Thread by @RommieAmaro

🚨Happy to share our newest labor of (nerd) love
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In situ dynamics of influenza glycoproteins illuminate their vulnerabilities

w/ @kanekiyom @LCasalino88 @chem_christian, J Lederhofer, Y Tsybovsky, I Wilson

#glycotime #compchem

biorxiv.org/content/10.110…

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We characterize dynamics of flu glycoproteins in a crowded protein environment via mesoscale (120 nm diameter, 160 million atom) molecular dynamics simulations of 2 evolutionary-linked glycosylated influenza A whole-virion models

Our simulations indicate that the interactions of proteins & glycans in the crowded viral surface facilitate 3 major glycoprotein motions, each of which reveals antigenically relevant states

First, we see an extensive tilting of the neuraminidase (NA) head...

This extreme tilt motion exposes the neuraminidase (NA) head underside to immune recognition, as seen by this monoclonal antibody disclosed by @kanekiyom & team

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---> a 'darkside' NA epitope!

We also see the hemagluttinin (HA) tilt extensively relative to the membrane.

This tilting facilitates the approach of "HA anchor epitope"-directed antibodies

... the tilting of the HA in the crowded viral surface exposes the membrane-adjacent anchor epitope region and provides access to antibodies

Third, we see the HA trimer 'breathe' open, intermittently revealing the cryptic epitope to which the recently disclosed, broadly protective, FluA-20 antibody binds...

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The HA trimer breathing is asymmetric, with transient opening & closing motions, and HA opens wide enough to accommodate (bind) the FluA-20 antibody

A benefit of these massive simulations is that they contain many (hundreds!) of copies of the proteins, which yield terrific statistics / sampling

This lets us characterize the kinetics of the sampled motions using 'cell-scale' or 'in situ' Markov state models - yay!

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Taken together, the breathing & tilting of the glycoproteins in the crowded surface gives new views into how the NA (red & light blue below) & HA (dark blue & purple below) may bind to & interact with sialoglycan receptors on host cells

Last but not least (!), we see large-scale dynamic interplay between the glycoproteins, many glycan-mediated interactions #glycotime , & formation of glycoprotein 'macro-clusters'

This was a massive effort over many years (w/ big COVID delays), esp by @LCasalino88 who ran all the simulations & made the gorgeous images/movies, @chem_christian who led the MSM work, the darkside antibody data from @kanekiyom & team, & input from Ian Wilson

Big thanks to @LabDurrant for his initial monumental influenza work, @NIH for funding, @NSF Blue Waters & @ORNLComputing Summit supercomputers.

We look forward to questions & feedback from the community!

/end