SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome

Abstract

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of 'cryptic' epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 'cryptic' pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

Prefusion conformation of SARS-CoV-2 receptor-binding domain favours interactions with human receptor ACE2

“…This strongly indicates that CoV-1 S become relatively much flexible, generating a large conformational ensemble with less potential for binding with hACE2. This result is consistent with the recent observations in an extensive 0.1 second MD simulation which noted a large opening of spike with presence multiple cryptic epitopes [40]. In contrast, when RBD binds with hACE2, CoV2-RBD-hACE2 becomes relatively more rigid than CoV1-RBD-hACE2, which favours proteolytic processing for membrane fusions.…”

“…This is in agreement with rigidity analysis (Figure 8A, Table2), where we have shown that SARS-CoV-2 retains its overall rigidity better than SARS-CoV-1. Furthermore, large-scale computing efforts via Folding@home project have carried out millisecond MD simulation [40], where it was shown the RBD domain in the up state of the SARS-CoV-1 exhibits higher deviation from the respective crystal structure in comparison to the SARS-CoV-2 [40]. Interestingly, one of the RBDs in SARS-CoV-1 that is initially in the down configuration transitions to the open configuration.…”

Accelerating COVID-19 Research Using Molecular Dynamics Simulation

“…Remarkably, over a million citizen scientists performed an unprecedented 0.1 s of MD simulations through the Folding@home computing project to create the world’s first Exascale computer and simulate protein dynamics of SARS-CoV-2. 82 This, in turn, revealed how the S-protein of SARS-CoV-2 uses conformational masking to evade host immunity and subsequently identified the hidden cryptic pockets that were not captured or were extremely difficult to capture in experiments. A consortium of high-performance computing (HPC) for research on COVID-19 was constituted in early 2020.…”

Molecular Dynamics Modeling of the SARS-CoV-2 Spike Protein at PH2 Through PH11.5

“…We performed detailed statistical analysis of RBD deviations and RBD-W H bonds provide a comparison of the movement of the residues in RBD (ARG319-PHE541), and even RBM (SER438-GLN506) [30,31]. These analyses intend to address the following widely known observations.…”

“…S protein is decorated extensively with glycans that aid in immune evasion by shielding potential antigens [32,33]. S protein uses a conformational masking strategy, wherein it predominantly adopts a closed conformation that retract the RBDs to escape immune surveillance mechanisms, and then the RBD needs to open to intersect with ACE2 [31].…”