Electrostatic effects on funneled landscapes and structural diversity in denatured protein ensembles

doi:10.1073/pnas.0813120106

Electrostatic effects on funneled landscapes and structural diversity in denatured protein ensembles

^aCenter for Theoretical Biological Physics and Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093; and
^bBeckman Institute, California Institute of Technology, Pasadena, CA 91125

Contributed by Harry B. Gray, December 23, 2008 (received for review December 3, 2008)

Abstract

The denatured state of proteins is heterogeneous and susceptible to general hydrophobic and electrostatic forces, but to what extent does the funneled nature of protein energy landscapes play a role in the unfolded ensemble? We simulate the denatured ensemble of cytochrome c using a series of models. The models pinpoint the efficacy of incorporating energetic funnels toward the native state in contrast with models having no native structure-seeking tendency. These models also contain varying strengths of electrostatic effects and hydrophobic collapse. The simulations based on these models are compared with experimental distributions for the distances between a fluorescent donor and the heme acceptor that were extracted from time-resolved fluorescence energy transfer experiments on cytochrome c. Comparing simulations to detailed experimental data on several labeling sites allows us to quantify the dominant forces in denatured protein ensembles.

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Footnotes

²To whom correspondence may be addressed. E-mail: hbgray{at}caltech.edu, winklerj{at}caltech.edu or pwolynes{at}ucsd.edu
Author contributions: P.W. and P.G.W. designed research; P.W. performed research; P.W., E.V.P., H.B.G., J.R.W., and P.G.W. contributed new reagents/analytic tools; P.W., E.V.P., H.B.G., J.R.W., and P.G.W. analyzed data; and P.W., E.V.P., H.B.G., J.R.W., and P.G.W. wrote the paper.
↵¹Present address: Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, NH 03755.
The authors declare no conflict of interest.