ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

Cooperative Intramolecular Hydrogen Bonding Strongly Enforces cis-Peptoid Folding

  • Andrew W. Wijaya
    Andrew W. Wijaya
    The Molecular Foundry, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
  • Andy I. Nguyen*
    Andy I. Nguyen
    The Molecular Foundry, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
    *[email protected]
  • Leah T. Roe
    Leah T. Roe
    The Molecular Foundry, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
    More by Leah T. Roe
  • Glenn L. Butterfoss
    Glenn L. Butterfoss
    Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
  • Ryan K. Spencer
    Ryan K. Spencer
    Department of Chemistry, Department of Chemical Engineering & Material Science, University of California, Irvine, California 92697, United States
  • Nan K. Li
    Nan K. Li
    The Molecular Foundry, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
    More by Nan K. Li
  • , and 
  • Ronald N. Zuckermann*
    Ronald N. Zuckermann
    The Molecular Foundry, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
    *[email protected]
Cite this: J. Am. Chem. Soc. 2019, 141, 49, 19436–19447
Publication Date (Web):November 25, 2019
Copyright © 2019 American Chemical Society

    Article Views





    Other access options
    Supporting Info (5)»


    Abstract Image

    Sequence-defined peptoids, or N-substituted glycines, are an attractive class of bioispired polymer due to their biostability and efficient synthesis. However, the de novo design of folded peptoids with precise three-dimensional structures has been hindered by limited means to deterministically control backbone conformation. Peptoid folds are generally destabilized by the cis/trans backbone-amide isomerization, and few side-chains are capable of enforcing a specific amide conformation. Here, we show that a novel class of cationic alkyl ammonium ethyl side-chains demonstrates significant enforcement of the cis-amide backbone (Kcis/trans up to 70) using an unexpected ensemble of weak intramolecular CH–O and/or NH–O hydrogen bonds between the side-chain and the backbone carbonyl moieties. These interactions are evidenced by X-ray crystallography, variable-temperature NMR spectroscopy, and DFT calculations. Moreover, these side-chains are inexpensive, structurally diverse, hydrophilic, and can be integrated into longer peptoid sequences via solid-phase synthesis. Notably, we extended these concepts to synthesize a water-soluble peptoid 10-mer that adopts one predominant fold in solution, as determined by multidimensional NMR spectroscopy. This decamer, to the best of our knowledge, is the longest linear peptoid sequence atomically characterized to retain a well-folded structure. These findings fill a critical gap in peptoid folding and should propel the development of peptoid applications in a broad range of contexts, from pharmaceutical to material sciences.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    The Supporting Information is available free of charge at

    • Full synthetic, physical, theoretical, and crystallographic details (PDF)

    • X-ray crystallographic data for 8·BPh4 (CIF)

    • X-ray crystallographic data for 11·BPh4 (CIF)

    • X-ray crystallographic data for 16·BPh4 (CIF)

    • NMR structure of 26 (PDB)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 46 publications.

