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Modulation of Polypeptide Conformation through Donor-Acceptor Transformation of Side-Chain Hydrogen Bonding Ligands



Ziyuan Song, Rachael A. Mansbach, Hua He, Kuo-Chih Shih, Ryan Baumgartner, Nan Zheng, Xiaochu Ba, Yinzhao Huang, Deepak Mani, Yun Liu, Yao Lin, Mu-Ping Nieh, Andrew L. Ferguson, Lichen Yin, Jianjun Chen


Synthetic polypeptides have received increasing attention due to their ability to form higher ordered structures similar to proteins. The control over their secondary structures, which enables dynamic conformational changes, is primarily accomplished by tuning the side-chain hydrophobic or ionic interactions. Herein we report a strategy to modulate the conformation of polypeptides utilizing donor-acceptor interactions emanating from side-chain H-bonding ligands. Specifically, 1,2,3-triazole groups, when incorporated onto polypeptide side-chains, serve as both H-bond donors and acceptors at neutral pH and disrupt the α-helical conformation. When protonated, the resulting 1,2,3-triazolium ions lose the ability to act as H-bond acceptors, and the polypeptides regain their α-helical structure. The conformational change of triazole polypeptides in response to the donor-acceptor pattern was conclusively demonstrated using both experimental and simulation based methods. We further showed the utility of this transition by designing smart, cell-penetrating polymers that undergo acid-activated endosomal escape in living cells.
Nature Communications


Polypeptide, small angle neutron scattering, hydrogen bonding


Song, Z. , Mansbach, R. , He, H. , Shih, K. , Baumgartner, R. , Zheng, N. , Ba, X. , Huang, Y. , Mani, D. , Liu, Y. , Lin, Y. , Nieh, M. , Ferguson, A. , Yin, L. and Chen, J. (2017), Modulation of Polypeptide Conformation through Donor-Acceptor Transformation of Side-Chain Hydrogen Bonding Ligands, Nature Communications, [online], (Accessed April 14, 2024)
Created June 30, 2017, Updated October 12, 2021