Dynamic Asymmetry Exposes 2019-nCoV Prefusion Spike

Abstract

The novel coronavirus (2019-nCoV) spike protein is a smart molecular machine that instigates the entry of coronavirus to the host cell causing the COVID-19 pandemic. In this study, a symmetry-information-loaded structure-based Hamiltonian is developed using recent Cryo-EM structural data to explore the complete conformational energy landscape of the full-length prefusion spike protein. The study finds the 2019-nCoV prefusion spike to adopt a unique strategy by undertaking a dynamic conformational asymmetry that results in two prevalent asymmetric structures of spike where one or two spike heads rotate up to provide better exposure to the host-cell receptor. A few unique interchain interactions are identified at the interface of closely associated N-terminal domain (NTD) and receptor binding domain (RBD) playing a crucial role in the thermodynamic stabilization of the up conformation of the RBD in the case of the 2019-nCoV spike. The interaction-level information decoded in this study may provide deep insight into developing effective therapeutic targets.

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

“…C) Movement of the S1 subunit makes it possible for spike protein to assume conformations where alL S1 units are down, one S1 unit is up, two S1 units are up, or all S1 units are up. Reproduced from [ 95 ] with permission from ACS, https://pubs.acs.org/doi/10.1021/acs.jpclett.0c01431 . Further permission related to the material excerpted should be directed to the ACS.…”

Comparative molecular dynamics study of the receptor-binding domains in SARS-CoV-2 and SARS-CoV and the effects of mutations on the binding affinity

“…While the ‘up’ conformation corresponds to the receptor-accessible state, the ‘down’ conformation corresponds to the receptor-inaccessible state. Out of the two conformations, the ‘up’ conformation is thought to be less stable (Roy et al., 2020 ; Wrapp et al., 2020 ). In addition, the RBD contains a receptor-binding motif (RBM), which is its most functional segment because of its direct involvement in the attachment to ACE2 (Li et al., 2005 ) and whose physiochemical properties are the direct determinants of this binding affinity.…”

Structural analysis of COVID-19 spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection.

“…The ACE2 receptor is the access point for SARS-CoV-2 entry and further infection in the healthy human cell (Hofmann and Pöhlmann 2004). A hinge-like movement happens when the virus's receptor-binding domain attaches with the ACE2 receptor increasing interchain surface accessibility (Lan et al 2020;Roy et al 2020;Yan et al 2020). Multiple sequence alignment of the ACE2 receptor revealed high sequence similarity/identity among different mammalian species (Letko et al 2020).…”