Transition States in Protein Folding

Thursday, January 17, 2008 - 11:25am - 11:55am
EE/CS 3-180
Thomas Weikl (Max Planck Institute for Colloids and Interfaces)
Small single-domain proteins often exhibit only a single free-energy
barrier, or transition state, between the denatured and the native state.
The folding kinetics of these proteins is usually explored via mutational
analysis. A central question is which structural information on the
transition state can be derived from the mutational data. To interpret these
data, we have developed models that are based (a) on the substructural
cooperativity of helices and hairpins, and (b) on splitting up
mutation-induced stability changes of a protein into components for its
substructures. We obtain a consistent structural interpretation of
mutational Phi-values by fitting few parameters that describe the degrees of
structure formation of helices and hairpins in the transition state. Our
models explain how mutations at a given site can lead to different
Phi-values, and capture non-classical Phi-values smaller than 0 or larger
than 1, which have been difficult to interpret. Non-classical Phi-values
simply arise, e.g., if mutations stabilize a helix or hairpin, but
destabilize its tertiary interactions.


[1] C. Merlo, K. A. Dill, and T. R. Weikl, PNAS 102, 10171 (2005).

[2] T. R. Weikl and K. A. Dill, J. Mol. Biol. 365, 1578 (2007).

[3] T. R. Weikl, Biophys. J., in press (2008).
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