{"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.","authors":"Harrison C Oven, Glenn P A Yap, Neal J Zondlo","doi":"10.1002/prot.26701","DOIUrl":null,"url":null,"abstract":"<p><p>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 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<sub>α</sub> 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<sub>γ</sub> and Pro C-H<sub>α</sub> 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 CO<sub>i</sub>•••HN<sub>i+3</sub> or CO<sub>i</sub>•••HN<sub>i+4</sub> 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 3<sub>10</sub>-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<sub>γ</sub> capable of engaging in a hydrogen bond with the amide N-H of the i + 2 (type I β-turn or 3<sub>10</sub>-helix; Ser χ<sub>1</sub> t) or i + 3 (α-helix; Ser χ<sub>1</sub> g<sup>+</sup>) residue. Non-proline cis amide bonds can also be stabilized by C-H/O interactions.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1190-1205"},"PeriodicalIF":3.2000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proteins-Structure Function and Bioinformatics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/prot.26701","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/15 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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 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-Hα 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 Oγ and Pro C-Hα 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 COi•••HNi+3 or COi•••HNi+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 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 Oγ capable of engaging in a hydrogen bond with the amide N-H of the i + 2 (type I β-turn or 310-helix; Ser χ1 t) or i + 3 (α-helix; Ser χ1 g+) residue. Non-proline cis amide bonds can also be stabilized by C-H/O interactions.
期刊介绍:
PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.