An atomic-scale model of a virus that infects the Salmonella bacterium. Credit: C. Hryc and the Chiu Lab, Baylor College of Medicine.
This sphere could be a prototype design for the 2018 World Cup official match soccer ball, but you won’t see it dribbled around any soccer fields. The image is actually an atomic-scale model of a virus that infects the Salmonella bacterium. Like a soccer ball, both are approximately spherical shapes created by a combination of hexagonal (six-sided) and pentagonal (five-sided) units. Wah Chiu, a biochemist at Baylor College of Medicine, and his colleagues used new computational methods to construct the model from more than 20,000 cryo-electron microscopy (cryo-EM) images. Cryo-EM is a sophisticated technique that uses electron beams for visualizing frozen samples of proteins and other biological specimens.
The researchers’ model, published in a recent issue of PNAS, shows the virus’ protein shell, or capsid, that encloses the virus’ genetic material. Each color shows capsid proteins having the same interactions with their neighbors. The fine resolution allowed researchers to identify the protein interactions essential to building a stable shell. They developed a new approach to checking the accuracy and reliability of the virus model and reporting what parts are the most certain. The approach could be used to evaluate other complex biological structures, potentially leading to better quality models and new avenues for drug design and development.
This research is funded in part by NIH under grants R01GM079429, P01GM063210, P41GM103832, PN2EY016525, T15LM007093.
The following images show a few ways in which cutting-edge research tools are giving us clearer views of viruses—and possible ways to disarm them. The examples, which highlight work involving HIV and the coronavirus, were funded in part by our Biomedical Technology Research Resources program.
Uncloaking HIV’s Camouflage
HIV capsid with (right, red) and without (left) a camouflaging human protein. Credit: Juan R. Perilla, Klaus Schulten and the Theoretical and Computational Biophysics Group, University of Illinois at Urbana-Champaign.
To sneak past our immune defenses and infect human cells, HIV uses a time-honored strategy—disguise. The virus’ genome is enclosed in a protein shell called a capsid (on left) that’s easily recognized and destroyed by the human immune system. To evade this fate, the chrysalis-shaped capsid cloaks itself with a human protein known as cyclophilin A (in red, on right). Camouflaged as human, the virus gains safe passage into and through a human cell to deposit its genetic material in the nucleus and start taking control of cellular machinery.
Biomedical and technical experts teamed up to generate these HIV models at near-atomic resolution. First, structural biologists at the Pittsburgh Center for HIV Protein Interactions used a technique called cryo-electron microscopy (cryo-EM) to get information on the shape of an HIV capsid as well as the capsid-forming proteins’ connections to each other and to cyclophilin A. Then experts at the Resource for Macromolecular Modeling and Bioinformatics fed the cryo-EM data into their visualization and simulation programs to computationally model the physical interactions among every single atom of the capsid and the cyclophilin A protein. The work revealed a previously unknown site where cyclophilin A binds to the capsid, offering new insights on the biology of HIV infection. Continue reading
The molecular visualization technique known as cryo-electron microscopy (cryo-EM) was recently named the “2015 Method of the Year” by the journal Nature Methods. In a recent blog post, NIH Director Francis Collins explains how the technology works and just how rapidly it has advanced. He writes, “Today’s cryo-EM is so powerful that researchers can almost make out individual atoms!” He also notes, “These dramatic advances serve as a reminder of the ways in which basic technological innovation can open new realms of scientific possibility.”
We fund many scientists who are developing and applying cryo-EM to bring the details of biological structures into unprecedented focus. Here are two examples of their work and its potential impact. Continue reading