SECONDARY STRUCTURE FORMATION IN N-SUBSTITUTED PEPTIDES

A systematic conformational analysis on several model peptides with N- substituted amino acids was performed on the basis of ab initio MO the ory at the HF/6-31G and HF/3-21G levels with inclusion of solvation e ffects to study the influence of N-substitution on the formation of ty pically secondary structural elements, e.g. beta sheets, helices and t urns. The conformational flexibility of some structures was examined b y means of molecular dynamics simulations in the gas phase and in solu tion. The results show a restriction of the conformational flexibility of the peptide chain after introduction of an N-substituted amino aci d. N-substitution makes beta sheet formation more difficult. Several c onsecutive N-substituted amino acids in a sequence lead to conformers different from those found on the energy hypersurface of the correspon ding N-unsubstituted peptides. There is a strong tendency to form peri odically helical conformations, e.g, the polyglycine II or the alpha h elix, which can be extended over several N-substituted amino acid resi dues. As long as 1<--4 hydrogen bond formation remains possible, the m ajor types of beta turns can be formed with a distinct preference for the beta II and beta VIa turns. The beta I rum in particular is consid erably destabilized. (C) Munksgaard 1997.