Transcript Topomer Search Model: 2-state protein folding kinetics

Topomer Search Model:
2-state protein folding kinetics
Presented by
Alison Fraser, Christine Lee,
Pradhuman Jhala, Corban Rivera
Outline
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Overview and Problem Definition
Topomer Search Model
Model Definitions and Relationships
Conclusion
Introduction
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The topomer search model: A simple,
quantitative theory of two-state protein
folding kinetics. by D. Makarov and K.
Plaxo (Protein Science 2003)
Simple single-domain proteins folding
kinetics
single-exponential, two-state process
 smooth energy landscape (no discrete traps and
fine-scale heterogeneous roughness
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Question and Proposed Answer
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Why do some simple proteins fold a million
times more rapidly than others?
Folding rates vary due to topological frustration
and difficulty of diffusing into the correct, native
topology
Mid to late nineties - emerging idea that the
“search for the correct gross topology may be an
important contributor to the folding barrier”
The Discovery
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1998 – empirical measure of topological
complexity highly correlated with experimentally
observed folding rates of two state proteins
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Measure of topology termed relative contact order
Defined as the average sequence separation between
all pairs of residues in contact in the native structure
in relative to the total length of the protein
R ~ 0.9 captures ¾ variance in folding rates
Observations and Problem
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Counterintuitive -> of 2 proteins with
same average contact separation, longer
protein folds faster
Empirical measures of topology correlating
well with folding rates
Sequence-distant contacts per residue
 Fraction of contacts that are sequence distant
 Total contact distance
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 Goal is to define a model to explain
topology-rate relationship
Modeling Folding Rates
Native Sequence Distant Pairs
Folding Rate
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The probability of finding the correct
Topology
The predicted folding rate
Correlation
Contact Order
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Contact order of a
protein chain is the
average separation
along the sequence of
amino acids of points
in physical contact in
the folded protein,
divided by the length
of the protein
Relationship between folding
rate and contact order
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log (kf /QD) = log (λκ) +
QDlogK
λκ = 3800 s-1 and <K> =
0.86
Kf Observed folding rate
QD in Gaussian Chain,
probability of achieving the
native topomer, in reality,
closely related to contact
order
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Once the denatured state adopts a native-like
topology, then any given sequence distant
native pair has, on average, a 45% chance of
being in proximity
Proximity is an orientation in which elements
con collide and form contacts more rapidly
than the rate limiting step (B  C transition)
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Native interactions
(C  D transition)
neither sufficient to
ensure folding nor
determinant of relative
barrier heights
How can we improve the topomer
search model?
Chain-length dependence
 The mean field approximation
 Native interactions
 Non-two-state folding
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Chain-length dependence
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Topomer search model allows one to look at
length dependence independently of topology.
A counter intuitive relationship arises, finding
that longer protein tend to fold more quickly
than predicted.
This gives rise to statistically significant
improvement.
Improvement with Chain-length
dependence
r=0.88
r = 0.92-0.93
Mean-field approximation
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Mean field approximation is just that, an
approximation.
Additional parameters beyond simple counting
the number of sequence distant native pairs are
needed.
But studies have shown only large loop
extensions (a 59-residues loop insert) show
significant changes in two-state folding rates.
Native interactions
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Topomer search model ignores all the detailed
chemical interactions that define the native
state
Found to define relative rates for topologically
simple proteins (QD < 4) as seen by Myers and
Oas 2001 and Islam et al. 2002.
Non-two-state folding
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Current topomer search model based on very
smooth folding energy landscape of two state
proteins.
For non-two–state folding
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Folding kinetics could be defined by the rate of
escape from intermediate states rather than by the
rate of topomer sampling
Predicting these kinetics of the intermediate
escapes will prove to be difficult.