Visual Science, in collaboration with virologists from the National Center for Biotechnology in Madrid, has produced the first 3D model of the entire A/H1N1 virus, better known as the common flu. The model reflects the current state of scientific knowledge about the virus based on the latest research in the fields of molecular biology, microscopy, and X-ray crystallography. A product of Visual Science’s non-profit Viral Park project, which has already modeled HIV, the Ebola virus, and the Human Papilloma Virus (HPV), the influenza model could help educate the general public and promote further scientific research.
We consider such 3D models a novel and effective method of presenting and promoting scientific knowledge of ubiquitous human viruses,said Visual Science founder and CEO Ivan Konstantinov.
Because no single field of science has produced an image of the virus at an atomic or molecular level, the Visual Science team relied on data from dozens of scientific articles, expert analysis from leading research groups, and molecular modeling by the company’s own specialists.
The influenza virus is a widespread, highly contagious, and rapidly evolving pathogen. Symptoms often resemble those of the common cold, but complications from influenza pose a grave risk to young children, the elderly, and people with a weakened immune system. The last century saw three major influenza pandemics. The Spanish Flu (1918-1920) killed an estimated 50 million people — 2-5 percent of the world’s population — more than World War I or the Black Death. The Asian Flu and Hong Kong Flu, which struck in the 1950s and 1960s respectively, took a combined 2.5 million lives. Advances in antiviral drugs, improved preventive measures, and better monitoring have saved millions of lives in recent years, but up to 500,000 people still die annually from influenza and related illnesses, and new strains are constantly emerging. Influenza doesn’t limit itself to humans. Many other species, from birds to cattle, contract the flu, and the virus has been known to acquire deadly properties while circulating in non-human populations.
The influenza virus’s size and complexity made it a challenge to model, leading the Visual Science team to compile the best research from across the biological sciences, like assembling a puzzle with an only a rough sketch as a guide. The viruses are so tiny — usually 30-200 nm, thousands of times thinner than a human hair — and complex that no existing imaging technology is powerful enough to capture an entire virus at an atomic resolution. Even electron microscopes provide only a vague image of the virions and their component parts, including hundreds of macromolecules. Likewise, X-ray crystallography or nuclear magnetic resonance methods (NMR), technologies that are usually used to determine the structure of viral proteins, shed light on individual proteins but reveal little about the structures of large complexes, flexible parts of molecules, and protein regions hidden inside lipid membranes. Partly because of the limitations of X-ray crystallography, the structural dimensions of some viral proteins are still undetermined. Some molecules cannot be easily crystallized due to their flexibility, the flexibility of their components, or their location inside lipid membranes. Structures with any of these characteristics are often missing from the scientific literature and required clarification by the Visual Science team.
To ensure the accuracy of “missing” configurations, we relied on a detailed analysis of existing scientific literature, molecular modeling, and most importantly, the advice of world-renowned scientists. Each missing piece of the virion puzzle was fitted to the model with the greatest care and utmost attention to scientific accuracy. We generated missing information about protein interactions by applying computer-based analysis known as “bioinformatics,” which allowed us to predict the structure of certain proteins by comparing them to proteins with a similar structure and amino acid sequence. Experts in our Molecular Modeling and Dynamics Department — Ph.D.-level scientists with backgrounds in molecular, structural, computational biology, and graphic design — rigorously analyzed available crystallographic data to model missing fragments of the virion. The result of their work is a scientifically rigorous model that combines data from the scientific literature with our own original data and input from leading experts. It’s a project that Visual Science was uniquely suited to tackle. Our expertise and active participation in the scientific community are unique and unprecedented in the world of scientific and medical design.
The influenza virion measures about 80-120 nm in diameter. Most are roughly spherical, but influenza virions can sometimes be filamentous. The virus’s shape is determined by a layer of matrix protein underneath the influenza membrane. The membrane contains two types of surface proteins and a number of protein channels. The viral genome is represented by eight separate RNA molecules that are bound to structural proteins, forming form large spirals. Genome complexes and proteins needed to complete the viral life cycle are found in the very center of the virion.
Strains of the virus differ from each other mostly by two surface proteins that accumulate mutational changes very quickly, increasing strain diversity. When co-infection of a cell by different strains of influenza occurs, newly-formed virions can receive combinations of surface proteins from both strains, which also increases viral diversity. This, in turn, further complicates influenza treatment.
— Hemagglutinin binds to cell receptors to allow the viral membrane to fuse with the membrane of a cell vesicle and deliver the viral genome into the cytoplasm.
— Neuraminidase helps newly formed virus particles separate from the host cell membrane and travel to a new cell.
— A matrix protein is the major structural component of the virus. It determines the shape of the particle and plays a key role in its assembly by binding to both surface proteins in the membrane and to genome complexes.
— The M2 protein forms membrane channels that allow protons to enter a particle after it is inside the cytoplasm vesicle. The M2 protein is crucial for virus unpacking.
— Nucleoprotein packs fragments of viral RNA genome into condensed spiral complexes that are located inside the virus.
— Nuclear export protein transfers viral RNAs from the cell nucleus to the sites of particle assembly near the cell membrane.
— The polymerase complex makes new copies of the influenza RNA genome, some of which are used to make new viral proteins, while the rest are packed into new viral particles.
— The viral genome carries the information about the influenza proteins’ structure. It is comprised of eight RNA molecules of various lengths and a set of encoded proteins. The viral membrane is captured from the host cell during the budding of the virus. It is composed of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and cholesterol in proportions found in human cells.
The architecture of the viral genome was discussed with Dr. Jaime Martín-Benito to make our model match with the recent data of his research group. Dr. Martín-Benito also provided us with useful comments about the virion structure. In addition in the beginning of our work we communicated with Drs. Juan Ortín (Spanish National Centre for Biotechnology, Madrid, Spain), Takeshi Noda (University of Tokyo, Japan), Rob Ruigrok (Unit of Virus Host Cell Interactions, Grenoble, France) and Peter Rosenthal (MRC National Institute for Medical Research, London, UK) to clarify some general aspects of the influenza structure and the distribution of the surface proteins.
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