PREDICTION OF DIFFICULT SEQUENCES IN SOLID-PHASE PEPTIDE-SYNTHESIS

The common mechanistic origin of the phenomena of segment insolubility in solution-phase and sequence-related incomplete aminoacylations in solid-phase peptide synthesis is used as the basis of a model for difficult sequences in which partial β-sheet hydrogen bonding by the pendant peptide chains of the peptidoresin is the dominant causative principle. A predictive method based on optimized Chou and Pasman type coil conformational parameters is proposed for the identification of such difficult sequences and is tested by its successful application to 101 previously performed solid-phase peptide syntheses (986 aminoacylation reactions). The use of optimized chemical tactics, secondary structure disrupting reagents and tertiary amide linkages between amino acid residues is discussed with a view to improving the solid-phase synthesis of peptides containing difficult sequences. © 1990, American Chemical Society. All rights reserved.