Abstract
Multifunctionality is a common trait of many natural proteins and peptides, yet the rules to generate such multifunctionality remain unclear. We propose that the rules defining some protein/peptide functions are compatible. To explore this hypothesis, we trained a computational method to predict cell-penetrating peptides at the sequence level and learned that antimicrobial peptides and DNA-binding proteins are compatible with the rules of our predictor. Based on this finding, we expected that designing peptides for CPP activity may render AMP and DNA-binding activities. To test this prediction, we designed peptides that embedded two independent functional domains (nuclear localization and yeast pheromone activity), linked by optimizing their composition to fit the rules characterizing cell-penetrating peptides. These peptides presented effective cell penetration, DNA-binding, pheromone and antimicrobial activities, thus confirming the effectiveness of our computational approach to design multifunctional peptides with potential therapeutic uses. Our computational implementation is available at http://bis.ifc.unam.mx/en/software/dcf.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Algorithms
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Amino Acid Sequence
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Animals
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Antimicrobial Cationic Peptides / chemistry
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Antimicrobial Cationic Peptides / genetics
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Antimicrobial Cationic Peptides / physiology
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Cell-Penetrating Peptides / chemistry
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Cell-Penetrating Peptides / genetics
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Cell-Penetrating Peptides / physiology
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Cells, Cultured
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Computational Biology
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Drug Design*
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Escherichia coli / drug effects
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Escherichia coli / growth & development
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Machine Learning
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Mice
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Models, Statistical
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Molecular Sequence Data
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Nuclear Localization Signals
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Peptides / chemistry*
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Peptides / genetics
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Peptides / physiology
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Protein Binding
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Protein Engineering / methods*
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Protein Engineering / statistics & numerical data
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Protein Structure, Secondary
Substances
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Antimicrobial Cationic Peptides
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Cell-Penetrating Peptides
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DNA-Binding Proteins
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Nuclear Localization Signals
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Peptides
Grants and funding
The Alexander von Humboldt foundation number 31102732 and the PAPIIT grant number IN208014 in part supported this work to GDR; PAPIIT grant number IN206015 and CoNaCyT grant number CB2013-220515 in part supported this work to SCO. CD was supported by a postdoctoral fellowship from the National University of Mexico (UNAM). DACG (fellowship number 416264) and DMB (fellowship number 588372) were supported in part by CONACyT and are students of the Programa de Maestría y Doctorado en Ciencias Bioquímicas, UNAM, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.