Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 2, Pages 434-439Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0810218105
Keywords
energy landscape theory; random-field Ising model; native topology-based models
Categories
Funding
- National Institutes of Health [5R01GM44557]
- National Science Foundation-sponsored Center for Theoretical Biological Physics [PHY-0216576, 0225630]
- Ruth L. Kirschstein National Research Service Awards
- Division Of Physics
- Direct For Mathematical & Physical Scien [0225630] Funding Source: National Science Foundation
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Energy landscape theory requires that the protein-folding mechanism is generally globally directed or funneled toward the native state. The collective nature of transition state ensembles further suggests that sufficient averaging of the native interactions can occur so that the knowledge of the native topology may suffice for predicting the mechanism. Nevertheless, while simple homogeneously weighted native topology-based models predict the folding mechanisms for many proteins, for other proteins knowledge of the native topology, by itself, seems not to suffice in determining the folding mechanism. Simulations of proteins with differing topologies reveal that the failure of homogeneously weighted topology-based models can, however, be completely understood within the framework of a funneled energy landscape and can be quantified by comparing the fluctuation of entropy cost for forming contacts to the expected fluctuations in contact energy. To be precise, we find the transition state ensembles of proteins with all-alpha topologies, which are more uniform in the specific entropy cost of contact formation, have transition state ensembles that are more readily perturbed by differences in energetic weights than are the transition state ensembles of proteins with significant amounts of beta-structure, where the specific entropy costs of contact formation are more widely distributed. This behavior is consistent with a random-field Ising model analogy that follows from the free energy functional approach to folding.
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