Effective Design of Multifunctional Peptides by Combining Compatible Functions.
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.
Department of Biochemistry and Structural Biology, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Christian
C
Diener
Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Georgina
G
Garza Ramos Martínez
Department of Neurodevelopment and Physiology, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Daniel
D
Moreno Blas
Department of Biochemistry and Structural Biology, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico.
David A
DA
Castillo González
Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, Universidad Nacional Autónoma de México, Cuernavaca Morelos, México.
Gerardo
G
Corzo
Department of Neurodevelopment and Physiology, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Susana
S
Castro-Obregon
Department of Biochemistry and Structural Biology, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Gabriel
G
Del Rio
D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D000069550:Machine Learning; D051379:Mice; D015233:Models, Statistical; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods* / Q000706:statistics & numerical data; D017433:Protein Structure, Secondary
D023181:Antimicrobial Cationic Peptides; D057846:Cell-Penetrating Peptides; D004268:DNA-Binding Proteins; D019913:Nuclear Localization Signals; D010455:Peptides