Effect on the Conformation of a Terminally Blocked, (E) β,γ-Unsaturated δ-Amino Acid Residue Induced by Carbon Methylation

Peptides are well known to play a fundamental therapeutic role and to represent building blocks for numerous useful biomaterials. Stabilizing their active 3D-structure by appropriate modifications remains, however, a challenge. In this study, we have expanded the available literature information on the conformational propensities of a promising backbone change of a terminally blocked δ-amino acid residue, a dipeptide mimic, by replacing its central amide moiety with an (E) Cβ=Cγ alkene unit. Specifically, we have examined by DFT calculations, X-ray diffraction in the crystalline state, and FT-IR absorption / NMR spectroscopies in solution the extended vs. folded preferences of analogs of this prototype system either unmodified or possessing single or multiple methyl group substituents on each of its four -CH2-CH=CH-CH2- main-chain carbon atoms. The theoretical and experimental results obtained clearly point to the conclusion that increasing the number of adequately positioned methylations will enhance the...