{"doi":"10.1101/2024.03.14.585129","title":"Helical Twists and β-Turns in Structures at Serine–Proline Sequences: Stabilization of cis-Proline and type VI β-turns via C–H/O interactions","abstract":"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 (2 S ,4 S )-(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 exhibited cis -proline and a type VIa2 β-turn (BcisD). The cis -proline conformation was stabilized by a C–H/O interaction between Pro C–H α and the Ser side-chain oxygen. NMR data were consistent with stabilization of cis -proline by a C–H/O interaction in solution. The other crystallographically observed molecule had trans -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 and trans -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 γ and Pro C–H α were 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 +3 or C=O i •••H–N i +4 hydrogen bonds, with Ser as the i residue and Pro as the i +1 residue. These structures were overwhelmingly either type I β-turns or N-terminal capping motifs on α-helices or a 3 10 -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 γ capable of engaging in a hydrogen bond with the amide N–H of the i +2 (type I β-turn or 3 -helix; Ser χ 1 t ) or i +3 (α-helix; Ser χ 1 g + ) residue. Non-proline cis amide bonds can also be stabilized by C–H/O interactions. Abstract Figure Graphical Table of Contents","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":495553,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":562200,"name":"Glenn P. A. Yap","orcid":"0000-0003-0385-387X","position":1,"is_corresponding":false},{"id":428685,"name":"Neal J. Zondlo","orcid":"0000-0002-7417-8085","position":2,"is_corresponding":false},{"id":1270749,"name":"Harrison C. Oven","orcid":null,"position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-19T02:09:19.627139Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}