Secondary structure formation in N-substituted peptides.

Abstract

A systematic conformational analysis on several model peptides with N-substituted amino acids was performed on the basis of ab initio MO theory at the HF/6-31G* and HF/3-21G levels with inclusion of solvation effects to study the influence of N-substitution on the formation of typically secondary structural elements, e.g. beta sheets, helices and turns. The conformational flexibility of some structures was examined by means of molecular dynamics simulations in the gas phase and in solution. The results show a restriction of the conformational flexibility of the peptide chain after introduction of an N-substituted amino acid. N-substitution makes beta sheet formation more difficult. Several consecutive N-substituted amino acids in a sequence lead to conformers different from those found on the energy hypersurface of the corresponding N-unsubstituted peptides. There is a strong tendency to form periodically helical conformations, e.g. the polyglycine II or the alpha helix, which can be extended over several N-substituted amino acid residues. As long as 1<--4 hydrogen bond formation remains possible, the major types of beta turns can be formed with a distinct preference for the betaII and betaVIa turns. The betaI turn in particular is considerably destabilized.