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 proteoalkene mimic models were investigated computationally to determine whether these alkenes can stabilize the polyproline type II (PPII) conformation of collagen. Second-order Moller-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 ->pi* donation to stabilize PPII conformations, yet they are poor n.p* acceptors, shifting the global minima away from PPII conformations. For the proteo-alkene mimics, the lack of significant n ->pi* interactions and unstable PPII-like geometries explains their known destabilization of the triple helix in collagen-like peptides.

Automated summary

Fluoro- and chloro-alkene mimics of Gly-Pro and Pro-Pro can participate in n ->pi* donation to stabilize PPII conformations, but are poor n.p* acceptors. Proteo-alkene mimics lack significant n ->pi* interactions, leading to unstable PPII-like geometries.