Please use this identifier to cite or link to this item:
https://doi.org/10.1371/journal.pcbi.1003718
Title: | De Novo Design and Experimental Characterization of Ultrashort Self-Associating Peptides | Authors: | Smadbeck J. Chan K.H. Khoury G.A. Xue B. Robinson R.C. Hauser C.A.E. Floudas C.A. |
Keywords: | alanine isoleucine leucine methionine peptide phenylalanine self associating peptide tripeptide tryptophan tyrosine unclassified drug hydrogel peptide protein aggregate amino acid sequence amino terminal sequence article beta sheet carboxy terminal sequence controlled study crystal structure electron microscopy field emission scanning electron microscopy hydrogel hydrogen bond hydrophobicity point mutation process optimization protein aggregation protein assembly protein conformation protein folding protein function protein interaction protein motif protein structure X ray crystallography X ray diffraction biology chemistry metabolism molecular dynamics protein multimerization viscosity Computational Biology Crystallography, X-Ray Hydrogel Molecular Dynamics Simulation Peptides Protein Aggregates Protein Multimerization Viscosity |
Issue Date: | 2014 | Citation: | Smadbeck J., Chan K.H., Khoury G.A., Xue B., Robinson R.C., Hauser C.A.E., Floudas C.A. (2014). De Novo Design and Experimental Characterization of Ultrashort Self-Associating Peptides. PLoS Computational Biology 10 (7) : e1003718. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pcbi.1003718 | Rights: | Attribution 4.0 International | Abstract: | Self-association is a common phenomenon in biology and one that can have positive and negative impacts, from the construction of the architectural cytoskeleton of cells to the formation of fibrils in amyloid diseases. Understanding the nature and mechanisms of self-association is important for modulating these systems and in creating biologically-inspired materials. Here, we present a two-stage de novo peptide design framework that can generate novel self-associating peptide systems. The first stage uses a simulated multimeric template structure as input into the optimization-based Sequence Selection to generate low potential energy sequences. The second stage is a computational validation procedure that calculates Fold Specificity and/or Approximate Association Affinity (K* association) based on metrics that we have devised for multimeric systems. This framework was applied to the design of self-associating tripeptides using the known self-associating tripeptide, Ac-IVD, as a structural template. Six computationally predicted tripeptides (Ac-LVE, Ac-YYD, Ac-LLE, Ac-YLD, Ac-MYD, Ac-VIE) were chosen for experimental validation in order to illustrate the self-association outcomes predicted by the three metrics. Self-association and electron microscopy studies revealed that Ac-LLE formed bead-like microstructures, Ac-LVE and Ac-YYD formed fibrillar aggregates, Ac-VIE and Ac-MYD formed hydrogels, and Ac-YLD crystallized under ambient conditions. An X-ray crystallographic study was carried out on a single crystal of Ac-YLD, which revealed that each molecule adopts a ?-strand conformation that stack together to form parallel ?-sheets. As an additional validation of the approach, the hydrogel-forming sequences of Ac-MYD and Ac-VIE were shuffled. The shuffled sequences were computationally predicted to have lower K* association values and were experimentally verified to not form hydrogels. This illustrates the robustness of the framework in predicting self-associating tripeptides. We expect that this enhanced multimeric de novo peptide design framework will find future application in creating novel self-associating peptides based on unnatural amino acids, and inhibitor peptides of detrimental self-aggregating biological proteins. ? 2014 Smadbeck et al. | Source Title: | PLoS Computational Biology | URI: | https://scholarbank.nus.edu.sg/handle/10635/161948 | ISSN: | 1553734X | DOI: | 10.1371/journal.pcbi.1003718 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
Show full item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1371_journal_pcbi_1003718.pdf | 3.07 MB | Adobe PDF | OPEN | None | View/Download |
This item is licensed under a Creative Commons License