In the X-Men cinematic universe, the supervillain Mystique possesses a shape-shifting ability that allows her to deceive and evade her captors—she is able to mimic the appearance and voice of any person with exquisite precision. This unique shape-shifting ability is also observed among pathogens such as the dengue virus, which is able to evade recognition by the human immune system in a game of cat and mouse.
“In recent years, it has been shown that the dengue virus 2 strain (DENV2) can change the morphology of its shell-like ‘envelope’ upon transfer from the mosquito to a human host, and this correlates with an associated change in body temperature from 29°C to 37°C”, said one of the senior authors, Peter Bond, a Senior Principal Investigator at A*STAR’s Bioinformatics Institute (BII).
At lower temperatures (29°C), the DENV2 envelope protein has a ‘smooth appearance’ with three dimeric proteins bound tightly together to form a ‘raft’ that covers the surface of the virus. At temperatures resembling a high fever (40°C), these protein interactions are broken, giving the virus a ‘bumpy’ surface. Complicating matters, different DENV2 strains display a mixture of ‘smooth’ and ‘bumpy’ surfaces at 37°C.
In collaboration with colleagues at Duke-NUS Medical School and the University of Texas, Bond’s research group sought to uncover the molecular basis for this structural heterogeneity. Sheemei Lok at Duke-NUS used cryo-electron microscopy to compare two DENV2 strains that differed in surface morphology at 37°C. Mutating certain amino acid residues in the envelope protein transformed viruses with the ‘smooth’ surface into one with a ‘bumpy’ surface.
Going a step further, Bond and a Senior Researcher from his team, Jan Marzinek, used computational modeling approaches to predict why different DENV2 strains are adept at switching shapes. This revealed why the mutations led to the destabilization of protein dimer interactions, highlighting a key role played by these amino acids in maintaining viral surface structure. “Molecular dynamics simulations enable us to describe the conformational dynamics of the envelope at atomic resolution and predict the response to in silico mutations,” explained Bond.
“The ability to predict which viral strains are likely to undergo morphological changes at different temperatures could lead to new tailored approaches for treating dengue infections, with different therapeutic antibodies chosen based on the disease stage, such as the presence of fever,” he said.
In addition to applying these computational predictions on other serotypes of the dengue virus, the team is also now studying the viral envelope structure of SARS-CoV-2, the novel coronavirus that causes COVID19.
The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute (BII).