Back to Search
Start Over
A Computational Assay that Explores the Hemagglutinin/Neuraminidase Functional Balance Reveals the Neuraminidase Secondary Site as a Novel Anti-Influenza Target
- Source :
- ACS central science, vol 4, iss 11, ACS Central Science, Vol 4, Iss 11, Pp 1570-1577 (2018), ACS Central Science, Amaro, Rommie E; Ieong, Pek U; Huber, Gary; Dommer, Abigail; Steven, Alasdair C; Bush, Robin M; et al.(2018). A Computational Assay that Explores the Hemagglutinin/Neuraminidase Functional Balance Reveals the Neuraminidase Secondary Site as a Novel Anti-Influenza Target. ACS CENTRAL SCIENCE, 4(11), 1570-1577. doi: 10.1021/acscentsci.8b00666. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/2fk411cc
- Publication Year :
- 2018
- Publisher :
- eScholarship, University of California, 2018.
-
Abstract
- Studies of pathogen–host specificity, virulence, and transmissibility are critical for basic research as well as for assessing the pandemic potential of emerging infectious diseases. This is especially true for viruses such as influenza, which continue to affect millions of people annually through both seasonal and occasional pandemic events. Although the influenza virus has been fairly well studied for decades, our understanding of host-cell binding and its relation to viral transmissibility and infection is still incomplete. Assessing the binding mechanisms of complex biological systems with atomic-scale detail is challenging given current experimental limitations. Much remains to be learned, for example, about how the terminal residue of influenza-binding host-cell receptors (sialic acid) interacts with the viral surface. Here, we present an integrative structural-modeling and physics-based computational assay that reveals the sialic acid association rate constants (kon) to three influenza sites: the hemagglutinin (HA), neuraminidase (NA) active, and NA secondary binding sites. We developed a series of highly detailed (atomic-resolution) structural models of fully intact influenza viral envelopes. Brownian dynamics simulations of these systems showed how structural properties, such as stalk height and secondary-site binding, affect sialic acid kon values. Comparing the kon values of the three sialic acid binding sites across different viral strains suggests a detailed model of encounter-complex formation and indicates that the secondary NA binding site may play a compensatory role in host-cell receptor binding. Our method elucidates the competition among these sites, all present on the same virion, and provides a new technology for directly studying the functional balance between HA and NA.<br />Atomistic mesoscale models of the influenza virus, coupled with Brownian dynamics simulations, provide a novel platform for interrogating the functional balance between neuraminidase and hemagglutinin.
- Subjects :
- 0301 basic medicine
Functional balance
General Chemical Engineering
Virulence
Bioengineering
Biology
Virus
Vaccine Related
03 medical and health sciences
chemistry.chemical_compound
Biodefense
Pandemic
2.2 Factors relating to the physical environment
Aetiology
QD1-999
030102 biochemistry & molecular biology
Prevention
General Chemistry
Virology
Influenza
Transmissibility (vibration)
3. Good health
Sialic acid
Chemistry
Infectious Diseases
Emerging Infectious Diseases
Good Health and Well Being
030104 developmental biology
chemistry
Chemical Sciences
Pneumonia & Influenza
biology.protein
Infection
Neuraminidase
Hemagglutinin-neuraminidase
Research Article
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- ACS central science, vol 4, iss 11, ACS Central Science, Vol 4, Iss 11, Pp 1570-1577 (2018), ACS Central Science, Amaro, Rommie E; Ieong, Pek U; Huber, Gary; Dommer, Abigail; Steven, Alasdair C; Bush, Robin M; et al.(2018). A Computational Assay that Explores the Hemagglutinin/Neuraminidase Functional Balance Reveals the Neuraminidase Secondary Site as a Novel Anti-Influenza Target. ACS CENTRAL SCIENCE, 4(11), 1570-1577. doi: 10.1021/acscentsci.8b00666. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/2fk411cc
- Accession number :
- edsair.doi.dedup.....a803ae15a82b06d699ce4b94d24a72a4