Theoretical prediction of substituent effects on the intrinsic folding properties of β-peptides

A systematic conformational analysis on blocked beta-amino acids as constituents of beta-peptides by ab initio MO theory reveals that the conformer pool of beta-peptide monomers is essentially determined by the conformation of simple submonomer fragments. The influence of single and multiple substitutions at the C(alpha) and C(beta) backbone atoms on the intrinsic folding properties of the monomers was estimated both in the single-molecule approximation and in a polar solvent continuum, applying a quantum-chemical SCRF model. Substitution at C(beta) has a higher impact on the beta-amino acid conformation than a substitution at C(alpha). It can be shown that the conformations of important periodic secondary structures in beta-peptides belong to the conformer pool of the monomers, even for those secondary-structure elements where H-bond formation appears only in longer sequences. Rules for design of special secondary-structure types by selection of an actual substituent pattern in the beta-amino acid constituents have been derived within the monomer approach.