Investigation of the effect of temperature on the structure of SARS-Cov-2 Spike Protein by Molecular Dynamics Simulations

Abstract

Statistical and epidemiological data imply temperature sensitivity of the SARS-CoV-2 coronavirus. However, the molecular level understanding of the virus structure at different temperature is still not clear. Spike protein is the outermost structural protein of the SARS-CoV-2 virus which interacts with the Angiotensin Converting Enzyme 2 (ACE2), a human receptor, and enters the respiratory system. In this study, we performed an all atom molecular dynamics simulation to study the effect of temperature on the structure of the Spike protein. After 200ns of simulation at different temperatures, we came across some interesting phenomena exhibited by the protein. We found that the solvent exposed domain of Spike protein, namely S1, is more mobile than the transmembrane domain, S2. Structural studies implied the presence of several charged residues on the surface of N-terminal Domain of S1 which are optimally oriented at 10-30 {degrees}C. Bioinformatics analyses indicated that it is capable of binding to other human receptors and should not be disregarded. Additionally, we found that receptor binding motif (RBM), present on the receptor binding domain (RBD) of S1, begins to close around temperature of 40 {degrees}C and attains a completely closed conformation at 50 {degrees}C. The closed conformation disables its ability to bind to ACE2, due to the burying of its receptor binding residues. Our results clearly show that there are active and inactive states of the protein at different temperatures. This would not only prove beneficial for understanding the fundamental nature of the virus, but would be also useful in the development of vaccines and therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/145086v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1e631eeorg.highwire.dtl.DTLVardef@1d83278org.highwire.dtl.DTLVardef@d98d3borg.highwire.dtl.DTLVardef@c75b7f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIStatistical and epidemiological evidence show that external climatic conditions influence the SARS-CoV infectivity, but we still lack a molecular level understanding of the same. C_LIO_LIHere, we study the influence of temperature on the structure of the Spike glycoprotein, the outermost structural protein, of the virus which binds to the human receptor ACE2. C_LIO_LIResults show that the Spikes S1 domain is very sensitive to external atmospheric conditions compared to the S2 transmembrane domain. C_LIO_LIThe N-terminal domain comprises of several solvent exposed charged residues that are capable of binding to human proteins. The region is specifically stable at temperatures ranging around 10-30{degrees} C. C_LIO_LIThe Receptor Binding Motif adopts a closed conformation at 40{degrees}C and completely closes at higher temperatures making it unsuitable of binding to human receptors C_LI