Stapling of two PEGylated side chains increases the conformational stability of the WW domain via an entropic effect
| Autor: | Katherine P. Thompson, Natalie A. Bécar, M.S. Smith, Joshua L. Price, Nathaniel P. Brown, Steven R. E. Draper, Qiang Xiao, K.L. Stern |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Protein Conformation Entropy Peptide Alkenes 010402 general chemistry 01 natural sciences Biochemistry Article Polyethylene Glycols WW Domains WW domain PEG ratio Side chain Physical and Theoretical Chemistry chemistry.chemical_classification biology 010405 organic chemistry Protein Stability Organic Chemistry Proteins Protein tertiary structure 0104 chemical sciences chemistry biology.protein Biophysics PEGylation Protein Conformation beta-Strand Conformational stability Asparagine Peptides Entropic force |
| Zdroj: | Organicbiomolecular chemistry. 16(46) |
| ISSN: | 1477-0539 |
| Popis: | Hydrocarbon stapling and PEGylation are distinct strategies for enhancing the conformational stability and/or pharmacokinetic properties of peptide and protein drugs. Here we combine these approaches by incorporating asparagine-linked O-allyl PEG oligomers at two positions within the β-sheet protein WW, followed by stapling of the PEGs via olefin metathesis. The impact of stapling two sites that are close in primary sequence is small relative to the impact of PEGylation alone and depends strongly on PEG length. In contrast, stapling of two PEGs that are far apart in primary sequence but close in tertiary structure provides substantially more stabilization, derived mostly from an entropic effect. Comparison of PEGylation + stapling vs. alkylation + stapling at the same positions in WW reveals that both approaches provide similar overall levels of conformational stability. |
| Databáze: | OpenAIRE |
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