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Secondary Structure Motifs Made Searchable to Facilitate the Functional Peptide Design

Cheng-Yu Tsai, Emmanuel O Salawu, Hongchun Li, Guan-Yu Lin, Ting-Yu Kuo, Liyin Voon, Adarsh Sharma, Kai-Di Hu, View ORCID ProfileYi-Yun Cheng, Sobha Sahoo, Lutimba Stuart, Chih-Wei Chen, Yuan-Yu Chang, Yu-Lin Lu, Ximai Ke, Chen-Chi Wu, Chung-Yu Lan, Hua-Wen Fu, Lee-Wei Yang
doi: https://doi.org/10.1101/651315
Cheng-Yu Tsai
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
2Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 10055, Taiwan
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Emmanuel O Salawu
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
3Bioinformatics Program, Institute of Information Sciences, Academia Sinica, Taipei 11529, Taiwan
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Hongchun Li
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
4Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
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Guan-Yu Lin
5Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Ting-Yu Kuo
5Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Liyin Voon
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Adarsh Sharma
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Kai-Di Hu
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Yi-Yun Cheng
6Praexisio Taiwan Inc. New Taipei 22180, Taiwan
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  • ORCID record for Yi-Yun Cheng
Sobha Sahoo
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Lutimba Stuart
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Chih-Wei Chen
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Yuan-Yu Chang
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Yu-Lin Lu
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Ximai Ke
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Chen-Chi Wu
2Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 10055, Taiwan
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Chung-Yu Lan
5Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
7Department of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan
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  • For correspondence: lwyang@life.nthu.edu.tw hwfu@life.nthu.edu.tw cylan@life.nthu.edu.tw
Hua-Wen Fu
5Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
7Department of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan
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  • For correspondence: lwyang@life.nthu.edu.tw hwfu@life.nthu.edu.tw cylan@life.nthu.edu.tw
Lee-Wei Yang
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
3Bioinformatics Program, Institute of Information Sciences, Academia Sinica, Taipei 11529, Taiwan
7Department of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan
8Physics Division, National Center for Theoretical Sciences, Hsinchu 30013, Taiwan
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  • For correspondence: lwyang@life.nthu.edu.tw hwfu@life.nthu.edu.tw cylan@life.nthu.edu.tw
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ABSTRACT

To ensure a physicochemically desired sequence motif to adapt a specific type of secondary structures, we compile an α-helix database allowing complicate search patterns to facilitate a data-driven design of therapeutic peptides. Nearly 1.7 million helical peptides in >130 thousand proteins are extracted along with their interacting partners from the protein data bank (PDB). The sequences of the peptides are indexed with patterns and gaps and deposited in our Therapeutic Peptide Design dataBase (TP-DB). We here demonstrate its utility in three medicinal design cases. By our pattern-based search engine but not PHI-BLAST, we can identify a pathogenic protein, Helicobacter pylori neutrophil-activating protein (HP-NAP), a virulence factor of H. pylori, which contains a motif DYKYLE that belongs to the affinity determinant motif DYKXX[DE] of the FLAG-tag and can be recognized by the anti-FLAG M2 antibody. By doing so, the known purification-tag-specific antibody is repurposed into a diagnostic kit for H. pylori. Also by leveraging TP-DB, we discovered a stretch of helical peptide matching the potent membrane-insertion pattern WXXWXXW, elucidated by MD simulations. The newly synthesized peptide has a better minimal inhibitory concentration (MIC) and much lower cytotoxicity against Candida albicans (fungus) than that of previously characterized homologous antimicrobial peptides. In a similar vein, taking the discontinued anchoring residues in the helix-helix interaction interface as the search pattern, TP-DB returns several helical peptides as potential tumor suppressors of hepatocellular carcinoma (HCC) whose helicity and binding affinity were examined by MD simulations. Taken together, we believe that TP-DB and its pattern-based search engine provide a new opportunity for a (secondary-)structure-based design of peptide drugs and diagnostic kits for pathogens without inferring evolutionary homology between sequences sharing the same pattern. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵¶ Authors who have equal contributions

  • The manuscript is largely revised. The text in the main manuscript is largely revised and refined for clarity, along with a new section on HCC suppressors is reported in the SI. In the main text, Table 3 and Figure 4 are newly added and Figure 3 is replaced.

  • http://dyn.life.nthu.edu.tw/design/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 22, 2021.
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Secondary Structure Motifs Made Searchable to Facilitate the Functional Peptide Design
Cheng-Yu Tsai, Emmanuel O Salawu, Hongchun Li, Guan-Yu Lin, Ting-Yu Kuo, Liyin Voon, Adarsh Sharma, Kai-Di Hu, Yi-Yun Cheng, Sobha Sahoo, Lutimba Stuart, Chih-Wei Chen, Yuan-Yu Chang, Yu-Lin Lu, Ximai Ke, Chen-Chi Wu, Chung-Yu Lan, Hua-Wen Fu, Lee-Wei Yang
bioRxiv 651315; doi: https://doi.org/10.1101/651315
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Secondary Structure Motifs Made Searchable to Facilitate the Functional Peptide Design
Cheng-Yu Tsai, Emmanuel O Salawu, Hongchun Li, Guan-Yu Lin, Ting-Yu Kuo, Liyin Voon, Adarsh Sharma, Kai-Di Hu, Yi-Yun Cheng, Sobha Sahoo, Lutimba Stuart, Chih-Wei Chen, Yuan-Yu Chang, Yu-Lin Lu, Ximai Ke, Chen-Chi Wu, Chung-Yu Lan, Hua-Wen Fu, Lee-Wei Yang
bioRxiv 651315; doi: https://doi.org/10.1101/651315

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