Slow folding of cross-linked alpha-helical peptides due to steric hindrance.
The folding process of a 16-residue alpha-helical peptide with an azobenzene cross-linker (covalently bound to residues Cys3 and Cys14) is investigated by 50 molecular dynamics simulations of 4 micros 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.
Paoli
B
B
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Pellarin
R
R
Caflisch
A
A
D000595:Amino Acid Sequence; D001391:Azo Compounds / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D001391:Azo Compounds; D003432:Cross-Linking Reagents; D010455:Peptides; C009850:azobenzene