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Investigating the conformational dynamics of Zika virus NS4B protein
Open accessPreprint — published as 10.1016/j.virol.2022.08.005
Abstract
Zika virus (ZIKV) NS4B protein is a membranotropic protein having multifunctional roles such as evasion of host-immune system, and induction of host membrane rearrangement for viral genome replication and processing of polyprotein. Despite its versatile functioning, its topology and dynamics are not entirely understood. Presently, there is no NMR or X-ray crystallography-based structure available for any flaviviral NS4B protein. Therefore, in this study, we have investigated the structural dynamics of Zika Virus NS4B protein through 3D structure models using molecular dynamics (MD) simulations approach and experiments. Subsequently, we employed a reductionist approach to understand the dynamics of ZIKV NS4B protein. For this, we studied its N-terminal (residues 1-38), C-terminal (residues 194-251), and cytosolic (residues 131-169) regions in isolation. Further, we have performed experiments to prove the maximum dynamics in its cytosolic region. Using a combination of computational tools and circular dichroism (CD) spectroscopy, we validate the cytosolic region as an intrinsically disordered protein region (IDR). The microsecond-long all atoms molecular dynamics and replica-exchange MD simulations complement the experimental observations. We have also analysed its behaviour under the influence of differently charged liposomes and macromolecular crowding agents which may have significance on its overall dynamics. Lastly, we have proposed a ZIKV NS4B protein model illustrating its putative topology consisting of various membrane-spanning and non-membranous regions. Highlights: Microsecond simulations of NS4B N-terminus and cytosolic regions exposed their dynamic nature. C-terminal region remains intact in presence lipid bilayer during 1 μs simulations. Spectroscopic results also reveal the cytosolic region as an intrinsically disordered region. Cytosolic region exhibits gain-of-structure property under helix inducing solvents.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Bhardwaj, T., Kumar, P., & Giri, R.
- Affiliations
- Indian Institute of Technology Mandi (IN)
- Corresponding author
- Giri, Rajanish
- Venue
- Virology
- Publisher
- openRxiv
- Published
- 2021-12-09
- Volume
- 575
- Pages
- 20-35
- ISSN
- 0042-6822 (ISSN-L)
- OpenAlex
- W4292501485
- Cited by
- 13
- References
- 1
- Citations by year
- 2025: 8 · 2023: 3 · 2022: 2
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Virology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, Ministry of Science and Technology, India (BT/11/ IYBA/2018/06)
- Department of Science and Technology, Ministry of Science and Technology, India (SPARC/2018-2019/P37/SL)
- Indian Council of Medical Research (58/6/2020/PHA/BMS)
- Ministry of Education, India (SPARC/2018\u20132019/P37/SL, 2019/P37/SL, SPARC/2018-2019/P37/SL)
- Indian Institute of Technology Mandi
- Scheme for Promotion of Academic and Research Collaboration
- Science and Engineering Research Board (CRG/2019/56003)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- protein conformational dynamics, intrinsically disordered proteins, membrane-spanning region, protein topology, circular dichroism, molecular dynamics simulation
- MeSH terms
- Zika Virus Infection, Zika Virus, Flavivirus, Humans, Lipids, Viral Nonstructural Proteins, Intrinsically Disordered Proteins
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