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Abstract Structures at serine‐proline sites in proteins were analyzed using a combination of peptide synthesis with structural methods and bioinformatics analysis of the PDB. Dipeptides were synthesized with the proline derivative (2S,4S)‐(4‐iodophenyl)hydroxyproline [hyp(4‐I‐Ph)]. The crystal structure of Boc‐Ser‐hyp(4‐I‐Ph)‐OMe had two molecules in the unit cell. One molecule exhibitedcis‐proline and a type VIa2 β‐turn (BcisD). Thecis‐proline conformation was stabilized by a C–H/O interaction between Pro C–H_αand the Ser side‐chain oxygen. NMR data were consistent with stabilization ofcis‐proline by a C–H/O interaction in solution. The other crystallographically observed molecule hadtrans‐Pro and both residues in the PPII conformation. Two conformations were observed in the crystal structure of Ac‐Ser‐hyp(4‐I‐Ph)‐OMe, with Ser adopting PPII in one and the β conformation in the other, each with Pro in the δ conformation andtrans‐Pro. Structures at Ser‐Pro sequences were further examined via bioinformatics analysis of the PDB and via DFT calculations. Ser‐Pro versus Ala–Pro sequences were compared to identify bases for Ser stabilization of local structures. C–H/O interactions between the Ser side‐chain O_γand Pro C–H_αwere observed in 45% of structures with Ser‐cis‐Pro in the PDB, with nearly all Ser‐cis‐Pro structures adopting a type VI β‐turn. 53% of Ser‐trans‐Pro sequences exhibited main‐chain CO_i•••HN_i+3or CO_i•••HN_i+4hydrogen bonds, with Ser as theiresidue and Pro as thei + 1 residue. These structures were overwhelmingly either type I β‐turns or N‐terminal capping motifs on α‐helices or 3₁₀‐helices. These results indicate that Ser‐Pro sequences are particularly potent in favoring these structures. In each, Ser is in either the PPII or β conformation, with the Ser O_γcapable of engaging in a hydrogen bond with the amide N–H of thei + 2 (type I β‐turn or 3₁₀‐helix; Serχ₁t) ori + 3 (α‐helix; Serχ₁g⁺) residue. Non‐prolinecisamide bonds can also be stabilized by C–H/O interactions. 

Enhancing MOF and PCC tunability: surface attachment exploredviaclick chemistry, alkylation, and electrostatic methods. 

Organobismuth-catalyzed 1,1-difluorocyclopropanation is an efficient method due to the ability to release CF₂in a controlled manner. Transmetallation step is more challenging to address with catalyst tuning than CF₂release. 

Despite the importance of proline conformational equilibria (trans versus cis amide, exo versus endo ring pucker) on protein structure and function, there is a lack of convenient ways to probe proline conformation. 4,4-Difluoroproline (Dfp) was identified to be a sensitive 19F NMR-based probe of proline conformational biases and of cis-trans isomerism. Within model compounds and disordered peptides, the diastereotopic fluorines of Dfp exhibit similar chemical shifts (FF = 0–3 ppm) when a trans X–Dfp amide bond is present. In contrast, the diastereotopic fluorines exhibit a large (FF = 5–12 ppm) difference in chemical shift in a cis X–Dfp prolyl amide bond. DFT calculations, X-ray crystallography, and solid-state NMR spectroscopy indicated that the FF directly reports on the relative preference of one proline ring pucker over the other: a fluorine which is pseudo-axial (i.e. the pro-4R-F in an exo ring pucker, or the pro-4S-F in an endo ring pucker) is downfield, while a fluorine which is pseudo-equatorial (i.e. pro-4S-F when exo, or pro-4R-F when endo) is upfield. Thus, when a proline is disordered (a mixture of exo and endo ring puckers, as at trans-Pro in peptides in water), it exhibits a small . In contrast, when the Pro is ordered (i.e. when one ring pucker is strongly preferred, as in cis-Pro amide bonds, where the endo ring pucker is strongly favored), a large  is observed. Dfp can be used to identify inherent induced order in peptides and to quantify proline cis-trans isomerism. Using Dfp, we discovered that the stable polyproline II helix (PPII) formed in the denatured state (8 M urea) exhibits essentially equal populations of the exo and endo proline ring puckers. In addition, the data with Dfp suggested the specific stabilization of PPII by water over other polar solvents. These data strongly support the importance of carbonyl solvation and n* interactions for the stabilization of PPII. Dfp was also employed to quantify proline cis-trans isomerism as a function of phosphorylation and the R406W mutation in peptides derived from the intrinsically disordered protein tau. Dfp is minimally sterically disruptive and can be incorporated in expressed proteins, suggesting its broad application in understanding proline cis-trans isomerization, protein folding, and local order in intrinsically disordered proteins.