Landscape approaches for determining the ensemble of folding transition states: Success and failure hinge on the degree of frustration
Open Access
- 18 January 2000
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 97 (2), 634-639
- https://doi.org/10.1073/pnas.97.2.634
Abstract
We present a method for determining structural properties of the ensemble of folding transition states from protein simulations. This method relies on thermodynamic quantities (free energies as a function of global reaction coordinates, such as the percentage of native contacts) and not on “kinetic” measurements (rates, transmission coefficients, complete trajectories); consequently, it requires fewer computational resources compared with other approaches, making it more suited to large and complex models. We explain the theoretical framework that underlies this method and use it to clarify the connection between the experimentally determined Φ value, a quantity determined by the ratio of rate and stability changes due to point mutations, and the average structure of the transition state ensemble. To determine the accuracy of this thermodynamic approach, we apply it to minimalist protein models and compare these results with the ones obtained by using the standard experimental procedure for determining Φ values. We show that the accuracy of both methods depends sensitively on the amount of frustration. In particular, the results are similar when applied to models with minimal amounts of frustration, characteristic of rapid-folding, single-domain globular proteins.Keywords
This publication has 58 references indexed in Scilit:
- Structure of the transition state in the folding process of human procarboxypeptidase A2 activation domainJournal of Molecular Biology, 1998
- Lattice models for proteins reveal multiple folding nuclei for nucleation-collapse mechanismJournal of Molecular Biology, 1998
- The changing nature of the protein folding transition state: implications for the shape of the free-energy profile for foldingJournal of Molecular Biology, 1998
- Submillisecond kinetics of protein foldingCurrent Opinion in Structural Biology, 1997
- Time-resolved biophysical methods in the study of protein foldingCurrent Opinion in Structural Biology, 1996
- Structure of the Transition State for Folding of a Protein Derived from Experiment and SimulationJournal of Molecular Biology, 1996
- Protein Folding Triggered by Electron TransferScience, 1996
- Movement of the position of the transition state in protein foldingBiochemistry, 1995
- First-Principles Calculation of the Folding Free Energy of a Three-Helix Bundle ProteinScience, 1995
- The folding of an enzymeJournal of Molecular Biology, 1992