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

Abstract

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. 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 nàπ* donation to stabilize PPII conformations, yet they are poor nàπ* acceptors, shifting the global minima away from PPII conformations. For the proteo-alkene mimics, the lack of significant nàπ* interactions and unstable PPII-like geometries explains their known destabilization of the triple helix in collagen-like peptides.

A fluoro-alkene mimic of Gly-trans-Pro produces a stable collagen triple helix

“…2). 22 Our results implied that the extra flexibility conferred by those local minima of the proteo-alkene significantly decreases the stability of the triple helix. Our calculations show that the fluoro-alkene model is less flexible near its PPII-like global minimum.…”

“…Our calculations show that the fluoro-alkene model is less flexible near its PPII-like global minimum. 22 Since fluorine is bigger than hydrogen, steric interactions may contribute as well. 22 The fluoro-alkene peptide has Δ T m + 13.3 °C higher than the proteo-alkene peptide, 12 suggesting that an increase in stability is afforded by steric and n→π* electronic interactions.…”

“…The global minimum of the Gly-Pro model fluoro-alkene as an n→π* acceptor has a Ψ angle of +117°, 22 which deviates significantly from the collagen triple-helix minimum at a Ψ angle of +167° (Fig. 3B).…”

“…We have shown computationally that the global minimum of the fluoro-alkene Gly-Pro model as an n→π* donor has a Ψ angle of +162°, 22 and the global minimum of the native peptide has a Ψ angle of +160°, 18 suggesting that this mimic would be geometrically compatible with the collagen triple helix (Fig. 3A).…”

“…Fortunately, the fluoro-alkene does not have local minima near the collagen-like global minimum that could cause conformational instability as for the proteo-alkene. 22…”