Conformational Analysis of Fluoro‑, Chloro‑, and Proteo-Alkene Gly–Pro and Pro–Pro Isosteres to Mimic Collagen

Collagen
is the most abundant human protein, with the canonical
sequence (Gly–Pro–Hyp)n in
its triple helix region. Cis–trans isomerization of the Xaa–Pro
amide has made two of these amide bonds the target of alkene replacement:
the Gly–Pro and the Pro–Hyp positions. The conformations
of Gly–Pro and Pro–Pro (as a Pro–Hyp model) fluoro-,
chloro-, and proteo-alkene mimic models were investigated computationally
to determine whether these alkenes can stabilize the polyproline type
II (PPII) conformation of collagen. Second-order Møller–Plesset
(MP2) calculations with various basis sets were used to perform the
conformational analyses and locate stationary points. The calculation
results predict that fluoro- and chloro-alkene mimics of Gly–Pro
and Pro–Pro can participate in n→π* donation to
stabilize PPII conformations, yet they are poor n→π*
acceptors, shifting the global minima away from PPII conformations.
For the proteo-alkene mimics, the lack of significant n→π*
interactions and unstable PPII-like geometries explains their known
destabilization of the triple helix in collagen-like peptides.