Rational design of hyper-glycosylated interferon beta analogs: A computational strategy for glycoengineering

•Analogs of IFN-β carrying one additional N-glycosylation site were examined.•Six desired analogs were identified using computer-based structural analyses.•Loop regions were considered as a target for addition of the new N-glycosylation. Glycoengineering has been successfully used to improve the phy...

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Bibliographic Details
Published in:Journal of molecular graphics & modelling 2015-03, Vol.56, p.31-42
Main Authors: Samoudi, Mojtaba, Tabandeh, Fatemeh, Minuchehr, Zarrin, Ahangari Cohan, Reza, Nouri Inanlou, Davoud, Khodabandeh, Mahvash, Sabery Anvar, Mohammad
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Analogs
Animals
Comparative modeling
Computation
Glycoengineering
Glycosylation
Humans
In silico design
Interferon beta
Interferon-beta - chemistry
Mathematical models
Molecular dynamics
Molecular Dynamics Simulation
Molecular Sequence Data
Molecular structure
Protein Engineering
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins
Sequence Alignment
Sequence Homology, Amino Acid
Sialic Acids - chemistry
Strategy
Structural Homology, Protein
Thermodynamics
Three dimensional
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Summary:•Analogs of IFN-β carrying one additional N-glycosylation site were examined.•Six desired analogs were identified using computer-based structural analyses.•Loop regions were considered as a target for addition of the new N-glycosylation. Glycoengineering has been successfully used to improve the physicochemical and pharmaceutical properties of therapeutics. One aspect of glycoengineering is to introduce new N-linked glycosylation consensus sequences (Asn, X, Thr/Ser) into desirable positions in the peptide backbone by mutational insertion to generate proteins with increased sialic acid content. In the current work, human interferon beta (huIFN-β) was used as a model to identify the potential positions for the addition of new N-glycosylation sites. A computational strategy was employed to predict the structural distortions and functional alterations that might be caused by the change in amino acid sequence. Accordingly, three-dimensional (3D) structures of the designed huIFN-β analogs were generated by comparative modeling. Molecular dynamics (MD) simulation was carried out to assess the molecular stability and flexibility profile of the structures. Subsequently, for the purpose of glycoengineering huIFN-β, analogs with 3D structures more similar to the wild-type huIFN-β and exposed Asn residue in the new N-glycosylation site were identified. These modeling procedures indicated that the addition of the new N-glycosylation site in the loop regions had lower constraining effects on the tertiary structure of the protein. This computational strategy can be applied to avoid alterations in the 3D structure of proteins caused by changes in the amino acid sequences, when designing novel hyper-glycosylated therapeutics. This in turn reduces labor-intensive experimental analyses of each analog.
ISSN:1093-3263
1873-4243
DOI:10.1016/j.jmgm.2014.12.001