    1. Dongjae Lee, Jieun Choi, Min June Yang, Chin-Ju Park, Jiwon Seo. Controlling the Chameleonic Behavior and Membrane Permeability of Cyclosporine Derivatives via Backbone and Side Chain Modifications. Journal of Medicinal Chemistry 2023, 66 (18) , 13189-13204.
    2. Carolynn M. Davern, Caroline Proulx. Late-Stage Chloride Displacements Enable Access to Peptoids with cis-Inducing Alkylammonium Side Chains. Organic Letters 2023, 25 (33) , 6195-6199.
    3. Sarah Alamdari, Kaylyn Torkelson, Xiaoqian Wang, Chun-Long Chen, Andrew L. Ferguson, Jim Pfaendtner. Thermodynamic Basis for the Stabilization of Helical Peptoids by Chiral Sidechains. The Journal of Physical Chemistry B 2023, 127 (27) , 6171-6183.
    4. Jugal Kishore Rai Deka, Biswajit Sahariah, Bani Kanta Sarma. Understanding the Cis–Trans Amide Bond Isomerization of N,N′-Diacylhydrazines to Develop Guidelines for A Priori Prediction of Their Most Stable Solution Conformers. The Journal of Organic Chemistry 2023, Article ASAP.
    5. Abigail Mae Clapperton, Jon Babi, Helen Tran. A Field Guide to Optimizing Peptoid Synthesis. ACS Polymers Au 2022, 2 (6) , 417-429.
    6. Ryu Yamasaki, Misuzu Harada, Rino Nagata, Ai Ito, Kazuo Fukuda, Iwao Okamoto. Conformational Switch of Benzanilide Derivative Induced by Acid; Effect of Pentafluorobenzoyl Group. The Journal of Organic Chemistry 2022, 87 (13) , 8469-8479.
    7. Ryan Thurston, Viviane Zantop, Kristen Sodam Park, Harald Maid, Anke Seitz, Markus R. Heinrich. pH-Dependent Conformational Switching of Amide Bonds─from Full trans to Full cis and Vice Versa. Organic Letters 2022, 24 (19) , 3488-3492.
    8. Meleppatt Sujith, E. Krishnan Vishnu, Subrahmanyam Sappati, Muhammed Shafeek Oliyantakath Hassan, Vinesh Vijayan, K. George Thomas. Ligand-Induced Ground- and Excited-State Chirality in Silicon Nanoparticles: Surface Interactions Matter. Journal of the American Chemical Society 2022, 144 (11) , 5074-5086.
    9. Maxwell O. Bowles, Caroline Proulx. Late-Stage N-Alkylation of Azapeptides. Organic Letters 2022, 24 (9) , 1768-1773.
    10. Linhai Jiang, Chunhua Tony Hu, Francesco De Riccardis, Kent Kirshenbaum. Elaborate Supramolecular Architectures Formed by Co-Assembly of Metal Species and Peptoid Macrocycles. Crystal Growth & Design 2021, 21 (7) , 3889-3901.
    11. Matthew F. D. Hurley, Justin D. Northrup, Yunhui Ge, Christian E. Schafmeister, Vincent A. Voelz. Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution. Journal of Chemical Information and Modeling 2021, 61 (6) , 2818-2828.
    12. Sally Jiao, Audra DeStefano, Jacob I. Monroe, Mikayla Barry, Nicholas Sherck, Thomas Casey, Rachel A. Segalman, Songi Han, M. Scott Shell. Quantifying Polypeptoid Conformational Landscapes through Integrated Experiment and Simulation. Macromolecules 2021, 54 (11) , 5011-5021.
    13. Haruki Funahashi, Masanori Tachikawa, Taro Udagawa. Determining if Reaction Selectivity Can Be Controlled by the H/D Isotope Effect in CH···O Interactions. Organic Letters 2020, 22 (24) , 9439-9443.
    14. Isabelle Wellhöfer, Janina Beck, Karla Frydenvang, Stefan Bräse, Christian A. Olsen. Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding. The Journal of Organic Chemistry 2020, 85 (16) , 10466-10478.
    15. Erik G. Dirdal, Malcolm A. Kelland. Synthesis and Investigation of Polymers of 2-Methacrylamido-caprolactam as Kinetic Hydrate Inhibitors. Energy & Fuels 2020, 34 (6) , 6981-6990.
    16. Jwwad M. Javed, Katherine Scukas, Michelle T. Nguyen, Amelia A. Fuller. Aromatic Residue Positioning Influences Helical Peptoid Structure in Aqueous Solution. Synlett 2024, 656
