Application of molecular dynamics simulations to design a dual-purpose oligopeptide linker sequence for fusion proteins

Rezaie, Ehsan; Mohammadi, Mozafar; Sakhteman, Amirhossein; Bemani, Peyman; Ahrari, Sajjad

doi:10.1007/s00894-018-3846-x

Cited by 14 publications

(7 citation statements)

References 43 publications

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“…The basic local alignment search tool (BLAST) analysis showed that the molecular weight of the four selected lysins was significantly smaller than that of common Salmonella phage lysins, with an average molecular weight of 7.32 kDa (Figure S2B–D). It has been found that high molecular weight fusion tags can affect the activity of the target fusion protein . Therefore, lysins with a low molecular weight may be more beneficial to reduce the effect on the domain of the AMPs of chimeric proteins.…”

Section: Resultsmentioning

confidence: 99%

“…It has been found that high molecular weight fusion tags can affect the activity of the target fusion protein. 40 Therefore, lysins with a low molecular weight may be more beneficial to reduce the effect on the domain of the AMPs of chimeric proteins. The interesting thing is that phage 36 endolysin and phage 36 lysozyme are the catalytic domain and the binding domain of lysin, respectively, which are uncommon in Salmonella phages (Figure S2B).…”

Section: ■ Resultsmentioning

confidence: 99%

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In Silico Development of Novel Chimeric Lysins with Highly Specific Inhibition against Salmonella by Computer-Aided Design

Meng

Zhou

Lü

et al. 2021

J. Agric. Food Chem.

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Four novel chimeric lysins (P361, P362, P371, and P372), which were the fusion of Salmonella phage lysins and novel antimicrobial peptide LeuA-P, were obtained using bioinformatics analysis and in silico design. The recombinant chimeric lysins were expressed in E. coli BL21(DE3) strain and showed highly specific inhibition against Salmonella. The minimal inhibitory concentrations (MICs) of P362 and P372 to S. typhi CMCC 50071 were 8 and 16 μg/mL, respectively. Both 1 × MIC P362 and P372 could increase the outer membrane permeability and cleave the cell wall peptidoglycan, causing the leakage of intracellular nucleic acids and proteins and ultimately killing Salmonella efficiently without drug resistance. The combination of P362, P372, and potassium sorbate reduced more than 3 log CFU/g counts of microorganisms in contaminated chilled chicken and extended the shelf life by 7 days. The strategy of antimicrobial peptide (AMP)−lysin chimera inspired the inability of phage lysin to specifically inhibit Gram-negative bacteria with dense outer membranes in vitro.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

In Silico Development of Novel Chimeric Lysins with Highly Specific Inhibition against Salmonella by Computer-Aided Design

Meng

Zhou

Lü

et al. 2021

J. Agric. Food Chem.

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“…They used two phenylalanine residues in both of their muteins and ∆E1080 in the mutein 1 versus E1080W in the mutein 2 was the key factor that caused more flexibility in the mutein 2 [66]. However, the difference was minor, so it probably did not disturb the functional behaviors of the protein [67][68][69]. Despite that, helix to coil transition in the mutant 2 may cause the alteration in function of protein, but only experimental analysis can approve or reject this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Engineering of Cytolethal Distending Toxin B by Its Reducing Immunogenicity and Maintaining Stability as a New Drug Candidate for Tumor Therapy; an In Silico Study

Keshtvarz

Mahboobi

Kieliszek

et al. 2021

Toxins

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The cytolethal distending toxin (CDT), Haemophilus ducreyi, is one of the bacterial toxins that have recently been considered for targeted therapies, especially in cancer therapies. CDT is an A-B2 exotoxin. Its catalytic subunit (CdtB) is capable of inducing DNA double strand breaks, cell cycle arrest and apoptosis in host eukaryotic cells. The sequence alignment indicates that the CdtB is structurally homologyr to phosphatases and deoxyribonucleases I (DNase I). Recently, it has been found that CdtB toxicity is mainly related to its nuclease activity. The immunogenicity of CDT can reduce its effectiveness in targeted therapies. However, the toxin can be very useful if its immunogenicity is significantly reduced. Detecting hotspot ectopic residues by computational servers and then mutating them to eliminate B-cell epitopes is a promising approach to reduce the immunogenicity of foreign protein-based therapeutics. By the mentioned method, in this study, we try to reduce the immunogenicity of the CdtB- protein sequence. This study initially screened residue of the CdtB is B-cell epitopes both linearly and conformationally. By overlapping the B-cell epitopes with the excluded conserve residues, and active and enzymatic sites, four residues were allowed to be mutated. There were two mutein options that show reduced antigenicity probability. Option one was N19F, G74I, and S161F with a VaxiJen score of 0.45 and the immune epitope database (IEDB) score of 1.80, and option two was N19F, G74I, and S161W with a VaxiJen score of 0.45 and IEDB score of 1.88. The 3D structure of the proposed sequences was evaluated and refined. The structural stability of native and mutant proteins was accessed through molecular dynamic simulation. The results showed that the mutations in the mutants caused no considerable changes in their structural stability. However, mutant 1 reveals more thermodynamic stability during the simulation. The applied approaches in this study can be used as rough guidelines for finding hot spot immunogen regions in the therapeutic proteins. Our results provide a new version of CdtB that, due to reduced immunogenicity and increased stability, can be used in toxin-based drugs such as immunotoxins.

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“…In addition, the dual-or multi-functional linkers are designed and applied in immunotoxin structures for different purposes. For example, the "EAAAKECCPGCCMEP" linker has been introduced as a linker that functions in both immunotoxin's imaging and steric hindrance prevention [22]. The selected toxin can be a bacterial toxin such as Pseudomonas exotoxin, diphtheria toxin, or shiga toxin and also can be a plant toxin such as ricin, saporin, and gelonin.…”

Section: Immunotoxinsmentioning

confidence: 99%

Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Heiat

Yeganeh

Alavian

et al. 2021

Toxins

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Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC emphasizes the need for a new high-efficiency treatment strategy. Immunotoxins are armed and rigorous targeting agents that can purposefully kill cancer cells. Unlike traditional chemotherapeutics, immunotoxins because of targeted toxicity, insignificant cross-resistance, easy production, and other favorable properties can be ideal candidates against HCC. In this review, the characteristics of proper HCC-specific biomarkers for immunotoxin targeting were dissected. After that, the first to last immunotoxins developed for the treatment of liver cancer were discussed. So, by reviewing the strengths and weaknesses of these immunotoxins, we attempted to provide keynotes for designing an optimal immunotoxin against HCC.

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Application of molecular dynamics simulations to design a dual-purpose oligopeptide linker sequence for fusion proteins

Cited by 14 publications

References 43 publications

In Silico Development of Novel Chimeric Lysins with Highly Specific Inhibition against Salmonella by Computer-Aided Design

In Silico Development of Novel Chimeric Lysins with Highly Specific Inhibition against Salmonella by Computer-Aided Design

Engineering of Cytolethal Distending Toxin B by Its Reducing Immunogenicity and Maintaining Stability as a New Drug Candidate for Tumor Therapy; an In Silico Study

Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

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