#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol

Abstract

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus obscure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized.

Breathing and Tilting: Mesoscale Simulations Illuminate Influenza Glycoprotein Vulnerabilities

“…Instead, cryoelectron microscopy (cryoEM) has been successful in characterizing the plastic behavior of the individual glycoprotein ectodomains, showing, for example, the existence of tilted HA conformations, or “breathing” HA heads − and open NA heads . Some of the above-mentioned difficulties can be allayed through computational studies, which can create specific, predefined mesoscale models and examine protein dynamics in situ. − Whole-virion scale simulations, whether coarse-grained − or all-atom, ,− can provide a detailed look at protein dynamics in a more realistic, crowded protein environment than simulations of discrete proteins. Additionally, such large simulations naturally afford statistical sampling for proteins of interest; i.e., an influenza virion will contain a few hundred HA proteins and a few dozen NA proteins, enabling the application of statistical analysis techniques, such as Markov state models (MSM), to quantify conformational transitions. ,− …”

Understanding Virus Structure and Dynamics through Molecular Simulations

“…As we enter the exascale computing era, we can expect longer, more detailed simulations to be performed with all-atom descriptions of complete systems becoming more common. For example, two of the largest all-atom studies to date are those of Casalino et al for the complete SARS-CoV-2 viral envelope (305M atoms, 0.2 μs) and of Dommer et al for a SARS-CoV-2 respiratory aerosol model (1B atoms, 0.0024 μs). It is particularly interesting to note the difficulty in building and equilibrating these systems, such that new tools and protocols are required, which are currently being developed. ,− González-Arias et al describe scalable analysis for the CG HIV-1 lipid envelope on the Frontera supercomputer.…”

New Insights into the Cooperativity and Dynamics of Dimeric Enzymes

“…Simulations of millions of particles at the microsecond level (μs) are now frequently utilized, and even millisecond level (ms) simulations can be conducted . High-performance computers specifically designed for biomolecular simulations, − or general-purpose high performance computing systems (HPC) can also be used to conduct simulations of over a billion particles . Using various machine learning algorithms in conjunction with these techniques enables the detection of more detailed structural transformations that may not otherwise be detected in biophysical experiments.…”