In Silico Study of Pertussis Toxin S1 for Recombinant Pertussis Vaccine Development in Indonesia

Ricky Rinaldi, Umi Baroroh, Fauzian Giansyah Rohmatulloh, Yusuf Sofyan Efendi, Mia Tria Novianti, Ade Rizqy Ridwan Firdaus, Toto Subroto, Muhammad Yusuf

Abstract


Pertussis or whooping cough is a disease caused by Bordetella pertussis bacteria, and the spread disease can be controlled by vaccination. Currently, some pertussis toxoids are prepared by chemical modification, which makes it possible to change the immunospecificity. To avoid altering the structure of toxoids, genetic modification is considered more harmless than chemical modification. A mutant of R9K/E129G is known to have lower toxicity and can be used as a component of the pertussis vaccine. However, the reason behind the low toxicity of this toxoid at the molecular level remains unclear. Hence, this study aimed to investigate the molecular mechanism behind the low toxicity of R9K/E129G using molecular dynamics simulation. The structure of the mutant was built using the homology modeling approach, and the behavior of wild-type and mutant toxoid were studied by molecular dynamics simulation for 300 ns. The changes in the structure in all systems were calculated by POVME, which was further investigated by molecular docking with NAD+ as the substrate. The results showed that the active site of the wild type was opened in the reducing environment while the mutant remained closed, which hindered the binding of NAD+. In conclusion, the dual mutation of R9K/E129G reduces pertussis toxoid's toxicity by preventing the catalytic site's opening. Therefore, this natural mutant can be further optimized in the development of a safer vaccine for pertussis.

 

Keywords: Pertussis toxin, R9K/E129G mutant, molecular dynamics simulation, NAD+ binding site, vaccine.


Full Text:

PDF

References


Nataprawira HM, Ayu S, Indriyani K, Olivianto E. Pertussis in Children : Problems in Indonesia. Emerg Med. 2018;8(3).

Seubert A, Oro UD, Scarselli M. Genetically detoxified implications for immunization and vaccines. Expert Rev. 2014;1191–204.

Carbonetti NH. Pertussis toxin and adenylate cyclase toxin: key virulence factors of. Futur Microbiol. 2010;5(3):455–69.

Jespers L, Jenne Â, Lasters I, Collen Â. Epitope Mapping by Negative Selection of Randomized Antigen Libraries Displayed on Filamentous Phage. J Mol Biol. 1997;

Donati C, Rappuoli R. Reverse vaccinology in the 21st century : improvements over the original design. Ann S NEW YORK Acad Sci. 2013;1–18.

Soria-guerra RE, Nieto-gomez R, Govea-alonso DO, Rosales-mendoza S. An overview of bioinformatics tools for epitope prediction : Implications on vaccine development. J Biomed Inform. 2014;

Efendi YS, Susanti D, Tritama E, Pasier L, Putri GNN, Raharso S, et al. Complete Genome Sequence of Bordetella pertussis Pelita III , the Production Strain for an Indonesian Whole-Cell Pertussis Vaccine. Genome Announc. 2017;5(17):12–3.

Fiser A, Do RK, Sali A. Modeling of loops in protein structures. Protein Sci. 2000 Sep;9(9):1753–73.

Lovell SC, Davis IW, III WBA, Bakker PIW de, Word JM, Prisant MG, et al. Structure validation by C α geometry: φ,ψ and C β deviation. Proteins: Structure. Funct Genet. 2003;50(3):437–50.

Sippl MJ. Recognition of errors in three-dimensional structures of proteins. Proteins Struct Funct Bioinforma. 1993 Dec;17(4):355–62.

Wiederstein M, Sippl MJ. ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007;35:407–10.

Case DA, Cheatham III TE, Darden T, Gohlke H, Luo R, Merz Jr. KM, et al. The Amber biomolecular simulation programs. J Comput Chem. 2005 Dec;26(16):1668–88.

Wagner JR, Sørensen J, Hensley N, Wong C, Zhu C, Perison T, et al. POVME 3.0: Software for Mapping Binding Pocket Flexibility. J Chem Theory Comput. 2017 Sep;13(9):4584–92.

Lovell SC, Davis IW, Iii WBA, Bakker PIW De, Word JM, Prisant MG, et al. Structure Validation by Cα Geometry : ϕ,ψand Cβ Deviation. PROTEINS Struct Funct Genet. 2003;450(August 2002):437–50.

Rostkowski M, Olsson MH, Søndergaard CR, Jensen JH. Graphical analysis of pH-dependent properties of proteins predicted using PROPKA. BMC Struct Biol. 2011;11(Cc).

Martínez L. Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. PLoS One. 2015;10(3):1–10.

Mart MA, Stuart AC, Roberto S, Melo F, Andrej S. Comperative Protein Structure Modeling of Genes and Genomes. Annu Rev Biophys Biomol Struct. 2000;291–325.

Yuen C, Asokanathan C, Cook S, Lin N, Xing D. Effect of different detoxification procedures on the residual pertussis toxin activities in vaccines. Vaccine. 2016;

Fukunishi Y, Nakamura H. Prediction of ligand-binding sites of proteins by molecular docking calculation for a random ligand library. Protein Sci. 2011;20:95–106.




DOI: https://doi.org/10.24198/ijcb.v1i1.40911

Refbacks

  • There are currently no refbacks.


This journal is indexed by : 

 

Creative Commons Attribution :

Creative Commons License
Indonesian Journal of Computational Biology by Universitas Padjadjaran is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Based on a work at http://jurnal.unpad.ac.id/ijcb/

Copyright © 2020 IJCB