Anna Jean Wirth, Yanxin Liu, Maxim B. Prigozhin, Klaus Schulten, and Martin
Gruebele.
Comparing fast pressure jump and temperature jump protein folding
experiments and simulations.
Journal of the American Chemical Society, 137:7152-7159, 2015.
(PMC: PMC4794261)
WIRT2015
The unimolecular folding reaction of small proteins is now amenable to a very
direct mechanistic comparison between experiment and simulation. We present such a
comparison of microsecond pressure and temperature jump refolding kinetics of the
engineered
WW domain FiP35, a model system for beta sheet folding. Both perturbations produce
experimentally a faster and a slower kinetic phase, the "slow" microsecond phase being
activated.
The fast phase shows differences between perturbation methods and is closer to the
downhill
limit by temperature jump, but closer to the transiently populated intermediate limit by
pressure
jump. These observations make more demands on simulations of the folding process
than just a
rough comparison of time scales. To complement experiments, we calculated several
pressure
jump and temperature jump all-atom molecular dynamics trajectories in explicit solvent,
where
FiP35 folded in five of the six simulations. We analyzed our pressure jump simulations by
kinetic modeling and found that the pressure jump experiments and MD simulations are
most
consistent with a 4-state kinetic mechanism. Together, our experimental and
computational data
highlight FiP35’s position at the boundary where activated intermediates and downhill
folding
meet, and we show that this model protein is an excellent candidate for further pressure
jump
molecular dynamics studies to compare experiment and modeling at the folding
mechanism level.
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