SCIENCE AT THE EDGE SEMINAR

Friday, 04 February 2011 at 11:30am

Room 1400 Biomedical and Physical Sciences Bldg.

Refreshments at 11:15


Speaker: Vincent Voelz
         Department of Chemistry, Stanford University

Title:   Coupling Theory and Experiment to Tame the Complexity of Protein Folding

Abstract:

Predicting the mechanism by which proteins self-assemble to their functional
folds remains elusive, despite its basic importance in biology and human
disease.  Over the last decade, new simulation methodologies have advanced our
understanding of protein folding considerably.  Aside from the inevitable
acceleration of computer hardware, a key advance has been the development of
Markov State Model (MSM) approaches, in which conformational dynamics is
modeled as transitions between metastable states.  These approaches, along
with large-scale distributing computing efforts, have recently been used to
model the folding of NTL9(1-39), a protein that folds on the millisecond
timescale. This and other MSM models of folding predict new views of the
folding reaction - a complex network of metastable intermediates, multiple
pathways, and compact unfolded states with residual structuring - yet,
experiments often report simple folding kinetics. To address this issue, we
move beyond simulations of small mini-proteins to study a larger,
slower-folding protein, ACBP (acyl-CoA binding protein), an 86-residue
four-helix bundle protein with a fast kinetic phase on the ~100 µs timescale
that we probed jointly with a combination of large-scale simulation and
smFRET, ultrafast mixing, and Trp-Cys contact quenching experiments.
Surprisingly, our results suggest that the fast kinetic phase is not due to
formation of a barrier-limited intermediate, but rather a much more
heterogeneous acquisition of unfolded-state structure.  Despite the complexity
of these underlying dynamics, the MSM model of ACBP predicts that
spectroscopic probes are most sensitive to two main dynamical timescales,
explaning how simple phenomenological models can arise from experiments.