TY - JOUR
T1 - Cooperative Intramolecular Hydrogen Bonding Strongly Enforces cis-Peptoid Folding
AU - Wijaya, Andrew W.
AU - Nguyen, Andy I.
AU - Roe, Leah T.
AU - Butterfoss, Glenn L.
AU - Spencer, Ryan K.
AU - Li, Nan K.
AU - Zuckermann, Ronald N.
N1 - Funding Information:
Work at the Molecular Foundry was supported by the Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. Additional support was provided by the DARPA Fold F(x) program. DFT calculations were carried out on the High Performance Computing resources at New York University Abu Dhabi. The funds for the 900 MHz NMR spectrometer in the QB3 Institute at University of California, Berkeley, were provided by the NIH Grant GM68933. Additionally, we would like to thank Dr. Nicholas Settineri of the UC Berkeley CheXray facility for his assistance in X-ray diffraction studies, Dr. Jeff G. Pelton for his assistance in NMR studies, and Victor R. Mann, Michael Connolly, and Zeming Wang for helpful discussions.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/12/11
Y1 - 2019/12/11
N2 - 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 (
K
cis/
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.
AB - 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 (
K
cis/
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.
KW - Amides/chemistry
KW - Crystallography, X-Ray
KW - Hydrogen Bonding
KW - Magnetic Resonance Spectroscopy
KW - Models, Molecular
KW - Molecular Structure
KW - N-substituted Glycines/chemical synthesis
KW - Peptoids/chemical synthesis
KW - Protein Folding
KW - Quaternary Ammonium Compounds/chemistry
KW - Solid-Phase Synthesis Techniques
KW - Stereoisomerism
KW - Thermodynamics
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U2 - 10.1021/jacs.9b10497
DO - 10.1021/jacs.9b10497
M3 - Article
C2 - 31765162
AN - SCOPUS:85075684909
SN - 0002-7863
VL - 141
SP - 19436
EP - 19447
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 49
ER -