Helical structure motifs made searchable for functional peptide design

• Published in: Nature communications 2022-01, Vol.13 (1), p.102-14, Article 102
• Main Authors: Tsai, Cheng-Yu, Salawu, Emmanuel Oluwatobi, Li, Hongchun, Lin, Guan-Yu, Kuo, Ting-Yu, Voon, Liyin, Sharma, Adarsh, Hu, Kai-Di, Cheng, Yi-Yun, Sahoo, Sobha, Stuart, Lutimba, Chen, Chih-Wei, Chang, Yuan-Yu, Lu, Yu-Lin, Ke, Simai, Ortiz, Christopher Llynard D., Fang, Bai-Shan, Wu, Chen-Chi, Lan, Chung-Yu, Fu, Hua-Wen, Yang, Lee-Wei
• Format: Article
• Language: English
• Subjects: 119/118; 631/114/129/2044; 631/114/2184; 631/114/2410; 631/114/469; 639/638/45/611; 82/75; Amino Acid Sequence; Amino Acids - chemistry; Amino Acids - metabolism; Animals; Antibodies; Antigens; Antiinfectives and antibacterials; Antimicrobial peptides; Antimicrobial Peptides - chemistry; Antimicrobial Peptides - metabolism; Antimicrobial Peptides - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Conserved sequence; Databases, Protein; Design; Drug Design - methods; Evolutionary conservation; Helices; Homology; Humanities and Social Sciences; Humans; Molecular Dynamics Simulation; multidisciplinary; Mutagenesis, Site-Directed; Mutation; Peptides; Protein Binding; Protein Conformation, alpha-Helical; Protein interaction; Protein structure; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Science; Science (multidisciplinary); Search engines; Secondary structure; Software; Structure-Activity Relationship; Therapeutic applications
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27655-0

The systematic design of functional peptides has technological and therapeutic applications. However, there is a need for pattern-based search engines that help locate desired functional motifs in primary sequences regardless of their evolutionary conservation. Existing databases such as The Protein Secondary Structure database (PSS) no longer serves the community, while the Dictionary of Protein Secondary Structure (DSSP) annotates the secondary structures when tertiary structures of proteins are provided. Here, we extract 1.7 million helices from the PDB and compile them into a database (Therapeutic Peptide Design database; TP-DB) that allows queries of compounded patterns to facilitate the identification of sequence motifs of helical structures. We show how TP-DB helps us identify a known purification-tag-specific antibody that can be repurposed into a diagnostic kit for Helicobacter pylori . We also show how the database can be used to design a new antimicrobial peptide that shows better Candida albicans clearance and lower hemolysis than its template homologs. Finally, we demonstrate how TP-DB can suggest point mutations in helical peptide blockers to prevent a targeted tumorigenic protein-protein interaction. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/ . Here, we present TP-DB; a pattern-based search engine based on 1.67 million helices from the Protein Database (PDB). We demonstrate the utility of TP-DB in identifying microbe-specific antigens, as well as the design of antimicrobial peptides and Protein-protein interaction blockers.