Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations

Chemical denaturants are the most commonly used perturbation applied to study protein stability and folding kinetics as well as the properties of unfolded polypeptides. We build on recent work balancing the interactions of proteins and water, and accurate models for the solution properties of urea a...

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Bibliographic Details
Published in:Journal of chemical theory and computation 2015-11, Vol.11 (11), p.5543-5553
Main Authors: Zheng, Wenwei, Borgia, Alessandro, Borgia, Madeleine B, Schuler, Benjamin, Best, Robert B
Format: Article
Language:English
Subjects:
Chlorides
Computer simulation
Construction
Denaturation
Mathematical models
Models, Molecular
Molecular Dynamics Simulation
Peptides
Peptides - chemistry
Polypeptides
Protein Denaturation
Proteins
Proteins - chemistry
Urea - chemistry
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Summary:Chemical denaturants are the most commonly used perturbation applied to study protein stability and folding kinetics as well as the properties of unfolded polypeptides. We build on recent work balancing the interactions of proteins and water, and accurate models for the solution properties of urea and guanidinium chloride, to develop a combined force field that is able to capture the strength of interactions between proteins and denaturants. We use solubility data for a model tetraglycine peptide in each denaturant to tune the protein–denaturant interaction by a novel simulation methodology. We validate the results against data for more complex sequences: single-molecule Förster resonance energy transfer data for a 34-residue fragment of the globular protein CspTm and photoinduced electron transfer quenching data for the disordered peptides C­(AGQ) n W in denaturant solution as well as the chemical denaturation of the mini-protein Trp cage. The combined force field model should aid our understanding of denaturation mechanisms and the interpretation of experiment.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.5b00778