folding process that contained four distinct
metastable states: the unfolded state, a more compact state with a
partially solvated hydrophobic core, a state with a well-packed
hydrophobic core but no native hydrogen bonds, and the folded state.
Detailed thermodynamic measurements of the folding transition
were carried out by Honda et al. [41] Their data show no evidence for
a significant folding intermediate and instead indicate that there is a
single, cooperative folding transition. In contrast, many of the simula-
tion studies have identified a partially folded state with native-like
hydrophobic contacts as a significant intermediate. This conflict
remains to be resolved; it is possible that one or more intermediates
exists, but at a population which is so small that folding is effectively
two-state.
Garcia and Sanbonmatsu were the first to apply a thermodynamic
sampling technique called replica exchange molecular dynamics to the
beta hairpin [42]. Replica exchange molecular dynamics is a method
to enhance sampling in molecular simulations by running multiple
coupled simulations of the same system at different temperatures.

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