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Updated: Mar 3, 2026
Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
Study of the mechanism of protonated histidine-induced conformational changes in the Zika virus dimeric envelope
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China.
Abstract:
The Zika virus has drawn worldwide attention because of the epidemic diseases it causes. It is a flavivirus that has an icosahedral protein shell constituted by an envelope glycoprotein (E-protein) and membrane protein (M-protein) in the mature virion. The multistep process of membrane fusion to infect the host cell is pH-induced. To understand the mechanism of the conformational changes in the (E-M)2 protein homodimer embedded in the membrane, two 200-ns accelerated dynamic simulations were performed under different pH conditions. The low pH condition weakens the interactions and correlations in both E-protein monomers and in the E-M heterodimer. The highly conserved residues, His249, His288, His323 and His446, are protonated under low pH conditions and play key roles in driving the fusion process. The analysis and discussion in this study may provide some insight into the molecular mechanism of Zika virus infection.
Insights
Zika virus infection involves pH-induced membrane fusion. Low pH weakens protein interactions, with specific histidine residues driving the fusion process for host cell entry.
Area of Science:
- Virology
- Structural Biology
- Molecular Biophysics
Background:
- Zika virus is a flavivirus causing epidemic diseases worldwide.
- Viral entry into host cells involves a pH-induced membrane fusion process.
- The mature Zika virion contains an envelope glycoprotein (E-protein) and membrane protein (M-protein).
Purpose of the Study:
- To elucidate the mechanism of conformational changes in the (E-M)2 protein complex during Zika virus infection.
- To investigate the role of pH in modulating the structural dynamics of the E-M heterodimer.
Main Methods:
- Two accelerated molecular dynamics simulations of 200-ns each were performed.
- Simulations were conducted under varying pH conditions to mimic physiological and endosomal environments.
- Analysis focused on inter-protein interactions, correlations, and the protonation states of key residues.
Main Results:
- Low pH conditions were observed to weaken interactions and correlations within E-protein monomers and the E-M heterodimer.
- Protonation of conserved histidine residues (His249, His288, His323, His446) occurred at low pH.
- These protonated histidine residues were identified as critical in driving the membrane fusion process.
Conclusions:
- The study provides molecular insights into the pH-dependent conformational changes of the Zika virus E-M protein complex.
- Understanding these changes is crucial for deciphering the mechanism of Zika virus host cell entry.
- The identified key residues offer potential targets for antiviral strategies.
