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


Zheng, Wenwei; Borgia, Alessandro; Borgia, Madeleine B; Schuler, Benjamin; Best, Robert B (2015). Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations. Journal of Chemical Theory and Computation, 11(11):5543-5553.

Abstract

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)nW 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.

Abstract

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)nW 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:10 November 2015
Deposited On:12 Jan 2016 14:49
Last Modified:16 Mar 2018 15:21
Publisher:American Chemical Society (ACS)
ISSN:1549-9618
Additional Information:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation copyright © American Chemical Society after peer review and technical editing by the publisher.
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.jctc.5b00778
PubMed ID:26574341

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