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Slow folding of cross-linked alpha-helical peptides due to steric hindrance

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B. Paoli; R. Pellarin; A. Caflisch

Journal: J. Phys. Chem. B
Year: 2010
Volume: 114
Issue: 5
Pages: 2023-2027
DOI: 10.1021/jp910216j
Type of Publication: Journal Article

Amino Acid Sequence; Azo Compounds; Cross-Linking Reagents; Kinetics; Molecular Dynamics Simulation; Molecular Sequence Data; Peptides; Protein Folding; Protein Structure, Secondary; Thermodynamics


The folding process of a 16-residue α-helical peptide with an azobenzene cross-linker (covalently bound to residues Cys3 and Cys14) is investigated by 50 molecular dynamics simulations of 4 μs each. The folding kinetics at 281 K show a stretched exponential behavior but become simpler and much faster when a distance restraint is used to emulate a nonbulky cross-linker. The free-energy basin of the helical state is divided into two subbasins by a barrier that separates helical conformations with opposite orientations of the Arg10 side chain with respect to the azobenzene cross-linker. In contrast, such barrier is not present in the helical basin of the peptide with the nonbulky cross-linker, which folds with speed similar to the unrestrained peptide. These results indicate that the cross-linker slows down folding because of steric hindrance rather than its restraining effect on the two ends of the helical segment.