Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

Abstract

The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed. We report the development of bottom-up coarse-grained (CG) models consistent with cryo-electron tomography data, and the use of CG molecular dynamics simulations to investigate viral binding and S2 core exposure. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces in a manner distinct from binding between soluble proteins, which processively induces S1 dissociation. We also simulate possible variant behavior using perturbed CG models, and find that ACE2-induced S1 dissociation is primarily sensitive to conformational state populations and the extent of S1/S2 cleavage, rather than ACE2 binding affinity. These simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

“…We reveal that the ACE2 binding energy is distributed between both the S1 and S2 subunits. The ACE2 binding to one S1 subunit promotes additional protomers to open in a cooperative manner, in line with previous reports 14,65 , causes rigidification of the RBD-s and the expulsion of the 630 loop from its unbound trimer position, which likely exposes the abutting S1-S2 cleavage site for easier protease cleavage. In the S2 subunit, the FPPR becomes more dynamic likely enabling the fusion peptide to engage the host cell membrane while also exposing the proximal S2′ site for cleavage.…”

Isolation, characterization, and structure-based engineering of a neutralizing nanobody against SARS-CoV-2

“…S1). Thus, unlike in the case of the BLI binding experiment using isolated RBD, not all the RBM are accessible to DL4 in the context of the S trimer on viral particles, reducing the apparent affinity of DL4 to S. Alternatively, the functional affinity between the S trimer and ACE2 dimer would be much higher than those reported which was measured using RBD and ACE2 monomers [ 40 ] due to avidity and positive cooperativity reasons [ [51] , [52] , [53] ]. To outcompete ACE2-RBD engagement, therefore, may require high concentrations of antibodies in the case of the monomeric DL4.…”

Organization of Upstream ESCRT Machinery at the HIV-1 Budding Site

“…A detailed description of the REM method to derive the CG attractive interprotein interactions from AA MD trajectories is provided in ref. (112,113), where REM was used to optimize attractive interactions between SARS-CoV-2 structural proteins.…”