Exploring the intrinsic dynamics of SARS-CoV-2, SARS-CoV and MERS-CoV spike glycoprotein through normal mode analysis using anisotropic network model

Abstract

COVID-19 caused by SARS-CoV-2 have become a global pandemic with serious rate of fatalities. SARS-CoV and MERS-CoV have also caused serious outbreak previously but the intensity was much lower than the ongoing SARS-CoV-2. The main infectivity factor of all the three viruses is the spike glycoprotein. In this study we have examined the intrinsic dynamics of the prefusion, lying state of trimeric S protein of these viruses through Normal Mode Analysis using Anisotropic Network Model. The dynamic modes of the S proteins of the aforementioned viruses were compared by root mean square inner product (RMSIP), spectral overlap and cosine correlation matrix. S proteins show homogenous correlated or anticorrelated motions among their domains but direction of C α atom among the spike proteins show less similarity. SARS-CoV-2 spike shows high vertically upward motion of the receptor binding motif implying its propensity for binding with the receptor even in the lying state. MERS-CoV spike shows unique dynamical motion compared to the other two S protein indicated by low RMSIP, spectral overlap and cosine correlation value. This study will guide in developing common potential inhibitor molecules against closed state of spike protein of these viruses to prevent conformational switching from lying to standing state.

Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

“…[30] and Xiong et al . [34] or taken into consideration in several other structural studies [20-24]. As such, we employ the two-state model shown in Figure 2, with one state representing all three RBD domains closed and the second state representing one RBD open.…”

“…4, unclear if any additional conformational states other than those with either all three RBD domains in the closed state or only one RBD open state are biologically relevant. Specifically, Yurkovetskiy et al [44] observed an occupancy for states with two or three RBD domains in the open conformation, but these were not observed by Gobeil et al [30] and Xiong et al [34] or taken into consideration in several other structural studies [20][21][22][23][24]. As such, we employ the two-state model shown in Figure 2 [30] and Xiong et al [34].…”

“…Normal Mode Analysis (NMA) methods are being employed in the study of different conformational states [23] and of different coronavirus variants [24]. These methods, however, are limited with respect to their ability to study the effects of mutations on dynamics due to the fact that such methods are either extremely taxing on computational resources (e.g., molecular dynamics) or agnostic to the nature of amino acids (e.g., traditional coarse-grained NMA methods).…”

Generative Adversarial Learning of Protein Tertiary Structures

“…As we note in Section 1 , we have known for a while that proteins are dynamic molecules that switch between different structures under physiological conditions. There has never perhaps been a better time when protein dynamics has been front and center in the public eye; we point here to a growing number of studies reported broadly in media showing the equilibrium motions of the receptor binding domain, the S1 subunit, of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein between a closed to a partially-open structure being key to its ability to bind to the human Angiotensin-converting enzyme 2 (ACE2) receptor and so mediate viral entry in human host cells [ 33 , 34 , 35 ]. Finding the structures that a protein accesses to regulate interactions with molecular partners in the cell is an important problem.…”

Biological characteristics and biomarkers of novel SARS-CoV-2 facilitated rapid development and implementation of diagnostic tools and surveillance measures

“…ACE2 receptors are present in almost all human organs as well as in the wide variety of cells including smooth muscle cells and endothelial cells of the lungs, stomach cells, colon, small intestine cells, liver cells, kidney cells, and also brain ( Shereen et al, 2020 ; Zhang et al, 2020a ). Recent findings revealed key structural differences and the intrinsic sequence of the RBDs of both of the SARS-CoV and SARS-CoV-2 ( Majumder et al, 2020 ). The precise understanding of the interaction of the SARS-CoV-2 virus with ACE2 human cells receptors is now revealed after detailed structural analysis RBD–ACE2 complex using X-ray crystallographic examinations ( Lan et al, 2020 ).…”