Characterization of the Folding Landscape of Monomeric Lactose Repressor: Quantitative Comparison of Theory and Experiment

Recent theoretical/computational studies based on simplified protein models and experimental investigation have suggested that the native structure of a protein plays a primary role in determining the folding rate and mechanism of relatively small single-domain proteins. Here, we extend the study of...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 41; pp. 14569 - 14574
Main Authors Das, Payel, Wilson, Corey J., Giovanni Fossati, Wittung-Stafshede, Pernilla, Matthews, Kathleen S., Clementi, Cecilia
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 11.10.2005
National Acad Sciences
Subjects
Bacterial Proteins - chemistry
Biological Sciences
Biophysical Phenomena
Biophysics
Comparative analysis
Computer Simulation
Equilibrium
Experimental data
Fluorescence
Free energy
High temperature
Kinetics
Lac Repressors
Modeling
Models, Molecular
Molecular dynamics
Population parameters
Protein Folding
Proteins
Repressor Proteins - chemistry
Simulation
Simulations
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Summary:Recent theoretical/computational studies based on simplified protein models and experimental investigation have suggested that the native structure of a protein plays a primary role in determining the folding rate and mechanism of relatively small single-domain proteins. Here, we extend the study of the relationship between protein topology and folding mechanism to a larger protein with complex topology, by analyzing the folding process of monomeric lactose repressor (MLAc) computationally by using a$G\bar{o}-like$Cαmodel. Next, we combine simulation and experimental results to achieve a comprehensive assessment of the folding landscape of this protein. Remarkably, simulated kinetic and equilibrium analyses show an excellent quantitative agreement with the experimental folding data of this study. The results of this comparison show that a simplified, completely unfrustrated Cα model correctly reproduces the complex folding features of a large multidomain protein with complex topology. The success of this effort underlines the importance of synergistic experimental/theoretical approaches to achieve a broader understanding of the folding landscape.
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To whom correspondence should be addressed. E-mail: cecilia@rice.edu.
Communicated by James L. Kinsey, Rice University, Houston, TX, July 12, 2005
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0505844102