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

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• 作者：Wenwei Zheng ; Alessandro Borgia ; Madeleine B. Borgia ; Benjamin Schuler ; Robert B. Best
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2015
• 出版时间：November 10, 2015
• 年：2015
• 卷：11
• 期：11
• 页码：5543-5553
• 全文大小：574K
• ISSN：1549-9626

文摘

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鈥揹enaturant interaction by a novel simulation methodology. We validate the results against data for more complex sequences: single-molecule F枚rster 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.