    17. Rui Zhang, Li-Hua He, Sui-Jun Liu, Jin-Sheng Liao, He-Rui Wen, Jing-Lin Chen, Feng Zhao. Multistimuli-responsive multicolor solid-state luminescence tuned by NH-dependent switchable hydrogen bonds. Dalton Transactions 2023, 53 (1) , 339-345.
    18. Camilla Di Mino, Andrew G. Seel, Adam J. Clancy, Thomas F. Headen, Támas Földes, Edina Rosta, Andrea Sella, Neal T. Skipper. Strong structuring arising from weak cooperative O-H···π and C-H···O hydrogen bonding in benzene-methanol solution. Nature Communications 2023, 14 (1)
    19. Rongmao Qiu, Xiaojing Li, Kui Huang, Weizhe Bai, Daoning Zhou, Gang Li, Zhao Qin, Yang Li. Cis-trans isomerization of peptoid residues in the collagen triple-helix. Nature Communications 2023, 14 (1)
    20. Hamish W.A. Swanson, Marwa El yaagoubi, Aquib Jawed, Varun Saxena, Martyn G.L. Merrilees, Tell Tuttle, Lalit M. Pandey, Ian W. Hamley, King Hang Aaron Lau. Peptoid Self‐Assembly: From Minimal Sequences to Functional Nanoassemblies and Biomedical Applications. 2023, 969-999.
    21. Anastasia E. Behar, Galia Maayan. The First Cu(I)‐Peptoid Complex: Enabling Metal Ion Stability and Selectivity via Backbone Helicity. Chemistry – A European Journal 2023, 29 (43)
    22. Kalpita Baruah, Debajit Kalita, Biswajit Sahariah, Jugal Kishore Rai Deka, Pratap Vishnoi, Bani Kanta Sarma. Sidechain‐Backbone Tetrel Bonding Interactions Provide a General Mechanism for trans ‐Peptoid Stabilization. Chemistry – A European Journal 2023, 29 (32)
    23. James R. B. Eastwood, Ethan I. Weisberg, Dana Katz, Ronald N. Zuckermann, Kent Kirshenbaum. Guidelines for designing peptoid structures: Insights from the Peptoid Data Bank. Peptide Science 2023, 115 (3)
    24. Moon Kedia, K. R. Soumya, Upasana Phukon, Isha Mishra, Reema L. Borkar, Palanichamy Vengadeshwaran, Mamina Bhol, Malaichamy Sathiyendiran. A double ouroboros-shaped noncovalent molecular dimer. CrystEngComm 2023, 25 (17) , 2518-2522.
    25. Bingyu Liu, Pengyao Xing. Hydrogen Bonded Foldamers with Axial Chirality: Chiroptical Properties and Applications. Chemistry – A European Journal 2023, 29 (4)
    26. Anyao Ma, Xinyan Yu, Mingzhen Liao, Wenxiao Liu, Sunting Xuan, Zhengbiao Zhang. Research Progress in Polypeptoids Prepared by Controlled Ring‐Opening Polymerizations. Macromolecular Rapid Communications 2023, 44 (1)
    27. Noah J. Daniecki, Megh R. Bhatt, Glenn P. A. Yap, Neal J. Zondlo. Proline C−H Bonds as Loci for Proline Assembly via C−H/O Interactions. ChemBioChem 2022, 23 (24)
    28. Manasa Purushotham, Bishwajit Paul, Siva Nageswara Rao Gajula, Biswajit Sahariah, Rajesh Sonti. Deciphering C–H⋯O/X weak hydrogen bonding and halogen bonding interactions in aromatic peptoids. New Journal of Chemistry 2022, 46 (41) , 19648-19657.
    29. Gaetano Angelici, Nicholus Bhattacharjee, Maxime Pypec, Laurent Jouffret, Claude Didierjean, Franck Jolibois, Lionel Perrin, Olivier Roy, Claude Taillefumier. Unveiling the conformational landscape of achiral all- cis tert -butyl β-peptoids. Organic & Biomolecular Chemistry 2022, 20 (40) , 7907-7915.
    30. Jungyeon Kim, Hiroka Kobayashi, Marin Yokomine, Yota Shiratori, Takumi Ueda, Koh Takeuchi, Koji Umezawa, Daisuke Kuroda, Kouhei Tsumoto, Jumpei Morimoto, Shinsuke Sando. Residue-based program of a β-peptoid twisted strand shape via a cyclopentane constraint. Organic & Biomolecular Chemistry 2022, 20 (35) , 6994-7000.
    31. Manasa Purushotham, Bishwajit Paul, Divya Maldepalli Govindachar, Ashutosh Kumar Singh, Ganga Periyasamy, Sebastian C. Peter. Ortho-halogen effects: n→π* interactions, halogen bonding, and deciphering chiral attributes in N-aryl glycine peptoid foldamers. Journal of Molecular Structure 2022, 1264 , 133276.
