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C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs.

ABSTRACT: Single molecular changes on a tripeptide can have dramatic effects on their self-assembly and hydrogelation. Herein, we explore C-terminal residue variation on two consistent ultrashort peptide backbones, i.e. acetylated-Leu-Ile-Val-Ala-Gly-Xaa and acetylated-Ile-Val-Xaa (Xaa?=?His, Arg, Asn). The objective of this study is to identify candidates that can form hydrogels for small-molecule drug (SMD) delivery. Haemolysis and cytotoxicity (with human adipose-derived mesenchymal stem cells) assays showed that the new soluble peptides (Xaa?=?His, Arg) are cytocompatible. Gelation studies showed that all but acetylated-Ile-Val-Arg could gel under physiological conditions. Longer peptidic backbones drive self-assembly more effectively as reflected in field emission scanning electron microscopy (FESEM) and circular dichroism spectroscopy studies. Rheological studies revealed that the resultant hydrogels have varying stiffness and yield stress, depending on the backbone and C-terminal residue. Visible spectroscopy-based elution studies with SMDs (naltrexone, methotrexate, doxorubicin) showed that besides the C-terminal residue, the shape of the SMD also determines the rate and extent of SMD elution. Based on the elution assays, infrared spectroscopy, and FESEM, we propose models for the peptide fibril-SMD interaction. Our findings highlight the importance of matching the molecular properties of the self-assembling peptide and SMD in order to achieve the desired SMD release profile.

SUBMITTER: Chan KH

PROVIDER: S-EPMC6244206 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs.

Chan Kiat Hwa KH Lee Wei Hao WH Ni Ming M Loo Yihua Y Hauser Charlotte A E CAE

Scientific reports 20181120 1

Single molecular changes on a tripeptide can have dramatic effects on their self-assembly and hydrogelation. Herein, we explore C-terminal residue variation on two consistent ultrashort peptide backbones, i.e. acetylated-Leu-Ile-Val-Ala-Gly-Xaa and acetylated-Ile-Val-Xaa (Xaa = His, Arg, Asn). The objective of this study is to identify candidates that can form hydrogels for small-molecule drug (SMD) delivery. Haemolysis and cytotoxicity (with human adipose-derived mesenchymal stem cells) assays ...[more]

PMID: 30459362

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Project description: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 β-strand conformation that stack together to form parallel β-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.

Dataset Information

C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs.

Publications

C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs.

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