Calculation of the Free Energy and Cooperativity of Protein Folding
Open Access
- 16 May 2007
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 2 (5), e446
- https://doi.org/10.1371/journal.pone.0000446
Abstract
Calculation of the free energy of protein folding and delineation of its pre-organization are of foremost importance for understanding, predicting and designing biological macromolecules. Here, we introduce an energy smoothing variant of parallel tempering replica exchange Monte Carlo (REMS) that allows for efficient configurational sampling of flexible solutes under the conditions of molecular hydration. Its usage to calculate the thermal stability of a model globular protein, Trp cage TC5b, achieves excellent agreement with experimental measurements. We find that the stability of TC5b is attained through the coupled formation of local and non-local interactions. Remarkably, many of these structures persist at high temperature, concomitant with the origin of native-like configurations and mesostates in an otherwise macroscopically disordered unfolded state. Graph manifold learning reveals that the conversion of these mesostates to the native state is structurally heterogeneous, and that the cooperativity of their formation is encoded largely by the unfolded state ensemble. In all, these studies establish the extent of thermodynamic and structural pre-organization of folding of this model globular protein, and achieve the calculation of macromolecular stability ab initio, as required for ab initio structure prediction, genome annotation, and drug design.Keywords
This publication has 64 references indexed in Scilit:
- The Protein Folding NetworkJournal of Molecular Biology, 2004
- Extending the treatment of backbone energetics in protein force fields: Limitations of gas‐phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulationsJournal of Computational Chemistry, 2004
- Exploring the Interplay between Topology and Secondary Structural Formation in the Protein Folding ProblemThe Journal of Physical Chemistry B, 2003
- Similarities between the spectrin SH3 domain denatured state and its folding transition stateJournal of Molecular Biology, 2000
- Replica-exchange molecular dynamics method for protein foldingChemical Physics Letters, 1999
- All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of ProteinsThe Journal of Physical Chemistry B, 1998
- Impact of Local and Non-local Interactions on Thermodynamics and Kinetics of Protein FoldingJournal of Molecular Biology, 1995
- Fluctuation and Cross-correlation Analysis of Protein Motions Observed in Nanosecond Molecular Dynamics SimulationsJournal of Molecular Biology, 1995
- Annealing Markov Chain Monte Carlo with Applications to Ancestral InferenceJournal of the American Statistical Association, 1995
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983