    32. Debajit Kalita, Biswajit Sahariah, Surya Pravo Mookerjee, Bani Kanta Sarma. Strategies to Control the Cis‐Trans Isomerization of Peptoid Amide Bonds. Chemistry – An Asian Journal 2022, 17 (11)
    33. Jin-Ye Lu, Qiu-Yun Chen, Su-Ci Meng, Chang-Jian Feng. A dye-andrographolide assembly as a turn-on sensor for detection of phthalate in both cells and fish. Analytica Chimica Acta 2022, 1195 , 339460.
    34. Maxime Pypec, Laurent Jouffret, Claude Taillefumier, Olivier Roy. First series of N -alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation. Beilstein Journal of Organic Chemistry 2022, 18 , 845-854.
    35. Radhe Shyam, Christiane Forestier, Nicolas Charbonnel, Olivier Roy, Claude Taillefumier, Sophie Faure. Solution‐Phase Synthesis of Backbone‐Constrained Cationic Peptoid Hexamers with Antibacterial and Anti‐Biofilm Activities. European Journal of Organic Chemistry 2021, 2021 (42) , 5813-5822.
    36. Claudine Nicole Herlan, Dominik Feser, Ute Schepers, Stefan Bräse. Bio-instructive materials on-demand – combinatorial chemistry of peptoids, foldamers, and beyond. Chemical Communications 2021, 57 (85) , 11131-11152.
    37. Trideep Rajale, Jacob C. Miner, Ryszard Michalczyk, M. Lisa Phipps, Jurgen G. Schmidt, Robert D. Gilbertson, Robert F. Williams, Charlie E. M. Strauss, Jennifer S. Martinez. Conformational control via sequence for a heteropeptoid in water: coupled NMR and Rosetta modelling. Chemical Communications 2021, 57 (77) , 9922-9925.
    38. Carolynn M. Davern, Brandon D. Lowe, Adam Rosfi, Elon A. Ison, Caroline Proulx. Submonomer synthesis of peptoids containing trans -inducing N -imino- and N -alkylamino-glycines. Chemical Science 2021, 12 (24) , 8401-8410.
    39. Maha Rzeigui, Zeynel Şahin, Olivier Roy, Tuğba Küçük, Ömer Göler, Devrim Atilla, Jameleddine Khiari, Fabienne Dumoulin, Claude Taillefumier. Peptoid-phthalocyanine architectures with different grafting positions: Synthetic strategy and photoproperties. Dyes and Pigments 2021, 189 , 109095.
    40. Resat Aksakal, Chiel Mertens, Matthieu Soete, Nezha Badi, Filip Du Prez. Applications of Discrete Synthetic Macromolecules in Life and Materials Science: Recent and Future Trends. Advanced Science 2021, 8 (6)
    41. Michael D. Connolly, Sunting Xuan, Natalia Molchanova, Ronald N. Zuckermann. Submonomer synthesis of sequence defined peptoids with diverse side-chains. 2021, 241-270.
    42. Claudine Nicole Herlan, Katharina Sommer, Patrick Weis, Martin Nieger, Stefan Bräse. Structural Diversity of Peptoids: Tube-Like Structures of Macrocycles. Molecules 2021, 26 (1) , 150.
    43. Yukiko Kamiya, Tadashi Satoh, Atsuji Kodama, Tatsuya Suzuki, Keiji Murayama, Hiromu Kashida, Susumu Uchiyama, Koichi Kato, Hiroyuki Asanuma. Intrastrand backbone-nucleobase interactions stabilize unwound right-handed helical structures of heteroduplexes of L-aTNA/RNA and SNA/RNA. Communications Chemistry 2020, 3 (1)
    44. Kevin L. Bicker, Steven L Cobb. Recent advances in the development of anti-infective peptoids. Chemical Communications 2020, 56 (76) , 11158-11168.
    45. Sunting Xuan, Ronald N. Zuckermann. Engineering the atomic structure of sequence-defined peptoid polymers and their assemblies. Polymer 2020, 202 , 122691.
    46. Xiangyu Liu, Heng Song, Xiaofang Zhai, Chen-Ho Tung, Wenguang Wang. Cobalt-catalyzed regioselective hydrohydrazination of epoxides. Organic & Biomolecular Chemistry 2020, 18 (8) , 1572-1576.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect