Probing the free energy landscape of the FBP28WW domain using multiple techniques

Periole, Xavier, Allen, Lucy R., Tamiola, Kamil, Mark, Alan E. and Paci, Emanuele (2009) Probing the free energy landscape of the FBP28WW domain using multiple techniques. Journal of Computational Chemistry, 30 7: 1059-1068. doi:10.1002/jcc.21128


Author Periole, Xavier
Allen, Lucy R.
Tamiola, Kamil
Mark, Alan E.
Paci, Emanuele
Title Probing the free energy landscape of the FBP28WW domain using multiple techniques
Journal name Journal of Computational Chemistry   Check publisher's open access policy
ISSN 0192-8651
Publication date 2009-05-01
Sub-type Article (original research)
DOI 10.1002/jcc.21128
Volume 30
Issue 7
Start page 1059
End page 1068
Total pages 10
Editor Charles L. Brooks
Gernot Frenking
Hiroshi Nakatsuji
Place of publication United States
Publisher John Wiley & Sons, Inc.
Collection year 2009
Language eng
Subject C1
030405 Molecular Medicine
Abstract The free-energy landscape of a small protein, the FBP 28 WW domain, has been explored using molecular dynamics (MD) simulations with alternative descriptions of the molecule. The molecular models used range from coarse-grained to all-atom with either an implicit or explicit treatment of the solvent. Sampling of conformation space was performed using both conventional and temperature-replica exchange MD simulations. Experimental chemical shifts and NOEs were used to validate the simulations, and experimental values both for validation and as restraints. This combination of different approaches has provided insight into the free energy landscape and barriers encountered by the protein during folding and enabled the characterization of native, denatured and transition states which are compatible with the available experimental data. All the molecular models used stabilize well defined native and denatured basins; however, the degree of agreement with the available experimental data varies. While the most detailed, explicit solvent model predicts the data reasonably accurately, it does not fold despite a simulation time 10 times that of the experimental folding time. The less detailed models performed poorly relative to the explicit solvent model: an implicit solvent model stabilizes a ground state which differs from the experimental native state, and a structure-based model underestimates the size of the barrier between the two states. The use of experimental values both as restraints, and to extract structures from unfolding simulations, result in conformations which, although not necessarily true transition states, appear to share the geometrical characteristics of transition state structures. In addition to characterizing the native, transition and denatured states of this particular system in this work, the advantages and limitations of using varying levels of representation are discussed.
Keyword protein folding
Q-Index Code C1
Q-Index Status Confirmed Code
Additional Notes Published Online: 22 Oct 2008

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Chemistry and Molecular Biosciences
 
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Created: Mon, 15 Jun 2009, 23:09:57 EST by Cameron Harris on behalf of School of Chemistry & Molecular Biosciences