title: Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations.
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.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry, University of Zürich , CH-8057 Zürich, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Borgia
authors.affiliation: Department of Biochemistry, University of Zürich , CH-8057 Zürich, Switzerland.
authors.forename: Madeleine B
authors.initials: MB
authors.lastname: Borgia
authors.affiliation: Department of Biochemistry, University of Zürich , CH-8057 Zürich, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schuler
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Best
mesh_terms: D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry; D011489:Protein Denaturation; D011506:Proteins / Q000737:chemistry*; D014508:Urea / Q000737:chemistry
chemical_list: D010455:Peptides; D011506:Proteins; C508725:Trp-cage peptide; D014508:Urea