Abstract
Beginning with simplified lattice and continuum ``minimalist'' models
and progressing to detailed atomic models, simulation studies have
augmented and directed development of the modern landscape perspective
of protein folding. In this review we discuss aspects of detailed
atomic simulation methods applied to studies of protein folding free
energy surfaces, using biased-sampling free energy methods and
temperature-induced protein unfolding. We review studies from each on
systems of particular experimental interest and assess the strengths
and weaknesses of each approach in the context of ``exact'' results
for both free energies and kinetics of a minimalist model for a
beta-barrel protein. We illustrate in detail how each approach is
implemented and discuss analysis methods that have been developed as
components of these studies. We describe key insights into the
relationship between protein topology and the folding mechanism
emerging from folding free energy surface calculations. We further
describe the determination of detailed ``pathways'' and models of
folding transition states that have resulted from unfolding studies.
Our assessment of the two methods suggests that both can provide, often
complementary, details of folding mechanism and thermodynamics, but
this success relies on (a) adequate sampling of diverse conformational
regions for the biased-sampling free energy approach and (b) many
trajectories at multiple temperatures for unfolding studies.
Furthermore, we find that temperature-induced unfolding provides
representatives of folding trajectories only when the topology and
sequence (energy) provide a relatively funneled landscape and
``off-pathway'' intermediates do not exist.
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