Dynamical 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 structural-topology based model Hamiltonian of C3 symmetric trimeric spike is developed to explore its complete conformational energy landscape using molecular dynamic simulations. The study finds 2019-nCoV to adopt a unique strategy by undertaking a dynamic conformational asymmetry induced by a few unique inter-chain interactions. This results in two prevalent asymmetric structures of spike where one or two spike heads lifted up undergoing a dynamic transition likely to enhance rapid recognition of the host-cell receptor turning on its high-infectivity. The crucial interactions identified in this study are anticipated to potentially affect the efficacy of therapeutic targets.One Sentence Summary: Inter-chain-interaction driven rapid symmetry breaking strategy adopted by the prefusion trimeric spike protein likely to make 2019-nCoV highly infective.We are in the midst of a global catastrophic situation due to coronavirus outbreak where every day the global death toll is biting the past count. While history has witnessed past pandemics (1-3), 2019 Novel Coronavirus (2019-nCoV) trends to outcompete them all by its rapid transmission in a short period to win the crown. As the name 'corona' (in Latin, it means crown), the accused of the outbreak makes use of a 'crown-shaped' molecular machine, the trimeric spike-protein to drive the virus entry into the host cells. 2019-nCoV is the newest addition of betacoronavirus genus (4). While the sequence and structural similarity to the severe acute respiratory syndrome coronavirus spike (SARS-CoV S) repute the identity of 2019-nCoV spike as SARS-CoV-2 S (5, 6), a recent study reported that the SARS-CoV-2 S has 10-20 fold higher affinity to human angiotensin-converting enzyme 2 (ACE2) receptor than that of SARS-CoV S (7).The large ectodomain of the S glycoprotein of the coronavirus uses the S1 subunit for receptor binding and the trimeric S2 stalk for host-cell membrane fusion (Fig. 1A) (8, 9). In SAR-CoV-2 S glycoprotein, the β-sheet-rich S1 subunit comprises an N terminal domain (NTD) and a receptor-binding domain (RBD) towards its C-terminus (CTD) (Fig. 1B). So far, static structural characterization reported that the RBD of S1 has an intrinsic hinge-like conformational was not certified by peer review)

A multiscale model of virus pandemic: Heterogeneous interactive entities in a globally connected world

“…For example, since the start of the COVID-19 pandemic, normal mode analysis and quantum mechanical computations have been used to better understand potential drug targets on viral proteins. This includes structural proteins, most importantly S-protein, which is involved in ACE2 receptor binding, 1,114 as well as nonstructural proteins, such as proteases. 56 The rapid emergence of COVID-19 has also spurred the development of novel methodologies to support the discovery of antiviral therapies, in particular in silico screening techniques of multiple compounds against SARS-CoV-2 proteins.…”

Intra- and intermolecular atomic-scale interactions in the receptor binding domain of SARS-CoV-2 spike protein: implication for ACE2 receptor binding

“…S-protein undergoes a conformational change during infection, in which the RBD of S1 carries out a hinge-like conformational movement into a receptor-binding active state. 36 In a recent paper 37 this mechanism has been analyzed for SARS-CoV-2 (6VSB), and it has been shown that an interaction between SER359 located in RBD and PRO561 located in SD2 is critically important for this conformational change. None of these amino acids have large PCs in our computations.…”

Neutralization of SARS-CoV-2 by destruction of the prefusion Spike

“…Spike exists initially in a pre-fusion state where the domains of S1 cloak the upper portion of the spike with the relatively small (~22 kDa) S1 RBD nestled at the tip. The RBD is predominantly in a 'down' state where the receptor binding site is inaccessible, however it appears that it stochastically flips up with a hinge-like motion transiently presenting the ACE2 receptor binding site (Roy, 2020;Song et al, 2018;Walls et al, 2020;Wrapp et al, 2020). ACE2 acts as a functional receptor for both SARS-CoV and SARS-CoV-2, binding to the latter with a 10 to 20-fold higher affinity (K D of ~15 nM), possibly contributing to its ease of transmission (Song et al, 2018;Wrapp et al, 2020).…”

“…. https://doi.org/10.1101/2020 protein is an attractive candidate for both vaccine development and immunotherapy. Potent nanomolar affinity neutralising human monoclonal antibodies against the SARS-CoV RBD have been identified that attach at the ACE2 receptor binding site (including M396, CR3014 and 80R (Ter Meulen et al, 2006;Sui et al, 2004;Zhu et al, 2007)).…”