Viruses are small intracellular parasites that invade the cells of virtually all known organisms. They reproduce by utilizing the cell's machinery to replicate viral proteins and genomic material, generally damaging or killing the host cell in the process; subsequentelly, a large number of newly generated viruses go on to infect other cells. Viruses are responsible for a wide variety of human diseases, ranging from the common (influenza and colds) to the exotic (AIDS, West Nile virus and Zika). Some viruses which are not dangerous to humans can also be exploited in technological applications, in addition, viruses find use in genetic engineering applications and increasingly in the design of new nanomaterials. At the very least, all viruses contain two components: the capsid (a protein shell), and a genome, consisting of either DNA or RNA. Some viruses also include accessory proteins to aid in infection, and in some cases a lipid bilayer to further protect their contents from the environment. The viral life cycle itself is deceivingly simple: viruses enter the cell, typically (but not always) through the interaction of their capsid with a receptor on the cell surface; the virus must then somehow disassemble its capsid to release its genetic material and any necessary helper proteins. The viral genome is then replicated and the proteins it codes for are synthesized to produce the raw material for the production of new viral particles; these new viruses then assemble and bud from the cell either through the membrane or upon cell death.

Spotlight: HIV, Cells, and Deception (Nov 2015)

HIV-1 Capsid

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When human immundeficiency virus (HIV) infects a human cell, it releases into the interior of the cell its capsid (made of about 1,300 identical so-called CA proteins), a closed, stable container that protects the viral genetic material (see also June 2013 highlight Elusive HIV-1 Capsid and August 2015 highlight Anatomy of a Dormant Killer). Once in the cell ― while avoiding detection by cellular proteins ― the capsid deceives the cell and directs the cell machinery to transport it to the nucleus. The human-cell protein Cyclophilin A (CypA) is thereby exploited to act against the cell's well being and to assist the HIV infection by getting the capsid to access the cell nucleus; this results in a delicate choreography accomplished by escaping anti-viral proteins in the cell and deceiving transport proteins at the nucleus, all of which contain a CypA domain that interacts directly with the capsid. Despite the availability of the crystal structure of the complex of CypA and CA proteins determined nearly 20 years ago, the mechanism by which CypA assists the capsid has been unclear due to the lack of information on CypA in complex with not one CA protein, but the entire capsid. In collaboration with experimental groups, computational biologist have shown in a recent report that the effects of CypA on the capsid are not only structural, but also dynamical. Thus, new therapeutic strategies may be envisioned through modulation of the dynamics of the capsid by small-molecule (drug) compounds that inhibit the binding of CypA to the capsid. More information is available on our retrovirus website and in a YouTube video.

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Publications Database
  • Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Gongpu Zhao, Juan R. Perilla, Ernest L. Yufenyuy, Xin Meng, Bo Chen, Jiying Ning, Jinwoo Ahn, Angela M. Gronenborn, Klaus Schulten, Christopher Aiken, and Peijun Zhang. Nature, 497:643-646, 2013.
  • Cyclophilin A stabilizes HIV-1 capsid through a novel non-canonical binding site. Chuang Liu, Juan R. Perilla, Jiying Ning, Manman Lu, Guangjin Hou, Ruben Ramalho, Gregory Bedwell, In-Ja Byeon, Jinwoo Ahn, Jiong Shi, Angela Gronenborn, Peter Prevelige, Itay Rousso, Christopher Aiken, Tatyana Polenova, Klaus Schulten, and Peijun Zhang. Nature Communications, 7:10714:(10 pages), 2016.
  • Dynamic allostery governs cyclophylin A-HIV capsid interplay. Manman Lu, Guangjin Hou, Huilan Zhang, Christopher L. Suiter, Jinwoo Ahn, In-Ja L. Byeon, Juan R. Perilla, Christopher J. Langmead, Ivan Hung, Peter L. Gor'kov, Zhehong Gan, William Brey, Christopher Aiken, Peijun Zhang, Klaus Schulten, Angela M. Gronenborn, and Tatyana Polenova. Proceedings of the National Academy of Sciences, USA, 112:14617-14622, 2015.
  • Atomic modeling of an immature retroviral lattice using molecular dynamics and mutagenesis. Boon Chong Goh, Juan R. Perilla, Matthew R. England, Katrina J. Heyrana, Rebecca C. Craven, and Klaus Schulten. Structure, 23:1414-1425, 2015.
  • HIV-1 capsid function is regulated by dynamics: Quantitative atomic-resolution insights by integrating magic-angle-spinning NMR, QM/MM, and MD. Huilan Zhang, Guangjin Hou, Manman Lu, Jinwoo Ahn, In-Ja L. Byeon, Christopher J. Langmead, Juan R. Perilla, Ivan Hung, Peter L. Gor'kov, Zhehong Gan, William W. Brey, David A. Case, Klaus Schulten, Angela M. Gronenborn, and Tatyana Polenova. Journal of the American Chemical Society, 138:14066-14075, 2016.
  • All-atom molecular dynamics of virus capsids as drug targets. Juan R. Perilla, Jodi A. Hadden, Boon Chong Goh, Christopher G. Mayne, and Klaus Schulten. Journal of Physical Chemistry Letters, 7:1836-1844, 2016.
  • Molecular dynamics simulations of the complete satellite tobacco mosaic virus. Peter L. Freddolino, Anton S. Arkhipov, Steven B. Larson, Alexander McPherson, and Klaus Schulten. Structure, 14:437-449, 2006.
  • Stability and dynamics of virus capsids described by coarse-grained modeling. Anton Arkhipov, Peter L. Freddolino, and Klaus Schulten. Structure, 14:1767-1777, 2006.
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